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In the context of focal and drug-resistant epilepsy, surgical resection of the epileptogenic zone may be the only therapeutic option for reducing or suppressing seizures. In many such patients, intracranial stereo-EEG recordings remain the gold standard for the epilepsy surgery work-up. Assessing the extent of the epileptogenic zone and its organisation is a crucial objective, and requires advanced methods of signal processing. Over the last ten years, considerable efforts have been made to develop signal analysis techniques for characterising the connectivity between spatially distributed regions. The aim of this study was to evaluate the changes in dynamic connectivity pattern under inter-ictal, pre-ictal and ictal conditions using signals derived from stereo-EEG recordings of 10 patients with Taylor-type focal cortical dysplasia. A causal linear multivariate method – partial directed coherence – and indices derived from graph theory were used to characterise the synchronisation property of the lesional zone (corresponding to the epileptogenic zone in our patients) and to distinguish it from other regions involved in ictal activity or not. The results show that a significantly different connectivity pattern (mainly in the gamma band) distinguishes the epileptogenic zone from other cortical regions not only during the ictal event, but also during the inter- and pre-ictal periods. This indicates that the lesional nodes play a leading role in generating and propagating ictal EEG activity by acting as the hubs of the epileptic network originating and sustaining seizures. Our findings also indicate that the cortical regions beyond the dysplasia involved in the ictal activity essentially act as “secondary” generators of synchronous activity. The leading role of the lesional zone may account for the good post-surgical outcome of patients with type II focal cortical dysplasia as resecting the dysplasia removes the epileptogenic zone responsible for seizure organisation. Furthermore, our findings strongly suggest that advanced signal processing techniques aimed at studying synchronisation and characterising brain networks could substantially improve the pre-surgical evaluation of patients with focal epilepsy, even in cases without an associated anatomically detectable lesion. ►Type-II focal cortical dysplasia is a model of drug-resistant epilepsy. ►PDC and graph indexes are appropriate tools to localise the epileptogenic zone. ►The lesional nodes play a leading role in the epileptogenic network. ►An abnormal connectivity characterises the inter-ictal activity of the lesional leads. ►Cortical regions outside dysplasia act as secondary sources of synchronous activity.

Epilepsy surgery is an option for people with focal onset drug-resistant (DR) seizures but a delayed or incorrect diagnosis of epileptogenic zone (EZ) location limits its efficacy. Seizure semiological manifestations and their chronological appearance contain valuable information on the putative EZ location but their interpretation relies on extensive experience. The aim of our work is to support the localization of EZ in DR patients automatically analyzing the semiological description of seizures contained in video-EEG reports. Our sample is composed of 536 descriptions of seizures extracted from Electronic Medical Records of 122 patients. We devised numerical representations of anamnestic records and seizures descriptions, exploiting Natural Language Processing (NLP) techniques, and used them to feed Machine Learning (ML) models. We performed three binary classification tasks: localizing the EZ in the right or left hemisphere, temporal or extra-temporal, and frontal or posterior regions. Our computational pipeline reached performances above 70% in all tasks. These results show that NLP-based numerical representation combined with ML-based classification models may help in localizing the origin of the seizures relying only on seizures-related semiological text data alone. Accurate early recognition of EZ could enable a more appropriate patient management and a faster access to epilepsy surgery to potential candidates.

Aim: In neuroscience research, data are quite often characterized by an imbalanced distribution between the majority and minority classes, an issue that can limit or even worsen the prediction performance of machine learning methods. Different resampling procedures have been developed to face this problem and a lot of work has been done in comparing their effectiveness in different scenarios. Notably, the robustness of such techniques has been tested among a wide variety of different datasets, without considering the performance of each specific dataset. In this study, we compare the performances of different resampling procedures for the imbalanced domain in stereo-electroencephalography (SEEG) recordings of the patients with focal epilepsies who underwent surgery. Methods: We considered data obtained by network analysis of interictal SEEG recorded from 10 patients with drug-resistant focal epilepsies, for a supervised classification problem aimed at distinguishing between the epileptogenic and non-epileptogenic brain regions in interictal conditions. We investigated the effectiveness of five oversampling and five undersampling procedures, using 10 different machine learning classifiers. Moreover, six specific ensemble methods for the imbalanced domain were also tested. To compare the performances, Area under the ROC curve (AUC), F-measure, Geometric Mean, and Balanced Accuracy were considered. Results: Both the resampling procedures showed improved performances with respect to the original dataset. The oversampling procedure was found to be more sensitive to the type of classification method employed, with Adaptive Synthetic Sampling (ADASYN) exhibiting the best performances. All the undersampling approaches were more robust than the oversampling among the different classifiers, with Random Undersampling (RUS) exhibiting the best performance despite being the simplest and most basic classification method. Conclusions: The application of machine learning techniques that take into consideration the balance of features by resampling is beneficial and leads to more accurate localization of the epileptogenic zone from interictal periods. In addition, our results highlight the importance of the type of classification method that must be used together with the resampling to maximize the benefit to the outcome.

Half of patients who have resective brain surgery for drug-resistant epilepsy have recurrent postoperative seizures. Although several single predictors of seizure outcome have been identified, no validated method incorporates a patient's complex clinical characteristics into an instrument to predict an individual's post-surgery seizure outcome. We developed nomograms to predict complete freedom from seizures and Engel score of 1 (eventual freedom from seizures allowing for some initial postoperative seizures, or seizures occurring only with physiological stress such as drug withdrawal) at 2 years and 5 years after surgery on the basis of sex, seizure frequency, secondary seizure generalisation, type of surgery, pathological cause, age at epilepsy onset, age at surgery, epilepsy duration at time of surgery, and surgical side. We designed the models from a development cohort of patients who had resective surgery at the Cleveland Clinic (Cleveland, OH, USA) between 1996 and 2011. We then tested the nomograms in an external validation cohort operated on over a similar period in four epilepsy surgery centres, in Brazil, France, Italy, and the USA. We assessed performance of the nomogram by calculating concordance statistics and assessing the calibration of predicted freedom from seizures with the reported freedom from seizures and Engel score of 1. The development cohort included 846 patients and the validation cohort included 604 patients. Variables included in the nomograms were sex, seizure frequency, secondary seizure generalisation, type of surgery, and pathological cause. In the development cohort, the baseline risk of complete freedom from seizures was 0·57 at 2 years and 0·40 at 5 years. The baseline risk of Engel score of 1 was 0·69 at 2 years and 0·62 at 5 years. In the validation cohort, the models had a concordance statistic of 0·60 for complete freedom from seizures and 0·61 for Engel score of 1. Calibration curves showed adequate calibration (judged by eye) of predicted and reported freedom from seizures, throughout the range of seizure outcomes. If validated in prospective cohorts, these nomograms could be used to predict seizure outcomes in patients who have been judged eligible for epilepsy surgery. Cleveland Clinic Epilepsy Center.

Dendritic spines are the postsynaptic sites for most excitatory glutamatergic synapses. We previously demonstrated a severe spine loss and synaptic reorganization in human neocortices presenting Type II focal cortical dysplasia (FCD), a developmental malformation and frequent cause of drug‐resistant focal epilepsy. We extend the findings, investigating the potential role of complement components C1q and C3 in synaptic pruning imbalance. Data from Type II FCD were compared with those obtained in focal epilepsies with different etiologies. Neocortical tissues were collected from 20 subjects, mainly adults with a mean age at surgery of 31 years, admitted to epilepsy surgery with a neuropathological diagnosis of: cryptogenic, temporal lobe epilepsy with hippocampal sclerosis, and Type IIa/b FCD. Dendritic spine density quantitation, evaluated in a previous paper using Golgi impregnation, was available in a subgroup. Immunohistochemistry, in situ hybridization, electron microscopy, and organotypic cultures were utilized to study complement/microglial activation patterns. FCD Type II samples presenting dendritic spine loss were characterized by an activation of the classical complement pathway and microglial reactivity. In the same samples, a close relationship between microglial cells and dendritic segments/synapses was found. These features were consistently observed in Type IIb FCD and in 1 of 3 Type IIa cases. In other patient groups and in perilesional areas outside the dysplasia, not presenting spine loss, these features were not observed. In vitro treatment with complement proteins of organotypic slices of cortical tissue with no sign of FCD induced a reduction in dendritic spine density. These data suggest that dysregulation of the complement system plays a role in microglia‐mediated spine loss. This mechanism, known to be involved in the removal of redundant synapses during development, is likely reactivated in Type II FCD, particularly in Type IIb; local treatment with anticomplement drugs could in principle modify the course of disease in these patients.

Abstract Objective The differential diagnosis between sleep-related hypermotor epilepsy (SHE) and disorders of arousal (DOA) may be challenging. We analyzed the stage and the relative time of occurrence of parasomnic and epileptic events to test their potential diagnostic accuracy as criteria to discriminate SHE from DOA. Methods Video-polysomnography recordings of 89 patients with a definite diagnosis of DOA (59) or SHE (30) were reviewed to define major or minor events and to analyze their stage and relative time of occurrence. The “event distribution index” was defined on the basis of the occurrence of events during the first versus the second part of sleep period time. A group analysis was performed between DOA and SHE patients to identify candidate predictors and to quantify their discriminative performance. Results The total number of motor events (i.e. major and minor) was significantly lower in DOA (3.2 ± 2.4) than in SHE patients (6.9 ± 8.3; p = 0.03). Episodes occurred mostly during N3 and N2 in DOA and SHE patients, respectively. The occurrence of at least one major event outside N3 was highly suggestive for SHE (p = 2*e-13; accuracy = 0.898, sensitivity = 0.793, specificity = 0.949). The occurrence of at least one minor event during N3 was highly suggestive for DOA (p = 4*e-5; accuracy = 0.73, sensitivity = 0.733, specificity = 0.723). The “event distribution index” was statistically higher in DOA for total (p = 0.012) and major events (p = 0.0026). Conclusion The stage and the relative time of occurrence of minor and major motor manifestations represent useful criteria to discriminate DOA from SHE episodes.

IntroductionApproximately one-third of people with epilepsy (PWE) experience resistance to treatment, including pharmacological therapies, epilepsy surgery, vagus nerve stimulation (VNS) and dietary interventions such as the ketogenic diet (KD). Emerging evidence suggests that the gut microbiota may influence seizure susceptibility and treatment response through the microbiota-gut-brain axis, potentially contributing to treatment resistance. The MiCrobiota-gut-brain Axis in Resistant Epilepsy project investigates how gut microbial features and associated host epigenetic signatures affect clinical outcomes in PWE undergoing diverse treatment strategies.Methods and analysisThis is a multicentre, prospective, longitudinal study involving four clinical centres in Italy and one self-financing partner. Participants aged 3–50 years will be enrolled and stratified into four intervention cohorts: newly diagnosed drug-naïve epilepsy scheduled to start anti-seizure medications, focal drug-resistant epilepsy (DRE) undergoing epilepsy surgery, DRE receiving VNS, and DRE initiating KD. Clinical assessments (including body mass index calculation, self-reported monthly seizure count, dietary evaluation, quality of life scale and gastrointestinal symptoms scale), electroencephalography, MRI and biological sample collection (stool and blood) will be obtained at baseline and longitudinally at two or three timepoints over a 12-month observation period. Gut microbiota changes over time will be assessed via metagenomics (using 16S ribosomal RNA sequencing) and metaproteomics; the associated host DNA methylation profiles will be obtained from blood using Illumina EPIC arrays. Primary endpoints include identification of microbial or host methylation changes predictive of therapeutic response (ie, reduction from baseline in monthly seizure count) to the intervention. Data will be analysed using multivariate models and mixed-effect regression. Further, omics data and corresponding metadata will be integrated using multi-omics approaches to identify molecular signatures biomarkers predictive of treatment response and prognosis in PWE.Ethics and disseminationThe study received ethical approval from the Research Ethic Board (Comitato Etico Territoriale Lombardia 3, ID 4896 – parere numero 4896_17.07.2024_N_bis). All participants or their legal guardians will provide written informed consent. Results will be disseminated through peer-reviewed publications, conference presentations or lay summaries targeting patient organisations.Trial registration numberClinicalTrials.gov Identifier NCT07010445, registered on 2 May 2025.

Introduction This study aims to review the magnetic resonance imaging (MRI) aspects of a large series of patients with focal cortical dysplasia type II (FCD II) and attempt to identify distinctive features in the two histopathological subtypes IIa and IIb. Methods We retrospectively reviewed the MRI scans of 118 patients with histological proven FCD IIa ( n  = 37) or IIb ( n  = 81) who were surgically treated for intractable epilepsy. Results MRI was abnormal in 93 patients (79 %) and unremarkable in 25 (21 %). A dysplastic lesion was identified in 90 cases (97 %) and classified as FCD II in 83 and FCD non-II in seven cases. In three cases, the MRI diagnosis was other than FCD. There was a significant association between the presence of cortical thickening ( p  = 0.002) and the “transmantle sign” ( p  < 0.001) and a correct MRI diagnosis of FCD II. MRI positivity was more frequent in the patients with FCD IIb than in those with FCD IIa (91 % vs. 51 %), and the detection rate of FCD II was also better in the patients with type IIb (88 % vs. 32 %). The transmantle sign was significantly more frequent in the IIb subgroup ( p  = 0.003). Conclusions The rates of abnormal MRI results and correct MRI diagnoses of FCD II were significantly higher in the IIb subgroup. Although other MRI stigmata may contribute to the diagnosis, the only significant correlation was between the transmantle sign and FCD IIb.

Objective Telemedicine can improve access and continuity of care for people with epilepsy (PwE), but its adoption across Italian epilepsy centers remains inadequately characterized. We conducted a nationwide cross‐sectional survey of all 75 epilepsy centers certified by the Italian Chapter of the International League Against Epilepsy (Lega Italiana Contro l'Epilessia, LICE) as of July 1, 2025. Methods The survey assessed center characteristics, telemedicine implementation, services provided, digital tool use, institutional recognition, satisfaction, barriers, advantages, and changes since COVID‐19. Associations with adoption were analyzed using chi‐squared or Fisher's exact tests. Results Telemedicine was currently used in 34 centers (45%), more frequently in higher‐level centers (p = 0.009), with no association to patient volume (p = 0.229) or geographic macroarea (p = 0.319). Adoption rates varied regionally: North (54.3%), Central (34.8%), South/Islands (41.2%). Follow‐up visits were the most common (91.2%), while first consultations (26.5%) and teleneurophysiology (23.5%) were less frequent. Messaging apps were widely used (median 4, IQR 3–5 on a 0–5 scale), whereas certified email and medical apps were less common (median 1). Nearly half of centers reported the absence of reimbursement. Satisfaction scores among professionals (five‐point Likert scale) were moderate to high (3.5 ± 0.9). Barriers included technical limitations, insufficient equipment, and inability to perform exams; perceived advantages included improved continuity of care, reduced outpatient visits, and enhanced patient's quality of life. Since the COVID‐19 pandemic, 38.2% reported reduced telemedicine use, 35.3% increased use, and 26.5% no change. Significance Less than half of LICE‐certified Italian epilepsy centers currently use telemedicine. Adoption remains uneven, with benefits recognized but important technical, organizational, and reimbursement‐related barriers limiting widespread and sustainable integration. Plain Language Summary Telemedicine could help people with epilepsy get more consistent care, but fewer than half of Italian epilepsy centers currently use it. A national survey found that use varies by region and is more common in higher‐level centers. Most telemedicine activity involves follow‐up visits, while first appointments and remote testing are rare. Many centers rely on simple messaging apps, and reimbursement is often missing. Staff generally view telemedicine positively, but technical problems, lack of equipment, and the inability to perform exams limit its usefulness. Since COVID‐19, some centers have reduced telemedicine use, while others have increased or maintained it. Overall, adoption remains uneven and is held back by practical and organizational barriers.

The current study, conceived with the contribution of the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) and the Epilepsy Study Group of the Italian Neurological Society (SIN), aimed to assess potential physician-related barriers to refer subjects for epilepsy surgery. All the members of SIN and LICE were invited by email to complete a 28-item online questionnaire. The survey items included: (1) individual and medical practice characteristics, (2) knowledge of current indications to select candidates for epilepsy surgery, (3) factors potentially affecting the attitude toward epilepsy surgery. Overall, 210 physicians completed the survey. More than half (63.3%) of the participants showed proper knowledge of the ILAE drug-resistance. Definition and almost two-thirds of them (71.9%) considered themselves adequately informed about indications, risks, and benefits of epilepsy surgery. Surgery was regarded as a valid option to be used as early as possible by 84.8% of the interviewees, and 71% of them estimated its complication rate to be low. However, more than half (63%) of the respondents reportedly referred patients for surgery only after the failure of 3–5 antiseizure medications. Overestimation of risks/complications of surgery and inadequate healthcare resources were identified as the main factor contrasting the patient referral for surgery by 43% and 40.5% of the participants, respectively. In conclusion, this survey confirms the existence of knowledge gap within both physicians and the healthcare system, as well as an educational need regarding epilepsy surgery. Further researches are warranted to define learning outcomes and optimize educational tools.