Focal cortical dysplasia (FCD) is a developmental abnormality of cortex commonly linked with drug-resistant seizures. Altered GABAergic activity is a key contributor to interictal discharges in FCD. In FCD, GABAA receptor associated epileptogenicity is dependent upon the age at seizure onset, as differential epileptogenic networks are observed in early and late onset FCD patients. But the contribution of GABAA receptor alteration to epileptogenic networks during development is unclear. We hypothesize that GABAergic signaling in FCD undergoes age-dependent molecular alterations, contributing to the development of distinct epileptogenic networks. In this study, we investigated age-dependent changes in GABA neurotransmitter levels, GABAA receptor α subunit expression, and GABAA receptor-mediated synaptic activity using the BCNU-rat model of FCD. GABA levels, mRNA, and protein expression of GABAA receptor α subunits were determined by HPLC, qPCR and western blot and spontaneous GABAergic activity from pyramidal neurons was recorded using whole cell patch-clamp technique. At postnatal days (P) 12 and 21, reduced expression of α1, 2 and 4 subunits were observed in FCD rats compared to control. Consistent with this, decreased amplitude and frequency of GABAergic events were observed in FCD rats. In contrast, at P30 and P65, decreased GABA levels, without changes in receptor expression, were observed in FCD rats. Consistently, reduction in the frequency of GABAergic events was observed in FCD rats compared to the control. Furthermore, treatment with tetrodotoxin (TTX) revealed that the observed alterations in GABAergic activity were predominantly action potential (AP)-dependent. Our findings indicate that distinct epileptogenic networks exist in FCD during early and late developmental stages. These networks are driven primarily by altered GABAergic activity, with early age changes linked to aberrant GABAA receptor configurations and late age changes associated with abnormal GABA levels.

To investigate how etiology and seizure localization influence ictal scalp electroencephalographic (EEG) patterns in temporal lobe epilepsy (TLE).

We retrospectively analyzed ictal EEG features from 504 focal seizures recorded in 189 TLE patients with various etiologies who underwent resective surgery.

For seizure onset patterns (SOPs), α/β onset was more common in the low-grade tumor group (38.4%) than in the hippocampal sclerosis (HS) group (14.1%, p < 0.001). The ictal EEG duration was shorter in the tumor group compared to the focal cortical dysplasia (FCD), HS, and non-specific groups (p < 0.05). Among mesial TLE patients, SOPs varied depending on the etiology. Within both the tumor and non-specific groups, SOPs and the spreading time to the contralateral hemisphere differed between mesial and neocortical origins. Ictal pattern (87.7%) and ictal theta activity (83.9%) correctly lateralized the seizure in most cases.

The ictal scalp pattern in TLE is influenced by both etiology and seizure localization. TLE associated with low-grade tumors exhibits distinct ictal EEG characteristics. Furthermore, ictal pattern and ictal theta activity are equally effective in lateralizing seizures, regardless of etiology.

This research examined how brain activity during seizures in people with temporal lobe epilepsy can be different based on what caused the epilepsy and where in the brain the seizure starts. We found that seizures caused by brain tumors have unique patterns in the brain's electrical activity. Additionally, we discovered that specific patterns and types of brain waves can help determine which side of the brain the seizure is occurring on, regardless of its cause.

Scalp-EEG incompletely covers the frontal lobe cortex. Underrepresentation of frontobasal or frontomesial structures, fast ictal spreading, and false lateralization impede scalp-EEG interpretation. Hence, we investigated the significance of scalp-EEG in the presurgical workup of frontal lobe epilepsy.

Using descriptive statistical methods and Pearson chi-squared test for group comparisons, we retrospectively investigated postsurgical outcome, interictal epileptiform discharges (iiEDs), and electrographic seizure patterns on scalp-EEG in 81 consecutive patients undergoing resective epilepsy surgery within the margins of the frontal lobe.

Postoperatively, patients with frontopolar iiEDs ( n = 7) or concordant frontopolar iiED focus and seizure-onset ( n = 2) were seizure free ( n = 7/7, Engel Ia). MRI-positive patients with frontopolar iiEDs or frontopolar seizure-onset ( n = 1/8 Engel Id, n = 7/8 Engel Ia) underwent surgery without stereo-EEG. Thirteen of 16 patients with frontolateral ( n = 8/10, Engel Ia), or left frontobasal ( n = 5/6, Engel Ia) seizure-onset undergoing further stereo-EEG, were seizure-free postoperatively. Seizure-onset prevalent over one electrode ( n = 37/44 Engel I, p = 0.02), fast activity (FA)/flattening at seizure-onset ( n = 29/33 Engel I, p = 0.02), FA/flattening during the seizure ( n = 38/46 Engel I, p = 0.05), or focal rhythmic sharp-/spike-/polyspike-and-slow waves during the seizure ( n = 24/31, Engel Ia, p = 0.05) were favorable prognostic markers. Interictal polyspike waves ( p = 0.006 for Engel Ia) and interictal paroxysmal FA ( p = 0.02 for Engel I) were unfavorable prognostic markers.

Frontopolar scalp-EEG findings serve as biomarkers for predicting favorable surgical outcome in lesional frontal lobe epilepsy. Consequently, careful analysis of scalp-EEG assists in bypassing stereo-EEG in these patients.

Hemifacial spasms (HFS) are common in neurological practice but can be mistaken for focal aware seizures without appropriate diagnostic workup. We present the case of a man in his 60s admitted for congestive heart failure (CHF) exacerbation, who developed left-sided weakness and HFS during hospitalization. Although his motor symptoms improved after receiving tenecteplase (TNK), the HFS persisted, prompting the use of continuous video-EEG to differentiate between cortical myoclonus and HFS. Video-EEG is essential for distinguishing HFS from focal aware seizures, identifying high-frequency ipsilateral muscle artifacts in HFS versus interictal or ictal EEG patterns contralateral to facial contractions in seizures. This case highlights key features to aid neurologists in differentiating these conditions.

This study aimed to evaluate the effectiveness and safety of everolimus in treating seizures associated with focal cortical dysplasia type 2 (FCD 2).

A prospective, crossover, placebo-controlled clinical trial (ClinicalTrials.gov: NCT03198949) enrolled patients aged 4-40 years with pathologically confirmed FCD 2 and a history of ≥3 seizures per month for two out of the 3 months prior to screening. The trial included a 4-week baseline phase, two 12-week core phases, and a 29-week extension phase. Patients received everolimus or placebo in a blinded manner during core phase I, with crossover to the alternate treatment in core phase II. Everolimus dosage started at 4.5 mg/m2/day, targeting a serum level of 5-15 ng/mL. The primary outcome was the proportion of patients achieving ≥50% seizure reduction from baseline in the last month of each core phase. Safety profiles were compared between groups.

Between May 11, 2017, and June 19, 2020, 21 patients completed the core phases. There was no significant difference in the primary outcome between everolimus and placebo groups (24% vs. 19%, p = 0.66). The patients showed varied responses. Three patients with a pathogenic variant in the MTOR gene or no genetic abnormalities achieved seizure freedom with everolimus in the last month of the core phase, while none of the patients with variants in other genes did. Adverse events, such as mucositis or skin ulceration, were more common with everolimus (19/21 vs. 7/21, p < 0.001). All adverse events resolved without study drug withdrawal.

Everolimus treatment for 12 weeks did not show overall superiority in reducing seizures compared to placebo. However, it showed promise, mostly in patients with a pathogenic variant in the MTOR gene, highlighting the need for further research into patient-specific factors influencing treatment response. The everolimus treatment was generally safe and manageable.

This study tested everolimus for reducing seizures in patients with focal cortical dysplasia type 2 (FCD 2). While the drug was not more effective than a placebo for most, few patients showed better results, with some becoming seizure-free. Side effects were common but manageable. More research is needed to understand why certain patients respond better to treatment.

Stereoelectroencephalography (SEEG), as a minimally invasive method that can stably collect intracranial electroencephalographic information over long periods, has increasingly been applied in the diagnosis and treatment of intractable epilepsy in recent years. Over the past 20 years, with the advancement of materials science and computer science, the application scenarios of SEEG have greatly expanded. Bibliometrics, as a method of scientifically analyzing published literature, can summarize the evolutionary process in the SEEG field and offer insights into its future development prospects.

This article selected all the literature records retrieved on November 4, 2024, from the Web of Science Core Collection (WoSCC). The search terms were as follows: "Stereo-electroencephalography" or "Stereo electroencephalography" or "Stereo-EEG" or "Stereo EEG" or "SEEG." The document types included were research articles and reviews. For analysis, VOSviewer, CiteSpace, and the R package "bibliometrix" were employed to analyze various aspects of the SEEG field, including authors, institutions, countries and regions, and research hotspots.

We reviewed a total of 1,383 non-duplicate literature records from 2002 to 2023, including 1,241 research articles, 116 review articles and 26 letters. Observing the annual publication trends, there has been an overall increase since 2002. The most influential journal in this field is Epilepsia. Other journals with considerable impact include Clinical Neurophysiology, Epileptic Disorders, Epilepsy Research, NeuroImage, and Epilepsy & Behavior. The top 5 most influential scholars are Bartolomei F, Tassi L, Nobili L, Russo GL, and Mc Gonigal A. As for the analysis of countries and regions, France occupies a leading position in this field with its early start, while China and the United States have also emerged as focal points since 2020. Research on SEEG has expanded beyond its initial use for localizing epileptic foci and thermo-coagulation treatments and have been employed as a medium to facilitate real-time prediction of epileptic seizures and enabling the exploration of brain network connectivity.

As a minimally invasive tool for collecting intracranial electroencephalographic signals, SEEG continues to offer vast potential for development and application. Advances in electrode materials and robotic-assisted stereotactic techniques, have enabled SEEG to simultaneously sample multiple brain regions, acquire electrical signals from deep brain structures. These advantages significantly enhance the precision of epileptic focus localization in diagnosis and treatment, addressing the limitations of subdural electrodes. Through bibliometric analysis, this paper traces the developmental trajectory of SEEG and identifying key technological milestones, thereby providing a reference for scholarly research directions.

Analyze the association between histopathology, seizure outcomes, and drug load of antiseizure medications (ASMs) 5-8 years after epilepsy surgery to inform preoperative decision-making and consultation.

In this retrospective, non-interventional, single-center study, patients who visited the epilepsy clinic at West China Hospital, Sichuan University from Jan 1, 2015 to Dec 31, 2020 were assessed. Patients with postoperative histopathology after epilepsy resection were included and categorized into 13 etiological groups. The primary outcomes were achieving Engel class 1 at 1, 2, 3, 5, and 8 years postoperative. Secondary outcomes included the use of ASMs and comparison of postoperative seizure outcomes between adults and children. Univariate and multivariable analyses were conducted to explore the association between clinical characteristics such as histopathology and seizure outcomes.

A total of 315 patients were include. Patients with embryonic dysplastic neuroepithelial tumor (DNT) achieved the best seizure outcomes (84.6 % Engel class 1). DNT (odds ratio, OR=0.103, 95 %CI=0.012-0.899), cavernous hemangiomas (OR=0.140, 95 %CI=0.024-0.819) and meningioma (OR=0.137, 95 %CI=0.021-0.910) were independently associated with a higher probability of seizure-free outcome. The results of epileptic seizures in adult and pediatric groups with different pathologies were significantly different, and the preoperative and postoperative ASM dosages were also different among adult patients with various etiologies. Additionally, multivariate analysis showed that early age at onset (adjusted hazard ratio (HR) = 1.754, 95 % CI=1.049-2.934, P=0.032), late surgical age (HR=0.569, 95 %CI=0.339-0.954, P=0.032), and longer duration from seizure onset to surgery (HR=1.735, 95 % CI=1.028-2.928, P=0.039) were independent predictors of unfavorable outcomes in epileptic seizures.

we demonstrated that the seizure outcomes of focal epilepsy have high pathological specificity, with histopathological diagnosis serving as a crucial and independent determinant of seizure outcome. Surgical assessment should be contemplated for all patients with presumed refractory focal epilepsy, irrespective of their age.

The advent of advanced brain imaging techniques has significantly enhanced the understanding and treatment of focal epilepsies, with identifiable brain lesions present in 80 % of cases. Despite this, surgical outcomes remain varied, often influenced by lesion type and location. Traditional lesion-centric approaches may overlook the complex organization of the epileptogenic zone (EZ), which often extends beyond the visible lesion, emphasizing the need for comprehensive presurgical evaluations like stereo-electroencephalography (SEEG) in some cases. This article delves into the concept of epileptogenic networks, moving beyond the notion of a lesional epileptic focus. Through SEEG, three primary network types have been identified: the Epileptogenic Zone Network (EZN), characterized by regions with heightened epileptogenicity and seizure initiation; the Propagation Zone Network (PZN), involving regions with delayed and less intense epileptic activity; and Non-Involved networks (NI). Quantitative measures, such as the epileptogenicity index (EI), aid in delineating these networks, revealing that EZN can be focal or networked, with the latter being more prevalent. The relationship between epilepsy-associated lesions and network organization is complex. Intrinsically epileptogenic lesions, like focal cortical dysplasia and periventricular nodular heterotopias, often generate epileptiform activities but may still involve broader epileptogenic networks. Non-intrinsically epileptogenic lesions, such as cavernomas and post-stroke lesions, typically lack inherent neuronal activity but can facilitate the development of extensive epileptogenic networks. Understanding the intricacies of these networks is crucial for optimizing surgical interventions. Recognizing that lesions may represent just one node within a broader epileptogenic network underscores the importance of comprehensive SEEG evaluations to achieve better surgical outcomes.

Accurate segmentation of focal cortical dysplasia (FCD) lesions from MR images plays an important role in surgical planning and decision but is still challenging for radiologists and clinicians. In this study, we introduce a novel transformer-based model, designed for the end-to-end segmentation of FCD lesions from multi-channel MR images.

The core innovation of our proposed model is the integration of a convolutional neural network-based encoder-decoder structure with a multiscale transformer to augment the feature representation of lesions in the global field of view. Transformer pathways, composed of memory- and computation-efficient dual-self-attention modules, leverage feature maps from varying depths of the encoder to discern long-range interdependencies among feature positions and channels, thereby emphasizing areas and channels relevant to lesions. The proposed model was trained and evaluated on a public-open dataset including MR images of 85 patients using both subject-level and voxel-level metrics.

Experimental results indicate that our model offers superior performance both quantitatively and qualitatively. It successfully identified lesions in 82.4% of patients, with a low false-positive lesion cluster rate of 0.176 ± 0.381 per patient. Furthermore, the model achieved an average Dice coefficient of 0.410 ± 0.288, outperforming five established methods.

Integration of the transformer could enhance the feature presentation and segmentation performance of FCD lesions. The proposed model has the potential to serve as a valuable assistive tool for physicians, enabling rapid and accurate identification of FCD lesions. The source code and pre-trained model weights are available at https://github.com/zhangxd0530/MS-DSA-NET .

This multiscale transformer-based model performs segmentation of focal cortical dysplasia lesions, aiming to help radiologists and clinicians make accurate and efficient preoperative evaluations of focal cortical dysplasia patients from MR images.

The first transformer-based model was built to explore focal cortical dysplasia lesion segmentation. Integration of global and local features enhances the segmentation performance of lesions. A valuable benchmark for model development and comparative analyses was provided.

Scalp EEG is one of the main tools in the clinical evaluation of epilepsy. In some cases intracranial Interictal Epileptiform Discharges (IEDs) are not visible from the scalp. Recent studies have shown the feasibility of revealing them in the EEG if their timings are extracted from simultaneous intracranial recordings, but their potential for the localization of the epileptogenic zone is not yet well defined.

We recorded simultaneous high-density EEG (HD-EEG) and stereo-electroencephalography (SEEG) during interictal periods in 8 patients affected by drug-resistant focal epilepsy. We identified IEDs in the SEEG and systematically analyzed the time-locked signals on the EEG by means of evoked potentials, topographical analysis and Electrical Source Imaging (ESI). The dataset has been standardized and is being publicly shared.

Our results showed that IEDs that were not clearly visible at single-trials could be uncovered by averaging, in line with previous reports. They also showed that their topographical voltage distributions matched the position of the SEEG electrode where IEDs had been identified, and that ESI techniques can reconstruct it with an accuracy of ∼2 cm. Finally, the present dataset provides a reference to test the accuracy of different methods and parameters.

Our study is the first to systematically compare ESI methods on simultaneously recorded IEDs, and to share a public resource with in-vivo data for their evaluation.

Simultaneous HD-EEG and SEEG recordings can unveil hidden IEDs whose origins can be reconstructed using topographical and ESI analyses, but results depend on the selected methods and parameters.

The International League Against Epilepsy (ILAE) is an organization of 120 national chapters providing the most widely accepted and updated guidelines on epilepsy. In 2022, the ILAE Task Force revised the prior (2011) classification of focal cortical dysplasias to incorporate and update clinicopathologic and genetic information, with the aim to provide an objective classification scheme. New molecular-genetic information has led to the concept of "integrated diagnosis" on the same lines as brain tumors, with a multilayered diagnostic model providing a phenotype-genotype integration. Major changes in the new update were made to type II focal cortical dysplasias, apart from identification of new entities, such as mild malformations of cortical development and cortical malformation with oligodendroglial hyperplasia. No major changes were made to type I and III focal cortical dysplasias, given the lack of significant new genetic information. This review provides the latest update on changes to the classification of focal cortical dysplasias with discussion about the new entities. The ILAE in 2017 updated the classification of seizure and epilepsy with 3 levels of diagnosis, including seizure type, epilepsy type, and epilepsy syndrome, which are also briefly discussed here.

Tailoring epilepsy surgery using intraoperative electrocorticography (ioECoG) has been debated, and modest number of epilepsy surgery centers apply this diagnostic method. We assessed the current evidence to use ioECoG-tailored epilepsy surgery for improving postsurgical outcome.

PubMed and Embase were searched for original studies reporting on ≥10 cases who underwent ioECoG-tailored surgery for epilepsy, with a follow-up of at least 6 months. We used a random-effects model to calculate the overall rate of patients achieving favorable seizure outcome (FSO), defined as Engel class I, ILAE class 1, or seizure-free status. Meta-regression was used to investigate potential sources of heterogeneity. We calculated the odds ratio (OR) for estimating variables on FSO:ioECoG vs non-ioECoG-tailored surgery (if included studies contained patients with non-ioECoG-tailored surgery), ioECoG-tailored epilepsy surgery in children vs adults, temporal (TL) vs extratemporal lobe (eTL), MRI-positive vs MRI-negative, and complete vs incomplete resection of tissue that generated interictal epileptiform discharges (IEDs). A Bayesian network meta-analysis was conducted for underlying pathologies. We assessed the evidence certainty using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE).

Eighty-three studies (82 observational studies, 1 trial) comprising 3,631 patients with ioECoG-tailored surgery were included. The overall pooled rate of patients who attained FSO after ioECoG-tailored surgery was 74% (95% CI 71-77) with significant heterogeneity, which was predominantly attributed to pathologies and seizure outcome classifications. Twenty-two studies contained non-ioECoG-tailored surgeries. IoECoG-tailored surgeries reached a higher rate of FSO than non-ioECoG-tailored surgeries (OR 2.10 [95% CI 1.37-3.24]; p < 0.01; very low certainty). Complete resection of tissue that displayed IEDs in ioECoG predicted FSO better compared with incomplete resection (OR 3.04 [1.76-5.25]; p < 0.01; low certainty). We found insignificant difference in FSO after ioECoG-tailored surgery in children vs adults, TL vs eTL, or MRI-positive vs MRI-negative. The network meta-analysis showed that the odds of FSO was lower for malformations of cortical development than for tumors (OR 0.47 95% credible interval 0.25-0.87).

Although limited by low-quality evidence, our meta-analysis shows a relatively good surgical outcome (74% FSO) after epilepsy surgery with ioECoG, especially in tumors, with better outcome for ioECoG-tailored surgeries in studies describing both and better outcome after complete removal of IED areas.

Our objective was to evaluate the relationship between scalp-EEG and stereoelectroencephalography (SEEG) seizure-onset patterns (SOP) in patients with MRI-negative drug-resistant focal epilepsy.

We analyzed retrospectively 41 patients without visible lesion on brain MRI who underwent video-EEG followed by SEEG. We defined five types of SOPs on scalp-EEG and eight types on SEEG. We examined how various clinical variables affected scalp-EEG SOPs.

The most prevalent scalp SOPs were rhythmic sinusoidal activity (56.8%), repetitive epileptiform discharges (22.7%), and paroxysmal fast activity (15.9%). The presence of paroxysmal fast activity on scalp-EEG was always seen without delay from clinical onset and correlated with the presence of low-voltage fast activity in SEEG (sensitivity = 22.6%, specificity = 100%). The main factor explaining the discrepancy between the scalp and SEEG SOPs was the delay between clinical and scalp-EEG onset. There was a correlation between the scalp and SEEG SOPs when the scalp onset was simultaneous with the clinical onset (p = 0.026). A significant delay between clinical and scalp discharge onset was observed in 25% of patients and featured always with a rhythmic sinusoidal activity on scalp, corresponding to similar morphology of the discharge on SEEG. The presence of repetitive epileptiform discharges on scalp was associated with an underlying focal cortical dysplasia (sensitivity = 30%, specificity = 90%). There was no significant association between the scalp SOP and the epileptogenic zone location (deep or superficial), or surgical outcome.

In patients with MRI-negative focal epilepsy, scalp SOP could suggest the SEEG SOP and some etiology (focal cortical dysplasia) but has no correlation with surgical prognosis. Scalp SOP correlates with the SEEG SOP in cases of simultaneous EEG and clinical onset; otherwise, scalp SOP reflects the propagation of the SEEG discharge.

We looked at the correspondence between the electrical activity recorded during the start of focal seizure using scalp and intracerebral electrodes in patients with no visible lesion on MRI. If there is a fast activity on scalp, it reflects similar activity inside the brain. We found a good correspondence between scalp and intracerebral electrical activity for cases without significant delay between clinical and scalp electrical onset (seen in 75% of the cases we studied). Visualizing repetitive epileptic activity on scalp could suggest a particular cause of the epilepsy: a subtype of brain malformation called focal cortical dysplasia.

Focal cortical dysplasias are abnormalities of the cerebral cortex associated with an elevated risk of neurological disturbances. Cortical spreading depolarization/depression is a correlate of migraine aura/headache and a trigger of migraine pain mechanisms. However, cortical spreading depolarization/depression is associated with cortical structural changes, which can be classified as transient focal cortical dysplasias. Migraine is reported to be associated with changes in various brain structures, including malformations and lesions in the cortex. Such malformations may be related to focal cortical dysplasias, which may play a role in migraine pathogenesis. Results obtained so far suggest that focal cortical dysplasias may belong to the causes and consequences of migraine. Certain focal cortical dysplasias may lower the threshold of cortical excitability and facilitate the action of migraine triggers. Migraine prevalence in epileptic patients is higher than in the general population, and focal cortical dysplasias are an established element of epilepsy pathogenesis. In this narrative/hypothesis review, we present mainly information on cortical structural changes in migraine, but studies on structural alterations in deep white matter and other brain regions are also presented. We develop the hypothesis that focal cortical dysplasias may be causally associated with migraine and link pathogeneses of migraine and epilepsy.

Fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) is routinely used for presurgical evaluation in many epilepsy centers. Hypometabolic characteristics have been extensively examined in prior studies, but the metabolic patterns associated with specific pathological types of drug-resistant epilepsy remain to be fully defined. This study was developed to explore the relationship between metabolic patterns or characteristics and surgical outcomes in type I and II focal cortical dysplasia (FCD) patients based on results from a large cohort.

Data from individuals who underwent epilepsy surgery from 2014 to 2019 with a follow-up duration of over 3 years and a pathological classification of type I or II FCD in our hospital were retrospectively analyzed. Hypometabolic patterns were quantitatively identified via statistical parametric mapping (SPM) and qualitatively analyzed via visual examination of PET-MRI co-registration images. Univariate analyses were used to explore the relationship between metabolic patterns and surgical outcomes.

In total, this study included data from 210 patients. Following SPM calculations, four hypometabolic patterns were defined including unilobar, multi-lobar, and remote patterns as well as cases where no pattern was evident. In type II FCD patients, the unilobar pattern was associated with the best surgical outcomes (p = 0.014). In visual analysis, single gyrus (p = 0.032) and Clear-cut hypometabolism edge (p = 0.040) patterns exhibited better surgery outcomes in the type II FCD group.

PET metabolic patterns are well-correlated with the prognosis of type II FCD patients. However, similar correlations were not observed in type I FCD, potentially owing to the complex distribution of the epileptogenic region.

In this study, we demonstrated that FDG-PET was a crucial examination for patients with FCD, which was a common cause of epilepsy. We compared the surgical prognosis for patients with different hypometabolism distribution patterns and found that clear and focal abnormal region in PET was correlated with good surgical outcome in type II FCD patients.

This study investigates the prevalence of pathogenic variants in the mechanistic target of rapamycin (mTOR) pathway in surgical specimens of malformations of cortical development (MCDs) and cases with negative histology. The study also aims to evaluate the predictive value of genotype-histotype findings on the surgical outcome.

The study included patients with drug-resistant focal epilepsy who underwent epilepsy surgery. Cases were selected based on histopathological diagnosis, focusing on MCDs and negative findings. We included brain tissues both as formalin-fixed, paraffin-embedded (FFPE) or fresh frozen (FF) samples. Single-molecule molecular inversion probes (smMIPs) analysis was conducted, targeting the MTOR gene in FFPE samples and 10 genes within the mTOR pathway in FF samples. Correlations between genotype-histotype and surgical outcome were examined.

We included 78 patients for whom we obtained 28 FFPE samples and 50 FF tissues. Seventeen pathogenic variants (22 %) were identified and validated, with 13 being somatic within the MTOR gene and 4 germlines (2 DEPDC5, 1 TSC1, 1 TSC2). Pathogenic variants in mTOR pathway genes were exclusively found in FCDII and TSC cases, with a significant association between FCD type IIb and MTOR genotype (P = 0.003). Patients carrying mutations had a slightly better surgical outcome than the overall cohort, however it results not significant. The FCDII diagnosed cases more frequently had normal neuropsychological test, a higher incidence of auras, fewer multiple seizure types, lower occurrence of seizures with awareness impairment, less ictal automatisms, fewer Stereo-EEG investigations, and a longer period long-life of seizure freedom before surgery.

This study confirms that somatic MTOR variants represent the primary genetic alteration detected in brain specimens from FCDII/TSC cases, while germline DEPDC5, TSC1/TSC2 variants are relatively rare. Systematic screening for these mutations in surgically treated patients' brain specimens can aid histopathological diagnoses and serve as a biomarker for positive surgical outcomes. Certain clinical features associated with pathogenic variants in mTOR pathway genes may suggest a genetic etiology in FCDII patients.

In medicine, abnormalities in quantitative metrics such as the volume reduction of one brain region of an individual versus a control group are often provided as deviations from so-called normal values. These normative reference values are traditionally calculated based on the quantitative values from a control group, which can be adjusted for relevant clinical co-variables, such as age or sex. However, these average normative values do not take into account the globality of the available quantitative information. For example, quantitative analysis of T1-weighted magnetic resonance images based on anatomical structure segmentation frequently includes over 100 cerebral structures in the quantitative reports, and these tend to be analyzed separately. In this study, we propose a global approach to personalized normative values for each brain structure using an unsupervised Artificial Intelligence technique known as generative manifold learning. We test the potential benefit of these personalized normative values in comparison with the more traditional average normative values on a population of patients with drug-resistant epilepsy operated for focal cortical dysplasia, as well as on a supplementary healthy group and on patients with Alzheimer's disease.

When planning for epilepsy surgery, multiple potential sites for resection may be identified through anatomical imaging. Magnetoencephalography (MEG) using optically pumped sensors (OP-MEG) is a non-invasive functional neuroimaging technique which could be used to help identify the epileptogenic zone from these candidate regions. Here we test the utility of a-priori information from anatomical imaging for differentiating potential lesion sites with OP-MEG. We investigate a number of scenarios: whether to use rigid or flexible sensor arrays, with or without a-priori source information and with or without source modelling errors. We simulated OP-MEG recordings for 1309 potential lesion sites identified from anatomical images in the Multi-centre Epilepsy Lesion Detection (MELD) project. To localise the simulated data, we used three source inversion schemes: unconstrained, prior source locations at centre of the candidate sites, and prior source locations within a volume around the lesion location. We found that prior knowledge of the candidate lesion zones made the inversion robust to errors in sensor gain, orientation and even location. When the reconstruction was too highly restricted and the source assumptions were inaccurate, the utility of this a-priori information was undermined. Overall, we found that constraining the reconstruction to the region including and around the participant's potential lesion sites provided the best compromise of robustness against modelling or measurement error.

Focal cortical dysplasia type II (FCDII) is the most common cause of drug-resistant focal epilepsy in children. Herein, we performed a deep histopathology-based genotype-phenotype analysis to further elucidate the clinico-pathological and genetic presentation of FCDIIa compared to FCDIIb. Seventeen individuals with histopathologically confirmed diagnosis of FCD ILAE Type II and a pathogenic variant detected in brain derived DNA whole-exome sequencing or mTOR gene panel sequencing were included in this study. Clinical data were directly available from each contributing centre. Histopathological analyses were performed from formalin-fixed, paraffin-embedded tissue samples using haematoxylin-eosin and immunohistochemistry for NF-SMI32, NeuN, pS6, p62, and vimentin. Ten individuals carried loss-of-function variants in the GATOR1 complex encoding genes DEPDC5 (n = 7) and NPRL3 (n = 3), or gain-of-function variants in MTOR (n = 7). Whereas individuals with GATOR1 variants only presented with FCDIIa, i.e., lack of balloon cells, individuals with MTOR variants presented with both histopathology subtypes, FCDIIa and FCDIIb. Interestingly, 50% of GATOR1-positive cases showed a unique and predominantly vacuolizing phenotype with p62 immunofluorescent aggregates in autophagosomes. All cases with GATOR1 alterations had neurosurgery in the frontal lobe and the majority was confined to the cortical ribbon not affecting the white matter. This pattern was reflected by subtle or negative MRI findings in seven individuals with GATOR1 variants. Nonetheless, all individuals were seizure-free after surgery except four individuals carrying a DEPDC5 variant. We describe a yet underrecognized genotype-phenotype correlation of GATOR1 variants with FCDIIa in the frontal lobe. These lesions were histopathologically characterized by abnormally vacuolizing cells suggestive of an autophagy-altered phenotype. In contrast, individuals with FCDIIb and brain somatic MTOR variants showed larger lesions on MRI including the white matter, suggesting compromised neural cell migration.

Focal or partial seizures are a common neurological disorder affecting adults. This review aims to provide an in-depth understanding of focal seizures in adults, including their classification, clinical presentation, etiology, diagnosis, and management. This article seeks to enhance awareness and knowledge among medical professionals and the general public by exploring the latest research and clinical insights. Standard electroencephalography (EEG) and recordings in presurgical electrode depth in humans provide a clear definition of patterns similar to focal seizures. Models of animals with partial seizures and epilepsy mimic seizure patterns with comparable characteristics. However, the network factors supporting interictal spikes, as well as the start, development, and end of seizures remain obscure. According to recent research, inhibitory networks are heavily implicated at the beginning of seizures, and extracellular potassium alterations help start and maintain seizure continuation. An increase in network synchronization, which may be caused by both excitatory and inhibitory pathways, is correlated with the cessation of a partial seizure. Recent research on temporal lobe focal seizures in human and animal models leads to the hypothesis that the active blocking of subcortical arousal processes brings on unconsciousness. Brainstem, basal forebrain, and thalamic arousal networks' neuronal firing is diminished during focal limbic seizures, and cortical arousal can be recovered when subcortical arousal circuits are engaged. These results suggest that thalamic neurostimulation may be therapeutic to restore arousal and consciousness during and after seizures. Targeted subcortical stimulation may increase arousal and consciousness when current treatments cannot halt seizures, enhancing safety and psychosocial function for epileptic patients. We embark on an investigation into adult focal seizures in this thorough review that goes beyond a cursory knowledge of their clinical symptoms.

Language lateralization in patients with focal epilepsy frequently diverges from the left-lateralized pattern that prevails in healthy right-handed people, but the mechanistic explanations are still a matter of debate. Here, we debate the complex interaction between focal epilepsy, language lateralization, and functional neuroimaging techniques by introducing the case of a right-handed patient with unaware focal seizures preceded by aphasia, in whom video-EEG and PET examination suggested the presence of focal cortical dysplasia in the right superior temporal gyrus, despite a normal structural MRI. The functional MRI for language was inconclusive, and the neuropsychological evaluation showed mild deficits in language functions. A bilateral stereo-EEG was proposed confirming the right superior temporal gyrus origin of seizures, revealing how ictal aphasia emerged only once seizures propagated to the left superior temporal gyrus and confirming, by cortical mapping, the left lateralization of the posterior language region. Stereo-EEG-guided radiofrequency thermocoagulations of the (right) focal cortical dysplasia not only reduced seizure frequency but led to the normalization of the neuropsychological assessment and the "restoring" of a classical left-lateralized functional MRI pattern of language. This representative case demonstrates that epileptiform activity in the superior temporal gyrus can interfere with the functioning of the contralateral homologous cortex and its associated network. In the case of presurgical evaluation in patients with epilepsy, this interference effect must be carefully taken into consideration. The multimodal language lateralization assessment reported for this patient further suggests the sensitivity of different explorations to this interference effect. Finally, the neuropsychological and functional MRI changes after thermocoagulations provide unique cues on the network pathophysiology of focal cortical dysplasia and the role of diverse techniques in indexing language lateralization in complex scenarios.

Human evolution has seen the development of higher-order cognitive and social capabilities in conjunction with the unique laminar cytoarchitecture of the human cortex. Moreover, early-life cortical maldevelopment has been associated with various neurodevelopmental diseases. Despite these connections, there is currently no noninvasive technique available for imaging the detailed cortical laminar structure. This study aims to address this scientific and clinical gap by introducing an approach for imaging human cortical lamina. This method combines diffusion-relaxation multidimensional MRI with a tailored unsupervised machine learning approach that introduces enhanced microstructural sensitivity. This new imaging method simultaneously encodes the microstructure, the local chemical composition and importantly their correlation within complex and heterogenous tissue. To validate our approach, we compared the intra-cortical layers obtained using our ex vivo MRI-based method with those derived from Nissl staining of postmortem human brain specimens. The integration of unsupervised learning with diffusion-relaxation correlation MRI generated maps that demonstrate sensitivity to areal differences in cytoarchitectonic features observed in histology. Significantly, our observations revealed layer-specific diffusion-relaxation signatures, showing reductions in both relaxation times and diffusivities at the deeper cortical levels. These findings suggest a radial decrease in myelin content and changes in cell size and anisotropy, reflecting variations in both cytoarchitecture and myeloarchitecture. Additionally, we demonstrated that 1D relaxation and high-order diffusion MRI scalar indices, even when aggregated and used jointly in a multimodal fashion, cannot disentangle the cortical layers. Looking ahead, our technique holds the potential to open new avenues of research in human neurodevelopment and the vast array of disorders caused by disruptions in neurodevelopment.

Electrophysiological characterization of live human tissue from epilepsy patients has been performed for many decades. Although initially these studies sought to understand the biophysical and synaptic changes associated with human epilepsy, recently, it has become the mainstay for exploring the distinctive biophysical and synaptic features of human cell-types. Both epochs of these human cellular electrophysiological explorations have faced criticism. Early studies revealed that cortical pyramidal neurons obtained from individuals with epilepsy appeared to function "normally" in comparison to neurons from non-epilepsy controls or neurons from other species and thus there was little to gain from the study of human neurons from epilepsy patients. On the other hand, contemporary studies are often questioned for the "normalcy" of the recorded neurons since they are derived from epilepsy patients. In this review, we discuss our current understanding of the distinct biophysical features of human cortical neurons and glia obtained from tissue removed from patients with epilepsy and tumors. We then explore the concept of within cell-type diversity and its loss (i.e., "neural homogenization"). We introduce neural homogenization to help reconcile the epileptogenicity of seemingly "normal" human cortical cells and circuits. We propose that there should be continued efforts to study cortical tissue from epilepsy patients in the quest to understand what makes human cell-types "human".

Focal cortical dysplasia (FCD), a common malformation of cortical development, is frequently associated with pharmacoresistant epilepsy in both children and adults. Adenosine is an inhibitory modulator of brain activity and a prospective anti-seizure agent with potential for clinical translation. Our previous results demonstrated that the major adenosine-metabolizing enzyme adenosine kinase (ADK) was upregulated in balloon cells (BCs) within FCD type IIB lesions, suggesting that dysfunction of the adenosine system is implicated in the pathophysiology of FCD. In our current study, we therefore performed a comprehensive analysis of adenosine signaling in surgically resected cortical specimens from patients with FCD type I and type II via immunohistochemistry and immunoblot analysis. Adenosine enzyme signaling was assessed by quantifying the levels of the key enzymes of adenosine metabolism, i.e., ADK, adenosine deaminase (ADA), and ecto-5'-nucleotidase (CD73). Adenosine receptor signaling was assessed by quantifying the levels of adenosine A2A receptor (A2AR) and putative downstream mediators of adenosine, namely, glutamate transporter-1 (GLT-1) and mammalian target of rapamycin (mTOR). Within lesions in FCD specimens, we found that the adenosine-metabolizing enzymes ADK and ADA, as well as the adenosine-producing enzyme CD73, were upregulated. We also observed an increase in A2AR density, as well as a decrease in GLT-1 levels and an increase in mTOR levels, in FCD specimens compared with control tissue. These results suggest that dysregulation of the adenosine system is a common pathologic feature of both FCD type I and type II. The adenosine system might therefore be a therapeutic target for the treatment of epilepsy associated with FCD.

Lesional epilepsy is a common and severe disease commonly associated with malformations of cortical development, including focal cortical dysplasia and hemimegalencephaly. Recent advances in sequencing and variant calling technologies have identified several genetic causes, including both short/single nucleotide and structural somatic variation. In this review, we aim to provide a comprehensive overview of the methodological advancements in this field while highlighting the unresolved technological and computational challenges that persist, including ultra-low variant allele fractions in bulk tissue, low availability of paired control samples, spatial variability of mutational burden within the lesion, and the issue of false-positive calls and validation procedures. Information from genetic testing in focal epilepsy may be integrated into clinical care to inform histopathological diagnosis, postoperative prognosis, and candidate precision therapies.

To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features.

We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes.

Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05).

The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes.

Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.

Non-invasive classification of focal cortical dysplasia (FCD) subtypes remains challenging from a radiology perspective. Quantitative imaging biomarkers (QIBs) have the potential to distinguish subtypes that lack pathognomonic features and might help in defining the extent of abnormal connectivity associated with each FCD subtype. A key motivation of diagnostic imaging is to improve the localization of a "lesion" that can guide the surgical resection of affected tissue, which is thought to cause seizures. Conversely, surgical resections to eliminate or reduce seizures provided unique opportunities to develop magnetic resonance imaging (MRI)-based QIBs by affording long scan times to evaluate multiple contrast mechanisms at the mesoscale (0.5 mm isotropic voxel dimensions). Using ex vivo hybrid diffusion tensor imaging on a 9.4 T MRI scanner, the grey to white matter ratio of scalar indices was lower in the resected middle temporal gyrus (MTG) of two neuropathologically confirmed cases of FCD compared to non-diseased control postmortem fixed temporal lobes. In contrast, fractional anisotropy was increased within FCD and also adjacent white matter tracts. Connectivity (streamlines/mm3) in the MTG was higher in FCD, suggesting that an altered connectivity at the lesion locus can potentially provide a tangible QIB to distinguish and characterize FCD abnormalities. However, as illustrated here, a major challenge for a robust tractographical comparison lies in the considerable differences in the ex vivo processing of bioptic and postmortem samples. Mesoscale diffusion MRI has the potential to better define and characterize epileptic tissues obtained from surgical resection to advance our understanding of disease etiology and treatment.

Focal cortical dysplasia (FCD) is a malformation of cortical development characterised by disruption of cortical cytoarchitecture. Classification of FCDs subtypes has initially been based on correlation of the histopathology with relevant clinical, electroencephalographic and neuroimaging features. A recently proposed classification update recommends a multilayered, genotype-phenotype approach, integrating findings from histopathology, genetic analysis of resected tissue and presurgical MRI. FCDs are caused either by single somatic activating mutations in MTOR pathway genes or by double-hit inactivating mutations with a constitutional and a somatic loss-of-function mutation in repressors of the signalling pathway. Mild malformation with oligodendroglial hyperplasia in epilepsy is caused by somatic pathogenic SLC35A2 mutations. FCDs most often present with drug-resistant focal epilepsy or epileptic encephalopathy. Most patients respond to surgical treatment. The use of mechanistic target of rapamycin inhibitors may complement the surgical approach. Treatment approaches and outcomes have improved with advances in neuroimaging, neurophysiology and genetics, although predictors of treatment response have only been determined in part.

Favorable seizure outcome is reported following resection of bottom-of-sulcus dysplasia (BOSD). We assessed the distribution of epileptogenicity and dysplasia in and around BOSD to better understand this clinical outcome and the optimal surgical approach.

We studied 27 children and adolescents with magnetic resonance imaging (MRI)-positive BOSD who underwent epilepsy surgery; 85% became seizure-free postresection (median = 5.0 years follow-up). All patients had resection of the dysplastic sulcus, and 11 had additional resection of the gyral crown (GC) or adjacent gyri (AG). Markers of epileptogenicity were relative cortical hypometabolism on preoperative 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and spiking, ripples, fast ripples, spike-high-frequency oscillation cross-rate, and phase amplitude coupling (PAC) on preresection and postresection electrocorticography (ECoG), all analyzed at the bottom-of-sulcus (BOS), top-of-sulcus (TOS), GC, and AG. Markers of dysplasia were increased cortical thickness on preoperative MRI, and dysmorphic neuron density and variant allele frequency of somatic MTOR mutations in resected tissue, analyzed at similar locations.

Relative cortical metabolism was significantly reduced and ECoG markers were significantly increased at the BOS compared to other regions. Apart from spiking and PAC, which were greater at the TOS compared to the GC, there were no significant differences in PET and other ECoG markers between the TOS, GC, and AG, suggesting a cutoff of epileptogenicity at the TOS rather than a tapering gradient on the cortical surface. MRI and tissue markers of dysplasia were all maximal in the BOS, reduced in the TOS, and mostly absent in the GC. Spiking and PAC reduced significantly over the GC after resection of the dysplastic sulcus.

These findings support the concept that dysplasia and intrinsic epileptogenicity are mostly limited to the dysplastic sulcus in BOSD and support resection or ablation confined to the MRI-visible lesion as a first-line surgical approach. 18 F-FDG PET and ECoG abnormalities in surrounding cortex seem to be secondary phenomena.

Tuberous sclerosis complex (TSC) is a neurogenetic disorder that affects multiple organ systems, including the heart, kidneys, eyes, skin, and central nervous system. The neurologic manifestations have the highest morbidity and mortality, in particular in children. Clinically, patients with TSC often present with new-onset seizures within the first year of life. TSC-associated epilepsy is often difficult to treat and refractory to multiple antiseizure medications. Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder. An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes. Therefore, it is important to treat TSC-associated epilepsy aggressively, whether it be with pharmacological therapy, surgical intervention, and/or neuromodulation. This review discusses current and future pharmacological treatments for TSC-associated epilepsy, as well as the importance of early surgical evaluation for refractory epilepsy in children with TSC and consideration of neuromodulatory interventions in young adults.

To assess the long-term outcome of the surgically remediable syndrome of frontal lobe epilepsy (FLE) associated with superior frontal sulcus (SFS)-related dysplasia.

We retrospectively reviewed the medical charts and surgical features of 31 patients with drug-resistant frontal lobe epilepsy in our centers between 2016 and 2018. All patients underwent surgical resection. According to the epileptogenic zone (EZ), localization and resection extent were classified as (1) pure SFS group (PS group), (2) associated SFS group (AS group), and (3) no SFS group (NS group). The general characteristics, neuroradiological findings, morbidity, pathology, and long-term seizure outcome after surgery were analyzed to extract the potential value of the surgery for SFS-related dysplasia.

Of 31 patients with FLE who underwent epilepsy surgery, 15 patients (nine men) were included PS group, five patients (five men) in the AS group, and 11 patients (eight men) in the NS group. Eleven patients detected abnormal focal signals in the presurgical MRI. Six patients in the PS group demonstrated the suspected focal cortical dysplasia (FCD) in the SFS detected with MRI. All patients demonstrated focal abnormal hypometabolism foci in the PET-MR co-registration. Twenty-five patients (80.6%) were seizure-free since surgery, including all 15 patients (100%) of the PS group, three in five patients (60%) of the AS group, and seven in 11 patients (63.6%) of the NS group. The difference in outcome between different groups was significant (p = 0.004, PS vs. AS group; p = 0.005, PS vs. NS group). As of the last follow-up (mean 66.2 ± 9.7months), 25 patients (80.6%) were seizure-free since surgery (Engel's class I). In addition, antiseizure medication was withdrawn in 19 patients (61.3%). Histologic examination of resected specimens revealed FCD in all 31 patients. The percentage of FCD II type was 100, 60, and 63.6% in the three different groups, respectively.

SFS-related dysplasia is a neuropathologic entity with a favorable postoperative outcome. FCD II is the most common type of SFS-related dysplasia. FDG-PET co-registered with MRI should be performed in patients with suspected SFS-related dysplasia, since it may depict areas of hypometabolism suggestive of dysplasia in the absence of MRI abnormalities.

The authors investigated alterations in functional connectivity (FC) and EEG power during ictal onset patterns of low-voltage fast activity (LVFA) in drug-resistant focal epilepsy. They hypothesized that such changes would be useful to classify epilepsy surgical outcomes.

In a cohort of 79 patients with drug-resistant focal epilepsy who underwent stereoelectroencephalography (SEEG) evaluation as well as resective surgery, FC changes during the peri-LVFA period were measured using nonlinear regression (h2) and power spectral properties within/between three regions: the seizure onset zone (SOZ), early propagation zone (PZ), and noninvolved zone (NIZ). Desynchronization and power desynchronization h2 indices were calculated to assess the degree of EEG desynchronization during LVFA. Multivariate logistic regression was employed to control for confounding factors. Finally, receiver operating characteristic curves were generated to evaluate the performance of desynchronization indices in predicting surgical outcome.

Fifty-three patients showed ictal LVFA and distinct zones of the SOZ, PZ, and NIZ. Among them, 39 patients (73.6%) achieved seizure freedom by the final follow-up. EEG desynchronization, measured by h2 analysis, was found in the seizure-free group during LVFA: FC decreased within the SOZ and between regions compared with the pre-LVFA and post-LVFA periods. In contrast, the non-seizure-free group showed no prominent EEG desynchronization. The h2 desynchronization index, but not the power desynchronization index, enabled classification of seizure-free versus non-seizure-free patients after resective surgery.

EEG desynchronization during the peri-LVFA period, measured by within-zone and between-zone h2 analysis, may be helpful for identifying patients with favorable postsurgical outcomes and also may potentially improve epileptogenic zone identification in the future.