Malformations of cortical development: Embryology and epilepsy

Abstract

One in seven patients with focal epilepsy has a malformation of cortical development (MCD) as underlying cause. Understanding normal cortical development combined with knowledge of where, when, and what goes wrong in different types of MCD provides insight into the mechanisms of epileptogenesis. Three different steps can be distinguished in the development of the neocortex: proliferation, migration, and organization. These three steps occur at different locations, partly overlapping in time. In this review, we illustrate and correlate normal embryology to the most common MCDs in epilepsy, namely, focal cortical dysplasia, heterotopia, and polymicrogyria, with discriminating imaging findings and clinical implications. By integrating current literature on embryology and imaging findings, we aim to provide insight into classification of cortical malformations and the consequences for workup and treatment. Illustrations of normal cortical embryology and early fetal development are supplemented with magnetic resonance images from our tertiary epilepsy center showing the three most frequently encountered malformations: focal cortical dysplasia (approximately half of identified MCDs at our center, consistent with literature), heterotopia (one third), and polymicrogyria (approximately 10%).

Keywords: focal cortical dysplasia; heterotopia; malformations of cortical development; polymicrogyria.

FIGURE 1

Overview of normal cortical development. (A) In embryonic week 5, the forebrain of the neural tube enlarges to form the secondary vesicles of telencephalon (blue) and diencephalon (pink). The telencephalon already consists of several cell layers (detail, right). The lining of the ventricular cavity filled with amniotic fluid consists of neural stem cells (blue) and radial glial cells (yellow); the outer surface consists of early migrated, pioneering neurons (green) that form the preplate (PP). (B) In embryonic week 8, the telencephalon has expanded hugely and is seen both rostrally and laterally of the diencephalon/thalamus (pink) bordering the third ventricle (III). In the telencephalon, different regions can be recognized. The striate (purple) will develop into the basal ganglia. The cavity has developed into lateral ventricles (Lat vent) lined with neural stem cells (blue located in the ventricular zone [VZ]). On the outer surface, the cortical plate (CP) has thickened into multiple layers of neurons (green) forming between the split preplate. The processes of the radial glial cell (yellow lines) have become increasingly longer; they continue to bridge the distance between VZ and CP to guide and feed the neurons. Drawings are by author M.C.H., based on histological specimens provided by embryology websites by Dr. Mark Hill (https://embryology.med.unsw.edu.au) and the Virtual Human Embryo project (https://www.ehd.org/virtual‐human‐embryo). (C) The telencephalon continues to develop and become more specialized during the fetal period. On this axial Balanced Fast Field Echo intrauterine magnetic resonance imaging (MRI) sequence, in fetal week 19–20, the basic pattern described in week 8 can still be recognized. The ventricles are lined with proliferating neural stem cells and radial glia in the ventricular zone (blue) and subventricular zone (light blue). The cortical plate (green) with neurons has been further thickened, and a faint impression for the insula is visible in the left hemisphere. The intermediate zone (IZ; yellow lines and arrows indicate radial glial processes) is very cell‐sparse, watery, and thus hyperintense on T2‐weighted images. (D) Coronal intrauterine MRI section through the frontal lobe and striate (purple). Again in fetal week 19–20, the basic pattern of migration of glutamate neurons is visible: The ventricles are lined with proliferating neural stem cells and radial glia in the ventricular zone (blue) and subventricular zone (light blue). The cortical plate (green) with neurons has been further thickened, and a faint impression for the insula is visible in the left hemisphere. The IZ (yellow lines and arrows indicate migration along radial glia) is very cell‐sparse, watery, and thus hyperintense. The γ‐aminobutyric acidergic neurons are born in the part of the subventricular zone overlying the striate and the medial and lateral ganglionic eminence (MGE and LGE; purple) and are beyond the scope of this overview.

FIGURE 2

Proliferation with neural stem cells (blue)/radial glia (yellow)/neurons (green). Before week 15 (a), the germinal matrix with proliferating cells consists of the ventricular zone with neural stem cells (blue) and radial glial cells (yellow with dark blue rim). The radial glial cells have two processes (yellow lines): a short arm to the ventricular surface (apical process) and a long arm to the basal membrane on the outside of the brain (basal process) to guide the neurons. During weeks 15–17 (b), outer radial glial cells (yellow with light blue rim) appear whose short arm no longer contacts the ventricular surface and whose cell body is located a little bit further from the ventricle. These outer radial glial cells form the subventricular zone. The neurons that are generated migrate along the ventricular and outer radial glial cells to the cortical plate. The outer cortical layers (green with light blue rim) arise from outer radial glial cells in the subventricular zone. CP, cortical plate; I, layer I, marginal zone; IZ, intermediate zone; SVZ, subventricular zone; VIb, layer VIb, subplate; VZ, ventricular zone.

FIGURE 3

Histologically proven focal cortical dysplasia (FCD) type IIb on coronal fluid‐attenuated inversion recovery image (A) with thickened cortex, blurring of the gray–white junction (curved arrow) and a transmantle sign (straight arrows). (B) In FCD type II, abnormal radial glial cells (red) generate balloon cells and abnormal neurons with a decreased apoptotic tendency. The abnormal cells can be found along the entire migratory trajectory accounting for the transmantle sign. Microscopically, in FCD II cortical layer I is broadened and recognizable; the rest of cortical lamination is no longer recognizable. In FCD type II, normal neurons can be identified between the dysmorphic neurons. Balloon cells, if present, are mainly found in layer I and at the location where layer VIb would be expected. Balloon cells near the gray–white matter boundary and hypomyelination of the subcortical white matter contribute to the blurring of the gray–white matter junction. CP, cortical plate; I, layer I, marginal zone; SVZ, subventricular zone; VIb, layer VIb, subplate; VZ, ventricular zone.

FIGURE 4

Migration with neural stem cells (blue)/radial glia (yellow)/neurons (green). The migrating neurons have to undergo morphological changes and adjust their cytoskeleton to navigate to and within each zone. The neurons have a pinlike extension in the ventricular zone that retracts to leave. Neurons in the intermediate zone have a multipolar shape. To pass the subplate, the neurons have to become elongated and bipolar. CP, cortical plate; GLM, glial limiting membrane; I, layer I, marginal zone; SVZ, subventricular zone; VIb, layer VIb, subplate; VZ, ventricular zone.

FIGURE 5

(A, B) Periventricular nodular heterotopia located along the posterior horn of the left ventricle with the same signal intensity as orthotopic cortex on axial T2‐weighted (A) and coronal inversion recovery images (B). (C) The neurons with the gene mutation fail to retract the pinlike extension, which prevents the neuron from leaving the ventricular zone. The most common mutation in periventricular heterotopia encodes for an actin‐binding protein, filamin A, and is X‐linked. In females with an FLNA mutation, approximately half of the neurons are affected (red); the complementary nonmutated half can migrate normally toward the cortical plate (green). CP, cortical plate; GLM, glial limiting membrane; I, layer I, marginal zone; SVZ, subventricular zone; VIb, layer VIb, subplate; VZ, ventricular zone.

FIGURE 6

Band heterotopia (straight arrow) paralleling the cortex on a T2‐weighted image of a newborn with unmyelinated T2 hyperintense white matter. (A) The thin orthotopic cortex has few and shallow sulci (curved arrow), compatible with pachygyria. (B) In band heterotopia, the neurons cannot switch from multipolar to bipolar mode (red) and end up just below the subplate.

FIGURE 7

Focused image of the cortical plate, showing normal cortical organization with radial glia (yellow)/neurons (green). The subplate/layer VIb serves as a waiting room for neurons entering the cortical plate. Reelin secreted by cells in layer I coordinates the normal positioning of cortical neurons in both supragranular and infragranular layers in an inside‐out fashion. The incoming neurons let go of their radial glial cell (detach, a). After arriving at their final position, the neuron relinquishes the ability to go through the cell cycle and assumes its final identity (terminal differentiation, b). GLM, glial limiting membrane; I, marginal layer, layer I secreting reelin; ig, infragranular layers IV–VIa connecting to thalamus and brain stem; sg, supragranular layers II–III with corticocortical connections; VIb, subplate, layer VIb.

FIGURE 8

(A) Polymicrogyria with bumpy cortex located in the perisylvian region on sagittal T1‐weighted images. (B) On coronal inversion recovery, the sharp gray–white matter junction (arrows) is visible, discriminating polymicrogyria from focal cortical dysplasia type II. (C) Gaps in the glial limiting membrane cause neurons, in this case especially from layer II and III (red), to overmigrate. Because of lack of covering by a basal membrane, opposing cortices can fuse and give the impression of thickened cortex. GLM, glial limiting membrane; I, marginal layer, layer I secreting reelin; ig, infragranular layers IV–VIa connecting to thalamus and brain stem; sg, supragranular layers II–III with corticocortical connections; VIb, subplate, layer VIb.

FIGURE 9

(A) In focal cortical dysplasia (FCD) type Ia, the neuron is incapable of detaching from the radial glial cell, resulting in a microcolumnar arrangement. The abnormality is not or is barely visible on magnetic resonance imaging (MRI). In the past 10 years, no histologically proven FCD Ia has been identified on MRI at our center. (B) FCD Ib is postulated to result from selective vulnerability and cell death. The “missing” layer depends on the mechanism and cause of the clastic event (hypoxia vs. hypoglycemia vs. other). Often an increase in number of γ‐aminobutyric acidergic tangentially migrated neurons is observed, which are assumed to fill the gap. (C) A rare case (one of two in 10 years) of histologically proven FCD type Ic visible on a coronal fluid‐attenuated inversion recovery image with subcortical hyperintensity (circle). The cortex seems a little thinner and not thickened as in FCD type II. The periventricular hyperintensity (dashed arrow) is probably gliosis (not included in the surgical specimen/no histology) and not a transmantle sign. GLM, glial limiting membrane; I, marginal layer, layer I secreting reelin; ig, infragranular layers IV–VIa connecting to thalamus and brain stem; sg, supragranular layers II–III with corticocortical connections; VIb, subplate, layer VIb.