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Type II focal cortical dysplasias (FCD II) are highly epileptogenic brain lesions characterized by severe cortical dyslamination and by the presence of abnormal giant cells defined as dysmorphic neurons and balloon cells (typical of FCD IIb). Why are type II focal cortical dysplasias frequently located at the bottom of sulcus? MRI abnormalities predominate in the bottom part of the sulcus with type II focal cortical dysplasia: a quantitative study. However, since the size of the developmental lesion has been correlated with the timing of the insult, it is likely that in more extensive non-BOSD dysplasias a higher number of cells with hyperactive mTOR signaling will be responsible for the more severe disruption.27 Finally, the present hypothesis is based mainly on the pathogenic role of bRGCs on brain development and folding. [Extracted from the article]

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low‐grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low‐grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies. [ABSTRACT FROM AUTHOR]

Objective: Activity‐dependent changes have been reported in animal models and in human epileptic specimens and could potentially be used as tissue biomarkers to evaluate the propensity of a tissue to generate seizure activity. In this context, cAMP‐response element binding protein (CREB) activation was specifically reported in human epileptic foci and related mainly to interictal spike activity. To get further insights into CREB activation in human epilepsy, we analyzed pCREB expression on brain tissue samples from patients who underwent surgery for drug‐resistant focal epilepsy, correlating this expression with intracranial stereo–electroencephalography (SEEG) recording in a subgroup. Methods: Neocortical specimens from patients with neuropathological diagnosis of no lesion (cryptogenic), malformations of cortical development,mainly type II focal cortical dysplasia (FCD), and hippocampi with and without hippocampal sclerosis have been analyzed by immunohistochemistry. Peritumoral cortex from non‐epileptic patients and autoptic samples were used as controls, whereas rat brains were used to test possible loss of pCREB antigenicity due to fixation procedures and postmortem delay. Results: pCREB was consistently expressed in layer II neuronal nuclei in regions with normal cortical lamination both in epileptic and non‐epileptic surgical tissues. In patients with SEEG recordings, this anatomical pattern was unrelated to the presence of interictal spike activity. Conversely, in the core of type II FCD, as well as in other developmental malformations, pCREB was scattered without any laminar specificity. Furthermore, quantitative data did not reveal significant differences between epileptic and non‐epileptic tissues, except for an increased immunoreactivity in the core of type IIB FCD lesion related mainly to reactive glial and balloon cells. Significance: The present data argue against the reliability of pCREB immunohistochemistry as a marker of epileptic focus but underscores its layer‐related expression, suggesting a potential application in the study of malformations of cortical development, a wide range of diseases arising from perturbations of normal brain development. [ABSTRACT FROM AUTHOR]

Objective: Several studies have reported that inhibitory networks are altered in dysplastic tissue obtained from epilepsy surgery specimens. A consistent decrease in the number of inhibitory interneuronal subpopulation that expresses parvalbumin (PV) was reported in postsurgical tissue from patients with focal cortical dysplasia (FCD). We tested if the decrease in PV protein expression observed in epileptic tissue corresponds to a parallel impairment in the γ-aminobutyric acid (GABA)ergic compartment. Methods: We analyzed postsurgical tissue from 30 surgically treated patients who underwent surgery for intractable epilepsy including 26 patients with FCD (types I, II, and III) and 4 patients without any microscopic visible lesion (cryptogenic) as controls. Serial sections were processed using in situ hybridization with GAD-65 and GAD-67 probes and immunocytochemistry with antibody against PV. The density of inhibitory PV-immunoreactive interneurons in relation to GABAergic cells was estimated in controls and in all different pathologic groups by using a two- and three-dimensional (2D and 3D) cell-counting technique. Field fraction and line profile analyses were added to estimate immunostaining proportion and distribution of PV signal generated in gray matter. Results: A reduction of PV-positive cells and PV-immunoreactivity was observed exclusively in FCD type I/III specimens compared with cryptogenic tissue from control patients with a poor postsurgical outcome. In FCD type II, a profound rearrangement in the cortical distribution of PV immunoreactivity was observed, without a quantitative reduction of the number of neurons and terminals. In situ hybridization did not reveal significant variations of GAD expression in any FCD subtype. Significance: Our study suggests a preservation of inhibitory networks in FCD postsurgical tissue, demonstrated by a substantial normal count of GABAergic neurons. A selective PV expression impairment is demonstrated in FCD type I and III and an abnormal, but not reduced, distribution of PV cells and terminals is confirmed in type II FCD. Possible functional consequences are discussed. [ABSTRACT FROM AUTHOR]

Summary Purpose: Neuropathologic investigations frequently reveal the presence of architectural cortical dysplasia in patients with temporal lobe epilepsy (TLE), sometimes as an isolated finding but more commonly associated with hippocampal sclerosis (HS) and white matter abnormalities. The histologic pattern and the developmental origin of these alterations are not clear, and their diagnostic criteria are poorly defined. The aim of this study was to investigate the expression patterns of layer-specific genes in cortical specimens from patients with TLE presenting different subtypes of cortical malformations in order to elucidate the disorganization of the laminar architecture of such epileptogenic abnormalities and provide evidence to enable a more objective neuropathologic diagnosis. Methods: We analyzed the expression patterns of CUX2, RORBETA, ER81, NURR1, and CTGF genes, respectively specific markers of layers II-III, IV, V, VI, and VIb, in surgical samples by means of in situ hybridization and compared them with those observed in control cortices. The pathologic samples included typical architectural dysplasia (group 1); temporal lobe sclerosis, a variant of architectural dysplasia (group 2); and white matter heterotopic neuronal aggregates, namely small lentiform nodules (group 3). These abnormalities may have been associated or not with HS. Key Findings: All of the genes had a laminar expression pattern in normal cortices, whereas groups 1 and 2 showed alterations mainly involving layers V and VI, and highlighted by the altered distribution of ER81- and NURR1-positive cells. The expression of ER81 and NURR1 genes was different among the groups, and atypical coexpression of NURR1 and CUX2 mRNA was detected in the neurons making up the small lentiform nodules. Significance: These findings indicate that defects in cortical organization involving the deeper cortical neurons may be a common etiopathogenic mechanism in group 1 and 2 cortical dysplasia, whether isolated or associated with HS, and that developmental disorders may also be present in the white matter (group 3). They also provide evidence that the layer-specific genes can be usefully used to investigate the neuropathology of human cortical dysplasia. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Epilepsy surgery is a treatment option for patients with seizures that do not respond to pharmacotherapy. The histopathological characterization of the resected tissue has an important prognostic value to define postoperative seizure outcome in these patients. However, the diagnostic classification process based on microscopic assessment remains challenging, particularly in the case of focal cortical dysplasia (FCD). Imaging mass spectrometry is a spatial omics technique that could improve tissue phenotyping and patient stratification by investigating hundreds of biomolecules within a single tissue sample, without the need for target‐specific reagents.An in situ proteomic technique called matrix‐assisted laser desorption/ionization mass spectrometry imaging (MALDI‐MSI) is here investigated as a potential new tool to expand conventional diagnosis on standard paraffin brain tissue sections. Unsupervised and region of interest‐based MALDI‐MSI analyses of sections from 10 FCD type IIb (FCDIIb) cases were performed, and the results were validated by immunohistochemistry.MALDI‐MSI identified distinct histopathological features and the boundaries of the dysplastic lesion. The capability to visualize the spatial distribution of well‐known diagnostic markers enabling multiplex measurements on single tissue sections was demonstrated. Finally, a fingerprint list of potential discriminant peptides that distinguish FCD core from peri‐FCD tissue was generated.This is the first study that explores the potential application of MALDI‐MSI in epilepsy postsurgery fixed tissue, by utilizing the well‐characterized FCDIIb features as a model. Extending these preliminary analyses to a larger cohort of patients will generate spectral libraries of molecular signatures that discriminate tissue features and will contribute to patient phenotyping. [ABSTRACT FROM AUTHOR]

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed. [ABSTRACT FROM AUTHOR]