Search Results (218)

Idiopathic epilepsy (IE) is a common chronic neurological disorder in dogs, and both its comorbidities and adverse effects of anti-seizure medication (ASM) can markedly reduce quality of life (QoL) for affected dogs and their caregivers. Concurrent conditions such as lower urinary tract infections (UTIs) may mimic ASM side effects or signs of disease progression, potentially leading to inappropriate dose adjustment or treatment discontinuation. This retrospective case series describes eight dogs with IE and Escherichia coli (E. coli) UTI, presenting with suspected worsening of ASM side effects. Reported deterioration lasted 1–55 days (mean 31), with behavioral changes (n = 5), lethargy (n = 5), new or worsened ataxia (n = 5), urinary incontinence (n = 3), polyuria (n = 3), polydipsia (n = 2), and additional signs such as weakness, exercise intolerance, panting, and cluster seizures. All dogs showed bacteriuria; urinary specific gravity was 1.020 ± 0.013 (mean ± standard deviation) [range; 1.002–1.042]. E. coli (>10⁶ CFU/mL) was isolated in all cases. Treatment with amoxicillin–clavulanic acid resulted in clinical improvement within 24–72 h; five dogs experienced UTI relapse, again with clinical deterioration. Findings emphasize the importance of recognizing and treating UTIs in epileptic dogs to avoid misinterpretation as ASM toxicity and possible worsening of seizure control. Prospective studies are needed to clarify potential links between ASM, urinary dilution, immune modulation, and infection risk. Full article

The relationship between sleep and epilepsy involves complex interactions between thalamocortical circuits, circadian mechanisms, and sleep architecture that fundamentally influence seizure susceptibility and cognitive outcomes. Epileptic activity disrupts essential sleep oscillations, particularly sleep spindles generated by thalamic circuits. Thalamic epileptic spikes actively compete with physiological sleep spindles, impairing memory consolidation and contributing to cognitive dysfunction in epileptic encephalopathy. This disruption explains why patients with epilepsy often experience learning difficulties despite adequate seizure control. Sleep stages show differential seizure susceptibility. REM sleep provides robust protection through enhanced GABAergic inhibition and motor neuron suppression, while non-REM sleep, particularly slow-wave sleep, increases seizure risk. These observations reveal fundamental mechanisms of seizure control within normal brain physiology. Circadian clock genes (BMAL1, CLOCK, PER, CRY) play crucial roles in seizure modulation. Dysregulation of these molecular timekeepers creates permissive conditions for seizure generation while being simultaneously disrupted by epileptic activity, establishing a bidirectional relationship. These mechanistic insights are driving chronobiological therapeutic approaches, including precisely timed antiseizure medications, sleep optimization strategies, and orexin/hypocretin system interventions. This understanding enables a paradigm shift from simple seizure suppression toward targeted restoration of physiological brain rhythms, promising transformative epilepsy management through sleep-informed precision medicine. Full article

Objective: Investigate patient characteristics, treatments used, treatment response, and factors associated with outcomes when managing SE in a pediatric population admitted to the emergency department (ED). Methods: This retrospective observational study included pediatric patients (age ≤ 18 years) with SE admitted to the ED at King Khalid University Hospital between 2015 and 2023. SE and refractory SE (RSE) were diagnosed according to the American Epilepsy Society (AES) definitions. The data included demographics, home medications, treatment sequences, medication dosing, and clinical outcomes. To assess appropriateness, the administered doses were compared with the AES standards for pediatric patients. Results: The study included 487 episodes of SE. The mean patient age was 6.1 ± 4.1 years, and most patients were males (57.3%) with a history of epilepsy (74.1%). Benzodiazepines (BDZs) were administered first in 83.0% of cases, with a 10.9% success rate, whereas anti-seizure medications (ASMs) were administered first in 17.0% of cases, with a 66.3% success rate (p < 0.0001). Surprisingly, medications administered at appropriate doses during the first round were significantly less effective compared to those that were underdosed (18.2% vs. 28.4%; p = 0.0222), mainly because of poor response to BDZs. Younger patients and those who received BDZs on their first medication round had higher hospital admission rates. Conclusions: ASMs were more effective than BDZs in managing pediatric patients with SE, regardless of the dosing precision. These findings point toward the adoption of personalized treatment strategies and may warrant early initiation of ASMs. National multicenter studies are needed to define a standardized pediatric SE protocol. Full article

Fetal exposure to antiseizure medications (ASMs) can impact organogenesis, resulting in elevated risk of congenital malformations. Despite longstanding clinical awareness of the teratogenic potential of ASMs, the molecular mechanisms remain largely unexplored. To address this multisystem impact of ASMs, an OMIC-based approach was considered to understand the impact of ASMs on methylome and subsequently on proteome and how folic acid (FA) supplementation can counter the teratogenic impact. The study employed an established in vitro embryonic cell line model system, treated with varying concentrations of first-generation ASMs, alone and in combination with FA. Integrated analyses included quantification of global DNA methylation, expression analysis of key epigenetic regulators (DNMTs and TETs), genome-wide methylation profiling using the 935K EPIC array, and LC-MS/MS-based proteomics analysis. The study identified that ASMs can induce global DNA hypomethylation, which was likely to be impacted by dysregulation of DNMT and TET expression. Interestingly, FA co-treatment partially restored DNA methylation as evidenced by global DNA methylation and epigenetic gene expression, and also by compensatory effect via one-carbon metabolism. Genome-wide DNA methylation revealed site-specific hypermethylation at key developmental genes, several of which were reversed with FA. Proteomics analysis identified downregulation of developmentally critical proteins, including those linked to key metabolic processes, while FA co-treatment reversed expression of several such proteins. Integrative methylome–proteome analysis revealed the coordinated regulation of target genes that are linked to congenital abnormalities. Together, these findings offer mechanistic insight into ASM-induced teratogenesis and support FA’s potential to mitigate epigenetic and proteomic disruptions. This integrated OMICs based approach identifies key biomarkers which can be used for therapeutic monitoring and help in optimizing maternal epilepsy management. Full article

Attraction of glioblastoma cells to potassium was suspected when glioblastoma cells clustered around dying cells and migrated towards serum (high [K⁺]) and increased potassium. Potassium channel proteins (KCN family, 90 members) mediating alterations in the transmembrane flux may provide K⁺ that releases H⁺ bound to inner membranes in cancer cells for cytosolic proton transfer, possibly conformational in water (Grotthuss), to extrusion sites. Cell settling and migration assay results led to collecting 70 studies, unbiased by the authors for inclusion of KCN genes, that detected KCN differentially expressed genes (DEGs). Of 53 KCN DEGs found among 29 malignancies, 62.3% encoded H⁺-sensitive proteins. KCN DEGs encoding H⁺-sensitive proteins were more prevalent in 50 studies involving one or more categories (seven oncogenes and histone/DNA modifiers) versus those with none; p = 0.0325. Pertinent genes for lactate outflow, etc., had relatively normal levels of expression. Brain tumors in REMBRANDT (database) showed altered expression of KCN genes encoding H⁺-sensitive proteins in glioblastomas versus less invasive oligodendrogliomas of patients on anti-seizure medications, with less KCNJ16/Kir5.1; p = 5.32 × 10⁻⁸ in glioblastomas. Altered H⁺-sensitive potassium flux via the KCN family, downstream of oncogenes and histone/DNA modifiers, putatively incites proton transfers for H⁺ release during pH reversal (pHi > pHe) in cancer. Full article

Epilepsy is a chronic neurological disease with a relatively high incidence in the pediatric population. Anti-seizure medication (ASM) may cause adverse drug reactions (ADRs), which may occur repeatedly. Objective: This study aimed to analyze the recurrence of ADRs caused by ASMs over a period of 122 months in hospitalized Mexican pediatric epilepsy patients. The patients were under monotherapy or polytherapy treatment, with valproic acid (VPA), phenytoin (PHT), and levetiracetam (LEV), among others. A total of 313 patients met the inclusion criteria: 211 experienced ADRs, whereas 102 did not. Patient sex, age, seizure type, nutritional status and related drugs were considered explanatory variables. Methods: Four statistical models were used to analyze recurrent events that were defined as “one or more ADRs occurred on a single day”, considering both the classification of ADR seriousness and the ASM causing the ADR. Results: A total of 499 recurrence events were identified. The recurrence risk was significantly greater among younger patients for both nonsevere and severe ADRs and among those with focal seizures for nonsevere ADRs. Interestingly, malnutrition was negatively associated with the risk of nonsevere ADRs, and obesity was positively associated with the risk of severe ADRs. Finally, LEV was associated with a significantly greater risk of causing nonsevere ADRs than VPA. However, LEV significantly reduced the risk of severe ADRs compared with VPA, and PHT increased the risk in comparison with VPA. In conclusion, this study offers a robust clinical tool to predict risk factors for the presence and recurrence of ASM-ADRs in pediatric patients with epilepsy. Full article

Background/Objectives: The aim of this study was to elucidate the associations between the use of various ASMs and systemic anti-inflammatory effects in a single large cohort using routine blood tests. Methods: Patients who underwent blood tests within three months of their first visit to our clinic were included. The systemic inflammatory index (SII, platelet × neutrophil/lymphocyte ratio), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), and fibrinogen–albumin ratio (FAR) were compared across specific ASMs. Data from a total of 1782 patients with epilepsy were analyzed. Results: Multiple linear regression analysis revealed that valproate use was significantly associated with lower SII, PLR, and FAR values. Additionally, carbamazepine and oxcarbazepine use were associated with the FAR, whereas topiramate use was associated with the PLR. When a dichotomized category for each inflammatory marker was used, dividing the lowest quartile and the other quartiles, VPA use was significantly associated with all four markers. Topiramate use was associated with lower SII, NLR, and PLR values, and carbamazepine use was associated with lower SII, FAR, and PLR values. Conclusions: These findings highlight the closer association between valproate, compared to other ASMs, and systemic inflammatory responses. These findings may offer valuable insights into the underlying mechanisms of the therapeutic effects of valproate. Full article

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access. Full article

The assessment of the efficacy of antiseizure medications (ASMs) in animal models of acute seizures has played a critical role in these drugs’ success in clinical trials for human epilepsy. One of the most widely used animal models for this purpose is the maximal electroshock seizure (MES) model. While there are numerous published reports on the efficacy of conventional ASMs in MES models, there is a need to expand the understanding on the brain concentrations that are needed to achieve optimal levels of efficacy in this model. We assessed the pharmacokinetic/pharmacodynamic (PK/PD) profiles of six ASMs, namely carbamazepine (CBZ), phenytoin (PHT), valproic acid (VPA), lacosamide (LSM), cenobamate (CNB), and retigabine (RTG), using MES models in mice and rats. EC₅₀ values for plasma and the brain were generally higher in mice than rats, with fold differences ranging from 1.3- to 8.6-fold for plasma and from 1.2- to 11.5-fold for brain. Phenytoin showed the largest interspecies divergence. These results suggest that rats may exhibit greater sensitivity to seizure protection in the MES model, likely reflecting species differences in metabolism and brain penetration. These findings highlight the value of considering concentration–response variations and species-specific differences when assessing the efficacy of both conventional ASMs and novel compounds exhibiting anticonvulsant activity. Full article

This study describes the development and validation of a fully automated workflow for serum sample preparation, enabling the quantitative determination of cannabidiol (CBD) and its active metabolite, 7-hydroxy-CBD, via liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) analysis. Implemented on an automated platform, the workflow performs key steps such as solvent dispensing, mixing, centrifugation, filtration, and supernatant transfer, producing 96-well plates ready for analysis. Human serum samples were obtained from patients with epilepsy treated with CBD. All samples were processed using both manual and automated methods to evaluate method agreement. Quantification was performed by LC–MS/MS with CBD-d₃ as the internal standard (IS). Method validation was conducted in accordance with European Medicine Agency (EMA) guidelines, confirming that the automated protocol meets the recommended acceptance criteria for both intraday and interday precision and accuracy. Calibration curves demonstrated excellent linearity across the concentration ranges. Comparative analysis using Passing–Bablok regression and Bland–Altman plots demonstrated strong agreement between the methods. These findings support the clinical applicability of the automated method for the therapeutic drug monitoring (TDM) of CBD and 7-hydroxy-CBD, and its robust performance and scalability provide a solid foundation for the development of an expanded analytical panel covering a broader range of antiseizure medications (ASMs), enabling more standardized TDM protocols in clinical practice. Full article

Background: The central variant of posterior reversible encephalopathy syndrome (cvPRES) is an atypical subtype of PRES. Although no unifying definitions exists, it is most often characterized by vasogenic edema involving “central” structures, such as the brainstem, subcortical nuclei, and spinal cord, with relative sparing of the parieto-occipital lobes. Methods: This systematic review and meta-analysis followed the PRISMA guidelines and was pre-registered on PROSPERO [CRD42023483806]. Both the Joanna Briggs Institute and New-Castle Ottawa scale were used for case reports and cohort studies, respectively. The meta-analysis was completed using R-Studio and its associated “metafor” package. Results: A comprehensive search in four databases yielded 70 case reports/series (n = 100) and 12 cohort studies. The meta-analysis revealed a pooled incidence rate of 13% (95% CI: 9–18%) for cvPRES amongst included cohort studies on PRES. Significant heterogeneity was observed (I² = 71% and a τ² = 0.2046). The average age of affected individuals was 40.9 years, with a slightly higher prevalence in males (54%). The most common etiological factor was hypertension (72%). Fifty percent had an SBP >200 mmHg at presentation and a mean arterial pressure (MAP) of 217.6 ± 40.82. Imaging revealed an increased T₂ signal involving the brain stem (88%), most often in the pons (62/88; 70.45%), and 18/100 (18%) cases of PRES with spinal cord involvement (PRES-SCI). Management primarily involved blood pressure reduction, with adjunctive therapies for underlying causes such as anti-seizure medications or hemodialysis. The MAP between isolated PRES-SCI and cvPRES without spinal cord involvement did not show significant differences (p = 0.5205). Favorable outcomes were observed in most cases, with a mortality rate of only 2%. Conclusions: cvPRES is most often associated with higher blood pressure compared to prior studies with typical PRES. The pons is most often involved. Despite the severity of blood pressure and critical brain stem involvement, those with cvPRES have favorable functional outcomes and a lower mortality rate than typical PRES, likely attributable to reversible vasogenic edema without significant neuronal dysfunction. Full article

Objectives: The aim of this study was to evaluate the effectiveness of sequential treatments with adrenocorticotropic hormone (ACTH) or ketogenic diet therapy (KDT) in infants with infantile epileptic spasms syndrome (IESS) who did not achieve seizure freedom after initial treatment with either KDT or ACTH. Methods: We conducted a cohort study following a parallel-cohort randomized controlled trial comparing KDT with ACTH as first-line treatment for IESS. Infants who failed to respond were switched per protocol to the alternative treatment (ACTH or KDT) or, if this was not feasible or unsuccessful, to anti-seizure medications (ASMs). The primary outcome was the frequency of sustained seizure freedom at last follow-up. Results: Of 101 infants allocated to the initial treatment phase, N = 67 required further treatment. Of these, 31% (21/67) achieved sustained seizure freedom after the second treatment phase, and 15% (7/46) after rescue treatment with ASMs. KDT as the second treatment achieved sustained seizure freedom in 50% (12/24), compared to 19% (3/16) with ACTH and 9% (2/22) with ASMs. The cumulative response rate after the first and second treatments was 64% for the KDT-ACTH sequence and 68% for the ACTH-KDT sequence. The cumulative response after all three treatment phases was 78% (KDT-ACTH-ASM) and 72% (ACTH-KDT-ASM), respectively. Conclusions: KDT is at least as effective as ACTH as a second treatment and significantly more effective than ASMs in achieving sustained seizure freedom in infants with IESS. Full article

Background: Oxidative stress is associated with the pathogenesis of epilepsy. Long-term treatment with anti-seizure medications (ASMs) may reduce antioxidant levels, which consequently impairs the brain’s ability to counteract oxidative damage. This study aimed to assess the concentrations of selected antioxidants (i.e., glutathione, retinol, and α- and γ-tocopherols) in children with epilepsy treated with polytherapy. Methods: The study included 21 children with epilepsy treated with ≥2 ASMs for at least 6 months (mean age 7.1 ± 4.4 years) and 23 control children without epilepsy (mean age 7.4 ± 3.9 years). Both groups were recruited at the Department of Pediatric Neurology, the Medical University of Silesia in Katowice (Poland). The concentrations of glutathione, retinol, and α- and γ-tocopherols were determined in blood serum by HPLC. The antioxidant levels were compared between sex and age subgroups of individuals with epilepsy. Results: In the group of individuals with epilepsy, the percentage of females was 38% and in the control group it was 30%. There were no differences in antioxidant levels between female and male individuals with epilepsy, nor between younger epileptic children (0–6 years) and older children (>6 years). Individuals with epilepsy had significantly lower glutathione levels than the control group (1.5 ± 0.3 µmol/L vs. 2.4 ± 1.2 µmol/L, respectively, p < 0.001). In turn, the ratios of both α-tocopherol/glutathione and γ-tocopherol/glutathione were higher in individuals with epilepsy than in the control group (p = 0.042 and p = 0.004, respectively). Individuals with epilepsy taking ASM combinations other than valproic acid (VPA) and levetiracetam (LEV) had a lower level of both retinol and glutathione than individuals on VPA and LEV treatment (for retinol 0.44 ± 0.13 µmol/L vs. 0.6 ± 0.1 µmol/L, respectively, p = 0.047, and for glutathione 1.3 ± 0.3 µmol/L vs. 1.8 ± 0.3 µmol/L, respectively, p = 0.003). In the individuals with epilepsy, the level of α-tocopherol decreased with age (r = −0.505, p = 0.019). In turn, in the control group, the levels of retinol and γ-tocopherol increased with age (r = 0.573, p = 0.004 and r = 0.461, p = 0.027, respectively). Conclusions: Glutathione levels significantly differed between children with and without epilepsy. The concentration of α-tocopherol decreased with age in pediatric individuals with epilepsy. The levels of both retinol and glutathione were higher in individuals with epilepsy taking VPA and LEV treatment compared to individuals on ASMs combination other than VPA and LEV. Full article

Background and Objectives: The use of antiseizure medications (ASMs) during pregnancy is critical to seizure control in women with epilepsy but raises concerns regarding the use of these drugs and their possible effect on the maternal serum biochemical markers used for second-trimester prenatal screening. The aim of this study was to assess the effect of ASMs on the levels of maternal serum alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG) assessed in the serum biomarker analyses part of second-trimester prenatal screening. Materials and Methods: This retrospective cohort study included 43 pregnant women in the ASM-exposed group (levetiracetam, lamotrigine, carbamazepine, or combined therapy) and 43 matched controls without medication use. Groups were matched based on maternal age, gravidity, parity, abortion history, gestational age at testing, body mass index, and smoking status with propensity score matching. Serum AFP, uE3, and hCG levels measured at 15–20 weeks of gestation were compared between groups. The incidence of fetal congenital anomalies or aneuploidies was also compared between groups. Results: Pregnant women in the ASM-exposed group had significantly higher maternal serum AFP (1.34 ± 0.42 vs. 1.01 ± 0.31 MoM; p < 0.001) and uE3 (1.28 ± 0.39 vs. 1.05 ± 0.34 MoM; p = 0.004) than the controls. However, hCG did not differ significantly between the groups (1.07 ± 0.46 vs. 1.01 ± 0.42 MoM; p = 0.523). Regarding the ASM subgroups (levetiracetam, lamotrigine, and carbamazepine), there were no significant differences in the serum biomarkers (p > 0.05). There was no significant difference between the ASM-exposed and control groups in terms of the incidence of congenital anomalies or aneuploidies (2.3% in the ASM-exposed group vs. 2.3% in the control group; p = 1.000). Conclusions: The use of ASMs during pregnancy significantly alters second-trimester maternal serum biochemical markers, including our primary concerns, AFP and uE3, which could cause inaccurate interpretations of second-trimester prenatal screening. Clinicians should carefully consider maternal medication exposure when interpreting these biochemical markers in pregnant women with epilepsy to prevent the misclassification of fetal risks and avoid unnecessary invasive procedures. Full article

Purpose: Cognitive decline is a major concern for nasopharyngeal carcinoma (NPC) survivors after radiotherapy (RT). We assessed whether the rates of cognitive decline in NPC survivors differed depending on the presence of epilepsy. Methods: Based on an ongoing prospective cohort study (NCT03908502), we included consecutive NPC patients with a history of radiotherapy who underwent a baseline and follow-up cognition assessment between January 2005 and December 2023. Patients who had a confirmed diagnosis of epilepsy before radiotherapy, had intracranial brain metastasis during follow-up, lacked baseline major clinical data, or lacked follow-up cognitive assessment of longer than six months were excluded. The outcome was cognitive function assessed by the Chinese version of the Montreal Cognitive Assessment (MoCA), with assessments being performed every 6 months through face-to-face interviews. Linear mixed-effect models were used to analyze the progression rate of MoCA scores by epilepsy status (incident, prevalent, or no epilepsy). Results: A total of 521 patients with a median follow-up period of 3.96 years were included in our study. The rate of decline in MoCA was significantly faster in patients with prevalent epilepsy compared with no epilepsy after adjusting for demographics, health behaviors, tumor-related history, complications, anti-seizure medication, and inflammatory blood index (estimate: −1.407; 95%CI: −2.419, −0.412; p = 0.007). However, the cognitive decline rate was similar in the incident epilepsy group compared with that in the non-epilepsy group (p = 0.126). Subgroup analysis showed that there was no significant difference in the effect of epilepsy status on cognitive deterioration among subgroups stratified by the pre-planned covariates. Conclusions: Global cognitive function declined more rapidly in NPC patients with prevalent epilepsy. The control of seizure attacks may be valuable to mitigate cognitive decline. Full article