Multimodal wearable EEG, EMG and accelerometry measurements improve the accuracy of tonic-clonic seizure detection.

Objective. This paper aims to investigate the possibility of detecting tonic-clonic seizures (TCSs) with behind-the-ear, two-channel wearable electroencephalography (EEG), and to evaluate its added value to non-EEG modalities in TCS detection.Methods. We included 27 participants with a total of 44 TCSs from the European multicenter study SeizeIT2. The wearable Sensor Dot (Byteflies) was used to measure behind-the-ear EEG, electromyography (EMG), electrocardiography, accelerometry (ACC) and gyroscope. We evaluated automatic unimodal detection of TCSs, using sensitivity, precision, false positive rate (FPR) and F1-score. Subsequently, we fused the different modalities and again assessed performance. Algorithm-labeled segments were then provided to two experts, who annotated true positive TCSs, and discarded false positives.Results. Wearable EEG outperformed the other single modalities with a sensitivity of 100% and a FPR of 10.3/24 h. The combination of wearable EEG and EMG proved most clinically useful, delivering a sensitivity of 97.7%, an FPR of 0.4/24 h, a precision of 43%, and an F1-score of 59.7%. The highest overall performance was achieved through the fusion of wearable EEG, EMG, and ACC, yielding a sensitivity of 90.9%, an FPR of 0.1/24 h, a precision of 75.5%, and an F1-score of 82.5%.Conclusions. In TCS detection with a wearable device, combining EEG with EMG, ACC or both resulted in a remarkable reduction of FPR, while retaining a high sensitivity.Significance. Adding wearable EEG could further improve TCS detection, relative to extracerebral-based systems.

Characterization and quantification of epilepsy patients with hospital episodes in Portugal: A multicenter retrospective study from Liga Portuguesa Contra a Epilepsia.

INTRODUCTION: Epilepsy affects around 50 million people worldwide and is associated with lower quality of life scores, an increased risk of premature death, and significant socio-economic implications. The lack of updated evidence on current epidemiology and patient characterization creates considerable uncertainty regarding the epilepsy burden in Portugal. The study aims to characterize and quantify the epilepsy patients who have been hospitalized, with medical or surgical procedures involved, and to analyze their associated comorbidities and mortality rates. METHODS: A multicenter retrospective study was conducted using hospital production data of epilepsy patients. The study included all patients diagnosed with epilepsy-related International Classification of Diseases-9/10 codes between 2015 and 2018 in 57 Portuguese National Health Service (NHS) hospitals (n = 57 institutions). Patient characterization and quantification were done for all patients with an epilepsy diagnosis, with specific analyses focusing on those whose primary diagnosis was epilepsy. Baseline, demographic, and clinical characteristics were analyzed using descriptive statistics. RESULTS: Between 2015 and 2018, a total of 80,494 hospital episodes (i.e., patient visit that generates hospitalization and procedures) were recorded, with 18 % to 19 % directly related to epilepsy. Among these epilepsy-related hospital episodes, 13.0 % led to short term hospitalizations (less than 24 h). Additionally, the average length of stay for all these epilepsy-related episodes was 8 days. A total of 49,481 patients were identified with epilepsy based on ICD-9/10 codes. The median age of patients was 64 years (min: 0; max: 104), with a distribution of 4.8 patients per 1,000 inhabitants. From the total of deaths (9,606) between 2015 and 2018, 14% were associated with patients whose primary diagnosis was epilepsy, with 545 of these being epilepsy-related deaths. Among patients with a primary diagnosis of epilepsy, the most common comorbidities were hypertension (24%) and psychiatric-related or similar comorbidities (15%), such as alcohol dependance, depressive and major depressive disorders, dementia and other convulsions. CONCLUSION: This study showed similar results to other European countries. However, due to methodological limitations, a prospective epidemiological study is needed to support this observation. Furthermore, the present study provides a comprehensive picture of hospitalized epilepsy patients in Portugal, their comorbidities, mortality, and hospital procedures.

The Effect of N-Carbamylglutamate Supplementation during the Last Third of Gestation on the Growth and Development of Fetuses Born to Nutrient-Restricted Twin-Bearing Ewes.

N-carbamylglutamate (NCG) is postulated to improve fetal growth in nutrient-restricted gestations when supplemented from day 35 to 110 of gestation, but the effects of supplementation from 100 days of gestation to birth have not been evaluated. The aim of this study was to evaluate the effect of oral NCG supplementation from 100 days of gestation (dga) to term in naturally nutrient-restricted grazing twin-bearing ewes, on the maternal body weight (BW), body condition score (BCS), placental morphology, fetal body and organ weights and blood biochemistry and antioxidant status in the ewe and fetuses. Eighteen twin-bearing ewes maintained under grazing management were randomly allocated to either a treatment group (NCG; n = 10), orally dosed once daily with 60 mg/kg of NCG from day 100 until 140 dga, or an unsupplemented control group (CON; n = 8). At 140 dga, blood gases, redox status, maternal and fetal plasma and fetal biometrics were obtained after caesarian section. The serum concentration of NCG was increased 15-fold in the NCG ewes compared to the CON. No major effects on dam or fetal body weight nor on blood biochemistry or antioxidant parameters were observed. These results indicate that NCG supplementation in mid-to-late gestation to grazing ewes was unable to rescue the negative production effects of severe natural nutritional restriction on both the dam and fetuses.

Chronic Undernutrition in Ovine Twin Pregnancies Abolishes Differences in Birth Weight Due to Sex: An Evaluation of the Role of Nutritional and Antioxidant Supplementation.

In twin pregnancies of discordant sex, the male fetus grows larger than the female co-twin. Our study aimed to determine the effect of the sex of co-twins on lambs' birth weight in ovine pregnancies developed under natural undernourishment. Additionally, we investigated whether the nutritional and/or antioxidant supplementation provided to ewes during pregnancy could modulate the potential effects associated with the sex of co-twins. Ninety-six birth records of twin pregnancies of sheep grazing the natural Patagonian prairies were analyzed. The animals were divided into four groups: control (no supplementation), N (concentrate supplementation, 100% NRC), A (antioxidant supplementation), and NA (concentrate + antioxidant supplementation). Supplementation occurred from day 35 of gestation onwards until lambing. There were no differences in female or male birth weight in the control undernourished group. However, in group N, females or males with sex-discordant co-twins had a higher birth weight than did those with co-twins of the same sex. Group A males with female co-twins had a higher birth weight compared to males whose co-twins were also males. In NA lambs, males had a higher birth weight compared to females, regardless of their co-twin's sex. Therefore, chronic undernutrition abolished the differences in birth weight due to fetal sex. Restoring maternal nutrition or antioxidant supplementation tends to normalize birth weight and restore the differences between females and males. This effect is enhanced with the combined supplementation of concentrated food and antioxidants.

Colostrum traits and newborn body weight and growth: comparison between single and twin underfed sheep pregnancies.

Maternal nutrition during gestation plays an important role in colostrum production, postnatal growth, and survival of newborn lambs, especially in twin gestations. This research aimed to investigate the effects of chronic natural undernutrition on colostrum traits and early lamb's postnatal growth born from single and twin sheep pregnancies developed in a restrictive prairie, representative of southern Patagonia. Single- and twin-bearing ewes (n = 20 per group) were maintained grazing in a natural pasture. At 140 days of gestation, ewes were placed in individual pens for lambing control. Colostrum was collected immediately after delivery and at 12, 24, and 36 h postpartum, for determination of yield and composition. Maternal blood was obtained at 140 days of gestation and at lambing for plasma glucose, progesterone, 17ß-estradiol, and IgG determination. Newborn lamb blood for determining glycaemia and IgG was collected at birth and at 12, 24, 36, and 120 h after birth. Lamb mortality and growth was assessed from birth until 30 days of life. No differences were observed in progesterone and 17ß-estradiol. There were no differences in colostrum yields and fat components, however single- had higher values of protein and lactose than twin-bearing ewes (p < 0.05 for both). Singletons had higher glycaemia than twins at 12 h postpartum (102.2 ± 32.8 vs. 73.4 ± 29.9 mg/dL, p < 0.05). Colostrum IgG content was similar at delivery but higher in single ewes at 12 and 24 h, reaching a similar values at 36 h (4.7 ± 9.7 and 5.8 ± 7.7 mg/mL in single and twin pregnancies, respectively). Newborn IgG was higher in singletons compared to twins at least until 48 h of life. Lams body weight was always superior in singleton than twins from birth until 30 days of life. Mortality did not differ during the first week of life, but it increased significantly only in twins until day 30 of life. Undernourishment in pregnant ewes affected colostrum quantity and quality, resulting in a lower postnatal growth and a higher mortality in twins. Alternative managements favoring fetal growth, birth weight and neonatal viability in twin sheep pregnancies are needed, when flocks are breed under harsh environments.

Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.

The goal of explaining black boxes in EEG seizure prediction is not to explain models' decisions.

Many state-of-the-art methods for seizure prediction, using the electroencephalogram, are based on machine learning models that are black boxes, weakening the trust of clinicians in them for high-risk decisions. Seizure prediction concerns a multidimensional time-series problem that performs continuous sliding window analysis and classification. In this work, we make a critical review of which explanations increase trust in models' decisions for predicting seizures. We developed three machine learning methodologies to explore their explainability potential. These contain different levels of model transparency: a logistic regression, an ensemble of 15 support vector machines, and an ensemble of three convolutional neural networks. For each methodology, we evaluated quasi-prospectively the performance in 40 patients (testing data comprised 2055 hours and 104 seizures). We selected patients with good and poor performance to explain the models' decisions. Then, with grounded theory, we evaluated how these explanations helped specialists (data scientists and clinicians working in epilepsy) to understand the obtained model dynamics. We obtained four lessons for better communication between data scientists and clinicians. We found that the goal of explainability is not to explain the system's decisions but to improve the system itself. Model transparency is not the most significant factor in explaining a model decision for seizure prediction. Even when using intuitive and state-of-the-art features, it is hard to understand brain dynamics and their relationship with the developed models. We achieve an increase in understanding by developing, in parallel, several systems that explicitly deal with signal dynamics changes that help develop a complete problem formulation.

Unsupervised EEG preictal interval identification in patients with drug-resistant epilepsy.

Typical seizure prediction models aim at discriminating interictal brain activity from pre-seizure electrographic patterns. Given the lack of a preictal clinical definition, a fixed interval is widely used to develop these models. Recent studies reporting preictal interval selection among a range of fixed intervals show inter- and intra-patient preictal interval variability, possibly reflecting the heterogeneity of the seizure generation process. Obtaining accurate labels of the preictal interval can be used to train supervised prediction models and, hence, avoid setting a fixed preictal interval for all seizures within the same patient. Unsupervised learning methods hold great promise for exploring preictal alterations on a seizure-specific scale. Multivariate and univariate linear and nonlinear features were extracted from scalp electroencephalography (EEG) signals collected from 41 patients with drug-resistant epilepsy undergoing presurgical monitoring. Nonlinear dimensionality reduction was performed for each group of features and each of the 226 seizures. We applied different clustering methods in searching for preictal clusters located until 2 h before the seizure onset. We identified preictal patterns in 90% of patients and 51% of the visually inspected seizures. The preictal clusters manifested a seizure-specific profile with varying duration (22.9 ± 21.0 min) and starting time before seizure onset (47.6 ± 27.3 min). Searching for preictal patterns on the EEG trace using unsupervised methods showed that it is possible to identify seizure-specific preictal signatures for some patients and some seizures within the same patient.

Resective Epilepsy Surgery and Respective Histopathological Diagnoses: A Retrospective Cohort Study.

INTRODUCTION: Over recent decades, brain resection for drug-resistant epilepsy has proven to be a valuable treatment option. The histopathological classification was of paramount value for patient management. The aims of this study were to characterize our resective epilepsy surgical series including the histopathological diagnoses and to understand the differences in clinical practice between two different periods of our epilepsy surgical programme. MATERIAL AND METHODS: We performed a retrospective cohort study, including patients with drug-resistant epilepsy that underwent resective surgery between 1997 and 2021 in the Coimbra University Hospital Centre. Histopathological diagnoses were classified into seven major conventional categories. For comparison purposes, the cohort was divided into two consecutive periods of 12 years. RESULTS: A total of 259 patients were included, from which 228 (88%) were adults at the time of surgery. The median disease duration prior to surgery was 14 (interquartile range 23) years. Fifty-five (21%) patients performed pre-surgical invasive work-up. The temporal lobe was the most frequently operated region (73%). Major and minor post-surgical complications were identified in 21 (8%) patients. A reduction in the number of antiepileptic drugs was possible in 96 (37%) patients after surgery. The most common histopathological diagnosis was hippocampal sclerosis, but among children it was long-term epilepsy associated tumour. Long-term epilepsy associated tumours, hippocampal sclerosis and vascular malformations had the best post-operative outcomes. Malformations of cortical development and glial scars had the worst outcomes. Regarding differences between the two periods, the absolute number of operated patients increased (119 versus 140), and the age at surgery was higher in the second period (p = 0.04). The number of malformations of cortical development increased (p = 0.01), but the number of other tumours (p = 0.01) and specimens with no lesion (p = 0.03) decreased in the same period. CONCLUSION: This study is in line with contemporaneous research, reinforcing the previous knowledge on the underlying structural aetiologies, clinical practice, and surgical outcomes over more than two decades of experience. Our data provide realistic expectations about epilepsy surgery and highlight the need for further improvements in diagnosis and treatment paradigm for people with chronic epilepsy.

Introdução: Nas últimas décadas, a cirurgia ressectiva demonstrou ser uma opção valiosa no tratamento da epilepsia farmacorresistente. A classificação histopatológica foi de grande importância na orientação do doente. Os objetivos deste estudo foram caracterizar a nossa série de cirurgia de epilepsia ressectiva incluindo os diagnósticos histopatológicos, e compreender as diferenças na prática clínica entre dois períodos diferentes do programa de cirurgia da epilepsia. Material e Métodos: Realizou-se um estudo de coorte retrospetivo, incluindo doentes com epilepsia farmacorresistente submetidos a cirurgia ressectiva entre 1997 e 2021 no Centro Hospitalar e Universitário de Coimbra. Os diagnósticos histopatológicos foram classificados em sete categorias. Para análise comparativa, a coorte foi dividida em dois períodos consecutivos de 12 anos. Resultados: Um total de 259 doentes foram incluídos, sendo 228 (88%) adultos aquando da cirurgia. A mediana da duração da doença antes da cirurgia foi de 14 (amplitude interquartil 23) anos. Cinquenta e cinco (21%) doentes realizaram investigação invasiva pré-cirúrgica. O lobo temporal foi a região mais frequentemente operada (73%). Complicações pós-cirúrgicas major e minor foram identificadas em 21 (8%) doentes. Uma redução no número de antiepiléticos foi observada em 96 (37%) doentes após a cirurgia. O diagnóstico histopatológico mais comum foi a esclerose do hipocampo, mas nas crianças foi o tumor associado a epilepsia de longa duração. Tumores associados a epilepsia de longa duração, esclerose do hipocampo e malformações vasculares tiveram os melhores resultados pós-operatórios. Malformações do desenvolvimento cortical e cicatrizes gliais tiveram os piores resultados. Relativamente às diferenças entre os dois períodos, o número absoluto de doentes operados aumentou (119 versus 140), e a idade aquando da cirurgia foi maior no segundo período (p = 0,04). O número de malformações do desenvolvimento cortical aumentou (p = 0,01), mas o número de outros tumores (p = 0,01) e amostras sem lesão (p = 0,03) diminuiu no mesmo período. Conclusão: Este estudo está de acordo com a literatura atual, reforçando o conhecimento prévio sobre as etiologias estruturais, prática clínica e resultados cirúrgicos ao longo de mais de duas décadas de experiência. Os dados analisados fornecem expectativas realistas sobre a cirurgia de epilepsia e destacam a necessidade de melhorias no paradigma de diagnóstico e tratamento destes doentes.

The Challenge of Somatic Variants in Focal Cortical Dysplasia.

Objective: The advent of next-generation sequencing (NGS) enabled the detection of low-level brain somatic variants in postsurgical tissue of focal cortical dysplasia (FCD). The genetic background of FCD Type I remains elusive, while the mammalian target of rapamycin (mTOR) pathway seems to have a relevant role in the pathogenesis of FCD Type II. Our goal was to uncover information on the molecular basis of FCD, performing whole genome sequencing (WGS) in postsurgical tissue to detect candidate brain-specific somatic variants, and evaluate their clinical significance. Design: WGS was performed using paired peripheral venous blood and postsurgical pathological brain deoxyribonucleic acid (DNA) samples. Libraries were prepared using the Roche KAPA HyperPrep polymerase chain reaction (PCR) free library preparation kit. Paired-end 150bp reads were generated on the Illumina NovaSeq platform. The FASTQ files were processed using the nf-core sarek pipeline (version 3.0) to call somatic variants, which were then annotated with ANNOVAR. A screening strategy was applied to obtain relevant variants. Results: Two female patients with drug-resistant epilepsy due to FCD who underwent surgical treatment were included. Regarding neuropathological diagnosis, one patient had FCD Type Ia and the other had FCD Type IIa. Five somatic nonsynonymous single nucleotide variants (SNVs) were detected using WGS, three in FCD Ia tissue (WDR24 p.Trp259Gly; MICAL1 p.Lys1036Arg; and KATNB1 p.Leu566Ile) and two in FCD IIa tissue (MATN4 p.Phe91Val and ANKRD6 p.His386Gln). All variants were predicted to be potentially pathogenic by at least two different tools. However, they were classified as variants of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG) criteria. Conclusion: Brain-specific somatic missense variants were identified by NGS in new candidate genes (WDR24, MICAL1, KATNB1, MATN4, and ANKRD6) using postsurgical FCD tissue, which may contribute to further understanding of the genetic background of FCD. All the reported genes were previously related to epilepsy and/or malformations of central nervous system (CNS) and cortical development. However, the pathogenicity assessment of these variants and, consequently, their impact on clinical practice still poses an important challenge.

Clinical Application of Pharmacokinetics to Appraise Adherence to Levetiracetam in Portuguese Epileptic Patients.

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients' quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000-3000) mg] than non-adherent over-consumers [1500 (1000-2000) mg] and non-adherent under-consumers [2000 (1500-3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33-36.36) mg/L], followed by adherent patients [22.05 (16.62-29.81) mg/L] and non-adherent over-consumers [17.50 (10.69-24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment.

The impact of cathodal tDCS on the GABAergic system in the epileptogenic zone: A multimodal imaging study.

Objectives: We aimed to investigate the antiepileptic effects of cathodal transcranial direct current stimulation (c-tDCS) and mechanisms of action based on its effects on the neurotransmitters responsible for the abnormal synchrony patterns seen in pharmacoresistant epilepsy. This is the first study to test the impact of neurostimulation on epileptiform interictal discharges (IEDs) and to measure brain metabolites in the epileptogenic zone (EZ) and control regions simultaneously in patients with pharmacoresistant epilepsy. Methods: This is a hypothesis-driven pilot prospective single-blinded repeated measure design study in patients diagnosed with pharmacoresistant epilepsy of temporal lobe onset. We included seven patients who underwent two sessions of c-tDCS (sham followed by real). The real tDCS session was 20 min in duration and had a current intensity of 1.5 mA delivered via two surface electrodes that had dimensions of 3 × 4 cm. The cathode electrode was placed at FT7 in the center whereas the anode at Oz in the center. After each session, we performed electroencephalographic recording to count epileptiform IEDs over 30 min. We also performed magnetic resonance spectroscopy (MRS) to measure brain metabolite concentrations in the two areas of interest (EZ and occipital region), namely, gamma-aminobutyric acid (GABA), glutamate (Glx), and glutathione. We focused on a homogenous sample where the EZ and antiepileptic medications are shared among patients. Results: Real tDCS decreased the number of epileptiform IEDs per min (from 9.46 ± 2.68 after sham tDCS to 5.37 ± 3.38 after real tDCS), p = 0.018, as compared to sham tDCS. GABA was decreased in the EZ after real c-tDCS stimulation as compared to sham tDCS (from 0.129 ± 0.019 to 0.096 ± 0.018, p = 0.02). The reduction in EZ GABA correlated with the reduction in the frequency of epileptiform IED per min (rho: 0.9, p = 0.003). Conclusion: These results provide a window into the antiepileptic mechanisms of action of tDCS, based on local and remote changes in GABA and neural oscillatory patterning responsible for the generation of interictal epileptiform discharges.

The landscape of common genetic drivers and DNA methylation in low-grade (epilepsy-associated) neuroepithelial tumors: A review.

Low-grade neuroepithelial tumors (LNETs) represent an important group of central nervous system neoplasms, some of which may be associated to epilepsy. The concept of long-term epilepsy-associated tumors (LEATs) includes a heterogenous group of low-grade, cortically based tumors, associated to drug-resistant epilepsy, often requiring surgical treatment. LEATs entities can sometimes be poorly discriminated by histological features, precluding a confident classification in the absence of additional diagnostic tools. This study aimed to provide an updated review on the genomic findings and DNA methylation profiling advances in LNETs, including histological entities of LEATs. A comprehensive search strategy was conducted on PubMed, Embase, and Web of Science Core Collection. High-quality peer-reviewed original manuscripts and review articles with full-text in English, published between 2003 and 2022, were included. Results were screened based on titles and abstracts to determine suitability for inclusion, and when addressed the topic of the review was screened by full-text reading. Data extraction was performed through a qualitative content analysis approach. Most LNETs appear to be driven mainly by a single genomic abnormality and respective affected signaling pathway, including BRAF p.V600E mutations in ganglioglioma, FGFR1 abnormalities in dysembryoplastic neuroepithelial tumor, MYB alterations in angiocentric glioma, BRAF fusions in pilocytic astrocytoma, PRKCA fusions in papillary glioneuronal tumor, between others. However, these molecular alterations are not exclusive, with some overlap amongst different tumor histologies. Also, clustering analysis of DNA methylation profiles allowed the identification of biologically similar molecular groups that sometimes transcend conventional histopathological classification. The exciting developments on the molecular basis of these tumors reinforce the importance of an integrative histopathological and (epi)genetic classification, which can be translated into precision medicine approaches.

Oxidative Stress and Fetal Growth Restriction Set Up Earlier in Undernourished Sheep Twin Pregnancies: Prevention with Antioxidant and Nutritional Supplementation.

Hypoxemia and oxidative stress, resulting in intrauterine growth restriction (IUGR) in undernourished twin sheep pregnancies, has been described in near-term studies. Our aim was to evaluate if the counteractive effects of maternal nutritional or antioxidant supplementation on the fetal redox status were evident before the accelerated fetal growth phase. Forty twin-bearing ewes grazing on natural Patagonian prairie were randomly assigned to four groups (n = 10 each; P: control ewes consuming mainly natural pasture; P+A: pasture plus antioxidants; P+C: pasture plus concentrate; P+A+C: pasture plus antioxidants and concentrate). Daily herbal antioxidants were supplemented in a feedstuff concentrate as a premix from day 35 until day 100 of gestation, when fetal venous cord blood samples and biometric measurements were obtained via cesarean section. The fetuses from group P were clearly hypoxemic. An analysis of variance showed that maternal antioxidant supplementation showed a trend of increased PO2, SatHb, and Ht, effects not observed in P+C fetuses. Antioxidants decreased the fetal MDA concentration (p < 0.05). Fetal TAC was increased by the antioxidants and concentrate (p < 0.05). Antioxidant supplementation showed a trend to increase fetal body weight but not biometry. The results suggest that negative effects of oxidative stress occur earlier than the overt growth arrest, and the maternal administration of antioxidants may constitute a good nutritional strategy for the early prevention of IUGR.

Cytogenomic Analysis of Long-Term Epilepsy-Associated Tumors Using an Array-Based CGH Strategy.

A palette of copy number changes in long-term epilepsy-associated tumors (LEATs) have been reported, but the data are heterogeneous. To better understand the molecular basis underlying the development of LEATs, we performed array-comparative genomic hybridization analysis to investigate chromosomal imbalances across the entire genome in 8 cases of LEATs. A high number of aberrations were found in 4 patients, among which deletions predominated. Both whole-chromosome and regional abnormalities were observed, including monosomy 19, deletion of 1p, deletions of 4p, 12p, and 22q, and gain of 20p. The common altered regions are located mainly on chromosomes 19 and 4p, identifying genes potentially involved in biological processes and cellular mechanisms related to tumorigenesis. Our study highlights new genomic alterations and reinforces others previously reported, offering new molecular insights that may help in diagnosis and therapeutic decision-making.

On the clinical acceptance of black-box systems for EEG seizure prediction.

Seizure prediction may be the solution for epileptic patients whose drugs and surgery do not control seizures. Despite 46 years of research, few devices/systems underwent clinical trials and/or are commercialized, where the most recent state-of-the-art approaches, as neural networks models, are not used to their full potential. The latter demonstrates the existence of social barriers to new methodologies due to data bias, patient safety, and legislation compliance. In the form of literature review, we performed a qualitative study to analyze the seizure prediction ecosystem to find these social barriers. With the Grounded Theory, we draw hypotheses from data, while with the Actor-Network Theory we considered that technology shapes social configurations and interests, being fundamental in healthcare. We obtained a social network that describes the ecosystem and propose research guidelines aiming at clinical acceptance. Our most relevant conclusion is the need for model explainability, but not necessarily intrinsically interpretable models, for the case of seizure prediction. Accordingly, we argue that it is possible to develop robust prediction models, including black-box systems to some extent, while avoiding data bias, ensuring patient safety, and still complying with legislation, if they can deliver human- comprehensible explanations. Due to skepticism and patient safety reasons, many authors advocate the use of transparent models which may limit their performance and potential. Our study highlights a possible path, by using model explainability, on how to overcome these barriers while allowing the use of more computationally robust models.

Intracranial recordings in humans reveal specific hippocampal spectral and dorsal vs. ventral connectivity signatures during visual, attention and memory tasks.

Invasive brain recordings using many electrodes across a wide range of tasks provide a unique opportunity to study the role of oscillatory patterning and functional connectivity. We used large-scale recordings (stereo EEG) within and beyond the human hippocampus to investigate the role of distinct frequency oscillations during real-time execution of visual, attention and memory tasks in eight epileptic patients. We found that activity patterns in the hippocampus showed task and frequency dependent properties. Importantly, we found distinct connectivity signatures, in particular concerning parietal-hippocampal connectivity, thus revealing large scale synchronization of networks involved in memory tasks. Comparing the power per frequency band, across tasks and hippocampal regions (anterior/posterior) we confirmed a main effect of frequency band (p = 0.002). Gamma band activity was higher for visuo-spatial memory tasks in the anterior hippocampus. Further, we found that alpha and beta band activity in posterior hippocampus had larger modulation for high memory load visual tasks (p = 0.004). Three functional connectivity task related networks were identified: (dorsal) parietal-hippocampus (visual attention and memory), ventral stream- hippocampus and hippocampal-frontal connections (mainly tasks involving face recognition or object based search). These findings support the critical role of oscillatory patterning in the hippocampus during visual and memory tasks and suggests the presence of task related spectral and functional connectivity signatures. These results show that the use of large scale human intracranial recordings can validate the role of oscillatory and functional connectivity patterns across a broad range of cognitive domains.

Predictors of seizure freedom, response and retention after 12 months of treatment with eslicarbazepine acetate: A post-hoc analysis of the Euro-Esli study.

Eslicarbazepine acetate (ESL) is a once-daily antiseizure medication (ASM) that is approved in Europe and the USA for the treatment of focal-onset seizures. The Euro-Esli study, which included over 2000 patients, investigated the real-world effectiveness, safety and tolerability of ESL when used in everyday clinical practice in Europe. This post-hoc analysis of Euro-Esli employed univariate and multivariate binary logistic regression analyses to investigate the relationship between demographic and baseline characteristics (including epilepsy- and treatment-related factors) and the likelihood of seizure freedom, response and retention in adult patients with focal seizures after 12 months of ESL treatment in the real-world setting. Multivariate analysis revealed that the factors associated with seizure freedom and response at 12 months (N = 1054) were generally those characterising patients who were relatively early in their disease course and/or less refractory to treatment, such as older age at onset of epilepsy, absence of seizures at baseline and lower number of concomitant ASMs at baseline. Although it was not possible to construct a multivariate model to predict retention on ESL treatment at 12 months, when the univariate regression model was adjusted for age and epilepsy duration, the factors found to be significantly associated with retention at 12 months (N = 1559) comprised shorter duration of epilepsy, absence of any seizures at baseline, lower baseline seizure frequency (<5 vs. ≥ 5 seizures/month), lower number of previous ASMs, lower number of concomitant ASMs, and the absence of concomitant use of lamotrigine at baseline. These findings therefore identify baseline characteristics that are predictive of the effectiveness of ESL treatment in clinical practice, which may help clinicians choose appropriate ASM therapy for patients.

Vitamin D deficiency in a Portuguese epilepsy cohort: who is at risk and how to treat.

The epilepsy-related risk factors for vitamin D deficiency, particularly the use of enzyme-inducing antiepileptic drugs (EIAEDs), and how to treat vitamin D deficiency in patients with epilepsy remain unclear. Our aims were to explore risk factors and the influence of EAIEDs in vitamin D status and to determine the efficacy of a daily dose of oral cholecalciferol (vitamin D3) in epileptic patients with vitamin D deficiency. Clinical data were collected and 25-hydroxyvitamin D (25(OH)D) serum levels were measured. All patients with vitamin D deficiency (25(OH)D ≤20 ng/mL) or insufficiency (25(OH)D from 21-29 ng/mL) were treated with 6,670 IU/day cholecalciferol for eight weeks and 25(OH)D was then remeasured. Descriptive and inferential statistics were employed. A total of 92 patients (44.6% males), with mean age of 41.0±14.8 years, were included. Measurements of 25(OH)D revealed that 79.3% patients had abnormal levels: 56.5% were vitamin D deficient and 22.8% were vitamin D insufficient. The statistically significant risk factors for vitamin D deficiency identified were: number of AEDs, treatment with EIAEDs, low sun exposure, high body mass index (BMI) and a high frequency of epileptic seizures. After treatment, 25(OH)D mean level increased by 98.99% (regardless of EIAED use or being overweight). In our sample, more than half of the adults with epilepsy showed 25(OH)D deficiency. Patients on EIAEDs had lower 25(OH)D levels. A daily dose of 6,670 IU cholecalciferol successfully led to the correction of 25(OH)D levels. A higher dose in obese patients or in patients taking EIAEDs may not be warranted and this should be considered in future guidelines for routine vitamin D deficiency treatment.

Maternal Supplementation with Herbal Antioxidants during Pregnancy in Swine.

The effects of a combined supplementation with herbal antioxidants during pregnancy on reproductive traits and piglet performance (number of live, dead, and mummified newborns and litter weight at birth and individual body weight at both birth and weaning) were assessed in a total of 1027 sows (504 treated and 523 control females) kept under commercial breeding conditions. The supplementation increased the number of live-born piglets (13.64 ± 0.11 vs. 12.96 ± 0.13 in the controls; p = 0.001) and the total litter weight, decreasing the incidence of low-weight piglets without affecting the number of stillbirths and mummified newborns. Such an effect was modulated by the number of parity and the supplementation, with supplementation increasing significantly the number of living newborns in the first, second, sixth, and seventh parities (0.87, 1.10, 1.49, and 2.51 additional piglets, respectively; p < 0.05). The evaluation of plasma vitamin concentration and biomarkers of oxidative stress (total antioxidant capacity, TAC, and malondialdehyde concentration, MDA) performed in a subset of farrowing sows and their lighter and heavier piglets showed that plasma levels of both vitamins were significantly higher in the piglets than in their mothers (p < 0.05 for vitamin C and p < 0.005 for vitamin E), with antioxidant supplementation increasing significantly such concentrations. Concomitantly, there were no differences in maternal TAC but significantly higher values in piglets from supplemented sows (p < 0.05). On the other hand, supplementation decreased plasma MDA levels both in the sows and their piglets (p < 0.05). Finally, the piglets from supplemented mothers showed a trend for a higher weaning weight (p = 0.066) and, specifically, piglets with birth weights above 1 kg showed a 7.4% higher weaning weight (p = 0.024). Hence, the results of the present study, with high robustness and translational value by offering data from more than 1000 pregnancies under standard breeding conditions, supports that maternal supplementation with herbal antioxidants during pregnancy significantly improves reproductive efficiency, litter traits, and piglet performance.