Focal Cortical Dysplasia

Abstract

Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.

Fig. 1

(A) FCD type IIb (labeled with anti-nestin antibodies; modified from 14; scale bar = 400 microns). Note loss of cortical lamination and ovoid shape of balloon cells. (B) Balloon cells (arrows) in cortical tuber (modified from 31; scale bar = 100 microns).

Fig. 2

Schematic depicting mTOR pathway components. Growth factor (GF) receptor-mediated signaling drives the mTOR pathway. Note the mTOR inhibitor rapamycin site of effect. At several key points, individual focal cortical dysplasia (FCD) subtypes are listed next to site of gene mutation in the pathway. For example, tuberous sclerosis complex (TSC) is associated with mutations in either TSC1 or TSC2, FCD with AKT mutations, and FFEVF to DEPDC5 mutations. Hemimegalencephaly has been linked to mutations in PI3K, MTOR. Megalencephaly (ME) has been associated with mutations in PI3K, TBC1D7, and MTOR. Pretzel syndrome (PS) is linked to STRADA mutations and is associated with ME and FCD. For other associations, see text.