Focal Cortical Dysplasia Cases Research Articles

Mcm2 labelling of balloon cells in focal cortical dysplasia

Balloon cells (BC) are the prominent and defining cellular component of type IIB Focal Cortical Dysplasia (FCD), a common cause of focal epilepsy in patients undergoing surgical treatment. BC are considered immature cells of uncommitted cellular differentiation having immunophenotypical characteristics of both neurones and glia. They are often located in the lower cortical layers and white matter underlying the dysplastic cortex, suggesting migratory arrest during development. We investigated the proliferative potential of BC in 15 cases of FCD from patients with a wide range of ages using immunohistochemistry for Mcm2 (mini chromosome maintenance protein) and Ki67. In the majority of cases, BC showed Mcm2 nuclear positivity. In addition, cells with intermediate neuronal-glial characteristics were labelled whilst the dysmorphic or hypertrophic pyramidal neuronal components of FCD were not. Ki67 labelled only occasional BC. These findings support the view that BC cells represent a pool of less differentiated glial cells with proliferative capacity which may have potential for delayed neuronal differentiation. Furthermore, as Mcm2 specifically identifies BC populations, this marker may be of diagnostic value in the subtyping of FCD lesions in patients with epilepsy.

Free Communications: Pathogenesis

Abstract Neurotransmitter Receptor Densities in Patients with Grade II Focal Cortical Dysplasia: Correlation with Clinical Characteristics. 1,2 Michiyo Kageyama, 1 Kazumi Matsuda, 1 Shigeko Nishimura, 1 Yuko Kubota, 1 Takayasu Tottori, 1 Tadahiro Mihara, 1 Kazuichi Yagi, 1 Koichi Baba, 1 Naotaka Usui, 1 Shuichi Umeoka, and 1 Tateki Fujiwara ( 1 Shizuoka Institute of Epilepsy and Neurological Disorders 2 Shizuoka Prefectural Psychiatric Hospital, Shizuoka, Japan ). Purpose: We previously investigated the neurotransmitter receptors in focal cortical dysplasia (FCD) by examining resected cortex samples from patients with intractable epilepsy. Quantitative studies demonstrated decreases in receptor densities in more severely dysplastic lesions, and showed great individual variations in receptor densities especially in Palmini Grade II FCD cases. To find the background of the variation in receptor densities in Grade II FCD, we conducted a quantitative analysis of receptor densities by in vitro autoradiography and examined the correlation with clinical characteristics. Methods: Twenty resected specimens from patients with intractable localization-related epilepsy were obtained. The ages at onset were 0–14 years (means ± SD: 6.5 ± 5.1 years); the ages at operation were 2–31 years (19.1 ± 10.2 years); and the intervals from onset to operation were 2–30 years (12.6 ± 8.6 years). Seizures occurred daily (n = 10), weekly (n = 8), or monthly (n = 2). The specimens were immediately frozen and used for in vitro autoradiography using 3H-CGP39653 as the ligand of N-methyl-d-asparate receptor (NMDAR), 3H-AMPA as the ligand of α-amino-3-hydroxy-5-methyl-4-isoxazol propionate receptor (AMPAR), and 125I-iomazenil as the ligand of the central benzodiazepine receptor (c-BZR). Histopathologic examinations were conducted in the specimens adjacent to those used for receptor density analysis, and confirmed a diagnosis of FCD in all cases. The lesions were classified according to severity of dysplasia into these three groups (Palmini 1994): Grades I, II, and III. In Grade II lesions, the receptor densities were quantified on the autoradiogram. Statistical analyses were performed using Spearman's rank correlation (ρ) to examine the correlation between receptor densities and three clinical characteristics; onset age, operation age, and interval from onset to operation. The correlation between receptor densities and seizure frequency was also analyzed using Kruskal-Wallis test and Scheffe's test as post hoc test. Results: (1) The mean receptor densities (fmol/mg tissue) in Grade II lesions were NMDAR: 42.7 (SD = 20.7); AMPAR: 14.2 (SD = 8.9); and c-BZR: 56.5 (SD = 28.9). (2) c-BZR densities correlated significantly with onset age (ρ= 0.722, p = 0.0016) and interval from onset to operation (ρ= 0.759, p = 0.0009). (3) NMDAR and AMPAR densities showed no significant correlation with clinical characteristics. Seizure frequency did not correlate with any receptor density. Conclusion: A positive correlation was found between c-BZR density and onset age or interval from onset to operation. Since c-BZR density showed a higher correlation with interval from onset to operation than with onset age, c-BZR may increase not only with age but also with disease progression. This result suggests the possible existence of a long-term inhibitory feedback mechanism in response to excitation in the epileptogenic area of Grade II FCD in patients with intractable epilepsy.

Cortical development and focal cortical dysplasia

A brief survey of cortical development is presented, focusing on neuronal migration and its alterations. Corticogenesis is achieved through ordered temporospatial steps, via the formation of transient structures, and successive waves of cell proliferation and migration (followed by cell differentiation and maturation), and apoptotic cell death. The appearance of the proliferative ventricular zone and marginal zone, and of the superficial primordial plexiform layer, is followed by the formation of the prospective layer I, of the subplate, whose neurons are destined to die, and of the cortical plate that will give rise to layers II‐VI. Cells arising in the ventricular zone migrate radially using radial glia as a scaffold, and are destined to form pyramidal cells. Cortical interneurons are mainly generated in the ganglionic eminence and migrate along axonal substrates following tangential routes. Disorders of this complex process lead to a wide range of alterations, and focal derangements of cortical organization have been grouped under the term focal cortical dysplasia (FCD). As the result of a neuropathological revision of FCD cases with intractable epilepsy, a novel classification comprising three subgroups of FCD has been introduced, and is supported by electroclinical and neuroimaging data, as well as by the postsurgical outcome of patients: i) architectural dysplasia, characterized by altered cortical lamination; ii) cytoarchitectural dysplasia, with the occurrence of giant neurons besides cortical dyslamination; iii) Taylor‐type cortical dysplasia, in which altered cortical lamination is consistently associated with the occurrence of giant, dysmorphic and ectopic neurons, and frequently with the so‐called balloon cells.

Expression and cellular distribution of multidrug transporter proteins in two major causes of medically intractable epilepsy: focal cortical dysplasia and glioneuronal tumors

The cell-specific distribution of multidrug resistance extrusion pumps was studied in developmental glioneuronal lesions, including focal cortical dysplasia (15 cases) and ganglioglioma (15 cases) from patients with medically intractable epilepsy. Lesional, perilesional, as well as normal brain regions were examined for the expression of the multidrug resistance gene 1 encoded P-glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) by immunocytochemistry. In normal brain MRP1 expression was below detection, whereas P-gp staining was present only in blood vessels. MRP1 and P-gp immunoreactivity was observed in dysplastic neurons of 11/15 cases of focal cortical dysplasia, as well as in the neuronal component of 14/15 ganglioglioma. Glial cells with astrocytic morphology within the lesion showed multidrug-resistant protein immunoreactivity (P-gp>MRP1). Moderate to strong MRP1 and P-gp immunoreactivity was observed in a population of large ballooned neuroglial cells. P-gp appeared to be most frequently expressed in glial fibrillary acidic protein-positive balloon cells (glial type), whereas MRP1 was more frequently expressed in microtubule-associated protein 2-positive balloon cells (neuronal type). In both types of lesions strong P-gp immunoreactivity was found in lesional vessels. Perilesional regions did not show increased staining in vessels or in neuronal cells compared with normal cortex. The predominant intralesional cell-specific distribution of multidrug transporter proteins supports the hypothesis of a constitutive overexpression as common mechanism underlying the intrinsic pharmaco-resistance to antiepileptic drugs of both malformative and neoplastic glioneuronal developmental lesions.

Focal cortical dysplasia of Taylor's balloon cell type: Mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis

Focal cortical dysplasia (FCD) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in tuberous sclerosis, are present in many cases (FCD(bc)). In these patients, a hyperintense funnel-shaped subcortical lesion tapering toward the lateral ventricle was the characteristic finding on fluid-attenuated inversion recovery magnetic resonance imaging scans. Surgical lesionectomy results in complete seizure relief. Although the pathogenesis of FCD(bc) remains uncertain, histopathological similarities indicate that FCD(bc) may be related pathogenetically to tuberous sclerosis. Here, we studied alterations of the TSC1 and TSC2 genes in a cohort of patients with chronic, focal epilepsy and histologically documented FCD(bc) (n = 48). DNA was obtained after microdissection and laser-assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD(bc) compared with 200 control individuals (exon 5, 2.3% FCD(bc) vs 0% C; exon 17, 35% FCD(bc) vs 1.0% C; exon 14, 37.8% FCD(bc) vs 15% C; exon 22, 45% FCD(bc) vs 23.8% C). Sequence alterations could be detected in FCD(bc) and in adjacent normal cells. In 24 patients, DNA was suitable to study loss of heterozygosity at the TSC1 gene locus in microdissected FCD(bc) samples compared with control tissue. Eleven FCD(bc) cases exhibited loss of heterozygosity. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Our findings indicate that FCD(bc) constitutes a clinicopathological entity with distinct neuroradiological, neuropathological, and molecular genetic features. These data also suggest a role of the TSC1 gene in the development of FCD(bc) and point toward a pathogenic relationship between FCD(bc) and the tuberous sclerosis complex.

Abnormal expression of cdk5 in focal cortical dysplasia in humans

Focal cortical dysplasia (FCD) is an important cause of refractory epilepsy in humans. The origin of its pathognomonic abnormal cell types and the links between abnormal cell morphology and epileptogenicity remain unknown. The developmentally-regulated kinase cdk5 and its neuronal activator p35 are known to be central to a number of key components in neuronal development, cellular morphology, cytoskeletal function, synaptic plasticity and neurodegeneration. Here we examine eight cases of human FCD for expression of cdk5. We show abnormal cdk5 immunoreactivity and aggregation of protein suggesting alterations in cdk5 may also be involved in this important epileptogenic human pathology.

Inhibitory interneurons in focal cortical dysplasia and microdysgenesis

Commonly identified cortical malformations in patients undergoing epilepsy surgery for intractable seizures include focal cortical dysplasia (FCD) and microdysgenesis (MD). Both are characterized by abnormalities in the cortical laminar architecture and in FCD the presence of dysplastic neurons and balloon cell glia are also observed. The aetiology and mechanisms of seizure genesis in these lesions is still questioned, as is the distinction of cellular changes that are developmental rather than a consequence of seizures. We investigated the distribution of calcium binding protein (calbindin‐CB, parvalbumin‐PV and calretinin‐CR), Neuropeptide Y and reelin positive cells in 12 cases of FCD and in 12 temporal lobectomy specimens from patients with hippocampal sclerosis with or without additional MD. The majority of FCD cases showed a reduction in PV interneurons but abnormal PV puncta around dysplastic neurons. Hypertrophic multipolar CB cells were commonly seen in FCD cases whereas smaller multipolar CB cells were present in MD. Altered NPY patterns were observed in FCD and a prominent superficial NPY plexus in some MD. Significantly higher numbers of reelin positive cells were present in layer I in MD compared with controls (P < 0.05) but were more variable in FCD with reduction of layer I reelin in some FCD cases.

Curved Planar Reconstruction of MR Images in Focal Cortical Dysplasia of the Brain

Purpose: To describe curved planar reconstruction imaging (CPRI) and determine its usefulness in the evaluation of focal cortical dysplasia of the brain. Materials and Methods: In 17 cases of focal cortical dysplasia [cortical dysplasia (n=9), schizencephaly (n=5), and heterotopia (n=3)], CPR images were created using a multiplanar reconstruction program and imaging data obtained during T1 magnetizationprepared rapid acquisition gradient-echo MR imaging. We assessed the precise configuration of abnormalities and their relation to adjacent gyri and sulci. Results: CPRI showed the brain cortex as a 2D panoramic image, demonstrating the precise configurations and locations of dysplasia-associated abnormalities and their relation to adjacent gyri and sulci, and the precise shape of the gray-white matter interface. Conclusion: CPRI can provide important radiological information about the extension and configuration of focal cortical dysplasia, and its relation to neighboring cortical structures. We believe that CPRI should form an essential part of the routine investigation of suspected cases of focal cortical dysplasia.

Imaging and radiological-pathological correlation in histologically proven cases of focal cortical dysplasia and other glial and neuronoglial malformative lesions in adults.

Focal cortical dysplasia (FCD) is a pathological entity first described in 1971. Other more subtle cortical malformations found in patients with epilepsy include microdysgenesis (MD), and glioneuronal hamartias. Although these glial and neuronoglial malformations have distinct histological features, there is terminological confusion in the radiological literature. Few cases have been reported in adults with both imaging and histology. We address these issues, giving a radiological-pathological correlation of histologically proven cortical malformations in adults. We describe clinical, radiological and histological features of 12 cases (five FCD, five MD with glioneuronal hamartias, and two hamartomas), unassociated with other conditions, and discuss them in the light of the literature. FCD is usually seen on MRI as cortical thickening, with or without signal change, which may extend into the adjacent white matter. On histology, abnormal neurons and/or glial cells, blurring of the grey-white matter interface, myelin pallor, demyelination, and gliosis may be found. Glioneuronal hamartias and hamartomas usually appear as complex masses on MRI. FCD and hamartias may be associated, and a combination of imaging findings may be seen on MRI. Atrophy of the ipsilateral hippocampus may be present on MRI in patients with hamartias, and minor cell loss on histology, but not definitive hippocampal sclerosis. Although the imaging findings of cortical malformations are protean, some characteristic MRI features, with histological correlates, may be found. The relevance of most of these observations remains unclear.

MRI of focal cortical dysplasia.

We studied nine cases of focal cortical dysplasia (FCD) by MRI, with surface-rendered 3D reconstructions. One case was also examined using single-voxel proton MR spectroscopy (MRS). The histological features were reviewed and correlated with the MRI findings. The gyri affected by FCD were enlarged and the signal of the cortex was slightly increased on T1-weighted images. The gray-white junction was indistinct. Signal from the subcortical white matter was decreased on T1- and increased on T2-weighted images in most cases. Contrast enhancement was seen in two cases. Proton MRS showed a spectrum identical to that of normal brain.