CHAPTER ELEVEN
CONGENITAL ABNORMALITIES OF THE CNS
AND HYDROCEPHALUS

MALFORMATIONS OF CORTICAL DEVELOPMENT AND NEURONAL MIGRATION DEFECTS

NORMAL CORTICAL DEVELOPMENT

The neurons and glial cells that form the cerebral cortex are generated around the ventricles of the brain and migrate to the cortex. Proliferating multipotential precursor cells form a thick layer around the ventricles, the proliferative neuroepithelium. The first wave of migration results in formation of a provisional cortex, the pre-plate. This is replaced by the permanent cortical plate. Glutamatergic neurons migrate to the cortex along a scaffold of cellular processes, the radial glia. The nuclei of the radial glial cells are located in the walls of the ventricles and their processes stretch vertically to the pial surface. In addition to providing guidance, the radial glial cells are also neuronal and glial precursors. Migrating neurons are guided by adhesion molecules that are present on their membranes and on radial glial fibers, and by chemical signals, some of which are produced by the pre-plate. The neurons that form the permanent cortical plate migrate in an inside out, outside last pattern. GABAergic (inhibitory) neurons are generated in the primordia of the basal ganglia and migrate to the cortex in a tangential direction. The proliferative neuroepithelium produces more neurons than are necessary to populate the cerebral cortex. Neurons that do not make working synapses die. Other neurons are eliminated by genetically programmed apoptosis.

Neurogenesis in fish, amphibians, birds, and rodents continues after birth. Until recently, it was thought that neurogenesis and migration in primates is completed by mid-gestation except for the hippocampus and the granular layer of the cerebellum, where it continues during early post-natal life. Recent research shows that neurogenesis also occurs in the adult brain. New neurons are generated in the periventricular area and migrate to the neocortex. The significance of this observation in terms of neuronal plasticity and CNS repair is not known.

Cortical development entails the generation of stem cells, their differentiation into neurons and glia, migration to the cortex, and organization into functional layers. These processes overlap. Impairment of any of these processes can cause a variety of malformations, the neuronal migration defects (NMDs), the major types of which are listed in the table below.

MALFORMATIONS OF CORTICAL DEVELOPMENT

ABNORMAL NEURONAL-GLIAL PROLIFERATION OR APOPTOSIS Microcephaly Megalencephaly

ABNORMAL NEURONAL MIGRATION Subependymal (periventricular) heterotopia Lissencephaly/subcortical band heterotopia Cobblestone cortex/congenital muscular dystrophy

ABNORMAL CORTICAL ORGANIZATION Polymicrogyria Cortical microdysgenesis

Four scenaria are possible in the NMDs:
1. Neurons do not migrate at all from the ventricles (periventricular heterotopia) or migrate half way (subcortical band heterotopia).
2. Some neurons reach the cortex but large numbers do not. No normal cortical layers are formed (lissencephaly, pachygyria, cobblestone cortex).
3. Neurons over-shoot the cortex and end up in the subarachnoid space (marginal-leptomeningeal glioneuronal heterotopia, cobblestone cortex).
4. The late stage of migration and cortical organization is disrupted (polymicrogyria).

Any of these outcomes, alone or in combination, may occur in the NMDs. The process of neuronal migration and cortical organization is tied to the process of cortical folding. Abnormal migration causes an abnormal gyral pattern. The nomenclature of the NMDs reflects the naked eye appearance of the cortex. In addition to abnormal folding, the cortex is usually thick and disorganized. Severe NMDs such as lissencephaly, cobblestone cortex, and polymicrogyria are associated with psychomotor retardation and intractable seizures.

Most NMDs have a genetic basis, and many genes causing NMDs have been discovered in recent years. Genotypes and phenotypes overlap. The same gene mutation can cause different phenotypes because a) mutations affect protein function differently and b) the effect of a given mutation may be moderated by somatic mosaicism or, in the case of x-linked genes, by skewed X inactivation (see below). Also, mutations of different genes cause a similar phenotype, probably by influencing common pathways involved in neuronal migration and cortical organization. In the past, the classification of NMDs was based on the phenotype. Now, gene defects are integrated into the classification schemes and one day may be the sole basis of classification.

The best known NMD in animals is the reeler, a naturally occurring mouse mutant in which the normal inside-out pattern of migration does not occur and each layer of migrating neurons is deposited below the previous one. As a result, the cortical layers are inverted. This NMD is caused by mutations of reelin, a protein secreted by the Cajal-Retzius cells of the preplate. Reelin is an important guidance signal for migrating neurons. The major pathological phenotypes of NMDs in humans are described below.

PATHOLOGY AND GENETICS OF NMDs

Periventricular heterotopia

Subependymal heterotopia

This NMD is characterized by unorganized islands of neurons that are present under the ependyma of the lateral ventricles. These neurons presumably failed to migrate, and differentiated in their original positions. Unilateral periventricular heterotopia occurs frequently with other NMDs and malformations, and may be an incidental finding in patients undergoing MRI testing for unrelated reasons. Bilateral periventricular nodular heterotopia (BPNH) is caused, most commonly, by mutations of the FLNA gene, located on Xq28. The produt of this gene, filamin-A, is an actin-binding protein that cross-links actin filaments and is important for the integrity of the cytoskeleton and cellular movement. BPNH is X-linked dominant, and is lethal in males. Because of random inactivation of the X chromosome in each cell, females have two populations of neurons: one normal, which migrates to the cortex, and one mutant, which does not. Females with PNH have normal intelligence but may have seizures.

Lissencephaly-Agyria (type 1 lissencephaly).

Lissencephaly	Lissencephaly	Lissencephaly	Pachygyria

Cortical sulci, in lissencephaly, are absent except, usually, for the Sylvian fissure. The cortex is thick and consists of the molecular and three neuronal layers. The deepest of these layers is also the thickest and most cellular, presumably comprised of neurons that migrated a certain distance from the ventricles but failed to reach their normal destinations. There is a small amount of myelinated white matter between the abnormal cortex and the ventricles. Patients with lissencephaly have severe psychomotor retardation and intractable seizures.
Type 1 lissencephaly is caused by: LIS1 mutations . Complete loss of LIS1 (on 17p13) is fatal. Deletion of one copy causes lissencephaly. The LIS1 protein forms complexes with other proteins that are crucial for cell division, migration, and intracellular transport. It is involved in platelet function. It localizes also in microtubules and may play a role in their regulation. Deletions of LIS1 and contiguous genes causes the Miller-Dieker Syndrome, which combine lissencephaly with dysmorphic facial features, visceral abnormalities, and polydactyly. Lissencephaly, in LIS1 mutations, is more severe in the occipital lobes. Mosaic LIS1 mutations cause subcortical band hterotopia (see below)
DCX mutations (X-linked lissencephaly-XLIS). The DCX gene on xq22.3-q23 encodes doublecortin,

Subcortical band heterotopia

a microtubule associated protein. This suggests that XLIS is due to an abnormality of the cytoskeleton of migrating neurons. Affected males have lissencephaly. Affected females have a mosaic cellular phenotype, i.e., some of their neurons are affected and others are not. This results in a less severe malformation, subcortical band heterotopia, in which the cortex develops normally but there is also a separate layer of misplaced neurons between the cortex and the ventricles. The malformation is more severe in the frontal lobes. Patients with subcortical band heterotopia have psychomotor retardation, seizures, and behavior problems.
ARX mutations. Lissencephaly, in these patients, may be associated with agenesis of the corpus callosum and ambiguous genitalia.
RELN and VLDLR mutations. The RELN gene, on 7q22, encodes a protein that binds with the very low-density lipoprotein receptor and other molecules that are involved in guidance of migrationg neurons. In humans, RELN and VLDLR mutations cause pachygyria with extreme cerebellar hypoplasia. RELN mutations cause the reeler mutant mouse, characterized by cerebellar hypoplasia and cerebral cortical malformation.

Pachygyria is a milder variant of lissencephaly, characterized by broad gyri and a thick cortex with an abnormal cytoarchitecture. Pachygyria is seen in metabolic CNS disorders, such as the Zellweger Syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and glutaric aciduria IIA. Two key features of the ZS and NALD, deficiency of plasmalogens and elevated very long chain fatty acids, may cause membrane abnormalities that could impair guidance of migrating neurons.

Cobblestone cortex (type 2 lissencephaly)

Cobblestone cortex	Cobblestone cortex

The cortex, in this NMD, displays irregular grooves imparting a cobblestone pattern. No cortical layers are present. Instead, there is an irregular scramble of neurons and molecular layer. The pia is interrupted, allowing neuroglial tissue to spread into and obliterate the subarachnoid space. The lateral ventricles are enlarged. Patients with cobblestone cortex have severe psychomotor retardation, seizures, visual loss, and congenital muscular dystrophy. Cobblestone lissencephaly occurs in several genetic diseases, the most common of which are the Walker-Warburg Syndrome, Fukuyama congenital muscular dystrophy, and muscle-eye-brain disease. These conditions have a wide phenotypic spectrum and are caused by mutations that affect protein glycosylation. Defective glycosylation of matrix proteins in the brain presumably impairs the interaction of migrating neurons with matrix elements, causing NMDs. In muscle, it causes defective glycosylation of the dystrophin-associated protein α-dystroglycan, resulting in congenital muscular dystrophy.

Polymicrogyria

Generalized PMG	Generalized PMG	PMG- MCA territory	Polymicrogyria

In polymicrogyria (PMG), the surface of the cerebral hemispheres shows multiple small bumps -it has been likened to Morocco leather- suggesting an excessive number of gyri. The number of cortical layers varies from 2 to 4 (most commonly 4). Different layer patterns may be present in the same brain. The cortical layers are irregularly over-folded and the molecular layer is fused, eliminating sulci and trapping leptomeningeal vessels. PMG can be diffuse or focal, bilateral or unilateral, symmetric or asymmetric. About two thirds of PMG are perisylvian. Other topographies are less common. Some cases of PMG show also periventricular gray matter heterotopias and other brain malformations, such as abnormal Sylvian fissures, agenesis of the corpus callosum, and cerebellar hypoplasia. Patients with PMG have and seizures, severe psychomotor retardation, and other neurological abnormalities.

The etiology and pathogenesis of PMG are diverse. Some forms of PMG are acquired and are caused by disruptions. PMG often occurs with fetal cytomegalovirus infection and prenatal hypoxic-ischemic encephalopathy, including vascular problems related to twinning. In such cases, layer five is damaged and layers superficial to it overfold and fuse. The damage probably occurs either after neuronal migration is completed or following the migration of layer six neurons. In the latter case, layer four, three, and two neurons pass through the damaged layer five and are arranged in an abnormal fashion superficial to it. The disruptive pathogenesis of polymicrogyria is supported by animal experiments. PMG is frequently seen in vascular territories or watershed areas, and in the borders of porencephalic cysts and schizencephaly. Some patients have schizencephaly in one hemisphere and PMG in the same vascular territory in the other hemisphere. The association of PMG and schizencephaly is so close that the two entities are considered as part of a spectrum. A recent study shows that the order of cortical layers in PMG is preserved but there is loss of neurons and fusion of the molecular layer. These findings imply that PMG is not caused by an abnormality of neuronal migration and support its disruptive pathogenesis in most cases.

Other forms of PMG have a genetic basis and are associated with mutations of WDR62, SRPX2, PAX6, TBR2, and other genes. Bilateral perisylvian PMG due to mutations of SRPX2, causes dysphasia and dyslexia. A form of bilateral frontoparietal PMG, associated with mutations of GPR56, resembles cobblestone lissencephaly. The neuropathology of genetic forms of PMG is not well defined.

Focal cortical dysplasia-microdysgenesis is characterized by focally thickened cortex with a disordered cytoarchitecture, large, abnormally oriented neurons, and hypertrophic astrocytes. Such lesions are often seen in specimens resected for epilepsy. The lesion is thought to represent a focal abnormality of neuronal migration and differentiation. It resembles the cortical lesions of tuberous sclerosis.

Major clinical-pathological phenotypes of NMDs are distinct and relatively rare. Minor or focal abnormalities such as focal polymicrogyria, a single or a few subependymal heterotopic nodules, and subarachnoid glial neuronal heterotopias are quite common.

Further reading
Barkovich AJ, Kuzniecki RI Jackson GD, Guerrini R, and Dobyns WB. A developmental and genetic classification for malformations of cortical evelopment. Neurology 2005;65:1873-87 PubMed

Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res 2006;173:322-33 PubMed

Guerini R, Dobyns WB, Barkovich AJ. Abnormal development of the human cerebral cortex: genetics, functional consequences and treatment options. Trends Neurosci 2008;31:154-62. PubMed

Leventer RJ, Jansen A, Pilz DT, et al. Clinical and imaging heterogeneity of polymicrogyria: a study of 328 patients. Brain 2010;133:1415 – 27 PubMed

Judkins AR, Martinez BS, Ferreira P, et al. Polymicrigyria Includes Fusion of th Molecular Layer and Decreased Neuronal Populations But Normal Cortical Laminar Organization. J Neuropathol Exp Neurol 2011;70:438-43. PubMed

Updated: June, 2010