Focal Cortical Dysplasia: A Review of Pathological Features, Genetics, and Surgical Outcome

Vincent Y. Wang, M.D. Ph.D.; Edward F. Chang, M.D.; Nicholas M. Barbaro, M.D.

Disclosures

Neurosurg Focus. 2006;20(1) 

In This Article

Classification of FCD

To further classify the pathological features associated with FCD, a panel of epileptologists and neuropathologists devised a classification scheme[42] in 2004 that has been widely adopted. They distinguished two types of dysplasia based on the presence or absence of dysmorphic neurons or balloon cells. In Type I FCD, there are no dysmorphic neurons or balloon cells. In Type IA, isolated architectural abnormalities, usually laminar or columnar disorganization, are found. Type IB is also characterized by architectural abnormalities, but giant cells or immature neurons are also seen. It is important to note that no abnormal cells are present in Type I FCD. On the other hand, abnormal neurons are found in type II FCD. In Type IIA, there are dysmorphic cells but no balloon cells. In Type IIB, both dysmorphic cells and balloon cells are found.

Some correlation exists between the neuropathological findings, clinical presentation, and radiographic findings for these types. Type I FCD can be clinically silent and found in healthy patients. Indeed, autopsy studies have revealed that FCD is found in about 1.7% of healthy brains.[6] Some patients with Type I FCD may have cognitive impairment instead of epilepsy.[42] Magnetic resonance imaging findings associated with Type I FCD may include focal cortical thickening, reduced demarcation of the gray-white matter junction, hyperdensity of gray and subcortical white matter on T2-weighted images, hypodensity of subcortical white matter on T1-weighted images, lobar hypoplasia, and atrophy of the white matter core.[1,2,11] On the other hand, Type II FCD is more likely to be associated with medically refractory epilepsy. On MR images, these lesions may be seen as focal areas of increased cortical thickness, blurring of the gray-white junction, increased signal intensity on T2 weighted images, or extension of cortical tissue with increased signal intensity from the surface to the ventricle.[1,2,3,8,11,26,32] Although different MR findings are associated with Types I and II FCD, there is significant overlap. Thus, a specific categorization of FCD cannot be made solely on the basis of MR imaging findings and must ultimately be based on histological findings.[11]

Investigation of Mechanisms Leading to Epilesy

Investigation of the mechanisms by which focal cortical dysplastic lesions cause epilepsy is an active area of research. There is evidence for both an increased excitatory state and decreased inhibition. Molecular characterization of these lesions has suggested several potential mechanisms that can lead to hyperactivity of these lesions. One such mechanism is altered expression of NMDA receptors, which are excitatory glutamate receptors that conduct calcium. They are composed of heterodimers of two families, NR1 and NR2.[51] Numerous studies have demonstrated that FCD lesions have an elevated expression of NR2A/B subunit proteins and their associated clustering protein PSD95 in the dysplastic neurons and that these substances have a low expression level in normal neuronal tissues.[15,34,37,53,54,55] There is some evidence to suggest a correlation between the elevation of NR2A/B subunit expression and the degree of in vivo epileptogenicity.[37] In one animal model of FCD, an NR2B receptor antagonist has raised the threshold of bicuculline-induced epileptic discharge, suggesting that NR2B subunits may have a functional role in the hyperexcitability of the dysplastic lesions.[16] Nevertheless, the exact mechanism by which elevation of NR2A/B subunit expression leads to epileptogenicity is still unclear.

Another class of glutamate receptors, AMPA receptors, has also been implicated in the pathogenesis of FCD. AMPA receptors are composed of four subunits (Glu R1-4) and conduct sodium. AMPA receptors interact with NMDA receptors by removing the magnesium blockade on the NMDA receptors. Elevated expression of GluR2/3 subunits has been found in FCD lesions.[23] Increased GluR4 messenger RNA expression has also shown in FCD neurons.[15] Whether the AMPA receptors contribute to the hyper-excitability through interaction with the NMDA receptors is unclear at this point.

In addition to hyperexcitability, decreased inhibition is also implicated in the pathogenesis of FCD. Early studies have shown that parvalbumin and calbindin D28K immunoreactive neurons, which are inhibitory GABAergic neurons, are absent in dysplastic lesions.[19] The reduction of GABAergic neurons has been confirmed by Spreafico, et al.,[46] who have shown that the level of glutamic acid decarboxylase, the rate-limiting enzyme for GABA synthesis, is greatly reduced in dysplastic regions resected from human patients. These authors have also reported differences in organization of GABAergic neurons in Types I and II cortical dysplasia. In lesions of Type I cortical dysplasia, which have no giant neurons or balloon cells, a reduction in parvalbumin and glutamic acid decarboxylase immunoreactivity has been found. In contrast, lesions of Type II cortical dysplasia have shown an overall reduction of parvalbumin, but the giant cells are surrounded by terminals that are positive for parvalbumin and glutamic acid decarboxylase.[46] This reduction of GABAergic neurons has also been seen in experimental models of cortical dysplasia.[43] In contrast, Calcagnotto, et al.,[7] have not found an overall reduction of glutamic acid decarboxylase expression in Type II dysplastic lesions. Instead, they have described a reorganization of GABAergic neurons, including parvalbumin-positive and calbindin-positive interneurons. In contrast to normal tissue, where these interneurons are found in layer II/III, the interneurons in dysplastic lesions were found to be evenly distributed in all cortical layers. In addition, they have found effects on GABA transport in dysplastic lesions, including reduced expression of GABA transporter. The overall effect of these alterations is reduced inhibitory postsynaptic current frequency in type II cortical dysplasia tissue. Thus, there is evidence for both increased excitation and reduced inhibition in various experimental models, as well as in human cortical dysplasia. The exact role of balloon cells in the production of an epilepsy phenotype is unknown.

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