Trends in Neurosciences
ReviewAbnormal development of the human cerebral cortex: genetics, functional consequences and treatment options
Introduction
Although the formation of the cerebral cortex is extremely complex, it can be grossly broken down into three main steps: cell proliferation, cell migration and cortical organization [1]. Cells proliferate in the germinal zones, within and adjacent to the walls of the lateral ventricles, then migrate along various pathways to the developing cortex where they disengage from the guide cell. Either during migration or after migrating into the proper cortical layer, the cells extend neurites and establish synaptic connections [2]. Disruption of these steps produces characteristic morphologic disturbances, typically abnormal sulcation and gyral patterns, that allow them to be classified into distinct entities which we have designated malformations of cortical development (MCD) (Table 1) [1].
To best classify MCD, imaging studies should be optimized. As a rule, thin-section T1- and T2-weighted magnetic resonance imaging (MRI) images should be acquired. For T1-weighted images, a volumetric spoiled gradient echo sequence (such as SPGR or MP-RAGE) should be acquired with partition size of 1–1.5 mm to allow the data to be reformatted in any plane. At a minimum, sagittal, coronal and axial images are necessary. For T2-weighted images, contrast between gray and white matter is best using conventional spin echo images. However, in the interest of saving time, fast spin echo (FSE; also called turbo spin echo) images might be better, especially if acquired as a 3D data set that can be reformatted. As white matter connectivity is important in function of the patient, it will become progressively more important to obtain sophisticated diffusion imaging techniques (diffusion tensor imaging, high-angular-resolution diffusion imaging, q-ball imaging) 3, 4 that allow mapping of the major white matter tracts. In neonates and infants less than 10 months old (before myelination), thin-section (1.5–3 mm) heavily T2-weighted spin echo images are optimal, whereas between the ages of 10 and 24 months, thin partitions of T1-weighted volumetric spoiled gradient echo images with heavy T1 weighting are best. Beyond age 2 years, standard adult protocols should be used.
The analysis of MCD has been very useful clinically and in helping genetic counseling. In addition, however, the analysis of these disorders has greatly aided our understanding of the processes of brain development. Analysis of groups of similarly affected patients has allowed us to specify causative genes (Table 1). Identification of the protein products of those genes often reveals involvement of those proteins in previously unsuspected pathways, and identification of those pathways leads to discovery of other causative genes. An excellent example of this process has been the analysis of congenital muscular dystrophies with CNS involvement. Once it was found that the biochemical problem in these disorders is impaired O-glycosylation of α-dystroglycan, mutations of many of the genes involved in that process were rapidly identified [5].
In the following sections, the genetic, imaging and functional aspects of some of the most common MCD will be discussed along with the options for treatment of associated epilepsy.
Section snippets
Focal cortical dysplasia
The term focal cortical dysplasia (FCD) designates a spectrum of abnormalities of the laminar structure of the cortex, variably associated with cytopathological features including giant (or cytomegalic) neurons, dysmorphic neurons and balloon cells 6, 7. Balloon cells are of uncertain lineage, exhibit an abundant pale-staining cytoplasm, peripherally positioned nuclei, no cellular processes and cell-surface markers for pluripotent stem cells [8]. Although attempts have been made to classify FCD
Lissencephaly
Lissencephaly (including both agyria and pachygyria) is the most severe of the known malformations from abnormal neuronal migration. Less severe defects in the same genes and developmental processes result in subcortical band heterotopia. In this group of malformations, neurons begin migration but are unable to complete it. To date, mutations of six genes have been associated with lissencephaly including LIS1, DCX, TUBA1A, RELN, VLDLR and ARX, whereas co-deletion of YWHAE with LIS1 appears to
Heterotopia
Heterotopia are clusters of normal neurons in abnormal locations. The most common type, periventricular nodular heterotopia (PNH), are rests of neurons that never begin migration, remaining adjacent to the lateral ventricles (Figure 1j). To date, ∼15 distinct PNH syndromes have been described [23]. The most common of these is classic bilateral PNH, which is much more frequent in females; more than 50% have mutations of the X-linked FLNA gene. Autosomal recessive microcephaly with PNH is a very
Polymicrogyria
The term polymicrogyria defines an excessive number of abnormally small gyri that produce an irregular cortical surface. It is a very common cortical malformation and is associated with a dizzying array of patterns and syndromes. Its pathogenesis is not understood; brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers [27], variably associated with an unlayered cortical structure. Today, polymicrogyria has been associated with mutations of only
Epileptogenesis, aberrant circuits and reorganization of cortical function: implications for surgical treatment of epilepsy in malformations of cortical development
Although not all MCD are equally epileptogenic, epilepsy is the most common clinical manifestation. Treatment with antiepileptic drugs is often ineffective and no controlled trial has been performed showing that any drug treatment is better than others in this group of malformations. When refractory to drugs, epilepsy is potentially amenable to curative treatment using a surgical approach. Diffuse MCD, involving most of the brain, such as lissencephaly, usually give rise to generalized or
Conclusion
MCD are an important cause of drug-resistant epilepsy. Some patients have obvious neurological impairment, but others show unexpected deficits that are detectable only by screening. Although no translational insights at the molecular pharmacological level have clearly emerged that might specifically target MCD-related epileptogenesis, the role of surgical treatment of epilepsy and its strategies are now relatively established. Localization of function based on anatomic landmarks might not be
Acknowledgements
This work was supported in part by a grant from the EU Sixth Framework Thematic Priority Life Sciences, Genomics and Biotechnology for Health, contract number LSH-CT-2006-037315 (EPICURE) (to R.G.).
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