Fully automatic segmentation of brain lacunas resulting from resective surgery using a 3D deep learning model.

The rapid and constant development of deep learning (DL) strategies is pushing forward the quality of object segmentation in images from diverse fields of interest. In particular, these algorithms can be very helpful in delineating brain abnormalities (lesions, tumors, lacunas, etc), enabling the extraction of information such as volume and location, that can inform doctors or feed predictive models. In this study, we describe ResectVol DL, a fully automatic tool developed to segment resective lacunas in brain images of patients with epilepsy. ResectVol DL relies on the nnU-Net framework that leverages the 3D U-Net deep learning architecture. T1-weighted MRI datasets from 120 patients (57 women; 31.5 ± 15.9 years old at surgery) were used to train (n=78) and test (n=48) our tool. Manual segmentations were carried out by five different raters and were considered as ground truth for performance assessment. We compared ResectVol DL with two other fully automatic methods: ResectVol 1.1.2 and DeepResection, using the Dice similarity coefficient (DSC), Pearson's correlation coefficient, and relative difference to manual segmentation. ResectVol DL presented the highest median DSC (0.92 vs. 0.78 and 0.90), the highest correlation coefficient (0.99 vs. 0.63 and 0.94) and the lowest median relative difference (9 vs. 44 and 12 %). Overall, we demonstrate that ResectVol DL accurately segments brain lacunas, which has the potential to assist in the development of predictive models for postoperative cognitive and seizure outcomes.

Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: Insights into pathophysiology and tissue characterization.

Introduction: Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. Methods: We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. Results: We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Discussion: Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

The Relationship Between Depression and Anxiety Symptoms of Adult PWE and Caregivers in a Tertiary Center.

Background: Although several studies have emphasized the association between epilepsy and psychiatric disorders, fewer have investigated the impact of epilepsy on caregivers' emotional status, mainly in adult people with epilepsy (PWE). Here we investigated depressive symptoms, suicidal ideation, and anxiety symptoms in a large group of adult PWE and their caregivers. Methods: We analyzed symptoms of depression [with the Beck Depression Inventory-II (BDI-II)], suicidal ideation (with BDI-II item 9), and anxiety symptoms (with the Beck Anxiety Inventory) in a large group of adult PWE [N = 548 (60% women; median age 41)] and caregivers [N = 191 (72% women; median age 47)] from a Brazilian tertiary center, considering sociodemographic and clinical aspects. We also applied the Liverpool Adverse Events Profile to assess anti-seizure drugs adverse events. Results: While the presence (p = 0.026) (and intensity, p = 0.007) of depressive symptoms and suicidal ideation (p = 0.02) were higher in PWE compared to caregivers, the proportion of clinical anxiety symptoms (p = 0.32) (and the intensity, p = 0.13) was similar in both groups. Although the rates of suicidal ideation were higher in focal epilepsy (20%), both generalized genetic epilepsy and caregivers also presented elevated frequencies (11%) of suicidal ideation. The analyses of 120 patient-caregiver dyads revealed that the intensity of depressive symptoms in PWE (but not anxiety) correlated with the intensity of depressive (r = 0.35; p < 0.001) and anxiety (r = 0.25; p = 0.01) symptoms in their caregivers. In the multivariate analyses of PWE, focal epilepsy (compared to GGE) was associated with clinical depressive symptoms (odds ratio, OR 2.1) and suicidal ideation (OR 3.2), while recurrent seizures (compared to the seizure-free group) were associated with suicidal ideation (OR 2.6) and anxiety symptoms (OR 2.1). Also, caregivers with anxiety symptoms were 8 times more likely to exhibit depressive symptoms, and those with depressive symptoms were 8 times more likely to present anxiety symptoms. Conclusion: Our study suggests that specific attention for the caregivers' mental health is as essential as PWE. There is an urgent need for more studies involving caregivers to identify their emotional distress and provide adequate treatment.

Interictal and postictal 18F-FDG PET/CT in epileptogenic zone localization.

Objective: To evaluate the performance of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography ( 18F-FDG PET/CT) in localizing epileptogenic zones, comparing 18F-FDG injection performed in the traditional interictal period with that performed near the time of a seizure. Materials and Methods: We evaluated patients with refractory epilepsy who underwent 18F-FDG PET/CT. The reference standards for localization of the epileptogenic zone were histopathology and follow-up examinations (in patients who underwent surgery) or serial electroencephalography (EEG) recordings, long-term video EEG, and magnetic resonance imaging (in patients who did not). The 18F-FDG injection was performed whether the patient had an epileptic seizure during the EEG monitoring period or not. The 18F-FDG PET/CT results were categorized as concordant or discordant with the reference standards. Results: Of the 110 patients evaluated, 10 were in a postictal group (FDG injection after a seizure) and 100 were in the interictal group. The 18F-FDG PET/CT was concordant with the reference standards in nine (90%) of the postictal group patients and in 60 (60%) of the interictal group patients. Among the nine postictal group patients in whom the results were concordant, the 18F-FDG PET/CT showed hypermetabolism and hypometabolism in the epileptogenic zone in four (44.4%) and five (55.6%), respectively. Conclusion: Our data indicate that 18F-FDG PET/CT is a helpful tool for localization of the epileptogenic zone and that EEG monitoring is an important means of correlating the findings. In addition, postictal 18F-FDG PET/CT is able to identify the epileptogenic zone by showing either hypometabolism or hypermetabolism.

Objetivo: Avaliar a capacidade da PET/CT FDG detectar a zona epileptogênica, com injeção da FDG realizada tanto no período interictal como perto de uma crise epiléptica. Materiais e Métodos: Foram avaliados pacientes com epilepsia de difícil controle que realizaram PET/CT FDG. A zona epileptogênica foi definida pelo follow up/anatomopatológico ou eletroencefalogramas (EEGs) seriados, telemetria e ressonância magnética. PET/CT FDG foi realizada independentemente se o paciente tinha crise epiléptica durante a monitoração com EEG ou no período interictal. Os resultados foram definidos como concordantes ou discordantes, comparando com a zona epileptogênica. Resultados: Foram incluídos no estudo 110 pacientes: 10 no grupo pós-ictal (injeção de FDG depois da crise) e 100 no grupo interictal. A PET/CT FDG foi concordante com a zona epileptogênica em nove pacientes do grupo pós-ictal (90%) e 60 pacientes do grupo interictal (60%). Entre os nove pacientes concordantes do grupo pós-ictal, quatro mostraram hipermetabolismo (44,4%) e cinco mostraram hipometabolismo na zona epileptogênica (55,6%). Conclusão: Nossos resultados confirmaram que a PET/CT FDG é uma ferramenta útil na localização da zona epileptogênica e a monitoração com EEG é muito importante para correlacionar os achados. Além disso, PET/CT FDG realizada no período pós-ictal é capaz de identificar a zona epileptogênica, mostrando tanto hipometabolismo como hipermetabolismo.

Histopathological Correlations of Qualitative and Quantitative Temporopolar MRI Analyses in Patients With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is a common cause of pharmacoresistant focal epilepsy. Here, we (1) performed a histological approach to the anterior temporal pole of patients with HS to evaluate cortical and white matter (WM) cell populations, alteration of myelin integrity and markers of neuronal activity, and (2) correlated microscopic data with magnetic resonance imaging (MRI) findings. Our aim was to contribute with the understanding of neuroimaging and pathophysiological mechanisms of temporal lobe epilepsy (TLE) associated with HS. We examined MRIs and surgical specimens from the anterior temporal pole from TLE-HS patients (n = 9) and compared them with 10 autopsy controls. MRIs from healthy volunteers (n = 13) were used as neuroimaging controls. Histological techniques were performed to assess oligodendrocytes, heterotopic neurons, cellular proliferative index, and myeloarchitecture integrity of the WM, as well as markers of acute (c-fos) and chronic (ΔFosB) activities of neocortical neurons. Microscopic data were compared with neuroimaging findings, including T2-weighted/FLAIR MRI temporopolar blurring and values of fractional anisotropy (FA) from diffusion-weighed imaging (DWI). We found a significant increase in WM oligodendrocyte number, both in hematoxylin and eosin, and in Olig2-stained sections. The frequencies of oligodendrocytes in perivascular spaces and around heterotopic neurons were significantly higher in patients with TLE-HS compared with controls. The percentage of 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase; a marker of myeloarchitecture integrity) immunopositive area in the WM was significantly higher in TLE-HS, as well as the numbers of c-fos- and ΔFosB-immunostained neocortical neurons. Additionally, we demonstrated a decrease in axonal bundle integrity on neuroimaging, with a significant reduction in the FA in the anterior temporal pole. No differences were detected between individuals with and without temporopolar blurring on visual MRI analysis, considering the number of oligodendroglial cells and percentage of WM CNPase-positive areas. Also, there was no relationship between T2 relaxometry and oligodendrocyte count. In conclusion, our histopathological data support the following: (1) the hypothesis that repetitive neocortical neuronal activity could induce changes in the WM cellular constitution and myelin remodeling in the anterior temporal pole from patients with TLE-HS, (2) that oligodendroglial hyperplasia is not related to temporal blurring or T2 signal intensity on MRI, and (3) that reduced FA is a marker of increase in Olig2-immunopositive cells in superficial temporopolar WM from patients with TLE-HS.

HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction.

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.

Interictal and postictal 18F-FDG PET/CT in epileptogenic zone localization / PET/CT FDG- 18F interictal e pós-ictal na localização da zona epileptogênica

Abstract Objective: To evaluate the performance of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography ( 18F-FDG PET/CT) in localizing epileptogenic zones, comparing 18F-FDG injection performed in the traditional interictal period with that performed near the time of a seizure. Materials and Methods: We evaluated patients with refractory epilepsy who underwent 18F-FDG PET/CT. The reference standards for localization of the epileptogenic zone were histopathology and follow-up examinations (in patients who underwent surgery) or serial electroencephalography (EEG) recordings, long-term video EEG, and magnetic resonance imaging (in patients who did not). The 18F-FDG injection was performed whether the patient had an epileptic seizure during the EEG monitoring period or not. The 18F-FDG PET/CT results were categorized as concordant or discordant with the reference standards. Results: Of the 110 patients evaluated, 10 were in a postictal group (FDG injection after a seizure) and 100 were in the interictal group. The 18F-FDG PET/CT was concordant with the reference standards in nine (90%) of the postictal group patients and in 60 (60%) of the interictal group patients. Among the nine postictal group patients in whom the results were concordant, the 18F-FDG PET/CT showed hypermetabolism and hypometabolism in the epileptogenic zone in four (44.4%) and five (55.6%), respectively. Conclusion: Our data indicate that 18F-FDG PET/CT is a helpful tool for localization of the epileptogenic zone and that EEG monitoring is an important means of correlating the findings. In addition, postictal 18F-FDG PET/CT is able to identify the epileptogenic zone by showing either hypometabolism or hypermetabolism.

Resumo Objetivo: Avaliar a capacidade da PET/CT FDG detectar a zona epileptogênica, com injeção da FDG realizada tanto no período interictal como perto de uma crise epiléptica. Materiais e Métodos: Foram avaliados pacientes com epilepsia de difícil controle que realizaram PET/CT FDG. A zona epileptogênica foi definida pelo follow up/anatomopatológico ou eletroencefalogramas (EEGs) seriados, telemetria e ressonância magnética. PET/CT FDG foi realizada independentemente se o paciente tinha crise epiléptica durante a monitoração com EEG ou no período interictal. Os resultados foram definidos como concordantes ou discordantes, comparando com a zona epileptogênica. Resultados: Foram incluídos no estudo 110 pacientes: 10 no grupo pós-ictal (injeção de FDG depois da crise) e 100 no grupo interictal. A PET/CT FDG foi concordante com a zona epileptogênica em nove pacientes do grupo pós-ictal (90%) e 60 pacientes do grupo interictal (60%). Entre os nove pacientes concordantes do grupo pós-ictal, quatro mostraram hipermetabolismo (44,4%) e cinco mostraram hipometabolismo na zona epileptogênica (55,6%). Conclusão: Nossos resultados confirmaram que a PET/CT FDG é uma ferramenta útil na localização da zona epileptogênica e a monitoração com EEG é muito importante para correlacionar os achados. Além disso, PET/CT FDG realizada no período pós-ictal é capaz de identificar a zona epileptogênica, mostrando tanto hipometabolismo como hipermetabolismo.