Figure 5-1. Early development of the nervous system. A to C, Cross sections show the transition from neural plate (A) to neural tube (C). D, A dorsal view of the neural plate shows the point of initial closure and the direction of closure (small arrows) toward anterior and posterior neuropores. Green arrows (A, B) represent induction of neural tube formation.
In the early stages, this closing neural plate and tube consist of a single layer, the ventricular zone, composed of a pseudostratified layer of fusiform cells undergoing DNA replication and cell division (mitosis). The nuclei in the cells of this zone migrate in a to-and-fro manner within the cell as mitosis takes place (Fig. 5-2A). The progenitor cells of this layer will give rise to the neurons and some glial cells of the mature nervous system and to the ependymal cells lining the ventricles.
Figure 5-2. Histogenesis of the neural tube from early stages, when there is just the ventricular zone (A), to later stages (B, C), when the marginal and intermediate zones appear external to the ventricular zone. Rostral to the spinal cord, the developing neural tube differentiates in a more complex manner (D) to accommodate more complex structures such as the cerebellar and cerebral cortices.
Immediately after the ventricular zone is formed, the marginal zone appears (Fig. 5-2B). This zone is at the abluminal aspect of the neural tube and consists of the processes of cells located within the ventricular zone, but it does not contain their nuclei. The marginal zone contains almost no cell bodies. This zone will be invaded by axons of neurons that are located in the intermediate zone.
The third area to appear is the intermediate zone. The intermediate zone is formed between the ventricular and marginal zones as the progenitor cells from the ventricular zone give rise to immature postmitotic neurons (Fig. 5-2C). These immature neurons migrate into the area immediately external to the ventricular zone, where they set up residence. The processes of some intermediate zone neurons continue to grow into the marginal zone. Although the term is no longer appropriate, the intermediate zone generally corresponds to what was formerly called the mantle layer.
The subventricular zone forms at the interface of the ventricular and intermediate zones (Fig. 5-2D). Unlike the nuclei in the cells of the ventricular zone, nuclei of subventricular zone cells generally do not migrate. The progenitor cells of the subventricular zone give rise to the macroglial cells of the CNS and to specific populations of developing neurons in the brainstem and forebrain.
The concept of the alar plate and basal plate is best viewed by recognizing that the development of the posterior horn (alar plate derivative) and anterior horn (basal plate derivative) is a dynamic process. The immature intermediate zone neurons that give rise to mature posterior or anterior horn neurons are the product of cell division in one zone with migration into and further development in a subsequently formed zone. It is helpful to think of the alar and basal plates as consisting of the ventricular zone and adjacent intermediate zone, which are, of course, dynamically changing as development occurs. The posterior part of the ventricular zone and adjacent intermediate zone represents the alar plate, whereas the corresponding layers in the anterior part of the developing neural tube represent the basal plate. As development proceeds, the ventricular zone will essentially disappear, while the intermediate zone with its maturing neurons will progressively enlarge to form its adult derivatives. Consequently, the adult derivatives are the products of cell division in the ventricular zone, migration and formation of the intermediate zone, and maturation within this intermediate zone.
The three-zone configuration described previously—ventricular zone, intermediate zone, and marginal zone—is the basic organizational plan from which the brain and spinal cord will arise. To a large extent, the development of the brainstem and forebrain is just a more elaborate version of this basic plan. There are individual developmental events unique to these zones of the CNS. In the metencephalon, the basic plan of the neural tube is modified to accommodate development of the cerebellar cortex. In the forebrain, the basic plan of the neural tube is modified to accommodate the development of the cerebral cortex.
The modification to accommodate the cerebral cortex is the appearance of the cortical plate and the subplate (Fig. 5-2D). The cortical plate forms at the interface of the marginal zone and the intermediate zone and is composed of neurons that originate from the ventricular zone; these postmitotic immature neurons traverse the intermediate zone, using the radially oriented processes of radial glia as a scaffold, to take up their position as the cortical plate. (It is emphasized that cell migration on radial glia is characteristically seen in all portions of the developing nervous system.) The subplate is a narrow region located immediately internal to the cortical plate. The cerebral cortex develops from the cortical plate and the marginal zone. In those portions of the neural tube that form the cerebral cortex, the marginal zone gives rise to layer/lamina I of the cortex, the cortical plate to layers/laminae II to VI, and the subplate and intermediate zone to portions of the subcortical white matter. The histogenesis of the cerebellar cortex is a slight modification of this plan due to the presence of an external germinal layer. This layer originates from the rhombic lip (an alar plate derivative) and is located within the marginal layer. These relationships are described later in this chapter.
BRAIN DEVELOPMENT
The first neural tissue appears at the end of the third week of embryonic development, when the embryonic disk is composed of ectoderm, mesoderm, and endoderm. A specialized part of the ectoderm, the neuroectoderm, gives rise to the brain, spinal cord, and peripheral nervous system (Fig. 5-1).
Induction
The notochord arises from axial mesoderm at about 16 days and is completely formed by the beginning of the fourth week. It defines the longitudinal axis of the embryo, determines the orientation of the vertebral column, and persists as the nucleus pulposus of the intervertebral disks. One important function of the notochord is induction: directing the overlying ectoderm to form the neural plate (Fig. 5-1A, B). Associated with this process is the production of cell adhesion molecules in the notochord. These molecules diffuse from the notochord into the neural plate and function to join the primitive neuroepithelial cells into a tight unit.
Within the neuroectoderm, some neuroepithelial cells elongate and become spindle shaped. This cellular elongation, also induced by the notochord, forms the neural plate and is completed by the end of the third week of gestation (Fig. 5-1A). The neural plate gives rise to most of the nervous system.
Primary Neurulation
The CNS develops from a hollow structure called the neural tube, which is produced by neurulation. There are two neurulation processes. Most of the neural tube forms from the neural plate by a process of infolding called primary neurulation. This part of the neural tube will give rise to the brain and to the spinal cord through lumbar levels. The most caudal portion of the neural tube, which will give rise to sacral and coccygeal levels of the cord, is formed by a process called secondary neurulation. Secondary neurulation is described in the next section. By about day 18 after fertilization, the neural plate begins to thicken at its lateral margins (Fig. 5-1B). This thickening elevates the edges of the neural plate to form neural folds. At about 20 days, the neural folds first contact each other to begin the formation of the neural tube. This fusion initially takes place on the dorsal midline at what will become cervical levels of the spinal cord and proceeds, zipper-like, in rostral and caudal directions (Fig. 5-1C, D). During the process, the lumen of the neural tube, called the neural canal, is open to the amniotic cavity both rostrally and caudally (Fig. 5-1D). The rostral opening, the anterior neuropore, closes at about 24 days, and the caudal opening, the posterior neuropore, closes about 2 days later.
Neurulation is brought about by morphologic changes in the neuroblasts, the immature and dividing future neurons in the ventricular zone. As mentioned previously, these cells are elongated and are oriented at right angles to the dorsal surface of the neural plate, which will be the inner wall of the neural canal. Microfilaments in each cell form a circular bundle parallel to the future luminal surface, whereas microtubules extend along the length of the cell. The contraction of the circular bundle of microfilaments causes the microtubules to splay out like the rays of a fan. This forms an elongated conical cell with its apex at the neural groove and its base at the edge of the neural fold. Neurulation does not occur in embryos exposed to colchicine, which depolymerizes microtubules, or to cytochalasin, which inhibits microfilament-based contraction.
Congenital malformations associated with defective neurulation are called dysraphic defects. The process of induction also means that the proper development of a structure is dependent on the proper development of its neighbors. There is an intimate relationship of neural tissue to the surrounding bone, meninges, muscles, and skin. Because of this relationship, a failure of neurulation often impairs the formation of these surrounding structures.
Several well-controlled clinical trials have proved that supplementation with the vitamin folic acid can reduce the incidence of neural tube defects. In the MRC Vitamin Study, carried out in Great Britain and published in 1991, women who had previously been delivered of a child with a dysraphic defect were assigned to either a folic acid supplementation group or a control group during a subsequent pregnancy. Folic acid supplementation reduced the incidence of neural tube defects by about 70% relative to that in untreated controls. The mechanism for this effect is not known at this time. It is thought that women who are delivered of infants with dysraphic defects have an inborn metabolic problem that is corrected by folate. One research group has suggested that the conversion of homocysteine to methionine, which requires folate as a cofactor, is the critical step. Dysraphic defects have also been observed in infants born to mothers who had circulating antibodies to the folate receptor. Because the neural plate and tube develop so early in pregnancy, it is important that physicians recommend folic acid supplementation (400 mcg/day) to all women who intend to have children, whether or not they are pregnant. In addition, drugs taken for epilepsy, such as valproic acid and carbamazepine, can cause dysraphic defects.
Congenital Nervous System Defects of Primary Neurulation
Most dysraphic disorders occur at the location of the anterior or posterior neuropore. Failure of the anterior neuropore to close results in anencephaly (Fig. 5-3). In this defect, the brain is not formed, the surrounding meninges and skull may be absent, and there are facial abnormalities. The defect extends from the level of the lamina terminalis, the site of anterior neuropore closure, to the region of the foramen magnum. Anencephaly occurs in about 5 of every 10,000 live births. Neonatal death is inevitable.
Figure 5-3. Lateral (A) and frontal (B) views of anencephaly. Note the associated cranial and facial abnormalities. (A Courtesy Dr. J. Fratkin.)
An encephalocele is a herniation of intracranial contents through a defect in the cranium (cranium bifidum) (Fig. 5-4A). The cystic structure may contain only meninges (meningocele), meninges plus brain (meningoencephalocele), or meninges plus brain and a part of the ventricular system (meningohydroencephalocele) (Fig. 5-4B-D). Encephaloceles are most common in the occipital region, but they may also occur in frontal and parietal locations. A more subtle defect in the same area is thought to be the cause of the Chiari I malformation, a congenital herniation of the cerebellar vermis through the foramen magnum, which may cause pressure on the medulla oblongata and cervical spinal cord (Fig. 5-5). This defect may go unnoticed until early adulthood and is often associated with a cavitation of the spinal cord (syringomyelia) or of the medulla (syringobulbia). The Chiari II malformation, also called the Arnold-Chiari malformation or deformity, is a similar defect associated with myelomeningocele (discussed later).
Figure 5-4. Sagittal views of occipital encephaloceles. Magnetic resonance image of meningohydroencephalocele (A) and drawings of meningocele (B), meningoencephalocele (C), and meningohydroencephalocele (D).
Figure 5-5. Sagittal magnetic resonance image of a patient with Arnold-Chiari malformation and with cavitations in the medulla (syringobulbia) and cervical spinal cord (syringomyelia).
Defects in the closure of the posterior neuropore cause a range of malformations known collectively as myeloschisis. The defect always involves a failure of the vertebral arches at the affected levels to form completely and fuse to cover the spinal cord (spina bifida). If that is the only defect and the skin is closed over it, the unseen condition is called spina bifida occulta (Fig. 5-6A, B). The site of the defect is usually marked by a patch of dark, coarse hairs. If the skin is not closed over the vertebral defect, leaving a patent aperture, the malformation is called spina bifida aperta.
Figure 5-6. Sagittal views of spina bifida malformations. Magnetic resonance image (A) and corresponding views showing spina bifida occulta (A, B) and spina bifida cystica (C, meningocele; D, meningomyelocele). CSF, cerebrospinal fluid.
As with occipital encephaloceles, a cystic mass (spina bifida cystica) may also accompany spina bifida (Fig. 5-6C, D). This saccular structure may contain only meninges and cerebrospinal fluid (CSF) (meningocele) or meninges and CSF plus spinal neural tissue (meningomyelocele). In the latter case, the neural tissue may be the lower part of the spinal cord or, more commonly, a portion of the cauda equina. Infants with meningomyelocele may be unable to move their lower limbs or may not perceive pain sensations from skin innervated by nerves passing through the lesioned area. These infants may also have other CNS malformations, such as hydrocephalus and the Arnold-Chiari malformation. The incidence of meningomyelocele is approximately 5 per 10,000 births.
Secondary Neurulation
The sacral and coccygeal segments of the spinal cord and their corresponding dorsal and ventral roots are formed by secondary neurulation (Fig. 5-1D). This process begins on day 20 and is complete by about day 42. A cell mass, the caudal eminence, appears just caudal to the neural tube and then enlarges and cavitates. The caudal eminence joins the neural tube, and its cavity becomes continuous with the neural canal.
Congenital Nervous System Defects of Secondary Neurulation
Myelodysplasia refers to malformations of the parts of the neural tube formed by secondary neurulation. The malformation is covered with skin in most cases, but the site may be marked by unusual pigmentation, hair growth, telangiectases (large superficial capillaries), or a prominent dimple. A common abnormality is tethered cord syndrome, in which the conus medullaris and filum terminale are abnormally fixed to the defective vertebral column. The sustained traction damages the cord and causes variable weakness, sensory loss and asymmetric growth of the legs and feet, and problems with bowel and bladder control. Infants born to mothers with diabetes mellitus can have the caudal regression syndrome, which affects the development of the embryonic structures in the caudal region, including the spinal cord.
Primary Brain Vesicles
During the fourth week after fertilization, in which the anterior neuropore closes, there is rapid growth of neural tissue in the cranial region. The three primary brain vesicles formed are prosencephalon (forebrain), mesencephalon (midbrain), and rhombencephalon (hindbrain) (Fig. 5-7A, B). At the rhombencephalon–spinal cord junction, there is a slight bend in the developing neural tube; this is the cervical flexure. A second bend in the neural tube at the level of the mesencephalon is the mesencephalic (or cephalic) flexure.
Figure 5-7. Developmental sequence from three primary to five secondary brain vesicles. Three brain vesicles (A, at about 4.75 weeks of gestation) divide into five vesicles (B, at about 6 weeks of gestation) with the appearance of additional flexures. In subsequent stages (C, at about 6.5 weeks of gestation; D, at about 8.5 weeks of gestation), there is rapid enlargement of forebrain regions, especially the telencephalon. Note that the ventricular spaces (dashed lines, A-D) follow the shape changes in the brain. Cranial nerves are indicated by Roman numerals.
Secondary Brain Vesicles
During the fifth week, the three primary brain vesicles are divided into five secondary brain vesicles (Fig. 5-7C, D). This requires two additional flexures. The pontine flexure divides the hindbrain into the myelencephalon caudally and the metencephalon rostrally. The mesencephalon does not partition further. The telencephalic flexure (shortened here from the longer term diencephalic-telencephalic sulcus) divides the forebrain into the diencephalon caudally and the telencephalon rostrally (Fig. 5-7C, D). The telencephalon (meaning “end-brain”) forms as an outpocketing of the forebrain and expands enormously, with its complex lobes, gyri, and sulci, to become the largest part of the brain.
Diencephalon and Cerebral Hemispheres
The main structures of the forebrain develop during the second month of gestation. Because the mesoderm in this region is simultaneously forming facial structures, abnormalities of forebrain development are often associated with facial defects (Fig. 5-3). The process of forebrain development is referred to as central induction.
At about the end of the fifth week, the telencephalon gives rise to two lateral expansions called the telencephalic (cerebral) vesicles (Fig. 5-7C, D). These are the primordia of the cerebral hemispheres. Their adult derivatives include the cerebral cortex and the subcortical white matter (including the internal capsule), the olfactory bulb and tract, portions of the basal ganglia, the amygdala, and the hippocampus. The diencephalon develops into the thalamic nuclei and associated structures and also gives rise to the optic cup, which eventually forms the optic nerve and retina. Septooptic dysplasia (the de Morsier syndrome) is a congenital dysgenesis of the diencephalon with hypoplasia of the optic nerve and hypothalamus-pituitary and midline structural defects, especially absence of the septum pellucidum and agenesis of the corpus callosum. Infants have congenital blindness and may have hypothyroidism, diabetes insipidus, and hypoadrenocorticism. By 10 weeks of development, the major structures of the CNS are clearly recognizable by their morphologic features, and immature versions of all structures in the brain are present by the end of the first trimester.
Defects of Prosencephalization
The sequence of events by which the primitive prosencephalon differentiates into the diencephalic and telencephalic vesicles is called prosencephalization. Failure of the prosencephalon to undergo cleavage results in a malformation called holoprosencephaly (Fig. 5-8A). In its most severe form (alobar holoprosencephaly), no discernible lobes develop. There is a large single forebrain ventricle, the thalamus is poorly developed, and many structures (corpus callosum, longitudinal cerebral fissure and falx cerebri, olfactory structures) are lacking. In semilobar holoprosencephaly (Fig. 5-8B-D), there is some separation of the forebrain into two discernible lobes (more prominent in occipital areas) and partial development of the falx cerebri. The hemispheres have some visible lobes and gyri, and there are rudimentary but enlarged lateral and third ventricles. These large ventricles are continuous one with the other, and midline structures, such as the septum pellucidum, that normally separate the ventricles are missing (Fig. 5-8C, D). Most infants with holoprosencephaly also have facial malformations. These may be as subtle as mild hypotelorism (unusually close-set eyes) or as obvious as the presence of only a single, midline eye (cyclops) accompanied by a rudimentary nasal structure (proboscis). In general, the more severe the brain malformation, the more severe the facial defect.
Figure 5-8. Alobar (A) and semilobar (B-D) holoprosencephaly. In the alobar form (A), the single brain vesicle has a horseshoe-shaped ventricle, and many major brain structures are absent. Although ventricles are present in the semilobar form (B and C, axial magnetic resonance image, T2-weighted; D, coronal magnetic resonance image, T1-weighted), they are enlarged, and midline structures, such as the septum and fornix, are missing. Note the continuity of the lateral ventricles (C), the continuity of the lateral and third ventricles, and enlarged temporal horns of the lateral ventricles (D).
Holoprosencephaly is associated with a number of environmental exposures, including alcohol, retinoic acid, and maternal diabetes. It is also associated with a number of syndrome disorders and trisomy 13 and trisomy 18. A number of gene defects have been implicated as a cause of holoprosencephaly. SHH (7q36) is one such gene whose disruption has caused similar congenital defects in animal models.
Infectious Diseases Causing Congenital Nervous System Defects
Fetal exposure to several common infectious diseases can cause congenital nervous system defects. The acronym TORCH is often used for the more common etiologic agents: toxoplasmosis, other agents (syphilis), rubella, cytomegalovirus, and h
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