NEURONAL PROLIFERATION AND MIGRATION DISORDERS
The complexity and duration of cortical neurogenesis and migration makes it a particularly vulnerable target for disruptions that result in broad range of brain disorders. These include a variety of epilepsies, intellectual disability, and potentially, disorders such as autism and attention deficit/hyperactivity disorder (ADHD). Many of these disorders, and the cell biologic and genetic analyses that better defined their pathogenesis as disruptions of cortical neuronal proliferation and migration, took advantage of structural imaging of the cortex by using magnetic resonance imaging to identify anatomic irregularities in the size, shape, and gyral and sulcal patterns of the cortical hemispheres. Nevertheless, a “normal” magnetic resonance imaging scan does not rule out microscopic localized gyral malformations or, most important, significant defects of the cortical layers and heterotopias of neurons that are initially des- tined for one cortical layer, but, due to altered migration, are found in an aberrant laminar location. Clearly, such disruptions of cortical neurogenesis and migration must result in altered circuits that lack the capacity to mediate maximally adaptive behaviors.
Defective Proliferation. A decrease in neuronal number may lead to microcephaly (microencephaly vera), whereas an increase may result in megalencephaly. Prenatal influences, including familial factors, are paramount in each abnormality. Microcephaly may be caused by a variety of genetic and environmental etiologies. It may be isolated or associated with other anomalies. Primary microcephaly results from a developmental insult giving rise to a reduced neuronal population. Secondary microcephaly occurs from an injury or insult to a previously normal brain.
Megalencephaly is classified as either anatomic or metabolic. It may be associated with neurofibromatosis, achondroplasia, or cerebral gigantism. Familial megalencephaly, the most common and benign form, is usually inherited through the father. Excessive postnatal growth also occurs often, suggesting hydrocephalus. Measurements of the parental head circumference and MRI scans showing normal ventricles aid in diagnosis. Approximately 70% of infants with microcephaly and 30% of those with megalencephaly have developmental defects.
Defective Migration. After proliferation in the sub-ependymal region, neurons migrate to the cortex. The neurons appear to follow radial glial cells like raindrops on telephone wires. Early migrations form the deepest cortical layers, and later migrations, the more superficial layers, ultimately forming a six-layer cortex. The cellular complement is greatest in the outer cortical layers, leading to an increased surface area, with buckling causing gyri to begin to appear between 26 and 28 weeks, and become increasingly complex in the final trimester. If the normal complement of neurons is absent, gyral formation does not take place, and lissencephaly (smooth brain, agyria) results (see Plate 1-5). An abnormally thick gyral formation is known as pachygyria. In this anomaly, the cortex lacks the six-layer configuration. Cerebral heterotopias appear to result from defective neuronal migration and subsequent accumulation of aberrant neurons anywhere between the ependyma and cortex (see Plate 1-5). Significant numbers of such heterotopias occurring in isolation are likely to result in some degree of intellectual disability. Most of the disorders of migration discussed previously have associated heterotopias. The presence of multiple small gyri having no resemblance to a normal gyral pattern, along with deranged lamination of the cortical mantle, is called polymicrogyria (see Plate 1-5). Schizencephaly is characterized by an abnormal cleft that joins the cortex and the ventricles. It is usually bilateral but can be unilateral. Malformed gyri (polymicrogyria) are aligned radially around the cleft.
Agenesis of the corpus callosum, partial or complete, is often accompanied by disorders stemming from defective neuronal migration. This results in developmental defects, seizures, mental retardation, and occasional hydrocephalus (see Plate 1-5). The diagnosis may be suggested by ocular hypertelorism, an antimongoloid slant to the eyes, and other midline facial defects. Aicardi syndrome, a sporadically occurring abnormality seen in female infants, is associated with retinal defects that suggest chorioretinitis, infantile spasms, hypsarrhythmia, and severe psychomotor retardation. Agenesis is one of the most common anomalies diagnosed by MRI in “idiopathic” psychomotor retardation (see Plates 1-5 and 1-6).