Malformations of cortical development and epilepsy

Abstract

Malformations of cortical development (MCDs) are an important cause of epilepsy and an extremely interesting group of disorders from the perspective of brain development and its perturbations. Many new MCDs have been described in recent years as a result of improvements in imaging, genetic testing, and understanding of the effects of mutations on the ability of their protein products to correctly function within the molecular pathways by which the brain functions. In this review, most of the major MCDs are reviewed from a clinical, embryological, and genetic perspective. The most recent literature regarding clinical diagnosis, mechanisms of development, and future paths of research are discussed.

Figure 1.

Sorting of microcephalies by morphologic characteristics. (A) Microcephaly with extremely small cerebellum and small pons. (B) Microcephaly with cerebellum and pons that are proportional and slightly disproportionately small compared with cerebrum. (C) Profound microcephaly with proportional cerebellum and brainstem that are disproportionately large compared with cerebrum. (D) Severe microcephaly with brainstem that is disproportionately large compared with cerebrum and cerebellum that is disproportionately large compared with brain stem. (E) Microcephaly with absence of the corpus callosum, interhemispheric cyst, and proportional brain stem and cerebellum with cerebrum; posterior fossa structures appear small because of mass effect from the supratentorial cyst. (F) Microcephaly with simplified cerebral gyral pattern, callosal hypoplasia, and severely disproportionately small brain stem and cerebellum.

Figure 2.

Diagram of portions of the mammalian target of rapamycin (mTOR) pathways associated with many aspects of cerebral cortical development, including transcription, cell growth, translation, proliferation/differentiation, and actin organization. As far as currently known, mTOR complex 1 (mTORC1) is more highly associated with cortical development than mTOR complex 2 (mTORC2). (Adapted from Lim and Crino 2013.)

Figure 3.

Lissencephaly secondary to TUBA1A (A,B) and LIS1 (C,D) mutations. Note that the child with the TUBA1A mutation is smaller, the corpus callosum (arrowheads) is thinner (difficult to see), and the cerebellum is small. Both are characterized by a band (B) of incompletely migrated neurons deep to the cortex.

Figure 4.

Magnetic resonance imaging (MRI) of patient with TUBB2B mutation showing many aspects of “tubulinopathies.” Sagittal image (A) shows short corpus callosum (cc), small pons (p), and small anterior lobe of cerebellum (white arrow). Coronal image (B) shows normal olfactory sulcus (arrowhead) and bulb (arrow) on the right, but absent sulcus and bulb on the left, an axonal pathfinding disorder. (C) Axial images show gray matter heterotopia (neuronal migration disorder, arrow), absent anterior limb of the internal capsule (axonal pathfinding disorder, arrowheads in C and D), and (D) abnormal sulcation in bilateral perisylvian cortex (arrows).

Figure 5.

Schematic of Reelin effects on terminal neuronal migration and images of brain with RELN mutation. (A) Schematic of neurons migrating along radial glial cell (RGC). The migrating neuron is unable to pass the primitive cortical zone (PCZ) before Reelin (RELN) from the Cajal–Retzius (CR) cells activates the Reelin pathway, resulting in a change in the conformation of integrin α5β1. This integrin is then able to adhere to fibronectin on CR cells in the molecular zone, allowing the neuron to pass through the PCZ and enter the outermost submolecular layer currently forming in the cortex. (B–D) show magnetic resonance imaging (MRI) of an infant with a RELN mutation. Note the small, smooth cerebellar vermis (large white arrow in B) and hemispheres (black arrows in D), the small pons (small white arrow in B), and the very simplified cerebral gyral pattern (in C and D) with a thick cerebral cortex (seen best in D).

Figure 6.

Periventricular nodular heterotopia (PNH). (A) An axial magnetic resonance imaging (MRI) scan shows nodules of gray matter intensity (arrows) along the left lateral ventricles, a characteristic appearance of PNH. (B) A schematic illustrating the mechanism of PNH formation. Disruption of neuroependyma, possibly because of disrupted vesicular trafficking, results in “gaps” in the membrane and disrupted neuroependymal attachment of the radial glial cells (RGCs). Neurons produced in the ventricular zone are not connected to the RGCs and are unable to migrate, remaining at or near the ventricular border as nodules of neurons.

Figure 7.

Cobblestone malformations. Phenotypes of cobblestone malformations vary with small, dysmorphic cerebella and brain stems (not shown) in addition to the cortical malformations. The latter may show (A) a microgyric pattern (black arrows), or (B) a pachygyric, lissencephalic-like pattern (white arrows). It is postulated that the former pattern results from (C) migration of relatively few neurons through small gaps in the pial limiting membrane, while the latter results from (D) larger gaps and greater number of neurons migrating into the subarachnoid space.