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Pathogenetic mechanisms of focal cortical dysplasia.

ABSTRACT: Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecular, and electrophysiologic aspects of FCDs was conducted. Disruption of the mammalian target of rapamycin (mTOR) signaling comprises a common pathway underlying the structural and electrical disturbances of some FCDs. Other mechanisms such as viral infections, prematurity, head trauma, and brain tumors are also posited. mTOR inhibitors (i.e., rapamycin) have shown positive results on seizure management in animal models and in a small cohort of patients with FCD. Encouraging progress has been achieved on the molecular and electrophysiologic basis of constitutive cells in the dysplastic tissue. Despite the promising results of mTOR inhibitors, large-scale randomized trials are in need to evaluate their efficacy and side effects, along with additional mechanistic studies for the development of novel, molecular-based diagnostic and therapeutic approaches.

SUBMITTER: Marin-Valencia I

PROVIDER: S-EPMC4107035 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Pathogenetic mechanisms of focal cortical dysplasia.

Marin-Valencia Isaac I Guerrini Renzo R Gleeson Joseph G JG

Epilepsia 20140523 7

Focal cortical dysplasias (FCDs) constitute a prevalent cause of intractable epilepsy in children, and is one of the leading conditions requiring epilepsy surgery. Despite recent advances in the cellular and molecular biology of these conditions, the pathogenetic mechanisms of FCDs remain largely unknown. The purpose if this work is to review the molecular underpinnings of FCDs and to highlight potential therapeutic targets. A systematic review of the literature regarding the histologic, molecul ...[more]

PMID: 24861491

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Project description:Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology.

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Pathogenetic mechanisms of focal cortical dysplasia.

Publications

Pathogenetic mechanisms of focal cortical dysplasia.

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