Seizure timing and circadian patterns: a comprehensive bibliographic review / Cronometragem das crises epilépticas e padrões circadianos: uma revisão bibliográfica abrangente

Epilepsy's cyclic nature, increasingly quantified through advancements in continuous electroencephalography (cEEG), reveals robust seizure cycles including circadian, multidien, and circannual rhythms. Understanding these cycles' mechanisms and clinical implications, such as seizure forecasting and optimized treatment timing, is crucial. Despite historical observations, detailed analysis of seizure timing cycles has become feasible only recently, necessitating further research to confirm generalizability and clinical relevance. This paper reviews current literature on circadian rhythms in epilepsy, focusing on temporal seizure patterns and identifying knowledge gaps. A comprehensive review of studies, primarily using PubMed, synthesizes key findings from 20 studies on the temporal dynamics of epileptic activity. Research shows consistent circadian rhythms in seizure activity, with distinct daily peaks. Seizures often follow daily patterns, termed "seizure rush hours," with specific seizure types linked to particular times and influenced by sleep-wake cycles. These findings underscore the importance of understanding temporal patterns in epilepsy. Understanding these rhythms can enhance seizure prediction, diagnosis, and personalized treatment strategies. The significant role of biological rhythms suggests that tailored treatments based on individual circadian profiles could improve patient outcomes and quality of life. Further research is essential to elucidate the mechanisms driving these influences and validate findings across diverse cohorts.

A natureza cíclica da epilepsia, cada vez mais quantificada por meio dos avanços na eletroencefalografia contínua (cEEG), revela ciclos de crises epilépticas (CE) robustos, incluindo ritmos circadianos, multidiários e circanuais. Compreender os mecanismos e as implicações clínicas desses ciclos, como a previsão de CE e a otimização do momento do tratamento, é crucial. Apesar das observações históricas, a análise detalhada dos ciclos de tempo das CE tornou-se viável apenas recentemente, exigindo mais pesquisas para confirmar a generalização e a relevância clínica. Este artigo revisa a literatura atual sobre ritmos circadianos na epilepsia, focando nos padrões temporais das CE e identificando lacunas no conhecimento. Uma revisão abrangente dos estudos, principalmente utilizando o PubMed, sintetiza os principais achados de 20 estudos sobre a dinâmica temporal da atividade epiléptica. A pesquisa mostra ritmos circadianos consistentes na atividade das CE, com picos diários distintos. As CE frequentemente seguem padrões diários, denominados "horários de pico das convulsões" ("seizure rush hours"), com tipos específicos de CE vinculados a determinados horários e influenciados pelos ciclos sono-vigília. Esses achados destacam a importância de entender os padrões temporais na epilepsia. Compreender esses ritmos pode melhorar a previsão, o diagnóstico e as estratégias de tratamento personalizado das CE. O papel significativo dos ritmos biológicos sugere que tratamentos personalizados com base nos perfis circadianos individuais podem melhorar os resultados e a qualidade de vida dos pacientes. Mais pesquisas são essenciais para elucidar os mecanismos que impulsionam essas influências e validar os achados em diversas coortes.

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP.

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Analysis of mechanism of core points in acupuncture and moxibustion treatment for epilepsy based on data mining. / åŸºäºŽæ•°æ®æŒ–æŽ˜æŽ¢è®¨é’ˆç¸æ²»ç–—ç™«ç—«æ ¸å¿ƒç©´ä½çš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To explore the mechanism of core points in acupuncture and moxibustion treatment for epilepsy by using data mining technique, so as to provide a reference for clinical practice and experimental research. METHODS: The data comes from relevant documents collected from CNKI, Wanfang, SinoMed, VIP, PubMed, Embase, Cochrane Library, EBSCO, Web of Science databases. The selected acupoints were analyzed in descriptive statistics, high-frequency acupoints group and core acupoint prescription. Further, potential target mining, "core acupoint prescription-target-epilepsy" network construction, protein-protein interactions (PPI) network establishment and core target extraction, gene ontology (GO) and KEGG gene enrichment analysis of the core acupoint prescription were carried out to predict its anti-epileptic potential mechanism. RESULTS: A total of 122 acupoint prescriptions were included. The core acupoint prescriptions were Baihui (GV20), Hegu (LI4), Neiguan (PC6), Shuigou (GV26) and Taichong (LR3). 277 potential targets were identified, among which 134 were shared with epilepsy. The core targets were extracted by PPI network topology analysis, including signal transducer and activator of transcription 3, tumor necrosis factor (TNF), interleukin (IL)-6, protein kinase B1, c-Jun N-terminal kinase, brain-derived neurotrophic factor, tumor protein 53, vascular endothelial growth factor A, Caspase-3, epidermal growth factor receptor, etc. The main anti-epileptic pathways of the core acupoints were predicted by KEGG enrichment, including lipid and atherosclerosis, neurodegeneration, phosphatidylinositol-3-kinase/protein B kinase signaling pathway, mitogen-activated protein kinase signaling pathway, cyclic adenosine monophosphate signaling pathway, TNF signaling pathway, IL-17 signaling pathway, hypoxia-inducible factor-1 signaling pathway, apoptosis, etc., involving neuronal death, synaptic plasticity, oxidative stress, inflammation and other related biological process. CONCLUSIONS: The core acupoint prescription of acupuncture and moxibustion intervention for epilepsy can act on multiple targets and multiple pathways to exert anti-epileptic effects, which can provide a theoretical basis for further clinical application and mechanism research.

Analysis of the action mechanisms and targets of herbal anticonvulsants highlights opportunities for therapeutic engagement with refractory epilepsy.

Epilepsy is a neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to diverse etiology, pathobiology, and pharmacotherapy-resistant variants. The anticonvulsive effects of herbal leads with biocompatibility and toxicity considerations have attracted much interest, inspiring mechanistic analysis with the view of their use for engagement of new targets and combination with antiseizure pharmacotherapies. This article presents a comprehensive overview of the key molecular players and putative action mechanisms of the most common antiepileptic herbals demonstrated in tissue culture and preclinical models. From the review of the literature, it emerges that their effects are mediated via five distinct mechanisms: (1) reduction of membrane excitability through inhibition of cation channels, (2) improvement of mitochondrial functions with antioxidant effects, (3) enhancement in synaptic transmission mediated by GABAA receptors, (4) improvement of immune response with anti-inflammatory action, and (5) suppression of protein synthesis and metabolism. While some of the primary targets and action mechanisms of herbal anticonvulsants (1, 3) are shared with antiseizure pharmacotherapies, herbal leads also engage with distinct mechanisms (2, 4, and 5), suggesting new drug targets and opportunities for their integration with antiseizure medications. Addressing outstanding questions through research and in silico modeling should facilitate the future use of herbals as auxiliary therapy in epilepsy and guide the development of treatment of pharmacoresistant seizures through rigorous trials and regulatory approval.

EEG changes induced by meditative practices: State and trait effects in healthy subjects and in patients with epilepsy.

The effect of meditation on brain activity has been the topic of many studies in healthy subjects and in patients suffering from chronic diseases. These effects are either explored during meditation practice (state effects) or as a longer-term result of meditation training during the resting-state (trait). The topic of this article is to first review these findings by focusing on electroencephalography (EEG) changes in healthy subjects with or without experience in meditation. Modifications in EEG baseline rhythms, functional connectivity and advanced nonlinear parameters are discussed in regard to feasibility in clinical applications. Secondly, we provide a state-of-the-art of studies that proposed meditative practices as a complementary therapy in patients with epilepsy, in whom anxiety and depressive symptoms are prevalent. In these studies, the effects of standardized meditation programs including elements of traditional meditation practices such as mindfulness, loving-kindness and compassion are explored both at the level of psychological functioning and on the occurrence of seizures. Lastly, preliminary results are given regarding our ongoing study, the aim of which is to quantify the effects of a mindfulness self-compassion (MSC) practice on interictal and ictal epileptic activity. Feasibility, difficulties, and prospects of this study are discussed.

The relationship between medication adherence and complementary medicine use in epilepsy patients.

OBJECTIVE: The aim of this research is to examine the usage of Complementary and Integrated Medicine (CIM) in individuals with epilepsy and the impact of CIM usage on medication adherence. MATERIALS AND METHODS: This descriptive and cross-sectional study was conducted in a university hospital in northern Turkey between July and October 2023, involving 101 individuals with epilepsy (PWE). Descriptive information forms and the Morisky Medication Adherence Scale-4 (MMS-4) were used as data collection tools. Descriptive statistics, t-tests, ANOVA, and post-hoc LSD analyses were employed for data evaluation. RESULTS: The participants consisted of 65.3 % males, 25.7 % were not working due to epilepsy, and 61.4 % with generalized epilepsy. The average MMS-4 score was found to be 3.08 ± 0.96. MMS-4 scores showed significant differences based on epilepsy type (F = 3.998, p = 0.021; η2 = 0.07). 76.2 % (n = 21) of the participants who used at least one CIM technique preferred "having a religious person read a prayer." CONCLUSION: Medication adherence in PWE was at a moderate level. Individuals with focal and secondary generalized epilepsy showed better medication adherence compared to those with generalized types. Of those participant who used at least one CIM technique to improve their general health or control seizures, the most common was "having a religious person read a prayer."

A Zebrafish-Based Platform for High-Throughput Epilepsy Modeling and Drug Screening in F0.

The zebrafish model has emerged as a reference tool for phenotypic drug screening. An increasing number of molecules have been brought from bench to bedside thanks to zebrafish-based assays over the last decade. The high homology between the zebrafish and the human genomes facilitates the generation of zebrafish lines carrying loss-of-function mutations in disease-relevant genes; nonetheless, even using this alternative model, the establishment of isogenic mutant lines requires a long generation time and an elevated number of animals. In this study, we developed a zebrafish-based high-throughput platform for the generation of F0 knock-out (KO) models and the screening of neuroactive compounds. We show that the simultaneous inactivation of a reporter gene (tyrosinase) and a second gene of interest allows the phenotypic selection of F0 somatic mutants (crispants) carrying the highest rates of mutations in both loci. As a proof of principle, we targeted genes associated with neurodevelopmental disorders and we efficiently generated de facto F0 mutants in seven genes involved in childhood epilepsy. We employed a high-throughput multiparametric behavioral analysis to characterize the response of these KO models to an epileptogenic stimulus, making it possible to employ kinematic parameters to identify seizure-like events. The combination of these co-injection, screening and phenotyping methods allowed us to generate crispants recapitulating epilepsy features and to test the efficacy of compounds already during the first days post fertilization. Since the strategy can be applied to a wide range of indications, this study paves the ground for high-throughput drug discovery and promotes the use of zebrafish in personalized medicine and neurotoxicity assessment.

Diet-derived circulating antioxidants and risk of epilepsy: A study combining metabolomics and mendelian randomization.

Background: Previous studies offer inconclusive results on the association between diet-derived circulating antioxidants and epilepsy. Objective: This study aims to assess oxidative stress presence in epilepsy patients' circulation and investigate the causal link between diet-derived circulating antioxidants and epilepsy. Methods: Untargeted metabolomics analysis was conducted on plasma samples from 62 epileptic patients and 20 healthy individuals to evaluate oxidative stress based on metabolite alterations in epilepsy patients' circulation. Two-sample Mendelian Randomization (MR) analysis examined the causation between diet-derived circulating antioxidants (measured by absolute levels and relative metabolite concentrations) and epilepsy, utilizing the inverse-variance weighted (IVW) method as the primary outcome, with complementary MR analysis methods (MR Egger, weighted median, weighted mode, and simple mode). Results: Untargeted metabolomics analysis revealed elevated circulating oxidizing metabolites (palmitic acid, oleic acid, linoleic acid, and myristic acid) and reduced reducing metabolites (glutamine) in epilepsy patients, providing robust evidence of oxidative stress. The IVW analysis indicated significantly reduced epilepsy risk (odds ratio: 0.552; 95% confidence interval: 0.335-0.905, P = 0.018) with genetically determined higher absolute circulating ß-carotene. However, other diet-derived circulating antioxidants (lycopene, retinol, ascorbic acid, and selenium) and antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbic acid, and retinol) did not significantly associate with epilepsy risk. Additional MR analysis methods and heterogeneity assessments confirmed the results' robustness. Conclusion: This study provides compelling evidence of oxidative stress in epilepsy patients' circulation. However, the majority of diet-derived circulating antioxidants (lycopene, retinol, ascorbic acid, vitamin E, and selenium) are unlikely to causally associate with reduced epilepsy risk, except for ß-carotene.

Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson's disease and in comorbidity with psychiatric disorders.

Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson's diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson's disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.

Gaps in treatment of epileptic seizures in a Zambian rural area.

BACKGROUND: Epilepsy is a multifactorial neurological disorder, including parasitic infections of the brain such as neurocysticercosis (NCC). People with epileptic seizures (PWES) in low and middle-income countries often do not receive appropriate treatment, which besides epileptic seizures, may also lead to reduced quality of life and possibly death. The objective of this study was to describe gaps in treatment of epileptic seizures in a Zambian rural area. METHODS: A cross-sectional study was conducted in Sinda district of Zambia between August and October 2018. PWES identified from clinic records and with the help of community healthcare workers were recruited. Two questionnaires, one to PWES and the other to local healthcare workers, were administered to describe the treatment gap. RESULTS: A total of 146 PWES and 43 healthcare workers were interviewed. Of the 146 PWES, 131 had taken anti-seizure medication (ASM) at some point since their seizure onset, of which 49.6% were on current treatment. Only 18.3% were on continuous ASM, an overall treatment gap of 83.6%. Over 55% of healthcare workers did not know the relationship between epilepsy and NCC. The risk factors associated with lack of appropriate treatment were stock-outs of ASMs, lack of diagnostic equipment, poor patient follow-up, and PWES opting for traditional medicine. CONCLUSION: The treatment gap is substantial in Sinda district. The causes are multifactorial, involving shortcomings at the level of healthcare facilities, communities, and individuals. Directed training of healthcare workers and significant improvements in the supply and dispensing of ASMs will be key in substantially reducing the gap.

Prescribing patterns for higher dose folic acid in pregnant women with epilepsy treated with antiseizure medication.

OBJECTIVE: This study was undertaken to characterize the use of higher doses of folic acid (≥1 mg daily) in relation to pregnancy in Denmark, Norway, and Sweden in women with epilepsy treated with antiseizure medication (ASM). METHODS: In this observational study, we used data from national medical birth, patient, and prescription registers in Denmark, Norway, and Sweden to retrospectively identify pregnancies in women with epilepsy treated with ASM from 2006 to 2017. The proportion of higher dose folic acid supplementation in pregnancies among women receiving ASM for epilepsy was calculated according to country of origin, time period, and type of ASM. Logistic regression with restricted cubic splines was used to model country-specific time trends. RESULTS: Among a total of 2 748 882 pregnancies, we identified 8695 (.3%) pregnancies after restricting the population to women with ASM-treated epilepsy. A prescription for higher dose folic acid was filled in 4719 (54.3%) of these pregnancies. The proportion supplemented with higher dose folic acid was highest in Sweden (74.3%) and lower in Norway (41.4%) and Denmark (34.3%). Furthermore, we observed a decreasing trend of higher dose folic acid use in Denmark and Norway from year 2012 to 2017. Among those who used higher dose folic acid, 42% did not start preconception supplementation with higher dose folic acid. SIGNIFICANCE: Supplementation with higher dose folic acid occurred in approximately half of pregnancies in women with ASM-treated epilepsy, with many not starting supplementation until after becoming pregnant. Considerable variability was observed in the use of higher dose folic acid across the countries, despite similar population characteristics and health care systems. Future guidelines should be simplified with clear recommendations developed in a collaborative manner by relevant specialists including neurologists, obstetricians, pediatricians, and public health specialists to enhance real-world applicability.

Epilepsy surgery perceptions among general neurologists and epilepsy specialists: A survey.

OBJECTIVE: Surgical intervention for drug-resistant epilepsy (DRE) is a safe and efficacious evidence-based treatment. Yet, neurologists have historically revealed hesitance in referring patients for surgical evaluations. The present study surveyed general neurologists and epilepsy specialists to assess their views and process in referring patients for specialized epilepsy care and epilepsy surgery. METHODS: A 14-item survey assessing epilepsy referrals and views of epilepsy surgery was distributed to all neurologists currently practicing in a large national integrated health system using REDCap. Responses were qualitatively analyzed and differences between general neurologists and epileptologists were assessed using chi-squared tests. RESULTS: In total, 100 responses were received from 67 general neurologists and 33 epileptologists with several similarities and differences emerging between the two groups. Both groups endorsed surgery and neuromodulation as treatment options in DRE, felt that seizure frequency rather than duration was relevant in considering epilepsy surgery, and indicated patient preference as the largest barrier limiting epilepsy surgery. General neurologists were more likely to require ≥ 3 ASMs to fail to diagnose DRE compared to epileptologists (45% vs. 15%, p < 0.01) who more often required ≥ 2 ASMs to fail. Epileptologists were also more likely than neurologists to try a new ASM (75.8% vs. 53.7%, p < 0.05) or optimize the current ASM (75.8% vs. 49.3%, p < 0.05) in DRE. General neurologists were more likely to consider epilepsy surgery to be less efficacious (p = 0.001) or less safe (p < 0.05). SIGNIFICANCE: Overall, neurologists appear to have generally positive opinions of epilepsy surgery, which is a change from prior literature and represents a changing landscape of views toward this intervention. Furthermore, epileptologists and general neurologists endorsed more similarities than differences in their opinions of surgery and steps to referral, which is another encouraging finding. Those gaps that remain between epileptologists and general neurologists, particularly in standards of ASM prescription, may be addressed by more consistent education about DRE and streamlining of surgical referral procedures.

Effects of sodium valproate and levetiracetam on posterior segment parameters in children with epilepsy.

PURPOSE: To evaluate changes in posterior segment parameters in pediatric patients with epilepsy using sodium valproate or levetiracetam monotherapy for at least 12 months. METHODS: This study included 45 children with generalized epilepsy aged 6-17 years and 32 age- and gender-matched healthy subjects. The patients were assigned to three groups: Group 1 included patients using valproate monotherapy at a dose of 20-40 mg/kg/day, group 2 included patients using levetiracetam monotherapy at a dose of 20-40 mg/kg/day, and group 3 consisted of healthy controls. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer-inner plexiform layer (mGCIPL) thicknesses were measured using spectral-domain optical coherence tomography (OCT). RESULTS: No significant differences were noted between the groups regarding age, gender distribution, visual acuity, spherical equivalent, and intraocular pressure (p > 0.05). The average and temporal, nasal, and superior quadrants RNFL values were significantly thinner in group 1 than in group 2 (p = 0.001, p = 0.023, p = 0.011, and p = 0.001, respectively) and group 3 (p < 0.001, p = 0.032, p < 0.001, and p = 0.001, respectively). The OCT parameters were similar in groups 2 and 3 (p > 0.05). A negative correlation was observed in group 1 between only the average mGCIPL and the treatment dose (r = - 0.501). In group 2, no significant correlation was found between OCT parameters and the duration of epilepsy treatment, dose of treatment, and age at treatment onset values (p > 0.05). CONCLUSION: These findings support that there is an association between sodium valproate treatment and the reduction of RNFL thickness in epilepsy. Levetiracetam treatment appears to be a safe option, but care should be taken regarding ocular side effects that may occur with long-term and high-dose use of sodium valproate.

Increased Thalamic Connectivity in Juvenile Myoclonic Epilepsy Based on Electroencephalography Source-Level Analysis.

Background: This study investigated alterations in the intrinsic thalamic network of patients with juvenile myoclonic epilepsy (JME) based on an electroencephalography (EEG) source-level analysis. Materials and Methods: We enrolled patients newly diagnosed with JME as well as healthy controls. The assessments were conducted in the resting state. We computed sources based on the scalp electrical potentials using a minimum-norm imaging method and a standardized, low-resolution, brain electromagnetic tomography approach. To create a functional connectivity matrix, we used the Talairach atlas to define thalamic nodes and applied the coherence method to measure brain synchronization as edges. We then calculated the intrinsic thalamic network using graph theory. We compared the intrinsic thalamic network of patients with JME with those of healthy controls. Results: This study included 67 patients with JME and 66 healthy controls. EEG source-level analysis revealed significant differences in the intrinsic thalamic networks between patients with JME and healthy controls. The measures of functional connectivity (radius, diameter, and characteristic path length) were significantly lower in patients with JME than in healthy controls (radius: 2.769 vs. 3.544, p = 0.015; diameter: 4.464 vs. 5.443, p = 0.024; and characteristic path length: 2.248 vs. 2.616, p = 0.046). Conclusions: We demonstrated alterations in the intrinsic thalamic network in patients with JME compared with those in healthy controls based on the EEG source-level analysis. These findings indicated increased thalamic connectivity in the JME group. These intrinsic thalamic network changes may be related to the pathophysiology of JME.

Advances in understanding the pathogenesis of epilepsy: Unraveling the molecular mechanisms: A cross-sectional study.

Introduction: Epilepsy is characterized by having two or more unprovoked seizures. Understanding the pathogenesis of epilepsy, requires deep investigation into the molecular mechanisms. This helps develop diagnostic techniques, treatments, and pharmacotherapy. It also enhances precision medicine and individualized treatment processes. This article reviews all the molecular mechanisms predisposing to epileptogenesis, presents the current diagnostic techniques and drug therapy, and suggests future perspectives in treating Epilepsy in a more comprehensive and holistic approach. Methodology: Four authors searched keywords concerning epilepsy at a molecular level, Epilepsy diagnostic techniques and technologies, and antiepileptic drug therapy and precision medicine. Separate search strategies were conducted for each concern and retrieved articles were reviewed for relevant results. Results: The traditional diagnostic techniques for Epilepsy and its pathogenesis are insufficient in highlighting dynamic brain changes. For this, emerging technologies including genetic sequencing and profiling, and functional neuroimaging techniques are prevailing. Concerning treatment, the current approach focuses on managing symptoms and stopping seizures using antiseizure medications. However, their usage is limited by developing resistance to such drugs. Some therapies show promise, although most antiseizure drugs do not prevent epilepsy. Discussion: Understanding epileptogenesis at a molecular and genetic level aids in developing new antiepileptic pharmacotherapy. The aim is to develop therapies that could prevent seizures or modify disease course, decreasing the severity and avoiding drug resistance. Gene therapy and precision medicine are promising but applications are limited due to the heterogeneity in studying the Epileptic brain, dynamically. The dynamic investigation of the epileptic brain with its comorbidities works hand-in-hand with precision medicine, in developing personalized treatment plans.

Electroencephalographic profile of Salvia amarissima Ortega and amarisolide A in the absence and presence of PTZ-induced seizures in mice.

Salvia amarissima Ortega is a plant used in traditional medicine to treat CNS's affections. Despite its depressant properties in anxiety and fibromyalgia, there is no scientific evidence about its capability to control seizure activity. This study aimed to investigate the effects of the S. amarissima aqueous extract (SAAE) and its metabolite amarisolide A (AMA) on the electrocorticographic (ECoG) activity. The ECoG profiles were previously and concurrently analyzed to the pentylenetetrazole (85 mg/kg, i.p.)-induced seizure behavior after thirty min of the administration of several doses of the SAAE (1, 10, 30, and 100 mg/kg, i.p.) and two doses of AMA (0.5 and 1 mg/kg, i.p.). A dosage of AMA (1 mg/kg,i.p.) was selected to explore a possible mechanism of action by using antagonists of inhibitory receptors such as GABAA (picrotoxin, 1 mg/kg, i.p.) or 5-HT1A of serotonin (WAY100635, 1 mg/kg, i.p.). Significant changes in the frequency bands and the spectral power were observed after the treatment alone. Additionally, SAAE and AMA produced significant and dose-dependent anticonvulsant effects by reducing the incidence and severity of seizures and increasing latency or survival. Both antagonists prevented the effects of AMA in the severity score of seizures and survival during the tonic-clonic seizures. In conclusion, our preclinical data support that S. amarissima possesses anticonvulsant properties, in part due to the presence of amarisolide A, mediated by different inhibitory mechanisms of action. Our scientific evidence suggests that this Salvia species and amarisolide A are potential neuroprotective alternatives to control seizures in epilepsy therapy.

Polysaccharide-rich extract of Genipa americana leaves protects seizures and oxidative stress in the mice model of pentylenetetrazole-induced epilepsy.

Plant polysaccharides have biological activities in the brain and those obtained from Genipa americana leaves present antioxidant and anticonvulsant effects in the mice model of pentylenetetrazole (PTZ)-induced acute seizures. This study aimed to evaluate the polysaccharide-rich extract of Genipa americana leaves (PRE-Ga) in the models of acute seizures and chronic epilepsy (kindling) induced by PTZ. In the acute seizure model, male Swiss mice (25-35 g) received PRE-Ga (1 or 9 mg/kg; intraperitoneal- IP), alone or associated with diazepam (0.01 mg/kg), 30 min before induction of seizures with PTZ (70 mg/kg; IP). In the chronic epilepsy model, seizures were induced by PTZ (40 mg/kg) 30 min after treatment and in alternated days up to 30 days and evaluated by video. Brain areas (prefrontal cortex, hippocampus, striatum) were assessed for inflammatory and oxidative stress markers. Diazepam associated to PRE-Ga (9 mg/kg; i.p.) increased the latency of seizures in acute (222.4 ± 47.57 vs. saline: 62.00 ± 4.709 s) and chronic models (6.267 ± 0.502 vs. saline: 4.067 ± 0.407 s). In hippocampus, PRE-Ga (9 mg/kg) inhibited TNF-α (105.9 ± 5.38 vs. PTZ: 133.5 ± 7.62 pmol/g) and malondialdehyde (MDA) (473.6 ± 60.51) in the chronic model. PTZ increased glial fibrillar acid proteins (GFAP) and Iba-1 in hippocampus, which was reversed by PRE-Ga (GFAP: 1.9 ± 0.23 vs PTZ: 3.1 ± 1.3 and Iba-1: 2.2 ± 0.8 vs PTZ: 3.2 ± 1.4). PRE-Ga presents neuroprotector effect in the mice model of epilepsy induced by pentylenetetrazole reducing seizures, gliosis, inflammatory cytokines and oxidative stress.

Criticality supports cross-frequency cortical-thalamic information transfer during conscious states.

Consciousness is thought to be regulated by bidirectional information transfer between the cortex and thalamus, but the nature of this bidirectional communication - and its possible disruption in unconsciousness - remains poorly understood. Here, we present two main findings elucidating mechanisms of corticothalamic information transfer during conscious states. First, we identify a highly preserved spectral channel of cortical-thalamic communication that is present during conscious states, but which is diminished during the loss of consciousness and enhanced during psychedelic states. Specifically, we show that in humans, mice, and rats, information sent from either the cortex or thalamus via δ/θ/α waves (∼1-13 Hz) is consistently encoded by the other brain region by high γ waves (52-104 Hz); moreover, unconsciousness induced by propofol anesthesia or generalized spike-and-wave seizures diminishes this cross-frequency communication, whereas the psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) enhances this low-to-high frequency interregional communication. Second, we leverage numerical simulations and neural electrophysiology recordings from the thalamus and cortex of human patients, rats, and mice to show that these changes in cross-frequency cortical-thalamic information transfer may be mediated by excursions of low-frequency thalamocortical electrodynamics toward/away from edge-of-chaos criticality, or the phase transition from stability to chaos. Overall, our findings link thalamic-cortical communication to consciousness, and further offer a novel, mathematically well-defined framework to explain the disruption to thalamic-cortical information transfer during unconscious states.

Drug resistant epilepsy and associated factors among children with epilepsies in tanzania: a cross-sectional study.

BACKGROUND: Epilepsy contributes to high morbidity among children and adolescents in developing countries. A quarter of all children with epilepsy will be resistant to anti-seizure medications (ASMs), with associated neurocognitive impairments and risk of higher mortality. This study aimed to estimate and characterize drug-resistant epilepsy (DRE) (defined as failure to achieve sustained remission after adequate trials of two tolerated and appropriately chosen ASMs) and its associated factors among children and adolescents with epilepsies attending the pediatric neurology clinic at Muhimbili National Hospital (MNH), Dar es Salaam Tanzania. METHODS: This cross-sectional study was conducted from June 2020 to June 2021. Children with epilepsies and who had been treated with ASMs for at least 3 months were eligible for inclusion. Exclusion criteria included children whose caregivers denied consent and those who exhibited acute medical conditions necessitating admission on the scheduled visit day. Data on demographic characteristics, perinatal history, detailed history of the seizures semiology, drug history, magnetic resonance imaging (MRI), and electroencephalography (EEG) results were obtained from caregivers and medical records available during recruitment. Seizures and epilepsies were classified using the 2017 International League Against Epilepsy (ILAE) classification. Logistic regression was used to determine factors associated with DRE. RESULTS: A total of 236 children and adolescents aged between 4 months and 15 years (Median age 72 months (IQR = 42-78)) were enrolled in this study. We found the proportion of DRE to be 14.8% in this cohort. Of the thirty-five patients with DRE, 60% had generalized epilepsy and almost 25% had a diagnosis of an epilepsy syndrome, the most common being Lennox-Gastaut syndrome (LGS). Structural abnormalities on brain MRI were seen in almost 80% of all patients with DRE, the most prevalent being cystic encephalomalacia, which was observed in 34% of patients. Patients using both ASMs and alternative therapies accounted for 9% of this cohort. The onset of seizures during the first month of life (aOR = 1.99; 95%CI 1.7-4.6; p = 0.031) and high initial seizure frequency (aOR = 3.6; 95%CI 1.6-8;p = 0.002) were found to be independently associated with DRE. CONCLUSION: The proportion of DRE in Tanzania is high. Patients with neonatal onset seizures and high initial seizure frequency should be followed up closely to ensure early diagnosis of DRE.

Preferences and experiences of parents/guardians of youth with epilepsy and intellectual disability on reproductive health counseling.

OBJECTIVE: To explore the experiences and preferences of parents/guardians of adolescents and young adults (AYA) of childbearing potential with co-occurring epilepsy and intellectual disability (ID) regarding counseling by neurologists on sexual and reproductive health (SRH) topics such as pregnancy, contraception, menstruation, and folic acid supplementation. METHODS: We conducted semi-structured interviews with parents/guardians of AYAs (12-28 years old) of childbearing potential with co-occurring epilepsy and ID, recruited from a tertiary-care children's hospital. We confirmed the diagnoses of epilepsy and ID with the patient's neurologist and parent/guardian. All degrees of ID (e.g. mild/moderate/severe) were eligible. We audio-recorded and transcribed interviews. Two coders performed qualitative thematic analysis. RESULTS: Twenty-five parents/guardians completed interviews. Themes included: (1) Parents/guardians believe their child to be immune from sexual abuse due to their supervision, yet desire counseling about abuse recognition and prevention, which they also report not occurring (2) A common opinion was that counseling on menstruation was more relevant to their child's life than counseling about pregnancy-related topics (3) Parents/guardians reported a lack of counseling on pregnancy-related topics such as folic acid supplementation and teratogenesis and generally also reported some degree of interest in hearing about these topics from neurologists (4) Parents/guardians also reported a lack of counseling on drug interactions between contraception and ASMs, and were highly interested in learning more about this topic (5) Parents/guardians want neurologists to initiate annual comprehensive SRH counseling at puberty about most topics, but report that they often initiate SRH discussions themselves. CONCLUSION: Parents/guardians of AYAs with epilepsy and ID prefer more frequent, neurologist-initiated, comprehensive conversations surrounding SRH particularly emphasizing menstruation and sexual abuse recognition/prevention. Findings may inform professional and patient education and health systems interventions including development of discussion guides and/or decision aides to improve SRH care for AYAs with epilepsy and ID.