Chapter 26. Malformations of the Nervous System in Relation to Ontogenesis

Embryonic development of the nervous system is a series of overlapping processes.1 To understand neural development, a traditional view of morphogenesis must be integrated with what we know about molecular genetic programming of the neural tube and fetal brain. Understanding these normal ontogenetic processes is necessary to comprehend neural malformations, which arise as disturbances in one or more of these processes. Malformations of the brain and spinal cord may be caused by genetic mutations or by environmental or acquired influences. Examples of acquired and environmental causes are teratogenic toxins and drugs, fetal ischemia and infarcts, intrauterine trauma from maternal trauma or invasive procedures, cerebral hemorrhages, and infections affecting the fetal brain.

Knowledge of neuroembryology provides insight into the pathogenesis and mechanisms of neural malformations and how the brain determines dysgeneses of many non-neurological structures, such as developmental craniofacial disorders. Molecular genetics has profoundly changed our understanding of the mechanisms of both normal and abnormal development of the nervous system. These advances, combined with medical advances in neuroimaging, clinical neurophysiology, and neuropathologic tissue examination, provide a way to understand malformations of the nervous system. Thus, this chapter is not presented as a traditional list of various known neural malformations, each with their clinical, radiologic, and pathologic findings; nor is it intended as a tabulation of known genetic mutations and deletions associated with specific dysgeneses. It is presented as a modern approach to better understand malformations in the context of development, a new neuroembryology that integrates descriptive morphogenesis and genetic programming.

Neural development is better thought of as a set of simultaneously occurring processes than as a set of sequential steps.

Traditional classifications list a series of developmental processes as a linear sequence of events, one following another. Some processes are indeed step-wise, each dependent upon the preceding one. Among these are:

• Gastrulation
• Establishment of the body axes
• Curling of the primitive neuroepithelium or neural plate to form the neural tube

All of these processes occur before maturation of individual cells and structural organization of the neural tube.

Other neurodevelopmental processes occur late in embryonic development. Synaptogenesis can only occur after the formation of dendrites and dendritic spines, maturation of the neuronal membrane to form synapses, and the synthesis of neurotransmitters and their release at axonal terminals. Myelination of axons does not occur during the projection phase of axonal growth before the axon has reached its target and initiated synapse formation.

However, most processes occur simultaneously, such that they must be considered in relation to one another. Among these are:

• Neuroblast migration
• Maturation of the neuroblast membrane capable of developing a resting membrane potential
• Projection of the axonal growth cone from the migratory neuroblast
• Vascular perfusion of the brain
• The formation of glial cells in relation to capillaries to form a blood–brain barrier

Nevertheless, it is useful both for classification and understanding to list the developmental processes and then consider them individually. This classification must integrate traditional morphogenesis with an understanding of molecular genetic programming of nervous system development. Finally, the relation of nervous system development to the development of non-neural tissues, or neural induction, must also be considered along with development of non-neural cells and tissue within the brain, such as the vascular system for cerebral perfusion, microglia (resident macrophages), and the development of the immune system. Table 26-1 lists the developmental processes considered in the next sections.

The (Perhaps) Outdated Concept of Germ Layers

The concept of germ layers, which give origin to various tissues, as primitive ectoderm, mesoderm, and endoderm, is a traditional and long-accepted basic concept in embryology, conceived in the 19th century and based upon the best embryologic morphologic observations of that time. This concept continued to be accepted until the advent of molecular genetics in the late 1980s and early 1990s, when this deeply ingrained idea began to seem artificial and arbitrary. Gene families are expressed in all three layers, both in initial stages of tissue differentiation and also in maturing and mature tissues. For example, the HOX gene family programs segmentation of the neural tube but also is essential in the development of mesodermal structures of the extremities, endochondral long bones and muscle, and some endocrine organs of endodermal derivation. Neural crest cells of ectodermal origin form many mesodermal structures.

Ganglia: Not Small, Simple Brains

Understanding the development of the brain requires a basic knowledge of ganglia, which are not simple brains, and the components of a simple brain. The differences between brains and ganglia are listed in Table 26-2. A scientific definition of a brain must exclude functional criteria, especially those involving intellect, language, problem-solving, and reasoning. To introduce unique human qualities, or even those of more complex animals, as criteria, removes the definition from the realm of objective science and misrepresents it as philosophy or religion.

Acute Functional Changes to Nervous System Not Invoked by Birth

In many systems of the body, such as the cardiovascular and pulmonary, the abrupt transition from an intrauterine to the extrauterine environment involves profound physiologic changes. The nervous system is not in this category, and the programmed rate of maturation of the central nervous system is not influenced by the time of birth, whether preterm or at term, inthe healthy infant. An infant born at 28 weeks gestation (3 months early) has the same neurological examination and EEG maturation and myelination pattern at postnatal age 3 months as a full-term neonate just born, unless hypoxemia or other pathologic conditions cause a delay in maturation. In assessing neurological maturation of preterm infants, conceptional age (gestational age at birth + chronological age since birth) always must be considered, including head circumference and size of the fontanelles. This is clinically important and makes it crucial that the developmental age of a child be considered when assessing his or her neurological function.

Gradients of Genetic Expression Along the Axes of the Neural Tube

Various developmental genes of the nervous system are expressed as early as gastrulation, the stage of the primitive streak and the Henson node. Others appear later during neural plate development and especially after the neural tube is formed. With the establishment of bilateral symmetry and the formation of the neural tube, three major axes are identified: longitudinal, vertical, and horizontal (Figure 26-1). Genes that are expressed this early are expressed in a gradient along one or more of the three neural axes, with strongest expression at one site and progressively diminishing expression distal to that site. In each of the axes, one of two gradients is possible: in the longitudinal axis, the gradient may either be rostrocaudal or caudorostral; in the vertical axis, the gradient is either dorsoventral or ventrodorsal; in the horizontal axis, it is mediolateral or lateromedial. The bending of the neural tube with the formation of flexures does not alter the axes, which bend with the tube and follow its contour.

Nearly all developmental processes of the neural tube are genetically programmed. Many of the genes that appear at various stages to mediate specific processes are known2-4 and many more remain to be discovered.

A majority of cerebral malformations may be understood in the context of these axes and gradients. In general, up-regulation of a gene results in hypertrophy or duplication of structures at its strongest site of expression; down-regulation results in hypoplasia or noncleavage or midline "fusion" of structures. Many genes are antagonistic to others, and the down-regulation of one may lead to an appearance of up-regulation of the other, but this overexpression of one gene function is not due to increased synthesis of that gene's product mRNA or protein. This relatively recent molecular genetic insight may be integrated with traditional descriptive morphogenesis to provide a new means of classifying CNS malformations.5

Neural Tube Development: Concentric Zones

At 6 weeks gestation, the neural tube is fully closed, but the concentric zones of internal architecture are not yet fully developed. At the level of the telencephalon, only two zones are found: a (peri-) ventricular zone of undifferentiated neuroepithelium with cells still in the mitotic/proliferative stage and a marginal zone as a peripheral rim that has relatively few cells (Figure 26-2). The neuroepithelium is densely cellular, with most tightly packed with large nuclei and sparse cytoplasm and very little intercellular neuropil. No ependymal differentiation is present at the ventricular surface.6

By 8 weeks gestation, four concentric zones can be distinguished histologically (Figure 26-3):

1. The ventricular zone is still prominent, forming the ventricular wall and surface.

2. The subventricular zone, also known as the germinal matrix is peripheral to the ventricular zone. It should be noted that this is an imprecise but traditional term used by neuropathologists but not by strict neuroembryologists. Radial glial cells differentiate within the subventricular zone and send their long, slender process centrifugally to the pial surface, but do not have attachments to the ventricular surface as do neuroepithelial cells of the ventricular zone.

3. The intermediate zone lies peripheral to the subventricular zone and is the future white matter of the centrum semiovale.

4. The cortical plate forms from the migratory neuroblasts in the middle of the marginal zone, thus dividing the marginal zone into three layers:

   • A superficial part that persists as the molecular layer, which will be layer 1 of the mature cortex
   • A middle layer that is the cortical plate proper
   • A deep layer between the cortical plate and the intermediate zone that is called the subplate zone

5. With maturation of the cortical plate, the subplate zone becomes incorporated into layer 6; hence it is a transitory lamina.

Elimination of Redundancies

A fundamental principle of development is the overproduction and subsequent reduction of excessive cells, axonal collaterals, dendritic spines, and synapses. Redundancy of neuroblasts in every part of the brain and spinal cord, mediated by apoptosis, may be modulated by the need for, and provides for the potential repair or replacement of, cells lost early in gestation by physical, metabolic, or toxic injury to the developing brain.

Two Fundamental CNS Plans of Architecture: Nuclear and Cortical

During development, two cellular arrangements are present throughout the neuraxis. A nucleus is a cluster of the same type of neurons for a common, though not necessarily identical, purpose. Cranial nerve nuclei are a good example. Most of the thalamus and the basal telencephalic nuclei (ie, "basal ganglia") are organized with nuclear architecture. Also, more than one type of neuron may be included in nuclei. Many nuclei include interneurons as well as primary sensory or motor neurons. Cortical architecture is a laminar arrangement of neurons of the same type in each layer, with synaptic connections between layers. Examples of cortical architecture are the cerebral neocortex, hippocampus (paleocortex), lateral geniculate body of the thalamus, superior colliculus (optic tectum of the rostral midbrain), cerebellar cortex, olfactory bulb, and retina. The cerebral cortical plate at mid-gestation is not yet a laminated structure, and has a fetal architecture that is more columnar than laminar, corresponding to the recently completed phase of neuroblast radial migration (Figure 26-4). In one type of focal cortical dysplasia, this columnar architecture persists (Figure 26-5).

Gyration

Because the mammalian brain has cortices with laminar architecture, but a limited cranium in which the brain must fit, an increase in surface area without a corresponding volume increase is necessary. This is accomplished in the mammalian brain with folding of the cortex to form gyri and sulci in the cerebrum and folia in the cerebellum. Fissures and sulci of the cerebral cortex are similar but not identical because they form differently (see section "Fissures, Sulci, and Gyri of the Cortex").

Thalamic Modulation of Ascending Sensory Information to Forebrain

Almost all primary sensory systems—somatosensory, proprioceptive, auditory, vestibular, visual, and taste—have synapses in the thalamus for modulation before relay to the sensory cortices. The notable exception is the olfactory system, in which olfactory nerve impulses are received in the olfactory bulbs and relayed via mitral and tufted neurons directly to neocortex, the entorhinal cortex (parahippocampal gyrus); local circuitry within the olfactory bulb functions as its own thalamus.7

Gastrulation

Gastrulation occurs at 16 days postconception. The formation of the Henson node and primitive streak establish bilateral symmetry as the basic body plan of all vertebrates, and the three axes of the body and of the CNS:

1. Longitudinal (cephalic and caudal ends

2. Vertical (dorsal and ventral surfaces)

3. Horizontal (medial and lateral in relation to the midline of the longitudinal axis)

Gastrulation also is the "birthday" of the nervous system, as it is the earliest time when neuroepithelium can be distinguished from other tissues.

Neurulation

Neurulation is the bending of the neural plate to form a tube and changes the orientation of surfaces and edges of the neural plate. The dorsal surface becomes the inner surface facing the lumen of the central canal and ventricles; it is lined by neuroepithelium and later by ependyma. The lateral margin of the neural plate closes the tube in the dorsal midline and neural crest arises from most of this edge.

Closure of the neural tube begins in the cervical region and progresses rostrally and caudally. The anterior neuropore closes at 24 days, and the posterior at 28 days. There are multiple sites of closure in the position of the anterior and posterior neuropore.

Secondary neurulation is the formation of the most caudal sacral segments of spinal cord, posterior to the site of closure of the posterior neuropore. This part of the spinal cord does not develop as a folding of the neural plate, but rather is a solid cone of neuroepithelium with an ependymal central canal forming within its core.

Induction

Induction is the influence of one embryonic tissue upon another, each of which differentiates into different mature tissues. Neural crest cells separate from the dorsal midline of the neural tube at the time of its closure. The incipient neural crest or progenitor cells develop at the lateral margin of the neural plate. Neural crest arises from three sites of the neural tube and each migrates to give rise to specific structures (Table 26-3):

1. Prosencephalic neural crest is generated in the dorsal part of the lamina terminalis, the same place that gives origin to the bridge for the corpus callosum. It migrates rostrally as a thin vertical sheet of cells in the midline to the nose and forehead, and forms the intercanthal ligament between the embryonic orbit.

2. Mesencephalic neural crest arises from the dorsal midline of the mesencephalic neuromere and rhombomeres r1 and r2. It migrates as streams of cells in the horizontal plane to form most of the craniofacial structure, including the orbits, all cartilage and membranous bone of the face and cranial vault (but not endochondral bone of the cranial base, basioccipital, exoccipital and supraoccipital bones), dura mater including falx and tentorium, leptomeninges over the brain (but not over the spinal cord), the globe of the eye (except the retina, optic nerve, choroid, lens, and cornea), blood vessels, nerve sheaths (including Schwann cells, but not axons), and melanocytes.

3. Rhombencephalic neural crest arises from rhombomeres r3 through r8 including the spinal cord. It migrates as blocks of cells in streams and forms most of the peripheral autonomic nervous system (including sympathetic chain and parasympathetic ganglia in GI tract), chromaffin tissue (adrenal medulla; carotid body), nerve sheaths, dorsal root ganglia, stria vasculosa over the hair cells of the cochlea, melanocytes, and adipocytes.

Migratory neural crest cells do not differentiate into their mature identity until they reach their terminal site. Abnormalities of neural crest, known in human medicine as "neurocristopathies," include many neurocutaneous syndromes and aganglionic megacolon (Hirschsprung disease). The mesencephalic origin of craniofacial structures also explains hereditary neurosensory deafness and craniofacial dysmorphisms also associated with many cerebral malformations.8

Segmentation

Segmentation of the neural tube or the formation of transitory physical compartments (neuromeres) restricts the longitudinal movement of cells during development.9 Segmentation is mediated by a group of genes called homeoboxes, which are restricted DNA sequences composed of exactly 183 DNA base pairs. Homeobox genes encode a class of proteins that share a common or very similar 60-amino acid motif, the hom-eodomain.10 Mammalian homeoboxes are identical to the segment polarity genes of invertebrates, and program the embryonic segmentation of the vertebrate neural tube.11 For example, HOX genes are essential for limb development and the anterior and posterior orientation of the arms and legs. The human EGR2 (Krox-20 in the mouse) is expressed only in rhombomeres r3 and r5 in the neural tube, and is an essential gene for myelination in the peripheral nervous system (PNS).12

Cellular Proliferation and Apoptosis

Neural development is redundant and generates more neurons than are needed. There is a subsequent reduction of this abundance via the mechanism of apoptosis (programmed cell death). Most mitoses occur in the neuroepithelium at the ventricular wall (m-phase).13,14 Neuroepithelial cells have long radial processes that span the neural tube, with end feet at the ventricular surface and the pial surface; nuclei travel to and fro within this thin cytoplasmic extension. When distal to the ventricular wall, the s-phase enables replication of DNA in preparation for the next mitosis.

If the mitotic spindle is oriented perpendicular to the ventricular surface (symmetrical mitosis), the two daughter cells each reenter the mitotic cycle. If the mitotic spindle is parallel to the ventricular wall, the cell next to the ventricle reenters the mitotic cycle and the other has completed its last mitosis and prepares for migration as a neuroblast. In the human, 33 mitotic cycles produce all the neurons of the cerebral cortex.15

There are 50% more motor neuroblasts produced in the spinal cord than needed, and this number is later reduced through apoptosis.16 The Bcl-2 family of proteins plays an integral role in regulating the time and rate of apoptosis,17 which usually occurs in undifferentiated or only incipiently differentiated neuroblasts. However, a second phase of apoptosis may involve more mature neurons during late development. Hormones and growth factors may influence the rate of apoptosis. This process is more complex than most developmental processes because there is no single gene or gene combination that intiates the cascade of events comprising apoptosis, which is programmed into every cell, but only expressed when trophic factors secreted by nearby cells remove the inhibitors of this process that normally preserve metabolic integrity.

Until recently, it was thought that the mature brain has no capacity to generate new neurons; however, potentially neurogenic stem cells within the brain have now been identified in the periventricular regions. These are most numerous in the region of the dentate gyrus of the hippocampus and in the olfactory bulb. In fact, there is a constant turnover of some neurons in both locations. Primary olfactory receptor neurons are continuously renewed, but interneurons (granule cells) in the olfactory bulb are also regenerated.18,19

Cellular Lineage and Differentiation

The origin and migration, or lineage, of any neural cell determines not only whether it will be as a neuron, glial cell, or ependymal cell within the neural tube, but also which type of neuron, which neurotransmitter it will synthesize, which receptors will form in its plasma membranes, and where it will project its axon. Glial cells similarly must differentiate as astrocytes, oligodendrocytes, and specialized astrocytes such as the transitory radial glial cells of the cerebrum or the permanent Bergmann glial cells of the cerebellar cortex. Lineage in general is genetically programmed, but may be induced to change if pathologic conditions ensue in the fetal brain.

The development of a stable resting membrane potential depends upon the formation of the ATPase energy pump. Associated with that are other maturational features of the neuron and its plasma membrane: membrane channels and receptors, neurotransmitter biosynthesis, neuron-specific proteins, and intermediate filaments.

Regulator genes are important factors not only in whether a progenitor cell will become a neuron, a glial or ependymal cell, but also in which type of cell within these categories it becomes. Some developmental disorders of the brain are due to mixed cellular lineage, as in tuberous sclerosis and hemimegalencephaly, in which cells not only express a mixture of neuronal and glial proteins but show morphologic and growth aberrations, sometimes even leading to neoplastic transformation.

Neuronal Differentiation

A neuron is a secretory cell with an electrically polarized membrane. Neuroblasts, however, are postmitotic cells with a committed neuronal lineage, but not yet mature enough to be neurons. The features of maturation that define neurons are:

1. Synthesis and expression of neuronal proteins and filaments, such as neuronal nuclear antigen (NeuN) and neurofilament proteins (NFP)

2. An energy-producing pump for maintaining a resting membrane potential, generally the Na/K adenosine triphosphatase (ATPase) pump

3. Development of specialized membrane receptors and ion channels

4. Neurosecretory functions to enable the biosynthesis of a neurotransmitter, and to transport it and package it in vesicles; ribosomes and rough endoplasmic reticulum and a Golgi apparatus are required.

It should be noted that the presence of neurites is is not sufficient to define a cell as a neuron. For example, chromaffin cells of the adrenal medulla and carotid body are not neurons without dendrites or axons.

Ependymal Differentiation

The fetal ependyma provides unique functions not required in the adult. Differentiation of the ependyma from the neuroepithelium at the ventricular surface arrests all mitotic activity at that site.20 Ependyma does not completely cover the lateral ventricular surface until 22 weeks gestation.21-23 Genetic and environmental influences, such as toxins, teratogens, and viral infections, can cause precocious differentiation of the ependyma. Early ependymal formation decreases the number of neurons and may result in microencephaly and other malformations with later functional correlates, such as mental retardation and epilepsy.

Fetal ependymal cells have basal processes that radiate into the parenchyma, but do not extend to the pial surface and do not guide migratory neuroblasts. They secrete molecules that help guide the intermediate trajectory of growing axons by either repelling them or attracting them. Both the neuronal targets of the roof plate and floor plate are ependymal, and the floor plate is the first cellular differentiation in the neural tube, even before closure. Figure 26-6 shows the normal relations of the sclerotome with the notochord in its centre to the neural tube overlying it, in the spinal cord of a 6-week human embryo; the notochord produces the gene Sonic hedgehog (SHH), which induces the floor plate of the neural tube and the first motor neuroblasts. Figure 26-7 shows the spinal cord roof plate ependymal processes in an 8-week fetus that extend dorsally in the midline to separate the developing dorsal columns of the two sides of the spinal cord by both acting as a physical barrier and by secreting glycosaminoglycans that repel growing axons, so that right-left orientation is not confused in the brain by aberrant decussations of these axons in the spinal cord. Figure 26-8 shows the growing axons in the dorsal columns in a longitudinal (frontal) section of the dorsal part of the spinal cord in a 6-week human embryo, impregnated with silver stain.

Disorders Related to Disturbances in Cell Lineage and Differentiation

Disturbances in neural cell lineage and differentiation are the cause of several human neural malformations. In these malformations, cells often show a mixed lineage with expression of both neuronal and glial proteins. Tuberous sclerosis is the prototype example.24 Another good example is hemimegalencephaly, with many cells of mixed lineage and abnormal architecture resulting from disturbed migration due both to abnormal radial glial cells and abnormalities in the migratory neuroblasts.25 Other examples include cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), dysembryoplastic neuroepithelial tumour (borderland between dysplasia and neoplasia), and the Taylor-type of focal cortical dysplasia.

Neuroblast and Glioblast Migrations

Almost all mature neurons migrate from their point of cellular origin to where they are in the mature nervous system. Cells migrate mainly centrifugally, to a distant site before completing their cellular maturation. Migration may proceed along radial glial processes or along axons.

Radial migration to the cerebral cortical plate is guided by a scaffold of slender radial processes of specialized astrocytes that differentiate in the subventricular zone and project their processes centrifugally to the pial surface (Figure 26-8). Neuroblasts and glioblasts are guided to their destination along the outside of these radial glial fibers, as if riding a monorail. The continued proliferation of radial glial cells in the subvenricular zone stops at midgestation.26 After migration is complete, the radial process retracts and most radial glial cells become fibrillary astrocytes of the white matter. In the cerebellar cortex, the specialized radial glial cells are called Bergmann cells; their soma is in the Purkinje cell layer, and their processes extend radially through the molecular zone to guide external granule cells to their mature site in the internal granular layer, beneath the row of Purkinje cells. Radial glia are also found in the early brainstem and spinal cord to guide neuroepithelial cells, but they are mixed with basal processes of ependymal cells, which extend for longer distances in the brainstem than in the telencephalon (Figure 26-9).

In addition to radial migration to the cerebral cortical plate, there also is tangential migration along several pathways from the ganglionic eminence of the embryonic forebrain that is part of the germinal matrix, along axons into the developing cortical plate. These neurons that arrive by tangential migration are GABAergic inhibitory interneurons of the cortex and they comprise about 18% to 20% of total cortical neurons. A subset of these neurons is identified by reactivity to calretinin in both the fetal and adult brain (Figure 26-10).

Migration depends upon characteristics of the migratory cells, the cells and molecules they secrete, as well as proteins in the extracelluar matrix that guide the migration. Many genes that mediate the migratory process have been identified, not only in the CNS but also in the migration of neural crest cells to the periphery. Mutation, down-regulation, or lack of expression of each produces characteristic malformations.4,5,27-29

Fissures, Sulci, and Gyri of the Cortex

Fissures and sulci are grooves that form in the smooth external surface of the cortex to facilitate folding, which increases the surface area without a concomitant augmentation of volume or mass of the brain tissue. Fissures form earlier than sulci and generally are deeper, but the principal difference is the forces that mediate their formation: fissures are a reaction to external physical stresses and bending of the brain, whereas sulci result from internal stresses due to an increased and growing volume of the parenchyma from growth of cells and especially the production of neurites and glial processes that form the neuropil between neurons. The development of the ventricular system influences the formation of fissures but not sulci because the ventricles act as an external force; even through they are enclosed within the brain, they are not part of the parenchyma.

Four fissures form in the forebrain: (1) the interhemispheric fissure that creates two telencephalic hemispheres from a single prosencephalon at 4 to 5 weeks gestation; (2) the hippocampal fissure that develops with rotation of the hippocampus ventrally from its initial dorsal position; (3) the sylvian fissure that results from telencephalic flexure or ventral bending of the caudal third of the primitive telencephalon, beginning at about 9 weeks and completed when the operculum completely covers the insula at 36 weeks; and (4) the calcarine fissure on the medial side of the occipital lobe, developing at about 12 weeks.30 More than 30 sulci form, beginning at about 22 weeks gestation. They follow a precise temporal and spatial pattern and create predictable identifiable gyri of the mature cerebral cortex. Fissures of the brainstem include the sagittal and transverse intercollicular fissures of the tectum of the midbrain and the fissure that forms at the pontomedullary junction to demarcate the caudal end of the basis pontis. The folia of the cerebellum, by contrast, correspond to gyri and sulci and develop in the vermis sooner than in the lateral hemispheres, but the parasagittal grooves that demarcate the vermis from the medial side of the lateral hemispheres are fissures.

Synaptogenesis

The formation of synapses depends not only upon axonal trajectories to reach the target neurons with which they form contact, but also the ability of the presynaptic neurons to synthesize secretory products (neurotransmitters) and to transport them distally within the axon and store them in synaptic vesicles at the axonal terminal. Furthermore, the postsynaptic membrane of the recipient neuron also must have matured to have developed a resting membrane potential and specialized receptors and membrane ion channels. The sequence of synaptogenesis in the brain is as precisely time-linked and spatially sequential as other developmental processes and may be demonstrated in tissue sections of human fetal and neonatal brain by immunocytochemical markers for synaptic vesicle proteins, such as synaptophysin.31Figure 26-11 shows the hippocampus of (A) a midgestational fetus, with strong synaptophysin reactivity limited to the molecular zone of the dentate gyrus and the CA2 sector of Ammon's horn, with weaker activity in CA3 and none in CA4, and (B) a full-term neonate with uniformly strong reactivity thoughout all grey matter structures of the dentate gyrus and Ammon's horn. Figure 26-12 shows synaptophysin in the frontal neocortex of (A) a 26-week fetus with reactivity limited to the molecular layer and the deep part of the cortical plate, and in ascending thalamocortical axons; (B) a full-term neonate with uniformly strong reactivity throughout the cortex. These may be combined with more specific tissue markers identifying specific neurotransmitters. Heterotopic neurons in the white matter are not "isolated" as they appear histologically, but are synaptically connected with each other and with the overlying cortex, and may contribute to epileptic circuitry.

Myelination

Myelination is dependent upon the cellular lineage of oligodendrocyte precursors and also by expression of genes directing the mature oligodendroglial cell to synthesize myelin lipoproteins.32-34 The wrapping of individual axons by oligodendroglial processes that synthesize myelin is a late process in neural development. It is not initiated until the growing axonal growth cone has passed through its intermediate trajectory and made synaptic contact with a target neuron. In most longitudinal pathways of the central nervous system, the entire axon acquires its myelin sheath at the same time; for example, the spinothalamic tracts. Some pathways myelinate along a proximal (near to the neuronal soma) to distal gradient. The corticospinal tract is an example of this pattern. In the full-term neonate, corticospinal axons possess myelin in the corona radiata, internal capsule, and middle third of the cerebral peduncle; minimal myelin is present in the basis pontis; and none is seen by conventional myelin stains in the pyramids or spinal cord.

Many normal axons never become myelinated. In the peripheral nervous system, the sympathetic nerves are an example. In the central nervous system, only 40% of axons of the corpus callosum are myelinated in the adult. These axons still function well. Myelination increases the speed of conduction along an axon by saltatory conduction between nodes of Ranvier, but this has no effect on the speed of thinking or movement.

The earliest axons to myelinate are the ventral roots of the spinal cord, at about 16 weeks gestation. As with other aspects of neural development, temporal and spatial sequences of myelination are precisely timed and predictable. Some pathways complete their "myelination cycle" early, within days or a couple of fetal weeks. Other are slower, even over years. The corpus callosum does not begin to myelinate until 4 months of age by MRI criteria, though myelin stains show early myelination in tissue sections at about 2 months. Myelination is not complete in the corpus callosum until adolescence. The last pathway to acquire myelin in normal development is the ipsilateral frontotemporal and frontoparietal association bundles, delayed to 32 years of age.35Table 26-4 lists major and some minor CNS pathways with the initiation and termination of their myelination cycles.

The development of major blood vessels, both arteries and venous sinuses and veins, is equally precise in its timing and coordination with neural development. The basilar artery initially is a pair of vessels at the base of the rostral neural tube, the longitudinal neural arteries. At about 4 weeks gestation, they undergo a true fusion to form the single midline basilar artery. At that time, the direction of blood flow is rostrocaudal because the early basilar artery is connected with the internal carotid arteries by a series of segmental communicating arteries, the most constant of which are named the trigeminal, otic, and hypoglossal arteries. The vertebral arteries form from a plexus of vessels. When these connect with the basilar artery and there is atrophy and disappearance of the transitory connections between the carotid and basilar artery, the direction of blood flow is reversed and becomes caudorostral. The anterior and middle cerebral arteries are formed separately from the internal carotid and only later fuse on each side with the carotid. The anterior cerebral artery arises in the first pharyngeal (brachial) pouch associated with rhombomere 1, and the middle cerebral artery arises from the second pharyngeal pouch and rhombomere 2. The posterior cerebral arteries arise from pharyngeal pouch 3 and fuse with the rostral end of the basilar artery. The circle of Willis, including the anterior and posterior communicating arteries, is the last major arterial element to form.

Stem cells persist in the human brain and are capable of proliferation and then differentiation as neurons. This is a relatively new finding and has challenged the long-held dogma that the brain had all the neurons it would ever have at birth, and that nerve cells were too specialized to regenerate or repair injuries. Stem cells in the adult human brain are localized mainly to the olfactory bulb and the hippocampus, around the dentate gyrus, but periventricular sites in the telencephalon also may contribute new neurons. Primary olfactory neurons are continually regenerated.

The term neural plasticity is used to describe many processes, but fundamentally involves all the processes of neural development. Proliferation of stem cells is only one aspect; others include the formation of new dendritic spines, synapses, and synaptic circuits. For example, in the hippocampus, synaptic remodeling is used to form new memories. This is also the basis of learning and problem-solving in the neocortex.

Plasticity is much greater in the fetal and postnatal immature brain, than in the adult mature brain. The result is that damage, such as early fetal infarcts, may not necessarily cause a permanent deficit because some functions can be transferred to other healthy parts of the brain. For example, language functions can sometimes develop in the right cerebral hemisphere if the left hemisphere is damaged early in gestation. Hemimegalencephaly is an asymmetrical malformation that develops early in fetal life, yet some children have no asymmetry of motor or sensory function because of the other side of the brain subserves both sides of the body. Similarly, hemicerebellar hemispheric infarcts early in gestation may not necessarily be expressed as ipsilateral tremor and dyssynergia because of the "rewiring" that enables the other preserved cerebellar hemisphere to provide motor coordination on both sides of the body.

Cysts form more readily in the fetal and postnatal brain than in the adult brain, which is more likely to form dense gliosis unless the infarct is very large. This is because the neonatal brain has about 6 times fewer astrocytes per unit volume of white matter than mature brain, and so is less able to mobilize glia. Thus, the neonatal brain tends to have larger infarcts because of the poor collateral circulation within the microvascular network of immature brain.

Historical Context

Until the era of molecular genetics of neural development, little was known about the pathogenesis of neural malformations, and thus they were classified in broad categories based upon descriptive morphology, such as disorders of neural tube closure, midline disorders, migratory disorders, and disturbances of cellular growth and differentiation. After it became clear that there is a precise spatial and temporal pattern of genetic expression in development, not only in the nervous system but in all other organs as well, classifications shifted to the opposite extreme, often ignoring morphogenesis and focusing on lists of gene defects. Morphology has been reintroduced by advances and refinements in neuroimaging, particularly magnetic resonance imaging (MRI), but these imaging techniques all have the inherent limitation of demonstrating only structural changes large enough to visualize with the naked eye. Microscopic differences in cells and protein and gene expression cannot be seen, even with the best imaging techniques available today. Thus the next frontier is to correlate anatomic findings in living patients with modern molecular genetics and modern neuropathology from postmortem studies of the same disorders.36 An additional frontier that is only in incipient stages of correlation is of neurophysiologic alterations, in EEG in particular, among the various malformations, with aberrations of developmental processes such as synaptogenesis.37

Dysgeneses as Disorders of Gradients of Genetic Expression in Axes of the Neural Tube

As discussed earlier, genetic up-regulation, in the vertical axis in particular, results in hypertrophy and/or duplication of structures; down-regulation results in hypoplasia and/or noncleavage or fusion of structures.

Holoprosencephaly

Holoprosencephaly (HPE) is a prototype malformation that well illustrates the genetic gradients in all three major axes of the neural tube, as well as disturbances in neural induction of craniofacial development (Figure 26-9).38,39 The strictly morphologic concept of holoprosencephaly is that it is a disorder of midline cleavage with several variants of uncertain relation to each other: alobar, semilobar, and lobar.40 In addition to identifying many additional details of abnormal macroscopic and microscopic structure in HPE, Golden presented this malformation as an abnormality of genetic programming with the variants being degrees of severity.40 We attempted to further recognize the variants of the malformation as an overall problem of down-regulation of genes, with the length of their gradients in each of the axes explaining the degrees of morphologic and clinical expression, as well as the midfacial hypoplasia in some, but not all, cases. It is now recognized that there are six, and perhaps eight, distinctive genes in which mutations may cause the same forms of HPE, and that these only represent about 20% of total cases examined genetically; undoubtedly there will be many more genes discovered in the future. HPE is thus not a single disease with one etiology, but rather a syndrome that can be associated with many different genetic defects, but that all have a common mechanism to produce a similar or identical end result.

The variations of the mediolateral gradient of gene expression may explain many clinical features of HPE, such as the extent of mental retardation and cognitive deficiencies and the presence and severity of epilepsy. Only 41% of children with HPE have epilepsy,42,43 by contrast with lissencephalic disorders, in which nearly 100% of patients are epileptic. Endocrine disorders also are complications of HPE,43,44 another aspect of the rostrocaudal gradient of the longitudinal axis reaching the diencephalon. A related disorder, septo-optic-pituitary dysplasia (de Morsier syndrome), shares many embryologic aspects with HPE.45

Neural Tube Disorders

In addition to HPE, many other disorders of embryonic development of the neural tube can also be explained by gradients of genetic expression (Figure 26-10). In the spinal cord, duplication of the dorsal horns is an expression of up-regulation of a dorsalizing gene in the vertical axis; duplication of the central canal and, in more extreme form, complete diplomyelia, are due to up-regulation of a ventralizing gene.38 Severe dysplasia of the spinal cord and a single midline ventral horn in the caudal regions of the spinal cord may occur in some cases of lumbosacral agenesis. This is explained by down-regulation of a ventralizing gene, Sonic hedgehog, but simultaneous disturbance in the caudorostral gradient of the longitudinal axis also is evident.38 In the cerebellum, up-regulation in the dorsoventral gradient is associated with cerebellar vermal hypertrophy, whereas down-regulation in this gradient may result in rhombencephalosynapsis or agenesis of the vermis with fusion of the two lateral cerebellar hemispheres and the dentate nuclei. In the forebrain (telencephalon and diencephalon), up-regulation in the dorsoventral gradient may produce an abnormally thick corpus callosum and duplication of the hippocampus on one or both sides (the hippocampus begins its development as a dorsal structure in humans, but later rotates to a more ventral position; in rodents it remains a dorsal structure even in adult life). Down-regulation of the dorsoventral gradient in the forebrain produces agenesis of the corpus callosum, hypoplasia of the hippocampus, and hypotelorism because of a defective intercanthal ligament arising from the prosencephalic neural crest. These examples serve to emphasize a general principle that many CNS malformations can be understood in the context of gradients of genetic expression.

Dysgeneses as Disorders of Segmentation of the Neural Tube

Compartmentalization of the neural tube into neuromeres was discussed earlier. As with the gradients, both up-regulation and down-regulation of segmentation homeobox genes may be the basis of some malformations. In general, up-regulation may cause ectopic expression of a gene in neuromeres where it is not normally expressed. Down-regulation, by contrast, results in hypoplasia or even aplasia of the particular neuromeres that rely upon that gene for their integrity. A good example is the rare malformation, congenital agenesis of the mesencephalon and metencephalon (midbrain and rostral pons), which corresponds to the embryonic mesencephalic neuromere and rhombomere 1 and part of r2.

Up-regulation of segmental homeobox genes in murine models causes ectopic expression, so that more rostral structures might form in more caudal segments than normal. The most likely and most common human dysgenesis that might be attributed to such up-regulation is the Chiari II and Chiari III malformations.46 This might also account for at least some cases of Chiari I malformations, but other mechanisms might also be involved. Chiari II malformations are nearly always associated with lumbosacral meningomyeloceles, and Chiari III also involves a posterior encephalocele. A molecular genetic segmental hypothesis of Chiari II malformation has been presented that can explain these other features, as well as the meningomyelocele.46,47 The candidate gene is one of the HOX family. This particular homeobox gene family is primordial in embryonic hindbrain segmentation, but they also are essential for the formation of endochrondral, but not membranous, bone. Most of the cranial vault and facial skeleton is membranous bone, derived from neural crest. The basioccipital, exoccipital, and supraoccipital bones, however, are endochondral. These bones are hypoplastic in Chiari II malformation, explaining the low insertion of the convergence of venous sinuses at the torcula, which reduces the volume of the infratentorial space of the posterior fossa. HOX gene mutations can cause this and also can cause multiple primary brainstem dysgenesis, including aqueductal stenosis, dysplasias of the inferior olivary nuclei, and "tectal beaking" of the inferior colliculi. Because the whole spinal cord is derived from rhombomere 8, posterior neural tube defects also might result, and would not necessarily be expressed at all levels of the spinal cord. Indeed, the meningomyelocele sometimes occurs at more rostral spinal levels.

Congenital Absence of Specific Types of Neurons

Regulator genes program late developmental events such as synaptogenesis and myelin formation. These genes are also are responsible for the differentiation of cell types, not only cellular lineage but the specific type of neuron or glial cell that develops, as discussed earlier.

In Dandy-Walker malformation and related disorders, a part of the cerebellum may be deficient, such as the posterior vermis, even though similar neurons with the same morphologic and metabolic profiles48 are normal. This may be explained not as a genetic program of individual neurons but as a defect in gradients. A difference between the partial vermal agenesis in Dandy–Walker and Joubert syndromes from rhombencephalosynapsis is that the medial sides of the two cerebellar hemispheres remain separated by an extension of the subarachnoid space to replace the vermis, rather than fusing.

Defects in genetic regulation of cellular differentiation and growth result not only in malformations in which the architecture of neural tissue is disrupted, but also cause abnormalities in individual cells. Regions of both abnormal tissue organization and abnormal cells are called hamartomas (Figure 26-11). The most prominent examples of these diseases are tuberous sclerosis,24 hemimegalencephaly,25 and dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease).1

Disorders of Neuroblast Migration

This group of cerebral malformations is one of the best understood, because many genes responsible for specific malformations are now known, and because many features can be recognized macroscopically, allowing establishment of the diagnosis with neuroimaging and confirmation with specific genetic studies. Many of these disorders have distinctive facial dysmorphisms and clinical neurological features that enable them to be suspected from the initial history and physical examination, before any laboratory investigations are even carried out.

Neurons do not and cannot migrate. Migratory cells of neuronal lineage are neuroblasts; hence the term "neuronal migration" is a misnomer and, despite its widespread use, is more properly designated neuroblast migration. Axons may form during migration, but dendritic arborization awaits final positioning of the neuroblast. Heterotopia are embryologically defined as cells displaced within their organ of origin, and ectopia are cells displaced outside their organ of origin. Considering the brain as an organ or origin, a neuron abnormally displaced in the deep white matter is heterotopic, and a neuron isolated in the leptomeninges is ectopic. Heterotopia may be single cells or may be groups of cells to form nodules large enough to visualize by imaging.

Disorders of neuroblast migration are often readily diagnosed by neuroimaging because abnormal migration is associated with heterotopia and abnormal gyration, or lack of gyration, of the cerebral cortex. These heterotopia and convolutional abnormalities are so characteristic that the diagnosis frequently can be diagnosed from the MRI even without confirmation by genetic studies or postmortem neuropathologic examination. Such disorders can be divided into groups based upon where the migratory arrest has occurred, that is, how far the neurons were able to migrate before stopping.

In some malformations, there is little or no migration radially from the subventricular zone, and periventricular nodular heterotopia results. Another group is characterized by partial migration with arrest of migratory neuroblasts in the subcortical white matter to form a sheet of gray matter, subcortical laminar heterotopia or band heterotopia (also called "double cortex"), but this term is a poor one because the heterotopia are not organized as laminar cortex. One of the known genes that is defective in periventricular nodular heterotopia is called Filamin-A (FLM-A); the best known gene causing subcortical laminar heterotopia is Doublecortin (DCX). Both of these genes are essential for building microtubles that allow cellular motility. A third group consists of abnormal positioning of neurons within the cortical plate so that the cerebral cortex itself is abnormally laminated and has disoriented and displaced neurons in the wrong layers. Reelin (RELN) is an essential gene and its protein product signals the correct organization of the cortical plate. Reelin is secreted by Cajal-Retzius neurons of the molecular zone present in the preplate plexus before the first wave of migratory neurons arrives. Defective RELN results in abnormal lamination and orientation of neurons in the cortex (Figure 26-12).6,27 The genes that cause Walker-Warburg syndrome or lissencephaly type II, POM-T1(locus 9q34.2) and POM-T2 (locus 14q24.3), are important for the glycolysation of the cytoskeletal protein α-dystroglycan, which connects the neuronal cytoskeleton to extracellular matrix proteins, which is required for cell movements.28,29 Striated muscle membranes also are affected, hence the coexpression of congenital muscular dystrophy. Overmigration beyond the pia mater into the leptomeninges, called glioneuronal heterotopia, also may occur. The breach in the glial limiting membrane and pia mater may be associated with a defect in the subpial granular glial layer of Brun. This feature is common to many neuroblast migratory disorders, but also is very common in holoprosencephaly, in which one of the more constant defects is a paucity or total absence of subpial granular glial cells of Brun.1

Disorders of Primary Neurulation

Anencephaly

Anencephaly occurs because of a failure of anterior neuropore closure. Since the anterior neuropore closes at less than 24 days, this disorder occurs within the first month of fetal development. Anencephaly affects the forebrain and variable portions of brainstem but several different subtypes may occur depending on the level of the defect. Holoacrania occurs with a defect to the foramen magnum. Meroacrania occurs with the defects slightly higher than the foramen magnum.

Approximately 75% of these children are stillborn. It is most common in whites, Irish, females, and children born to either very old or very young mothers. The risk of anencephaly in subsequent pregnancies is 5% to 7%.

Myeloschisis

Myeloschisis develops with failure of posterior neuropore closure. It is associated with iniencephaly, or a malformation of skull base. Most of these children are stillborn.

Encephalocele

An encephalocele is a restricted defect in anterior neural tube closure. These defects consist of a protrusion of brain and intracranial structures through a skull defect. These are typically migration defects or heterotopia involving these patients. Approximately 75% occur in the occipital region and 50% are associated with hydrocephalus.

Myelomeningocele

A myelomeningocele develops secondary to a restricted defect in posterior neural tube closure. There is a herniation of the spinal cord or meninges through a vertebral defect. Most of these defects occur in the lumbar region. Approximately 90% of the cases with lumbar defects have associated hydrocephalus. If the defect occurs in some other region, only 60% of the patients have hydrocephalus. The symptoms include motor, sensory, and sphincter dysfunction. Spina bifida occulta occurs with a defect in the vertebral arch but no abnormalities of the spinal cord or meninges.

Chiari Malformations

Type I Chiari malformation is an isolated displacement of the cerebellar tonsils into the cervical canal. This may be either congenital or acquired in patients with low intracranial pressure. The type I malformation can be associated with a syrinx, a kinked cervical spinal cord, and hydrocephalus. Most of the type I patients have no associated symptoms. In rare cases, the patient may have headaches, tinnitus, or ataxia. In severe cases, surgical decompression is the primary treatment.

Type II Chiari malformation occurs with displacement of the cerebellum into cervical canal, displacement of the medulla and fourth ventricle into the cervical canal, a long, thin medulla and pons, tectum deformity, and skull base and upper cervical spine defects. Hydrocephalus is a common complication secondary to fourth ventricle obstruction or aqueductal stenosis. Myelomeningocele occurs in all patients and 96% have cortex malformations (heterotopia, polymicrogyria, etc.). Brainstem malformations are less common but occur in three-quarters of patients. Other common findings include cerebellar dysplasia, thoracolumbar kyphoscoliosis, diastematomyelia (bifid cord), and syringomyelia. The patient usually presents as a neonate with neurological deterioration including respiratory failure, stridor, and hydrocephalus. Treatment includes surgical decompression and shunting. Severe neurological sequelae typically persist.

Type III Chiari malformation includes all of the features of the type II malformation with herniation of the occipital lobes, cerebellum, and brainstem into an associated low occipital or high cervical encephalocele. The neurological consequences are severe and the outcome is poor.

Meckel syndrome occurs in some patients following maternal hyperthermia or fever on days 20 to 26 following conception. The features includes encephalocele, microcephaly, microphthalmia, cleft lip, polydactyly, polycystic kidneys, and ambiguous genitalia.

Neural Tube Defects

Neural tube defects occur in association with a number of disorders including chromosomal abnormalities (trisomy 13, trisomy 18), teratogens (thalidomide, valproate, phenytoin), single mutant gene (Meckel syndrome), and as a multifactorial syndrome. Diagnosis is made by increased alpha-fetoprotein, increased acetylcholinesterase, and by ultrasound. These defects can in some cases be prevented by maternal supplemental folate. The recurrence rate in subsequent children is 2% to 3%.

Disorders of Secondary Neurulation—Occult Dysraphic States

The disorders of secondary neurulation have an intact dermal layer over the lesion but 80% have an overlying dermal lesion (dimple, hairy tuft, lipoma, or hemangioma). The spinal cord is frequently tethered. All patients have an abnormal conus and filum terminale. Most patients have vertebral defects. Siblings have a 4% chance of a disorder of primary neurulation.

1. Caudal regression syndrome—dysraphic sacrum and coccyx with atrophic muscle and bone

2. Myelocystocele—cystic central canal

3. Diastematomyelia—bifid cord

4. Meningocele—rare with no associated hydrocephalus

5. Lipomeningocele

6. Subcutaneous lipoma/teratoma

7. Dermal sinus

Disorders of Prosencephalic Development

Aprosencephaly is the absence of the telencephalon and diencephalon. Atelencephaly is the absence of the telencephalon but a normal diencephalon. The skull and skin are intact. These disorders are frequently associated with cyclopia, absent eyes, and abnormal limbs and genitalia.

Holoprosencephaly

Holoprosencephaly occurs with a defect in prosencephalic cleavage resulting in defective division of the hemispheres. All patients have anosmia because of absent olfactory bulbs and tracts. A single-lobed cerebrum and single ventricle are common. The optic nerve is either hypoplastic or single. There is agenesis of the corpus callosum. Neuronal migration defects are common. A number of caial defects can occur, including ethmocephaly (hypertelorism with proboscis between eyes), cebocephaly (single nostril), cyclopia (single eye with or without proboscis), and a cleft lip. Patients typically present with or develop seizures, apnea, decreased hypothalamic function, developmental delay, anosmia, and a single maxillary incisor. Several chromosomal abnormalities can lead to holoprosencephaly including trisomy 13, ring 13, and the SHH gene on chromosome 7. The recurrence rate for siblings is approximately 6%, and 2% are infants of diabetic mothers.

Dandy-Walker Malformation

The Dandy-Walker malformation occurs secondary to failed or delayed development of the foramen of Magendie. There is systic dilation of the fourth ventricle and cerebellar agenesis with maldevelopment of the cerebellar vermis. Hydrocephalus is a common complication. Many patients have agenesis of the corpus callosum, neuronal migration disorders (70%), a large inion, a large posterior fossa, cardiac anomalies, and urinary tract abnormalities. Seizures are a common complication.

Neuronal Proliferation and Migration Disorders

Disorders of Migration

Schizencephaly occurs with a cleft or space connecting the ventricle and the subarachnoid space. There is no associated gliosis. Heterotopia frequently occur in the wall of the cleft. In type I, the lips of the cleft are closed or in contact with each other. In type II, the lips of the cleft are open and do not touch. Schizencephaly may be genetic or related to a sporadic ischemic insult early in gestation.

Porencephaly is a variable communication between the ventricles and the subarachnoid space. Unlike schizencephaly, there is gliosis in the cleft wall. Porencephaly is felt to be secondary to ischemia later in gestation.

Lissencephaly is a disorder of migration with the development of few or no gyri. This results in a "smooth brain." Heterotopia occur frequently in lissencephaly. Type I lissencephaly is associated with a partial deletion of chromosome 17 (the LIS1 gene). Type II lissencephaly is associated with a disorganized cortex, neuronal overmigration, and a thickened, somewhat cobblestone-appearing cortex. Pachygyria is a subtype of lissencephaly with a few broad thick gyri. Seizures, mental retardation, and death at an early age are common.

Miller–Dieker syndrome is associated with lissencephaly. There is a large chromosome 17 deletion in 90% of cases. The clinical presentation includes microcephaly, seizures, hypotonia, poor feeding, craniofacial defects, cardiac defects, and genital abnormalities.

Polymicrogyria occurs with too many small gyri, giving the brain the appearance of a wrinkled chestnut. This disorder usually occurs secondary to an ischemic injury or infection resulting in poor migration. Polymicrogyia occurs in X-linked dominant Aicardi syndrome. Inherited peroxisomal disorders such as Zellweger syndrome (cerebro-hepato-renal syndrome) may also result in polymicrogyria.

Heterotopia or remains of neurons in the white matter occur secondary to arrested radial migration. These heterotopia are frequently associated with seizures. There are several subtypes: periventricular, laminar (in deep white matter), and band-like (between cortex and ventricular surface).