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Focal cortical dysplasia type IIIc (FCD‐IIIc) is histopathologically defined by the International League Against Epilepsy's classification scheme as abnormal cortical organization adjacent to epilepsy‐associated vascular malformations (VM). However, the incidence of FCD‐IIIc, its pathogenesis, or association with the epileptogenic condition remains to be clarified. We reviewed a retrospective series of surgical brain specimens from 14 epilepsy patients with leptomeningeal angiomatosis of Sturge‐Weber syndrome (LMA‐SWS; n = 6), cerebral cavernous malformations (CCM; n = 7), and an arteriovenous malformation (AVM; n = 1) to assess the histopathological spectrum of FCD‐IIIc patterns in VM. FCD‐IIIc was observed in all cases of LMA‐SWS and was designated as cortical pseudolaminar sclerosis (CPLS). CPLS showed a common pattern of horizontally organized layer abnormalities, including neuronal cell loss and astrogliosis, either manifesting predominantly in cortical layer (L) 3 extending variably to deeper areas with or without further extension to L2 and/or L4. Another pattern was more localized, targeting mainly L4 with extension to L3 and/or L5. Abnormal cortical layering characterized by a fusion of L2 and L3 or L4–L6 was also noted in two LMA‐SWS cases and the AVM case. No horizontal or vertical lamination abnormalities were observed in the specimens adjacent to the CCM, despite the presence of vascular congestion and dilated parenchymal veins in all VM. These findings suggest that FCD‐IIIc depends on the type of the VM and developmental timing. We further conclude that FCD‐IIIc represents a secondary lesion acquired during pre‐ and/or perinatal development rather than following a pathomechanism independent of LMA‐SWS. Further studies will be necessary to address the selective vulnerability of the developing cerebral neocortex in LMA‐SWS, including genetic, encephaloclastic, hemodynamic, or metabolic events. Cortical neuronal dyslamination (FCD‐IIIc) adjacent to leptomeningeal angiomatosis of Sturge‐Weber syndrome (LMA‐SWS) was mainly attributed to cortical pseudolaminar sclerosis (CPLS) characterized histologically by neuronal cell loss and astrogliosis of varying thickness and depth, organized parallel to the pial surface. Abnormal cortical layering showing a fusion of L2 and L3 or L4–L6 was also noted in LMA‐SWS cases and the AVM case; however, cortical dyslamination was not identified in CCM cases. These findings suggest that FCD‐IIIc depends on the type of the vascular malformation and developmental timing and that FCD‐IIIc represents a secondary lesion during pre‐ and/or perinatal development rather than following a pathomechanism independent of LMA‐SWS.

Temporal lobe epilepsy is the most prevalent form of drug-resistant focal epilepsy and is frequently associated with neuronal cell loss and astrogliosis in the hippocampus, i.e. hippocampal sclerosis (HS). In this study, we performed mass spectrometry-based proteomic profiling of microdissected hippocampal, neocortical, and white matter tissue obtained from TLE patients and respective control samples. In hippocampal TLE tissue, we observed significant upregulation of proteins involved in complement system activation, extracellular matrix (ECM) organization, and astrocyte reactivity, indicative of active inflammatory remodeling within the sclerotic hippocampus. Conversely, synaptic proteins, including glutamate and gamma-aminobutyric acid (GABA) receptors, along with other regulators of synaptic structure and function, were markedly downregulated. Interestingly, in neocortical and white matter regions from the same TLE patients, immune- and ECM-related proteins were downregulated or unchanged, whereas synaptic proteins were preserved or upregulated. These region-specific molecular signatures suggest that inflammatory-driven ECM remodeling is spatially restricted to the epileptogenic hippocampus, where it may contribute to synaptic destabilization and network dysfunction. Together, our findings support the hypothesis that inflammatory ECM remodeling in the hippocampus plays a central role in epileptogenesis in TLE. In contrast, the neocortical and white matter regions may undergo compensatory adaptions. The convergence of immune and ECM-related alterations on synaptic structures highlights a potential pathophysiological axis in epilepsy and points to novel molecular targets for therapeutic intervention.

Focal cortical dysplasia (FCD) are histopathologically categorized in ILAE type I to III. Mild malformations of cortical development (mMCD) including those with oligodendroglial hyperplasia (MOGHE) are to be integrated into this classification yet. Only FCD type II have distinctive MRI and molecular genetics alterations so far. Subtle FCD including FCD type II located in the depth of a sulcus are often overlooked requiring the use of dedicated sequences (MP2RAGE, FLAWS, EDGE) and/or voxel (VBM)- or surface-based (SBM) postprocessing. The added value of 7 Tesla MRI has to be proven yet.

Objective Children and adolescents with pharmacoresistant epilepsy (PRE) show marked individual cognitive and emotional variability not fully accounted for by demographic or clinical variables. This exploratory pilot study characterizes neuroanatomical abnormalities and their relationships with neuropsychological functioning in a pediatric patient cohort with PRE due to type II focal cortical dysplasia (FCD). Methods Retrospective data were obtained from patients with histopathologically confirmed FCD II who completed presurgical evaluations including high‐resolution 3T MRI and neuropsychological assessment. Voxel‐based morphometric MRI postprocessing using the Morphometric Analysis Program (MAP18) provided age‐adjusted quantitative characterizations of within‐lesion MRI features [Junction (gray–white matter junction blurring), Extension (abnormal gyration), and Thickness (cortical thickening in the regional lesion)]. Associations between MRI feature z‐scores and cognitive domain composite scores were evaluated using Pearson correlation coefficients and multivariable linear and logistic regression models, controlling for seizure side and site. Lesion ROI volumes were also analyzed to evaluate their associations with MRI feature z‐scores and neuropsychological function. Results We included 24 patients [mean age = 13.8; 58% male] with FCD IIa (n = 8; 33%) or FCD IIb (n = 16; 67%). Patients with FCD IIb had higher mean and maximum Junction z‐scores compared to those with FCD IIa (Cohen's d = 1.00 and 1.07). Mean and maximum Thickness z‐scores were negatively associated with attention (r = −0.32; r = −0.47) and general cognitive ability (GCA; r = −0.46; r = −0.41). Mean Thickness z‐scores were also negatively associated with visuospatial skills (r = −0.34). In regression models, higher mean and maximum Thickness were associated with poorer GCA scores (estimate (se): −14.98 (6.88), p = 0.042; −5.76 (2.41), p = 0.027, respectively), and higher maximum Thickness was associated with worse attention scores (estimate (se): −6.02 (2.60), p = 0.032). Lesion volumes were not associated with MRI feature z‐scores, cognition, self‐reported mood or anxiety. Significance Our findings showed that lesional neuroanatomical abnormalities, particularly increased cortical thickness, were associated with poorer cognitive performance in pediatric patients with FCD II. Future research in larger, more diverse samples is needed to identify other factors contributing to neuropsychological variability in this population. Plain Language Summary We studied 24 pediatric patients with pharmacoresistant epilepsy (PRE) and a confirmed diagnosis of focal cortical dysplasia type II (FCD II) to examine how MRI findings relate to thinking abilities. Patients with FCD IIb showed more pronounced MRI abnormalities than FCD IIa. Greater cortical thickening within the lesion was associated with difficulties in overall cognitive ability, attention, and visuospatial skills. After adjusting for seizure side and site, the relationships between cortical thickness and reduced overall cognitive ability and attention performance remained significant. Findings suggest that specific MRI features may serve as imaging markers of cognition in pediatric patients with FCD II.

Understanding seizure development requires an integrated knowledge of different scales of organization of epileptic networks. We developed a model of “epilepsy-in-a-dish” based on dissociated primary neuronal cells from neonatal rat hippocampus. We demonstrate how a single application of glutamate stimulated neurons to generate spontaneous synchronous spiking activity with further progression into spontaneous seizure-like events after a distinct latency period. By computational analysis, we compared the observed neuronal activity in vitro with intracranial electroencephalography (EEG) data recorded from epilepsy patients and identified strong similarities, including a related sequence of events with defined onset, progression, and termination. Next, a link between the neurophysiological changes with network composition and cellular structure down to molecular changes was established. Temporal development of epileptiform network activity correlated with increased neurite outgrowth and altered branching, increased ratio of glutamatergic over GABAergic synapses, and loss of calbindin-positive interneurons, as well as genome-wide alterations in DNA methylation. Differentially methylated genes were engaged in various cellular activities related to cellular structure, intracellular signaling, and regulation of gene expression. Our data provide evidence that a single short-term excess of glutamate is sufficient to induce a cascade of events covering different scales from molecule- to network-level, all of which jointly contribute to seizure development.

PurposeApart from patients with severe neurological deficits, it is not clear whether surgical or conservative treatment of lumbar disc herniations is superior for the individual patient. We investigated whether deep learning techniques can predict the outcome of patients with lumbar disc herniation after 6 months of treatment.MethodsThe data of 60 patients were used to train and test a deep learning algorithm with the aim to achieve an accurate prediction of the ODI 6 months after surgery or the start of conservative therapy. We developed an algorithm that predicts the ODI of 6 randomly selected test patients in tenfold cross-validation.ResultsA 100% accurate prediction of an ODI range could be achieved by dividing the ODI scale into 12% sections. A maximum absolute difference of only 3.4% between individually predicted and actual ODI after 6 months of a given therapy was achieved with our most powerful model. The application of artificial intelligence as shown in this work also allowed to compare the actual patient values after 6 months with the prediction for the alternative therapy, showing deviations up to 18.8%.ConclusionDeep learning in the supervised form applied here can identify patients at an early stage who would benefit from conservative therapy, and on the contrary avoid painful and unnecessary delays for patients who would profit from surgical therapy. In addition, this approach can be used in many other areas of medicine as an effective tool for decision-making when choosing between opposing treatment options, despite small patient groups.

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration. The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.

Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.

Objective To define and articulate research priorities in epilepsy identified by the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE), addressing key unmet needs across the spectrum of rare and complex epilepsies. Methods This position paper was developed through a structured collaborative process involving patient associations and experts from EpiCARE Working Groups, the EpiCARE Executive Committee, and its Research Council. Contributions were integrated and harmonized to establish a shared set of research priorities reflecting clinical, translational, and methodological perspectives. Results Six priority areas were identified and examined: prevention of epileptogenesis and disease‐modifying challenges; genetics and targeted therapies; improved surgical decision‐making; innovative trial designs and outcome measures; artificial intelligence for diagnosis and prediction; understanding and preventing comorbidities and mortality. For each priority, the paper discusses the current state of research, identifies challenges, and proposes strategic directions for future investigations. Significance This position paper provides a strategic framework to guide future research efforts, inform prioritization by funders and policymakers, and foster coordinated collaboration across stakeholders. By advancing these priorities, the epilepsy research community aims to improve patient care, reduce health disparities, and develop innovative solutions to address the complexities of epilepsy. Plain Language Summary This position paper, developed by the European Reference Network for Rare and Complex Epilepsies (EpiCARE) in collaboration with its Patient Advocacy Group, defines six areas of research priorities in epilepsy. Each section describes key challenges, current knowledge, and areas for improvement. They focus on preventing epilepsy, developing targeted therapies, improving surgery and clinical trials, using artificial intelligence to support diagnosis, and addressing comorbidities such as cognition, sleep, and overall health. Each provides a roadmap for clinicians and researchers to guide their research projects within their areas of expertise. Collectively, these priorities converge on actions for improving diagnosis, treatment, and patient outcomes through European collaboration and sustainable research efforts.

The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the genetic landscape and genotype–phenotype correlation of this enigmatic and often difficult‐to‐classify epilepsy‐associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next‐generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)‐like tumor component, were separately studied. A mean post‐surgical follow‐up time‐period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R, IRS2 copy number gain (CNG) and a KIAA1549‐BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG‐like features. Follow‐up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki‐67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular‐genetic differentiation from the cohort of low‐grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio‐neuronal GG variants. Our results strongly point to activation of the MAP kinase pathway in the vast majority of ganglioglioma (GG). Composite genetic alterations were found in cases with histologically distinct tumor components firstly, i.e. GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor, or an oligodendroglioma‐like tumor. Seizure recurrence is inclined to ganglioglioma with atypical histopathology features (i.e. GG containing a ki‐67 proliferation index above 5% or GG with PXA component).