Development of the Nervous System (Gross Anatomy of the Brain) Part 3

Abnormalities in Development of the Nervous System

Spina Bifida

Spina bifida, called myeloschisis, occurs when the posterior neuropore fails to close. It is manifested by a failure of the vertebral canal to close, and spina bifida follows. Two types of spina bifida have been described: spina bifida occulta and spina bifida aperta (also called spina bifida cystica). Spina bifida occulta represents a simple defect of mesodermal origin in which one or more vertebrae fails to close (Fig. 2-6B). With this type of spina bifida, there is no involvement of the meninges or the underlying spinal cord, and the overlying skin is closed. As a result, there may be improper development of the spinal cord, which can be detected by radiography. In general, there are few neurologic symptoms associated with this disorder except if there is bony compression of the exposed area of spinal cord or if there are fat deposits that form in the exposed region.

Spina bifida aperta involves the protrusion of either the meninges alone (called a meningocele) or spinal cord together with the meninges (called a meningomyelocele).

A meningocele is a condition that typically involves the lumbar and sacral portions of the spinal cord and is covered by the meninges and by overlying skin. There is little evidence of motor or sensory deficits, although this disorder may produce defects in the development of the vertebral column and lower aspect of the spinal cord (called myelodysplasia).

A meningomyelocele involves herniation of the spinal cord (or brainstem) and adjoining meninges through the defect in the vertebral column. This condition, which is much more common than meningocele, is not limited to a specific region of spinal cord. In fact, not only can it affect any of the regions of spinal cord, but it can also involve the brainstem. A meningomyelocele produces much more severe deficits than does a meningocele. In particular, it may produce symptoms characteristic of a partial or total transection of the cord, especially if it involves the cervical region. It may also involve hydrocephalus and its associated sensory, motor, and autonomic deficits.

A related disorder involving the brainstem and cerebellum is called the Arnold-Chiari malformation. Because the vertebral column grows faster than the spinal cord, the cerebellum and parts of the medulla are displaced and, consequently, pulled through the foramen magnum. This effect will block the flow of CSF that normally passes from the roof of the fourth ventricle to the cisterns, causing hydrocephalus.

Examples of abnormalities in the development of the brain and spinal cord. (A) The normal arrangement of the vertebra and associated spinal cord. (B) Figure illustrates a given vertebra and the neural tube where the posterior arch failed to close. It is an example of spina bifida occulta. It is characterized by the absence of the vertebral lamina at a particular level or levels, the effect of which is to allow the meninges to be exposed. (C) An example of an encephalocele, a defect in the cranium in which there is an occipital herniation, causing a protrusion, in this case, of the meninges alone.

FIGURE 2-6 Examples of abnormalities in the development of the brain and spinal cord. (A) The normal arrangement of the vertebra and associated spinal cord. (B) Figure illustrates a given vertebra and the neural tube where the posterior arch failed to close. It is an example of spina bifida occulta. It is characterized by the absence of the vertebral lamina at a particular level or levels, the effect of which is to allow the meninges to be exposed. (C) An example of an encephalocele, a defect in the cranium in which there is an occipital herniation, causing a protrusion, in this case, of the meninges alone.


A developmental abnormality in the formation of the central canal is called syringo(hydro)myelia. In this condition, there is a cavitation filled with CSF in the region of the central canal, which damages the crossing fibers of the spinothalamic tract, the net effect of which is to cause segmental loss of pain and temperature.Clinically, children with this anomaly have motor dysfunction from interruption of the corticospinal tract, which travels through the spinal cord. A full diagnosis is often made by magnetic resonance imaging (MRI) of the lower spine. These children are typically treated with surgical closure of the defect.

Tethered Cord

Tethered cord involves the anchoring of the lowest part of the spinal cord to the sacrum. The malformation can result in sensory and motor deficits of the lower extremities as well as bladder difficulties, back pain, and scoliosis.


Encephalocele, which constitutes a failure of portions of the anterior neuropore to close, is manifested by the protrusion of a sac from the cranium consisting of portions of the meninges and CSF, glial tissue, and brain substance with or without the ventricles. This anomaly is rarely an isolated occurrence and is usually associated with abnormalities of the cerebral hemispheres, cerebellum, and mid-brain. Similar malformations have been produced in animals experimentally from exposure to teratogens (a drug or agent taken by the mother during pregnancy that causes an abnormality in development) during early gestation. Clinical findings are variable and depend upon the extent and location of the sac; however, mental retardation and corticospinal tract dysfunction (such as weakness) are two of the most commonly encountered problems among children with this anomaly. Figure 2-6C depicts an example of an occipital encephalocele.

Cerebral malformations may also result in neonatal and infantile seizures, although many other factors may contribute to infantile seizures, such as metabolic disorders, hypocalcemia, and injury in delivery. Seizures can be treated with antiepileptic drugs, but this approach can be a problem if the seizures are not associated with electroen-cephalographic discharges.

Neutral tube defects can be detected by several methods, including ultrasound examination and amniocentesis. Amniocentesis is a procedure based on the assumption that a-fetoprotein, a principal component of fetal serum, leaks out into the amniotic fluid when the neural tube is not closed. This leakage results in significantly elevated levels of this protein, which enables its detection.

Dandy-Walker Syndrome

Dandy-Walker syndrome appears to involve the congenital absence of the lateral apertures (of Luschka) and the median aperture (of Magendie), which, through lack of communication with the remainder of the ventricular system, can be one cause of hydrocephalus. As a result of this malformation, there is a partial or complete agenesis of the cerebellar vermis, in addition to cystic dilation of the posterior fossa communicating with the fourth ventricle. Other malformations may be found in approximately 68% of patients, the most common of which is the absence of a corpus callosum.

Clinically, the most common problem seen with this defect is macrocephaly, or an enlarged cranium. Other problems those with this syndrome may have include vomiting, headaches, delayed acquisition of motor skills, breathing problems, truncal ataxia (a lack of coordination in the trunk), and cranial nerve problems. All of these symptoms and signs are a result of hydrocephalus, compression of portions of the posterior fossa, and absence of the cerebellar vermis. A definitive diagnosis is made with the use of a computed tomography (CT) scan or an MRI of the head. This condition may also be treated with surgery, which may include decompression of the cyst and the insertion of a shunt, which serves to redirect the CSF from the brain to another part of the body better able to absorb it, such as the peritoneum.


Anencephaly consists of partial or complete absence of the brain with associated defects of the cranial vault and scalp. It occurs as a result of a severe failure of the anterior neuropore to close at the 21st to 26th day of gestation. Portions of the cranial bones may be absent, and the exposed tissue underneath becomes a fibrous mass containing degenerated neural and glial tissue. The cerebellum, brainstem, and spinal cord may be present but are often small and malformed. The eyes are well developed, but the optic nerves are usually absent. In addition, the pituitary gland and adrenal glands may be small or absent. Commonly, the arms are relatively large compared to the legs. This anomaly is not compatible with life.

Mechanisms Underlying Neural Development

In discussing the development of the nervous system, it is useful to consider the mechanisms that govern such events as induction of differentiation of cells, neuronal generation and cell death, how neurons are guided to their respective targets, and how synapses are formed. Each of these mechanisms is briefly reviewed here.

Signal Induction and Neural Cell Differentiation

How a cell differentiates depends upon its position in the embryo where it can be exposed to specific inductive signals, the type of transcription factors present in the cell, and the types of receptors and molecules present in the cell. Ectodermal tissue (from which neural tissue emanates) undergoes neural differentiation. Differentiation of neural plate cells is directly determined by the presence of organizer proteins, such as follistatin, noggin, and chordin, which block the suppressive effects of bone morphogenetic protein and which lead to the expression of transcription factors in the developing cells.

How the cells develop after neural induction is dependent upon their positions along the medial-to-lateral axis, which ultimately is transformed into a dorsal-to-ventral axis, and an anterior-to-posterior axis. The positions along these axes determine the specialized properties of these cells, which, in turn, control their signaling characteristics and, thus, provide the patterning mechanism for the arrangement of cells in the future spinal cord, brainstem, and forebrain. In this manner, cells of mesodermal origin determine the fate of neural cells in the ventral aspect of the neural plate, whereas non-neural cells of ectodermal origin determine the fate of cells that lie in its dorsal aspect. Such a mechanism would explain why cells in the dorsal aspect of the neural plate form neural crest cells and sensory neurons, whereas cells in the ventral aspect form motor neurons.

Cells in the notochord induce a protein called sonic hedgehog, which, in turn, induces differentiation in floor plate cells, ventral motor neurons, and interneurons. Interactions between sonic hedgehog and the receptor complex in cells lead to regulation of several protein kinases, causing activation of a series of transcription factors, in which the specific concentration of sonic hedgehog differentially affect induction of motor neurons, floor plate cells and interneu-rons. In development of the brainstem, a series of swellings appear along the neural tube. These swellings are referred to as rhombomeres. These rhombomeres contain neurons (sensory and motor) that innervate the various branchial arches. One class of genes called the Hox genes are expressed in different domains along the anterior- posterior axis of the developing brainstem and can be identified in different rhombomeres. It is likely that the Hox gene is regulated by other transcription factors as well as by cells in the organizer region of mesodermal tissue, thus governing the degree to which differentiation will take place in the brainstem and forebrain as well as the anatomical positions that specific types of neurons will occupy within these regions.

Neuronal Generation and Cell Death

The process of the cell becoming a neuron presumably involves a variety of complex transcription factors as well as the presence and interaction of a host of proteins that serve signaling and modulating functions, in part, by extending over the cell surface and which are encoded by the genes notch and delta. With respect to these two proteins, notch serves as a receptor for delta, which functions as a ligand. Delta can produce significant activation of notch activity, which can prevent the cell from becoming a neuron. In contrast, if notch activation is low, then the likelihood of that cell becoming a neuron is increased. This is an important process because the embryonic nervous system has the potential for generating too many neurons.

Factors Affecting Formation and Survival of Neurons

1. Bone morphogenic protein. This protein controls induction in the neural tube.

2. Timing associated with migration of neurons. Development of such zones as the cerebral and cerebellar cortices where the particular cell layer in either of these cortices to which a neuron will migrate is dependent upon the time at which migration begins.

3. Influence of signals from neuronal target. When axon terminals make contact with their target, these contacts determine not only the nature of the neurotrans-mitter of the presynaptic neuron, but they also have an important impact on its survivability. Neurotrophic factors, such as nerve growth factor, bind with and interact to several classes of receptors. These include tyrosine kinases as well as lower affinity receptors in which intracellular signals are transmitted through transduction pathways dependent upon membrane lipids. When neurotrophic factors (also called neuro-trophins) are eliminated, cell death often ensues. This process is called apoptosis and involves shrinkage and fragmentation into membrane-bound bodies and phagocytosis of the cell. It appears that apoptosis is triggered by an active biochemical process involving transcription of a variety of genes and that the presence of a neurotrophic factor blocks the activation of the biochemical process, leading to apoptosis.

How Axons are Directed to Their Targets and Synapses are Formed: Neurochemical Specificity

There is neurochemical specificity of the developing axon and its target structure. The way in which the growing axon can sense cues is via a specialized expanded structure at the end of the growing axon called a growth cone. The growth cone is capable of converting these cues into signals that direct and control the cytoskeleton of the axon, thus directing the extent of its growth and directionality. The sensory properties of the growth cone are generated by many filament-like extensions called filopodia, which contain receptors. When these receptors are activated by environmental cues, they direct the growing axon by causing it to keep moving forward, turn, or withdraw. In addition to the mechanism described above, a second mechanism is also possible. Growth cones may come in contact with specific molecules that are present either on the cell surface or in an extracellular matrix, which is composed of substances generated by cells but that are not connected to cells. Concerning the molecules present on the cell surface, one class consists of glycoproteins called cadherins, which are calcium dependent. The cadherin molecules are present on both the growth cone and cell surface, thus enabling two identical molecules to recognize and bind to each other. A second group of molecules promoting adhesion include immunoglobulin molecules, which are not calcium dependent. As immunoglobulin molecules of the same kind may bind to each other, different classes of molecules may also bind to one another. The extracellular matrix contains a number of different classes of molecules such as collagen, fibronectin, and laminin. Because the growth cone contains receptors called integrins, which bind to these molecules, the binding process sets off a series of events in the axon that directs its growth. The directionality taken by an axon can also be influenced by inhibitory signals. Such inhibitory signals, which serve to prevent the growth of axons, may be situated on either the cell surface or in the extracellular matrix. One class of such inhibiting molecules is called sema-phorins, and the receptors for this class are immunoglobulins. Collectively, the actions of both the positive responses of the growth cone to environmental cues as well as the reaction of the axon to inhibitory signals ultimately determine the extent of growth and directionality of the growing axon.

Our best understanding of how synapses are formed is derived from studies involving the neuromuscular junction. The critical event in synapse formation takes place when the growth cone of the axon makes contact with the developing muscle fiber. This contact initiates the process of synapse formation as both presynaptic and postsynaptic differentiation takes place. The growth cone is transformed into a nerve terminal, and the region of the muscle receiving contact from the nerve terminal (i.e., postsynaptic site) begins to develop specialized properties. Two key features should be noted here. The first is that this process results in the activation of genes encoding acetylcholine receptor subunits. The second is that the motor neuron synthesizes a protein called agrin, which is transported down the axon where it binds to the postsynaptic receptor. The importance of agrin in the formation of the neuromuscular junction has been shown in experiments that demonstrated a marked decrease in the number of the neuromuscular junctions in agrin-deficient mice or when antibodies against agrin are introduced into the nerve-muscle preparation. It has been suggested that a receptor tyrosine kinase (called muscle-specific kinase) may serve as the key receptor for agrin. Because agrin does not bind directly to muscle-specific kinase, it is likely that a second cytoplasmic protein subunit called rapsyn is required for muscle-specific kinase to be effective and for signaling in the process of differentiation of the neuromuscular junction. In the developing neuromuscular junction, one additional feature should be indicated, namely, that the presynaptic neuron secretes a transmembrane protein called neuregulin. Neuregulin increases or stimulates the synthesis in the expression of the acetylcholine receptor in the muscle and, in this manner, contributes to the specialization of the postsynaptic receptor.

During development, synapses are continuously eliminated. It has been suggested that reduction in input from the presynaptic neuron may be the basis for this phenomenon in which the presynaptic neuron is actually retracted from its connection with the postsynaptic neuron. The most likely effect of synapse elimination would appear to be changes in the extent of convergence as well as divergence of neuronal inputs onto postsynaptic neurons in the CNS.

Clinical Case


Jimmy is a 4-month-old infant who was the product of a normal, full-term pregnancy. His parents thought that his health was fine until he developed spells upon awakening from sleep. These spells consisted of sudden, bilateral contractions of the muscles of the neck, trunk, and limbs occurring in clusters every 20 seconds for periods of 20 to 30 minutes. Each contraction lasted only a second or two and was often followed by a tonic contraction.The contractions involved flexion of the head, trunk, and limbs. He often cried between spells, and his parents noted some abnormal eye movements at these times as well.


The pediatric neurologist reviewed videotape of the spells and examined the infant. Jimmy had just recently begun to smile, and his motor tone was diffusely somewhat diminished. An electroencephalogram (EEG) showed an irregular pattern of high-voltage slow waves and epileptiform spikes (hypsarrhythmia). A magnetic resonance imaging scan of Jimmy’s brain showed several areas of ectopic cortical tissue in the superficial white matter of the left frontal lobe. His doctor started him on corticosteroids (to reduce possible brain swelling),and the episodes stopped.


The spells described are examples of infantile spasms, a type of seizure, typically first manifesting between the fourth and seventh month of life.They often occur in clusters and are abrupt contractions of the neck, trunk, and limb muscles.The most common type is flexor spasms, often called "Salaam spasms." Infantile spasms are most commonly seen as either part of a syndrome called West Syndrome or a triad of infantile spasms, mental retardation, and a chaotic pattern seen on the EEG called hypsarrhythmia. Infantile spasms are caused by many different problems including neonatal infections, anoxic-ischemic insults surrounding birth, cerebral malformations, diffuse brain damage, metabolic problems, and genetic problems. Developmental delay often accompanies the presence of infantile spasms.

A gray matter heterotopia is a type of migrational disorder where cells of the gray matter fail to reach their destination. This may be caused by a variety of toxic, metabolic, and infectious disorders. Migrational disorders may occur any time from the second month of gestation until the postnatal period.


Abnormalities in Development of the Nervous System




Spina bifida occulta

Failure of posterior neuropore (vertebral column) to close

Bony defect; few neurological signs


Herniation of meninges without herniation of neural tissue

Usually involves sacral and lumbar portions of spinal cord; few sensory or motor deficits although deficits in development of vertebral column may occur


Herniation of both meninges and neural tissue (i.e.,spinal cord or brainstem) through defect in vertebral column

Spinal cord: spina bifida aperta can result in significant sensory and motor deficits of spinal cord; Brainstem: Arnold-Chiari malformation, in which parts of medulla are pulled through foramen magnum,can result in hydrocephalus, major sensory and motor dysfunction, and loss of bladder control


Obstructive (e.g., aqueduct stenosis); communicating (e.g., choroid plexus papilloma)

Associated with a variety of abnormalities described in this table (e.g.,Arnold-Chiari malformation, encephalocele, Dandy-Walker syndrome) can result in a wide variety of disorders affecting sensory and motor systems, mental retardation, and epilepsy


Cavitation around the central canal of spinal cord, which is filled with cerebrospinal fluid

Can result in segmental loss of pain and temperature, bilaterally

Tethered cord

Anchoring of lowest part of spinal cord to sacrum

Some sensory and motor deficits of lower extremities, back pain, and bladder difficulties


Portions of anterior neuropore fail to close

Seizures, mental retardation, weakness of motor functions due to dysfunction of corticospinal tract

Dandy-Walker syndrome

Congenital absence of lateral (foramen of Luschka) and medial (foramen of Magendie) apertures

Macrocephaly (enlarged cranium), agenesis of cerebellar vermis, hydrocephalus, vomiting, headaches, delayed acquisition of motor skills, breathing problems


Failure of closure of the anterior neuropore

Partial or complete absence of brain; this condition is not compatible with life

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