Assessing the extent and determinants of socioeconomic inequalities in epilepsy in the UK: a systematic review and meta-analysis of evidence.

BACKGROUND: Socioeconomic inequalities in epilepsy incidence and its adverse outcomes are documented internationally, yet the extent of inequalities and factors influencing the association can differ between countries. A UK public health response to epilepsy, which prevents epilepsy without widening inequalities, is required. However, the data on UK epilepsy inequalities have not been synthesised in a review and the underlying determinants are unknown. METHODS: In this systematic review and meta-analysis, we searched six bibliographic databases (MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus) and grey literature published between Jan 1, 1980, and Feb 21, 2024, to identify UK studies reporting epilepsy incidence or epilepsy-related adverse outcomes by socioeconomic factors (individual level or area level). We included longitudinal cohort studies, studies using routinely collected health-care data, cross-sectional studies, and matched cohort studies and excluded conference abstracts and studies not reporting empirical results in the review and meta-analysis. Multiple reviewers (KJB, EC, SER, WOP, and RHT) independently screened studies, KJB extracted data from included studies and a second reviewer (SM or EC) checked data extraction. We used Critical Appraisal Skills Programme checklists to assess quality. We used random-effects meta-analysis to pool incident rate ratios (IRRs) and synthesised results on adverse outcomes narratively. This study was registered on PROPSPERO (CRD42023394143). FINDINGS: We identified 2471 unique studies from database searches. We included 26 studies, ten of which reported epilepsy incidence and 16 reported epilepsy-related adverse outcomes according to socioeconomic factors. Misclassification, participation, and interpretive biases were identified as study quality limitations. Meta-analyses showed an association between socioeconomic deprivation and epilepsy incidence, with greater risks of epilepsy incidence in groups of high-deprivation (IRR 1·34 [95% CI 1·16-1·56]; I2=85%) and medium-deprivation (IRR 1·23 [95% CI 1·08-1·39]; I2=63%) compared with low-deprivation groups. This association persisted in the studies that only included children (high vs low: IRR 1·36 [95% CI 1·19-1·57]; I2=0%). Only two studies examined factors influencing epilepsy incidence. There is limited evidence regarding UK inequalities in adverse outcomes. INTERPRETATION: Socioeconomic inequalities in epilepsy incidence are evident in the UK. To develop an evidence-based public health response to epilepsy, further research is needed to understand the populations affected, factors determining the association, and the extent of inequalities in adverse outcomes. FUNDING: Epilepsy Research Institute UK.

A Review of Concordance and Quality in Clinical Guidelines for Hormonal Contraceptives to Mitigate Drug-Drug Interactions in Women With Epilepsy.

PURPOSE: Concomitant use of hormonal contraceptive agents (HCAs) and enzyme-inducting antiepileptic drugs (EIAEDs) may lead to contraceptive failure and unintended pregnancy. This review identified and evaluated concordance and quality of clinical treatment guidelines related to the use of HCAs in women with epilepsy (WWE) receiving EIAEDs. METHODS: Relevant clinical guidelines were identified across four databases and were independently evaluated for quality utilizing the AGREE-II protocol instrument. Quality in this context is defined as the rigor and transparency of the methodologies used to develop the guideline. Guidelines were further assessed in terms of concordance and discordance with the latest body of knowledge concerning the use of hormonal contraception in the presence of EIAEDs. RESULTS: A total of n = 5 guidelines were retrieved and evaluated. Overall guideline scores ranged from 17% to 92%, while individual domain scores ranged from 0% to 100%. Contraceptive guidelines consistently recommended the use of intrauterine systems and long-acting injectables in the presence of EIAEDs, recommended against the use of oral, transdermal, and vaginal ring contraceptives, and differed regarding recommendations related to implants. Guidelines agreed regarding recommendations that women treated with EIAEDs should receive intrauterine systems and long-acting injectables; however, the suggested frequency of administration of injectable contraceptives differed. The use of intrauterine systems in this population is supported by evidence, but there is uncertainty surrounding the use of long-acting injectables and contraceptive implants. CONCLUSIONS: To mitigate the risk of unintended pregnancy and its consequences, recommendations related to implants and long-acting injectable contraceptives should be evidence-based.

The Effectiveness of Medical Adherence Mobile Health Solutions for Individuals With Epilepsy: Protocol for a Systematic Review.

BACKGROUND: Epilepsy requires continuous management and treatment to optimize patient outcomes. The advancement of digital health has led to the development of various mobile health (mHealth) tools designed to enhance treatment adherence among individuals with epilepsy. These solutions offer crucial support through features such as reminders, educational resources, personalized feedback, assistance with managing costs, shared decision-making, and access to supportive communities. To design effective medication adherence mHealth solutions, it is essential to evaluate the effectiveness of existing mHealth tools, understand the unique circumstances of different patients, and identify the roles of health care professionals within the digital care pathway. Existing studies on epilepsy primarily focus on self-management, whereas the effectiveness and usability of medical adherence mHealth solutions often remain overlooked. Furthermore, the involvement of health care professionals in digital care pathways for epilepsy as well as the impact of adherence mHealth solutions on the patient experience have not been adequately explored. OBJECTIVE: This study aims to assess the effectiveness of current mHealth solutions designed to improve medical adherence among patients with epilepsy. Furthermore, the study will examine the experiences of patients using mHealth solutions for maintaining medical adherence in epilepsy care. Finally, this review intends to determine the roles of health care professionals within mHealth systems aimed at supporting adherence to medication among patients with epilepsy. METHODS: A systematic literature review has been selected as the appropriate method to address the research questions, adhering to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The inclusion and exclusion criteria have been carefully selected, and both qualitative and quantitative analyses will be used to analyze the results. The expected results will mainly focus on the comparison, classification, and analysis of the effectiveness of current medical adherence mHealth tools. Moreover, the patient experiences using available medical adherence mHealth tools for epilepsy will be assessed. Finally, the role of health care professionals in the epilepsy digital care pathway will be explored, with emphasis on medical adherence. RESULTS: The initial search, full-text screening, and data extraction have been carried out. Thirty-three papers were included in the final stage of the review. The study is expected to be completed by October 2024. CONCLUSIONS: To enhance the digital care pathway for epilepsy, a medical adherence mHealth solution should be personalized, manage medications, include an alarm system, track seizures, support consultations, and offer updated treatment plans. This study aims to understand how findings from the research questions can improve mHealth solutions for individuals with epilepsy. Insights from this research on the effectiveness of current mHealth adherence solutions will provide guidance for developing future mHealth systems, making them more efficient and effective in managing epilepsy. TRIAL REGISTRATION: PROSPERO CRD4202347400; https://tinyurl.com/48mfx22e. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55123.

Oral health assessment of epilepsy patients from a tertiary hospital in Asia.

INTRODUCTION: Oral health problems are frequently overlooked in patients with epilepsy. We evaluate the oral health status of epilepsy patients from a tertiary teaching hospital. MATERIALS AND METHODS: We conducted a cross-sectional study of epilepsy patients from the neurology clinic, Hospital Canselor Tuanku Muhriz, Kuala Lumpur. The dental assessment included the decayed, missing and filled teeth (DMFT) criteria, as well as the plaque and periodontal status by dentists. RESULTS: A total of 151 patients were recruited. The median age of onset of epilepsy was 16 (IQR 7-30) years, with generalised seizures at 59.6% and focal seizures in 40.4% of patients. Fair or poor oral health was present in 59 (39.1%) and gingivitis was seen in 65 (43%). The median DMFT decayed (D), missing (M) and filled teeth (FT) was 3 (IQR 1- 7). The median age of patients with fair or poor oral health was older (40 years, IQR 31-51) than the patients with excellent or good oral health (33 years, IQR 26-45), (p=0.014). Multivariate logistic regression analysis showed that carbamazepine (Odds Ratios, OR: 3.694; 95% Confidence Intervals, 95%CI: 1.314, 10.384) and hypertension (OR 6.484; 95%CI: 1.011, 41.594) are the risk factors for fair or poor oral health. Phenytoin use is 4.271 times more likely to develop gingivitis (OR 4.271; 95% CI: 1.252, 14.573). CONCLUSION: Factors that contribute to fair or poor oral health include age, antiseizure medications like phenytoin and carbamazepine, and hypertension. Effective preventive strategies should be implemented to maintain oral health in epilepsy patients.

Primary somatosensory cortex CB1 and 5­HT1A receptors interaction in the penicillin model of epilepsy.

Cannabinoid and serotonin systems regulate many biological processes. The aim of the present study was to investigate the functional interaction between the cannabinoid and serotonergic systems of the primary somatosensory region (S1) of the brain in epileptiform activity caused by penicillin. The ACEA (an agonist of CB1 receptor), AM­251 (an antagonist of CB1 receptor), 8­OH­DPAT (an agonist of 5­HT1A receptor) and WAY­100635 (an antagonist of 5­HT1A receptor) were administered into the S1 after the same site administration of penicillin in urethane­anesthetized rats. Electrocorticographic recording was done for a 90­min period. The spike waves number and amplitude were recorded in 15­min intervals. Areas under the curve (AUC) of the above­mentioned spike alterations was calculated in 90 min. Spike waves with frequency of 30/min and amplitude of 1.3 mV were appeared after penicillin microinjection. The ACEA (50 ng), 8­OH­DPAT (500 ng) and ACEA (10 ng) plus 8­OH­DPAT (100 ng) reduced epileptiform activity. The AM­251 (50 ng) and WAY­100365 (500 ng) prevented the reducing effects of ACEA (50 ng) and 8­OH­DPAT (500 ng). The AM­251 alone increased spike waves frequency. The AUC results supported the effects of the above­mentioned treatments. The results showed that activating CB1 and 5­HT1A receptors in the S1 may reduce the epileptiform activity caused by penicillin. Therefore, alone and together activation of central CB1 and 5­HT1A receptors might be considered in the management of epilepsy treatment.

Intracerebroventricular administration of the exercise hormone irisin or acute strenuous exercise alleviates epileptic seizure-induced neuroinflammation and improves memory dysfunction in rats.

BACKGROUND: Status epilepticus is a common and potentially life-threatening neurological emergency with a high risk for cognitive and neurobiological impairment. Our aim was to evaluate the neuroprotective effects of centrally administered irisin and acute exhausting exercise against oxidative brain injury and memory dysfunction due to a pentylenetetrazole (PTZ)-induced single seizure. Male Sprague Dawley rats with intracerebroventricular (icv) cannulas were randomly divided into intraperitoneally (ip) saline-injected control and PTZ-injected (45 mg/kg) seizure groups. Both the control and PTZ groups were then treated with irisin (7.5 µg/kg, 2 µl, icv), saline (2 µl, icv) or were forced to an acute bout of strenuous exercise before the ip injection of saline (control) or PTZ. Seizures were evaluated using the Racine score. To evaluate memory performance, a passive avoidance test was performed before and after PTZ injection. Following euthanasia at the 24th hour of seizure induction, brain tissues were removed for histopathological examination and for evaluating oxidative damage, antioxidant capacity, and neurotransmitter levels. RESULTS: Glutamate/GABA imbalance observed in PTZ rats was corrected by irisin administration (p < 0.001/p < 0.01), while irisin prevented the generation of reactive oxygen species and lipid peroxidation (p < 0.05 - 0.001) and replenished the antioxidant catalase and glutathione levels (p < 0.01-0.01) in the cerebral tissue, and reduced the histologically evident neuronal injury due to a single seizure (p < 0.05 - 0.01). Irisin also delayed the onset of seizures (p < 0.05) and improved memory dysfunction (p < 0.05), but did not affect the severity of seizures. The acute exhaustive swimming exercise completed before PTZ-seizure depressed glutamate level (p < 0.001), maintained the oxidant/antioxidant balance, alleviated neuronal injury (p < 0.05 - 0.01) and upregulated cerebral BDNF expression (p < 0.05). CONCLUSION: In conclusion, acute high-intensity exercise or exogenously administered irisin provides neuroprotection by maintaining the balance of excitatory/inhibitory neurotransmitters and oxidant/antioxidant systems.

Peripheral nesfatin-1 reduces basal brain activity but has limited effect on epilepsy-like conditions.

In this study, we investigated the effects of peripheral nesfatin-1 on basal brain activity and 4-aminopyridine (4-AP)-induced epileptiform activity, and its relationship with the electrocorticogram (ECoG) power spectrum and EEG bands. Forty-nine male Wistar rats were divided into seven groups: control sham, 4-AP (2.5 mg/kg i.p.), Nesfatin-1 (1, 2, and 4 µg/kg i.p.), Nesfatin-1 (2 µg/kg) post-treatment, and Nesfatin-1 (2 µg/kg) pre-treatment. Recordings were conducted for 70 min under ketamine/xylazine (90/10 mg/kg) anesthesia. In the post-treatment group, nesfatin-1 was injected 20 min after 4-AP induction. In the pre-treatment groups, nesfatin-1 was administered following basal recordings and before 4-AP injection. 4-AP induced epileptiform activity in all animals, peaking at 30 min. Nesfatin-1 (2 µg/kg) reduced basal brain activity (p < 0.05) and decreased alpha, delta, and theta bands in ECoG. Post-treatment of nesfatin-1 did not affect 4-AP-induced activity (p > 0.05) but increased gamma band activity (p > 0.05). Pre-treatment of nesfatin-1 reduced epileptiform activity between 50 and 60 min (p < 0.05), decreased delta bands, and increased gamma bands (p > 0.05). We conclude that peripheral nesfatin-1 modulates normal brain activity but has limited effects on abnormal discharges.

PVT1 regulates hippocampal neuron apoptosis and inflammation in epilepsy by miR-206-3p-dependent regulation of CAMK4.

This study was designed to dissect the function of plasmacytoma variant translocation 1 (PVT1) in hippocampal neuron injury in epilepsy and its possible molecular basis. Status epilepticus (SE) mouse model was built and primary hippocampal neurons were isolated. qRT-PCR and Western blot were applied to quantify the levels of related genes and proteins. Cell proliferation and apoptosis were examined by CCK-8, EdU, and flow cytometry assays. Inflammatory factors were detected using ELISA analysis. Dual-luciferase reporter and RIP assays were carried out to validate the relationship between miR-206-3p and PVT1 or CAMK4. PVT1 and CAMK4 were increased, and miR-206-3p was downregulated in the hippocampus and hippocampal neurons of SE mice. Knockdown of PVT1 or CAMK4 abated SE-induced proliferation inhibition, apoptosis, and inflammation in hippocampal neurons. Mechanistically, PVT1 could sponge miR-206-3p to upregulate the expression of CAMK4 in hippocampal neurons. Moreover, downregulation of miR-206-3p reversed the inhibitory effects of PVT1 knockdown on SE-induced apoptosis and inflammation in hippocampal neurons. Similarly, overexpression of CAMK4 abolished miR-206-3p-evoked arrest of apoptosis and inflammation in hippocampal neurons under SE condition. Collectively, PVT1 contributed to SE-induced apoptosis and inflammation in hippocampal neurons by modulating the miR-206-3p/CAMK4 axis, offering a novel insight into the prevention of epilepsy.

Efficacy of anti-seizure medications and alternative therapies (ketogenic diet, CBD, and quinidine) in KCNT1-related epilepsy: A systematic review.

OBJECTIVE: KCNT1-related epilepsies encompass three main phenotypes: (i) epilepsy of infancy with migrating focal seizures (EIMFS), (ii) autosomal dominant or sporadic sleep-related hypermotor epilepsy [(AD)SHE], and (iii) different types of developmental and epileptic encephalopathies (DEE). Many patients present with drug-resistant seizures and global developmental delays. In addition to conventional anti-seizure medications (ASM), multiple alternative therapies have been tested including the ketogenic diet (KD), cannabidiol (CBD-including Epidyolex © and other CBD derivatives) and quinidine (QUIN). We aimed to clarify the current state of the art concerning the benefits of those therapies administered to the three groups of patients. METHODS: We performed a literature review on PubMed and EMBase with the keyword "KCNT1" and selected articles reporting qualitative and/or quantitative information on responses to these treatments. A treatment was considered beneficial if it improved seizure frequency and/or intensity and/or quality of life. Patients were grouped by phenotype. RESULTS: A total of 43 studies including 197 patients were reviewed. For EIMFS patients (32 studies, 135 patients), KD resulted in benefit in 62.5% (25/40), all types of CBD resulted in benefit in 50% (6/12), and QUIN resulted in benefit in 44.6% (25/56). For (AD)SHE patients (10 studies, 32 patients), we found only one report of treatment with KD, with no benefit noted. QUIN was trialed in 8 patients with no reported benefit. For DEE patients (10 studies, 30 patients), KD resulted in benefit for 4/7, CBD for 1/2, and QUIN for 6/9. In all groups, conventional ASM are rarely reported as beneficial (in 5%-25% of patients). SIGNIFICANCE: Ketogenic diet, CBD, and QUIN treatments appear to be beneficial in a subset of patient with drug-resistant epilepsy. The KD and CBD are reasonable to trial in patients with KCNT1-related epilepsy. Further studies are needed to identify optimal treatment strategies and to establish predictive response factors. PLAIN LANGUAGE SUMMARY: We performed an extensive review of scientific articles providing information about the therapeutic management of epilepsy in patients with epilepsy linked to a mutation in the KCNT1 gene. Conventional anti-seizure treatments were rarely reported to be beneficial. The ketogenic diet (a medical diet with very high fat, adequate protein and very low carbohydrate intake) and cannabidiol appeared to be useful, but larger studies are needed to reach a conclusion.

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis.

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization. Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions. Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis. Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant. Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers. Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2.

Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y1 receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca2+ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders.

Behavioural and neurodevelopmental characteristics of SYNGAP1.

BACKGROUND: SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID. METHODS: Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires. RESULTS: Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15). CONCLUSION: For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management.

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A boy, aged 7 months, presented with severe global developmental delay (GDD), refractory epilepsy, hypotonia, nystagmus, ocular hypertelorism, a broad nasal bridge, everted upper lip, a high palatal arch, and cryptorchidism. Genetic testing revealed a de novo heterozygous missense mutation of c.364G>A(p.E122K) in the EEF1A2 gene, and finally the boy was diagnosed with autosomal dominant developmental and epileptic encephalopathy 33 caused by the EEF1A2 gene mutation. This case report suggests that for children with unexplained infancy-onset severe to profound GDD/intellectual disability and refractory epilepsy, genetic testing for EEF1A2 gene mutations should be considered. This is particularly important for those exhibiting hypotonia, nonverbal communication, and craniofacial deformities, to facilitate a confirmed diagnosis.

The critical dynamics of hippocampal seizures.

Epilepsy is defined by the abrupt emergence of harmful seizures, but the nature of these regime shifts remains enigmatic. From the perspective of dynamical systems theory, such critical transitions occur upon inconspicuous perturbations in highly interconnected systems and can be modeled as mathematical bifurcations between alternative regimes. The predictability of critical transitions represents a major challenge, but the theory predicts the appearance of subtle dynamical signatures on the verge of instability. Whether such dynamical signatures can be measured before impending seizures remains uncertain. Here, we verified that predictions on bifurcations applied to the onset of hippocampal seizures, providing concordant results from in silico modeling, optogenetics experiments in male mice and intracranial EEG recordings in human patients with epilepsy. Leveraging pharmacological control over neural excitability, we showed that the boundary between physiological excitability and seizures can be inferred from dynamical signatures passively recorded or actively probed in hippocampal circuits. Of importance for the design of future neurotechnologies, active probing surpassed passive recording to decode underlying levels of neural excitability, notably when assessed from a network of propagating neural responses. Our findings provide a promising approach for predicting and preventing seizures, based on a sound understanding of their dynamics.

An Epilepsy-Associated CILK1 Variant Compromises KATNIP Regulation and Impairs Primary Cilia and Hedgehog Signaling.

Mutations in human CILK1 (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent to the human CILK1 A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the intrinsically disordered C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEFs) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia, and upregulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild-type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. The CILK1 A615T mutant protein was not increased to the same level as the wild-type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single-residue variant of CILK1 is compromised, and this impairs the maintenance of primary cilia and Hedgehog signaling.

Women's health in focus: Real-world data on valproate prescriptions during pregnancy - a cohort study in Catalonia (Spain).

OBJECTIVES: To characterise the exposure to valproate within a cohort of pregnant women using electronic health records (EHRs) from Catalonia (System for the Development of Research in Primary Care, SIDIAP). DESIGN: Drug-utilisation cohort study covering the period from January 2011 to June 2020. The study included pregnancy episodes of women from Catalonia identified by the algorithm. SETTING: Data were sourced from SIDIAP, a comprehensive EHR repository that includes information from various data sources: recorded prescriptions (both hospital and primary care), diagnoses and sociodemographic characteristics identified by primary care physicians, and sexual and reproductive health data from ASSIR (used by gynaecologists and midwives). PARTICIPANTS: Women aged 12-50 with at least one pregnancy episode occurred during January 2011-June 2020 and at least a prescription of valproate during pregnancy. PRIMARY AND SECONDARY OUTCOMES: Primary outcomes included valproate exposure, measured through prevalence and cumulative incidence in pregnancy episodes and by trimester. The impact of regulatory measures (risk mitigation measures, RMMs) was assessed, and prescriptions over time were analysed using interrupted time series analysis. Secondary outcomes included health issues, pregnancy outcomes, smoking habits and socioeconomic characteristics. RESULTS: A total of 99 605 pregnancies were identified, with at least 3.03‰ (95% CI 2.69‰ to 3.39‰) exposed to valproate at some point (302 pregnancies, 276 women). The median pregnancy duration was 38.30 weeks (IQR 12.6-40.1), and the median age at pregnancy was 32.37 years (IQR 27.20-36.56). Epilepsy was the most frequent health issue. The prevalence and cumulative incidence of valproate prescriptions decreased during pregnancy and increased postpregnancy. The RMMs implemented in 2014 led to a reduction in monthly valproate prescriptions during pregnancy in this cohort. CONCLUSIONS: The study highlights the decline in valproate prescriptions during pregnancy due to RMMs and underscores the need for standardised methodologies in future studies to ensure the safety of pregnant patients and optimise scientific evidence.

Epilepsy in Patients With Primary CNS Lymphoma: Prevalence, Risk Factors, and Prognostic Significance.

BACKGROUND AND OBJECTIVES: Epilepsy is a common comorbidity of brain tumors; however, little is known about the prevalence, onset time, semiology, and risk factors of seizures in primary CNS lymphoma (PCNSL). Our objectives were to determine the prevalence of epilepsy in PCNSL, to identify factors associated with epilepsy, and to investigate the prognostic significance of seizures in PCNSL. METHODS: We performed an observational, retrospective single-center study at a tertiary neuro-oncology center (2011-2023) including immunocompetent patients with PCNSL and no history of seizures. We collected clinical, imaging, and treatment data; seizure status over the course of PCNSL; and oncological and seizure outcome. The primary outcome was to determine the prevalence of epilepsy. Furthermore, we aimed to identify clinical, radiologic, and treatment-related factors associated with epilepsy. Univariate analyses were conducted using the χ2 test for categorical variables and unpaired t test for continuous variables. Predictors identified in the unadjusted analysis were included in backward stepwise logistic regression models. RESULTS: We included 330 patients, 157 (47.6%) were male, median age at diagnosis was 68 years, and the median Karnofsky Performance Status score was 60. Eighty-three (25.2%) patients had at least 1 seizure from initial diagnosis to the last follow-up, 40 (12.1%) as the onset symptom, 16 (4.8%) during first line of treatment, 27 (8.2%) at tumor progression and 6 (1.8%) while in remission. Focal aware seizures were the most frequent seizure type, occurring in 43 (51.8%) patients. Seizure freedom under antiseizure medication was observed in 97.6% patients. Cortical contact (odds ratio [OR] 8.6, 95% CI 4.2-15.5, p < 0.001) and a higher proliferation index (OR 5.7, 95% CI 1.3-26.2, p = 0.02) were identified as independent risk factors of epilepsy. Patients with PCNSL and epilepsy had a significantly shorter progression-free survival (median progression-free survival 9.6 vs 14.1 months, adjusted hazard ratio 1.4, 95% CI 1.0-1.9, p = 0.03), but not a significantly shorter overall survival (17 vs 44.1 months, log-rank test, p = 0.09). DISCUSSION: Epilepsy affects a quarter of patients with PCNSL, with half experiencing it at the time of initial presentation and potentially serving as a marker of disease progression. Further research is necessary to assess the broader applicability of these findings because they are subject to the constraints of a retrospective design and tertiary center setting.

Mortality among veterans with epilepsy: Temporal significance of traumatic brain injury exposure.

OBJECTIVE: Epilepsy is associated with significant mortality risk. There is limited research examining how traumatic brain injury (TBI) timing affects mortality in relation to the onset of epilepsy. We aimed to assess the temporal relationship between epilepsy and TBI regarding mortality in a cohort of post-9/11 veterans. METHODS: This retrospective cohort study included veterans who received health care in the Defense Health Agency and the Veterans Health Administration between 2000 and 2019. For those diagnosed with epilepsy, the index date was the date of first antiseizure medication or first seizure; we simulated the index date for those without epilepsy. We created the study groups by the index date and first documented TBI: (1) controls (no TBI, no epilepsy), (2) TBI only, (3) epilepsy only, (4) TBI before epilepsy, (5) TBI within 6 months after epilepsy, and (6) TBI >6 months after epilepsy. Kaplan-Meier estimates of all-cause mortality were calculated, and log-rank tests were used to compare unadjusted cumulative mortality rates among groups compared to controls. Cox proportional hazard models were used to compute hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 938 890 veterans, 27 436 (2.92%) met epilepsy criteria, and 264 890 (28.22%) had a TBI diagnosis. Mortality was higher for veterans with epilepsy than controls (6.26% vs. 1.12%; p < .01). Veterans with TBI diagnosed ≤6 months after epilepsy had the highest mortality hazard (HR = 5.02, 95% CI = 4.21-5.99) compared to controls, followed by those with TBI before epilepsy (HR = 4.25, 95% CI = 3.89-4.58), epilepsy only (HR = 4.00, 95% CI = 3.67-4.36), and TBI >6 months after epilepsy (HR = 2.49, 95% CI = 2.17-2.85). These differences were significant across groups. SIGNIFICANCE: TBI timing relative to epilepsy affects time to mortality; TBI within 6 months after epilepsy or before epilepsy diagnosis was associated with earlier time to death compared to those with epilepsy only or TBI >6 months after epilepsy.