Focal cortical dysplasia pathology: diagnostic difficulty, classification, and utility for pathogenesis
Ozge Kapar1, Zahide Mail Gurkan2, Muge Dolgun3
11Department of Pathology, Istanbul University.
Insights
Focal cortical dysplasia (FCD) is common in pediatric epilepsy. mTOR pathway activation, particularly in FCD type II, suggests targeted therapies may benefit patients with treatment-resistant epilepsy.
Area of Science:
- Neuropathology
- Epileptology
- Molecular Genetics
Background:
- Focal cortical dysplasia (FCD) is a leading cause of pediatric treatment-resistant epilepsy.
- The International League Against Epilepsy (ILAE) classification categorizes FCD histopathologically.
- mTOR pathway mutations are increasingly recognized as a key etiology in FCD.
Purpose of the Study:
- Determine FCD incidence in epilepsy patients.
- Investigate FCD histomorphological and immunohistochemical features.
- Correlate clinicopathological findings and demonstrate mTOR pathway activation for targeted therapy development.
Main Methods:
- Retrospective analysis of 183 surgical epilepsy tissue samples.
- Histopathological subtyping of FCD according to ILAE classification.
- Immunohistochemical staining using NeuN, neurofilament H (NF-H), and pS6 antibodies to assess mTOR pathway activation.
Main Results:
- FCD was diagnosed in 32 cases (17.5%).
- NeuN staining identified specific architectural changes in FCD subtypes Ia, IIIa, and Ib.
- pS6 expression, indicating mTOR pathway activation, was prominent in dysmorphic neurons and balloon cells of all FCD type II cases.
Conclusions:
- pS6 expression in FCD type II supports its genetic basis.
- While mTOR pathway mutations are implicated, they don't fully explain activation in all FCD type II cases.
- Integrated clinicopathological and genetic classification, alongside mTOR pathway inhibitors, represent future therapeutic directions.
Objective:
In the histopathological examination of treatment-resistant epilepsy, focal cortical dysplasia (FCD) is the most common diagnosis in the pediatric group. FCD is classified histopathologically according to the International League Against Epilepsy (ILAE) classification. In the last decade since the ILAE classification has been released, molecular genetic studies have revealed mTOR pathway-related mutations as a major etiology. The objective of this study was to determine the incidence of FCD in treatment-resistant epilepsy patients, explore histomorphological and immunohistochemical features, examine clinicopathological correlation, demonstrate mTOR pathway activation using a pS6 antibody immunohistochemically, and try to introduce a candidate for possible targeted therapies.
Methods:
Paraffin blocks and slides of tissue from patients with treatment-resistant epilepsy were reexamined retrospectively. Histopathological subtypes of FCD were determined according to the ILAE classification. NeuN and neurofilament H (NF-H) staining were performed, and additionally a pS6 antibody was used to demonstrate mTOR pathway activation.
Results:
In 32 cases diagnosed with FCD, or 17.5% of 183 surgical epilepsy materials, there were no significant differences in the statistical analysis of clinical variables between the ILAE FCD subtypes. Recommended antibody NeuN revealed microcolumnar alignment in the FCD type Ia and IIIa groups and the loss of lamination in the type Ib group. Another recommended antibody, NF-H, was not found to be useful in discriminating between normal and dysmorphic neurons. pS6 expression, showing mTOR pathway activation, was observed in dysmorphic neurons and balloon cells in all FCD type II cases.
Conclusions:
Significant pS6 expression in FCD type II represents the genomic nature of the disease noted in the literature. Nevertheless, the known MTOR gene and mTOR pathway-related mutations remain behind proportionally to explain the mTOR pathway activation in all FCD type II cases. Clinicopathologically and genetically integrated classification and usage of mTOR pathway inhibitors in treatment are expected as a recent evolution.
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