Basic mechanisms of epileptogenesis in pediatric cortical dysplasia

Abstract

Cortical dysplasia (CD) is a neurodevelopmental disorder due to aberrant cell proliferation and differentiation. Advances in neuroimaging have proven effective in early identification of the more severe lesions and timely surgical removal to treat epilepsy. However, the exact mechanisms of epileptogenesis are not well understood. This review examines possible mechanisms based on anatomical and electrophysiological studies. CD can be classified as CD type I consisting of architectural abnormalities, CD type II with the presence of dysmorphic cytomegalic neurons and balloon cells, and CD type III which occurs in association with other pathologies. Use of freshly resected brain tissue has allowed a better understanding of basic mechanisms of epileptogenesis and has delineated the role of abnormal cells and synaptic activity. In CD type II, it was demonstrated that balloon cells do not initiate epileptic activity, whereas dysmorphic cytomegalic and immature neurons play an important role in generation and propagation of epileptic discharges. An unexpected finding in pediatric CD was that GABA synaptic activity is not reduced, and in fact, it may facilitate the occurrence of epileptic activity. This could be because neuronal circuits display morphological and functional signs of dysmaturity. In consequence, drugs that increase GABA function may prove ineffective in pediatric CD. In contrast, drugs that counteract depolarizing actions of GABA or drugs that inhibit the mammalian target of rapamycin (mTOR) pathway could be more effective.

Keywords: Balloon cells; Cortical dysplasia; Dysmorphic neurons; Epileptogenesis; mTOR pathway.

Figure 1

Different classification systems used to define cortical dysplasia (CD) types based on the presence of architectural and cellular abnormalities. In the original description of focal cortical dysplasia (FCD) by Taylor et al. 6, different types were not defined but the authors noticed that not all cases presented with balloon cells. The ILAE classification of CD is currently the more widely accepted. We also include the relationship of different types of structural lesions with clinical manifestations, as well as potential cellular mechanisms that could participate in the generation of epileptic discharges

Figure 2

Simplified diagram of architectural and cellular abnormalities in cortical dysplasia (CD) compared with normal cortex. In CD type I, laminar organization becomes more tenuous and pyramidal neuron misorientation, with or without tortuous processes, is profuse. Immature pyramidal neurons also are observed, sometimes organized as microcolumns or as clusters. In CD type II, lamination is almost lost except for a distinct layer I. Balloon cells can be seen mainly in the upper layers and in white matter. Dysmorphic cytomegalic pyramidal neurons and cytomegalic interneurons are scattered throughout the cortical plate. In addition, clusters of immature pyramidal neurons can be seen. The role of granular and polymorphic neurons in dysplastic cortex remains unknown. This diagram was inspired by a figure in reference 72.

Figure 3

Simplified diagram of possible mechanisms of hyperexcitability in cortical dysplasia (CD) types I and II compared with normal cortex. In normal cortex, pyramidal neuron output is tightly regulated by inhibitory GABAergic interneurons. In CD type I, neuronal disorganization and microcolumns/clusters of immature pyramidal neurons contribute to hyperexcitability due to depolarizing actions of GABA on these neurons. In CD type II, in addition to increased excitation caused by immature pyramidal neurons, cytomegalic pyramidal neurons and cytomegalic interneurons intensify the generation and propagation of epileptic discharges. In contrast, balloon cells which lack synaptic inputs and are unable to fire action potentials are probably not involved in epileptogenesis, but could play an antiepileptic role by buffering glutamate and K⁺.