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Background: Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. Objectives: To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). Animals: Study included 56 client‐owned dogs newly diagnosed with IE. Methods: This was a prospective multicenter, open‐label, uncontrolled study. All dogs were ASM‐naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7‐14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12‐week maintenance treatment period were compared with those from the 4‐ to 12‐week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. Results: Fifty‐six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7‐8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0‐48.0) μg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. Conclusions and Clinical Importance: Our study suggests that ZNS monotherapy is effective and well‐tolerated in dogs with newly diagnosed IE. [ABSTRACT FROM AUTHOR]

Ultrathin molecularly imprinted polymer (MIP) films were deposited on the surfaces of ZnO nanorods (ZNRs) and nanosheets (ZNSs) by electropolymerization to afford extended-gate field-effect transistor sensors for detecting phenytoin (PHT) in plasma. Molecular imprinting efficiency was optimized by controlling the contents of functional monomers and the template in the precursor solution. PHT sensing was performed in plasma solutions with various concentrations by monitoring the drain current as a function of drain voltage under an applied gate voltage of 1.5 V. The reliability and reproducibility of the fabricated sensors were evaluated through a solution treatment process for complete PHT removal and PHT adsorption-removal cycling, while selectivity was examined by analyzing responses to chemicals with structures analogous to that of PHT. Compared with the ZNS/extracted-MIP sensor and sensors with non-imprinted polymer (NIP) films, the ZNR/extracted-MIP sensor showed superior responses to PHT-containing plasma due to selective PHT adsorption, achieving an imprinting factor of 4.23, detection limit of 12.9 ng/mL, quantitation limit of 53.0 ng/mL, and selectivity coefficients of 3–4 (against tramadol) and ~ 5 (against diphenhydramine). Therefore, we believe that the MIP-based ZNR sensing platform is promising for the practical detection of PHT and other drugs and evaluation of their proper dosages. [ABSTRACT FROM AUTHOR]

Abstract Background Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. Objectives To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). Animals Study included 56 client‐owned dogs newly diagnosed with IE. Methods This was a prospective multicenter, open‐label, uncontrolled study. All dogs were ASM‐naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7‐14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12‐week maintenance treatment period were compared with those from the 4‐ to 12‐week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. Results Fifty‐six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7‐8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0‐48.0) μg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. Conclusions and Clinical Importance Our study suggests that ZNS monotherapy is effective and well‐tolerated in dogs with newly diagnosed IE.

Seyhan Taskin,1 Seyma Ozsoy,2 Ziya Cakir3 1Department of Physiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey; 2Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey; 3Vocational Higher School of Health Services, Tokat Gaziosmanpasa University, Tokat, TurkeyCorrespondence: Seyhan Taskin, Department of Physiology, Faculty of Medicine, Harran University, Osmanbey Campus, Haliliye, Sanliurfa, 63300, Turkey, Tel +90 4143183000, Fax +90 414318 31 92, Email seyhan_taskin@yahoo.comPurpose: A combination of antiepileptic drugs and antioxidants may be an effective treatment by restoring the disrupted redox balance and reducing oxidative stress exposure to neurons. This study aims to evaluate the effects of valproate and vitamin B12 on oxidative stress in an experimental epilepsy model induced by penicillin when administered alone or in combination.Patients and Methods: 35 male Wistar rats were used in this study. The rats were divided into five groups, which were saline group, 1 mg/kg, 2 mg/kg Vit B12 groups and Sodium valproate group Sodium valproate + Vit B12 group. The epileptic activity was induced by 500 IU of penicillin injection. Sodium valproate and Vitamin B12 were administered 30 min after penicillin administration. Electrocorticogram recordings were taken for 2 hours post-treatment and serum parameters were assessed for oxidative stress markers using spectrophotometric method.Results: There is statistically significant difference between the groups in total antioxidant status, total oxidant status, and oxidative stress index value (p=0.013; p˂0.001; p˂0.001, respectively). The valproate+vitamin B12 group showed elevated total thiol and native thiol levels, along with reduced disulphide levels, resulting in the lowest OSI value.Conclusion: These findings suggest the combined treatment effectively reduces oxidative stress. This study provides valuable insights into the antioxidant properties of valproate and vitamin B12, positioning them as potential agents for managing epilepsy. Understanding the efficacy and reliability of antioxidant strategies in epilepsy management could contribute significantly to advancements in epilepsy therapeutics.Keywords: epilepsy, animal model, antiepileptic drug, Vitamin B12, oxidative stress

Abstract The current study developed an innovative design for the production of smart multifunctional core-double shell superparamagnetic nanoparticles (NPs) with a focus on the development of a pH-responsive drug delivery system tailored for the controlled release of Phenytoin, accompanied by real-time monitoring capabilities. In this regard, the ultra-small superparamagnetic iron oxide@silica NPs (IO@Si MNPs) were synthesized and then coated with a layer of gelatin containing Phenytoin as an antiepileptic drug. The precise saturation magnetization value for the resultant NPs was established at 26 emu g-1. The polymeric shell showed a pH-sensitive behavior with the capacity to regulate the release of encapsulated drug under neutral pH conditions, simultaneously, releasing more amount of the drug in a simulated tumorous-epileptic acidic condition. The NPs showed an average size of 41.04 nm, which is in the desired size range facilitating entry through the blood–brain barrier. The values of drug loading and encapsulation efficiency were determined to be 2.01 and 10.05%, respectively. Moreover, kinetic studies revealed a Fickian diffusion process of Phenytoin release, and diffusional exponent values based on the Korsmeyer-Peppas equation were achieved at pH 7.4 and pH 6.3. The synthesized NPs did not show any cytotoxicity. Consequently, this new design offers a faster release of PHT at the site of a tumor in response to a change in pH, which is essential to prevent epileptic attacks.

Abstract Introduction It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. Methods A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. Results PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. Conclusion Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies.

Many physical and chemical properties of solids, such as strength, plasticity, dispersibility, solubility and dissolution are determined by defects in the crystal structure. The aim of this work is to study in situ dynamic, dispersion, chemical, biological and surface properties of lacosamide powder after a complete cycle of mechanical loading by laser scattering, electron microscopy, FR-IR and biopharmaceutical approaches. The SLS method demonstrated the spontaneous tendency toward surface-energy reduction due to aggregation during micronisation. DLS analysis showed conformational changes of colloidal particles as supramolecular complexes depending on the loading time on the solid. SEM analysis demonstrated the conglomeration of needle-like lacosamide particles after 60 min of milling time and the transition to a glassy state with isotropy of properties by the end of the tribochemistry cycle. The following dynamic properties of lacosamide were established: elastic and plastic deformation boundaries, region of inhomogeneous deformation and fracture point. The ratio of dissolution-rate constants in water of samples before and after a full cycle of loading was 2.4. The lacosamide sample, which underwent a full cycle of mechanical loading, showed improved kinetics of API release via analysis of dissolution profiles in 0.1 M HCl medium. The observed activation-energy values of the cell-death biosensor process in aqueous solutions of the lacosamide samples before and after the complete tribochemical cycle were 207 kJmol−1 and 145 kJmol−1, respectively. The equilibrium time of dissolution and activation of cell-biosensor death corresponding to 20 min of mechanical loading on a solid was determined. The current study may have important practical significance for the transformation and management of the properties of drug substances in solid form and in solutions and for increasing the strength of drug matrices by pre-strain hardening via structural rearrangements during mechanical loading. [ABSTRACT FROM AUTHOR]

Introduction: It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. Methods: A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. Results: PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. Conclusion: Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies. [ABSTRACT FROM AUTHOR]

The current study developed an innovative design for the production of smart multifunctional core-double shell superparamagnetic nanoparticles (NPs) with a focus on the development of a pH-responsive drug delivery system tailored for the controlled release of Phenytoin, accompanied by real-time monitoring capabilities. In this regard, the ultra-small superparamagnetic iron oxide@silica NPs (IO@Si MNPs) were synthesized and then coated with a layer of gelatin containing Phenytoin as an antiepileptic drug. The precise saturation magnetization value for the resultant NPs was established at 26 emu g-1. The polymeric shell showed a pH-sensitive behavior with the capacity to regulate the release of encapsulated drug under neutral pH conditions, simultaneously, releasing more amount of the drug in a simulated tumorous-epileptic acidic condition. The NPs showed an average size of 41.04 nm, which is in the desired size range facilitating entry through the blood–brain barrier. The values of drug loading and encapsulation efficiency were determined to be 2.01 and 10.05%, respectively. Moreover, kinetic studies revealed a Fickian diffusion process of Phenytoin release, and diffusional exponent values based on the Korsmeyer-Peppas equation were achieved at pH 7.4 and pH 6.3. The synthesized NPs did not show any cytotoxicity. Consequently, this new design offers a faster release of PHT at the site of a tumor in response to a change in pH, which is essential to prevent epileptic attacks. [ABSTRACT FROM AUTHOR]

There are limited data on severe cutaneous adverse reactions (SCARs) associated with antiepileptic medications. The current study aims to investigate the clinical and epidemiological characteristics of antiepileptic medication-induced SCARs in hospitalized children. This five-year retrospective study was conducted at Isfahan University of Medical Sciences, Iran. The study included all children with a diagnosis of SCARs secondary to antiepileptic medications as defined by the World Health Organization (WHO). In our study SCARs were categorized into three groups: drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and a group with symptoms overlapping between maculopapular eruptions (MPE) and DRESS. Among 259 children with SCARs induced by antiepileptic medications, 199 (76.83%), 42 (16.22%), and 18 (6.95%) had overlapping MPE/DRESS, DRESS, and SJS/TEN, respectively. Phenobarbital was the most common offending drug among SCARs. The multinomial logistic regression model revealed that lymphadenopathy increased DRESS occurrence by 35 times compared to overlapping MPE/DRESS. Girls were at risk of SJS/TEN approximately 6 times more than boys. Age, weight, and mucosal involvement affected hospitalization duration in children with SCARs related to antiepileptic medication. There are some similarities and differences in the clinical and epidemiological features of Iranian children suffering from antiepileptic medication-induced SCARs. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) prognosis is incredibly poor and is often associated with considerable morbidity. Seizures are commonly present in these patients, and their biopsychosocial impact can be dangerous. The use of antiepileptic drugs (AEDs) as primary prophylaxis remains controversial. This systematic review and meta-analysis aim to evaluate the efficacy of AED prophylaxis in patients with BM. MEDLINE via PubMed, Web of Science, EMBASE, and Cochrane were searched for articles pertinent to AED prophylaxis use in patients with BM. Patients with BM previously treated for cancer who were seizure naive at the time of inclusion were included. Data regarding patient characteristics, type of AED, prior treatments, and groups at a high risk of seizure were extracted. Seizure prevalence was obtained. Eight studies were included in this systematic review and meta-analysis; 1902 total patients with BM were included, with 381 receiving antiepileptic prophylaxis, and 1521 receiving no prophylaxis. Although the odds of a seizure in the treatment group was found to be 1.158 times the odds of a seizure in the control group, the odds ratio was not statistically significant (t-statistic = 0.62, P value = 0.5543). There was no significant difference in the odds of seizure development in control groups compared to patients receiving prophylactic antiepileptic therapy. As patients with BM present with heterogeneity in tumor characteristics and receive various treatment modalities, future research is needed to identify groups that may benefit more significantly from AED prophylaxis. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is pivotal in maintaining neuronal physiology within the brain. This review delves into the alterations of the BBB specifically in the context of geriatric epilepsy. We examine how age-related changes in the BBB contribute to the pathogenesis of epilepsy in the elderly and present significant challenges in pharmacotherapy. Subsequently, we evaluate recent advancements in drug delivery methods targeting the BBB, as well as alternative approaches that could bypass the BBB's restrictive nature. We particularly highlight the use of neurotropic viruses and various synthetic nanoparticles that have been investigated for delivering a range of antiepileptic drugs. Additionally, the advantage and limitation of these diverse delivery methods are discussed. Finally, we analyze the potential efficacy of different drug delivery approaches in the treatment of geriatric epilepsy, aiming to provide insights into more effective management of this condition in the elderly population. [ABSTRACT FROM AUTHOR]

Therapeutic management of epilepsy is usually long term; thus, patient tolerability of prescribed antiepileptic drugs should be a major consideration as it affects compliance to therapy. The aim of this study was to determine the impact of pharmaceutical care services on antiepileptic drug tolerability among patients living with epilepsy. This study was an open, randomized, controlled, longitudinal and two-arm parallel prospective study with a 6-month patient follow-up period. Patients were recruited from the neurology and medical out-patient clinics of two selected epilepsy referral centres. Recruited patients were randomized into one of the two study groups: pharmaceutical care (PC) or usual care (UC) groups. Patients in the UC group received the usual care provided in the hospitals, while patients in the PC group received PC services in addition to the usual care provided in the hospitals. The impact of PC on patient tolerability of antiepileptic drugs was evaluated using a patient judged antiepileptic drug tolerabiltity scale. The evaluation was done at baseline (pre-intervention), 3 months and 6 months post-intervention. Patients in the PC group had a significantly lower antiepileptic drug tolerability score than those of the UC group at 3 months and 6 months - (Pre-intervention: 0.97 versus 1.13; t = −1.081; p = 0.281), (3 months: 1.13 versus 0.71; t = 3.084; p = 0.001), (6 months: 1.00 versus 0.60; t = 3.083; p = 0.001), indicating a significant improvement in the tolerability of antiepileptic drugs among those in the PC group over time. Pharmaceutical care interventions that included education and counseling services significantly improved tolerability of antiepileptic drugs among patients living with epilepsy. [ABSTRACT FROM AUTHOR]

Objective Antiepileptic drugs used in the treatment of epilepsy patients have a negative effect on bone tissue, but as far as we know, tooth root resorption has not been investigated in these patients. The aim of this study was to evaluate the prevalence of external and internal root resorption and its distribution according to resorption sites in epilepsy patients using antiepileptic drugs. Material and Method Panoramic radiographs obtained before dental treatment were evaluated. While the case group consisted of only those with epilepsy, the control group included healthy subjects. The presence/absence of external and internal resorption of all teeth (except the third molars), region of resorption (cervical, middle, and apical region of the root), age, and sex were recorded in an excel file. Independent sample t-test or MannWhitney U test according to normality of distribution and a chi-square test to compare categorical variables were used. Results The resorption in 93 (21.9%) of 424 patients (236 healthy subjects and 188 epileptic patients), the groups did not significantly differ by the presence of external and internal resorption (p = 0.089 and 0.746). It was more common in those over 30 years and males (p = 0.018 and 0.013). Conclusion We concluded that the presence of resorption in epilepsy patients was not different from healthy subjects. However, in patients with epilepsy, resorption was mostly seen in the lower molars and middle 1/3 regions. Clinicians should consider our results when treating these patients. [ABSTRACT FROM AUTHOR]

Refractory status epilepticus (RSE) is defined as the persistence of either clinical or electrographic seizures despite the administration of appropriate doses of an initial benzodiazepine and suitable second-line antiepileptic drugs (AEDs). The Neurocritical Care Society and the American Epilepsy Society have proposed a treatment paradigm for the management of convulsive status epilepticus (CSE). The third-line therapy in refractory CSE may involve general anesthesia using intravenous midazolam, propofol, or other agents, while recent evidence supports the use of ketamine to manage RSE in both adults and children. However, although these treatment strategies are frequently employed in nonconvulsive status epilepticus (NCSE), the efficacy of AEDs and anesthetics in NCSE has not been thoroughly investigated. Recent evidence has demonstrated the safety and efficacy of newer AEDs, including levetiracetam and lacosamide, in the treatment of status epilepticus (SE) and RSE, which also encompasses NCSE. Use of multiple combinations of various intravenous AEDs can also be considered in NCSE before the administration of general anesthesia. In addition, AEDs alone exhibit limited effectiveness in managing SE for new-onset RSE (NORSE) and its subset, febrile infection-related epilepsy syndrome. Therefore, in cases of refractory status, it is imperative to explore treatment options beyond AEDs, including immunotherapy and the incorporation of a ketogenic diet. The present review suggests treatment approaches for RSE based on subgroups, including CSE, NCSE, and NORSE. A discussion of recent clinical studies on AEDs and anesthetics in the management of RSE, as well as proposed treatment methods for NORSE, is also provided.

Neuroelectric disruptions such as seizures and cortical spreading depolarization may contribute to the development of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH). However, effects of antiepileptic drug prophylaxis on outcomes remain controversial in SAH. The authors investigated if prophylactic administration of new-generation antiepileptic drugs levetiracetam and perampanel was beneficial against delayed neurovascular events after SAH. This was a retrospective single-center cohort study of 121 consecutive SAH patients including 56 patients of admission World Federation of Neurological Surgeons grades IV − V who underwent aneurysmal obliteration within 72 h post-SAH from 2013 to 2021. Prophylactic antiepileptic drugs differed depending on the study terms: none (2013 − 2015), levetiracetam for patients at high risks of seizures (2016 − 2019), and perampanel for all patients (2020 − 2021). The 3rd term had the lowest occurrence of delayed cerebral microinfarction on diffusion-weighted magnetic resonance imaging, which was related to less development of DCI. Other outcome measures were similar among the 3 terms including incidences of angiographic vasospasm, computed tomography-detectable delayed cerebral infarction, seizures, and 3-month good outcomes (modified Rankin Scale 0 − 2). The present study suggests that prophylactic administration of levetiracetam and perampanel was not associated with worse outcomes and that perampanel may have the potential to reduce DCI by preventing microcirculatory disturbances after SAH. Further studies are warranted to investigate anti-DCI effects of a selective α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist perampanel in SAH patients in a large-scale prospective study. [ABSTRACT FROM AUTHOR]

Objective: In the present study, we describe a novel class of small‐molecule synthetic compounds that ameliorate seizure‐like behavior, using an electroshock assay to examine seizure duration in Caenorhabditis elegans. We also examine the hypothesis that these compounds, which we have called resveramorphs (RVMs), act by an irreversible binding mechanism. Methods: Our electroshock assay examines seizure duration in C. elegans and can be used as a drug‐screening platform for the identification of novel anti‐seizure agents. The use of C. elegans allows for a rapid and efficient method of drug screening that may take years in other higher‐order model organisms. A novel wash method, paired with our electroshock assay, allows us to discern differences in biological activity when the C. elegans are incubated in different drug solutions, to establish whether these compounds can be "washed" off. Results: One of the RVMs (RVM‐3), reported here for the first time, was found to be potent at picomolar concentrations. Insights also provided information on the potential mechanisms of action of this compound. Covalent binding is thought to provide a strong irreversible bond because of a change in structure between two of the novel RVMs described in this work. This was also discerned through the novel wash method paired with our electroshock assay. Significance: RVM‐3 was evaluated using our assay and found to possess anti‐seizure activity at picomolar concentrations. These insights also provide information on the potential mechanisms of action of these compounds, which may include covalent binding. This was also discerned through a novel wash method paired with our electroshock assay. [ABSTRACT FROM AUTHOR]

Objective: Excessive pathology testing is associated with ED congestion, increased healthcare costs and adverse patient health outcomes. This study aimed to determine the frequency, yield and influence of pathology tests among patients presenting to the ED with atraumatic recurrent seizures. Methods: This was a retrospective cohort study conducted at a level 4 adult ED in Australia and included atraumatic patients presenting to ED with recurrent seizures over a 4‐year period (2017–2020). The primary outcome was the frequency of pathology tests. Additionally, the proportion of abnormal pathology test results and the association between pathology tests and change in management were assessed. Results: Of the 398 eligible presentations, 346 (86.9%, 95% confidence interval [CI] 83.3–89.9%) underwent at least one pathology test. In total 18.3% (n = 517) of pathology tests had an abnormal result which led to 15 changes in ED management among 12 presentations. Patients who had an abnormal pathology test result were more likely to undergo a change in antiepileptic drug management (odds ratio 2.08, 95% CI 1.23–3.65; P = 0.008). Conclusion: Most patients presenting to the ED with atraumatic recurrent seizures underwent pathology tests. Abnormalities were frequently detected but were uncommonly associated with change in management. Abnormal pathology test results were associated with changes in antiepileptic drug management although rarely led to acute changes in patient management. This study suggests that pathology tests may be excessively requested in this population. [ABSTRACT FROM AUTHOR]

Background: Cutaneous adverse reactions (CARs) are one of the most important reasons for anti-seizure medication (ASM) discontinuation in epilepsy. However, such discontinuations can cause an increase in seizures. This study investigates the risk factors for ASM-related rash recurrence in children. Methods: This retrospective case-control study consisted of the patient group with a single rash due to ASMs (group 1), the patient group with rash recurrence (group 2), and the control group. While the demographic and clinical features of group 1 and the control group were compared in terms of a single rash, group 1 and group 2 were compared for rash recurrence. Results: Group 1, group 2, and control group consisted of 112, 33, and 166 patients, respectively. Female gender was a risk factor for a single rash (P < 0.001) but not for recurrence (P = 0.439). Presence of atopic disease [odds ratio (OR): 9.5, 95% confidence interval (CI): 3.8-23.1, P < 0.001], family history of drug allergy (OR: 26.3, 95% CI: 9.6-72.1, P < 0.001), and polytherapy (OR: 23.5, 95% CI: 8.7-62.9, P < 0.001) were risk factors for rash recurrence. Aromatic nature of both the ASMs associated with the first rash (OR: 14.4, 95% CI: 3.2-63.2, P < 0.001) and rash recurrence (OR: 11.3, 95% CI: 4.6-27.5, P < 0.001) were determined as risk factors separately. Conclusion: Careful use of aromatic drugs may prevent recurrence of ASM-related CAR in children, particularly in cases of personal history of allergic disease and family history of drug allergy. [ABSTRACT FROM AUTHOR]

Objective: Historically, approximately half of those with newly diagnosed epilepsy have responded to and tolerated the first antiseizure medication (ASM), but there are few contemporary real‐world data. Third‐generation ASMs have improved tolerability and are increasingly used according to prescription data. We aimed to describe current ASM selection and retention in adult onset focal epilepsy in western Sweden. Methods: A multicenter retrospective cohort study was performed at five public neurology care providers in western Sweden (nearly complete coverage in the area). We reviewed 2607 medical charts and included patients diagnosed with nongeneralized epilepsy after January 1, 2020 who had a seizure onset after age 25 years (presumed focal onset) and were started on ASM monotherapy. Results: A total of 542 patients (median age at seizure onset = 68 years, interquartile range = 52–77) were included. Most patients received levetiracetam (62%) or lamotrigine (35%), with levetiracetam being more common among men and those with structural causes or short epilepsy duration. During follow‐up (median = 471.5 days), 463 patients (85%) remained on the first ASM. Fifty‐nine (18%) patients discontinued levetiracetam, and 18 (10%) ended treatment with lamotrigine (p =.010), most commonly because of side effects. In a multivariable Cox regression model, the discontinuation risk was higher for levetiracetam than lamotrigine (adjusted hazard ratio = 2.01, 95% confidence interval = 1.16–3.51). Significance: Levetiracetam and lamotrigine were the dominating first ASMs for adult onset focal epilepsy in our region, indicating good awareness of problems with enzyme induction or teratogenicity of older drugs. The most striking finding is the high retention rates, perhaps reflecting a shift toward an older epilepsy population, higher tolerability of newer ASMs, or suboptimal follow‐up. The finding that treatment retention differed among patients receiving levetiracetam and lamotrigine aligns with the recent SANAD II results. It suggests lamotrigine may be underutilized in our region and that education efforts are needed to ensure it is considered the first choice more often. [ABSTRACT FROM AUTHOR]

Many physical and chemical properties of solids, such as strength, plasticity, dispersibility, solubility and dissolution are determined by defects in the crystal structure. The aim of this work is to study in situ dynamic, dispersion, chemical, biological and surface properties of lacosamide powder after a complete cycle of mechanical loading by laser scattering, electron microscopy, FR-IR and biopharmaceutical approaches. The SLS method demonstrated the spontaneous tendency toward surface-energy reduction due to aggregation during micronisation. DLS analysis showed conformational changes of colloidal particles as supramolecular complexes depending on the loading time on the solid. SEM analysis demonstrated the conglomeration of needle-like lacosamide particles after 60 min of milling time and the transition to a glassy state with isotropy of properties by the end of the tribochemistry cycle. The following dynamic properties of lacosamide were established: elastic and plastic deformation boundaries, region of inhomogeneous deformation and fracture point. The ratio of dissolution-rate constants in water of samples before and after a full cycle of loading was 2.4. The lacosamide sample, which underwent a full cycle of mechanical loading, showed improved kinetics of API release via analysis of dissolution profiles in 0.1 M HCl medium. The observed activation-energy values of the cell-death biosensor process in aqueous solutions of the lacosamide samples before and after the complete tribochemical cycle were 207 kJmol−1 and 145 kJmol−1, respectively. The equilibrium time of dissolution and activation of cell-biosensor death corresponding to 20 min of mechanical loading on a solid was determined. The current study may have important practical significance for the transformation and management of the properties of drug substances in solid form and in solutions and for increasing the strength of drug matrices by pre-strain hardening via structural rearrangements during mechanical loading.

Background: Withdrawal of antiseizure medication treatment (ASM) can be considered after completion of antitumour treatment in glioma patients who no longer suffer from seizures. We compared the risk for recurrent seizures after ASM withdrawal between patients with short-term, medium-term versus long-term seizure freedom after antitumour treatment. Methods: In this retrospective observational study, the primary outcome was time to recurrent seizure, from the starting date of no ASM treatment up to 36 months follow-up. Cox proportional hazards models were used to study the effect of risk factors on time to recurrent seizure. Stratification was done with information known at baseline. Short-term seizure freedom was defined as ≥ 3 months, but < 12 months; medium-term as 12–24 months; and long-term as ≥ 24 months seizure freedom from the date of last antitumour treatment. Results: This study comprised of 109 patients; 31% (34/109) were in the short-term, 29% (32/109) in the medium-term, and 39% (43/109) in the long-term group. A recurrent seizure was experienced by 47% (16/34) of the patients in the short-term, 31% (10/32) in the medium-term, and 44% (19/43) in the long-term group. Seizure recurrence risk was similar between patients in the short-term group as compared to the medium-term (cause-specific adjusted hazard ratio [aHR] = 0.65 [95%CI = 0.29–1.46]) and long-term group (cause-specific aHR = 1.04 [95%CI = 0.52–2.09]). Conclusions: Seizure recurrence risk is relatively similar between patients with short-term, medium-term, and long-term seizure freedom after completion of antitumour treatment. [ABSTRACT FROM AUTHOR]

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged. [ABSTRACT FROM AUTHOR]

Although many anti-seizure medications (ASMs) are available, treatment failure, known as drug-resistant epilepsy (DRE), still occurs in around 30% of children with epilepsy. Second-line ASMs are usually used as substitution therapy in DRE to control seizures, although international consensus is not available yet. Previous studies focus on comparing the ASMs, whether as add-on or substitution therapy, mainly conducted in newly diagnosed epilepsy. However, the study that investigated first-line ASMs as substitution therapy compared to second-line ones, particularly among DRE children, is still lacking. A randomized controlled trial (RCT) enrolling 102 participants, aged 1-18, at three referral hospitals in Indonesia will be conducted, dividing them into intervention and control groups. The intervention group will be treated with first-line ASMs as the substitution therapy, while the other in the control group will get second-line ASMs. The primary outcome measure is the proportion difference of responders between groups who get first-line and second-line ASMs in 14 weeks of intervention. Clinical trial registration: ClinicalTrials.gov, identifier NCT05697614. [ABSTRACT FROM AUTHOR]

Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. The reported shortest synthetic route for pynegabine contains six steps and involves the manipulation of highly toxic methyl chloroformate and dangerous hydrogen gas. To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald–Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents. [ABSTRACT FROM AUTHOR]

Background: Status Epilepticus (SE) is a life-threatening neurological emergency requiring appropriate therapy to terminate seizure activity. SE is managed with supportive measures and ultra-short-acting benzodiazepines. However, limited data is available in the paediatric population regarding the next best option when this fails. This study aimed at finding new data to recommend levetiracetam or phenytoin as the second-line option. Methods: One hundred and thirty-seven patients with status epilepticus were randomized into two groups; group-I was given IV Levetiracetam (LEV) at 20 mg/kg/dose over 5 minutes followed by a maintenance dose of 20mg/kg/dose BID, whereas Group II received phenytoin at 20mg/kg IV loading dose followed by a maintenance dose of 5-8 mg/kg/day divided BID. The primary outcome was seizure cessation, defined as the termination of the apparent convulsion 30 min after the administration of phenytoin or levetiracetam. Secondary outcomes were the use of different anti-convulsants for continued management, admittance to critical treatment, and severe adverse events (including mortality, Stevens-Johnson syndrome, rash, airway problems, cardiovascular instability, extravasation, and severe agitation). Data was recorded via a clinical proforma and was analyzed by SPSS software version 25. All numerical data were expressed in mean±SD forms, and frequency was determined for qualitative baseline data. Secondary outcomes were tested through the χ2 test, A p-value of ≤0.05 was considered statistical significance. Results: Levetiracetam terminated seizures in 94% of children compared to 77% in those treated with phenytoin. The mean time to seizure termination was 19.94±3.76 minutes for the LEV Group as compared to 23.791±9.1 min for the PHT group. (p=0.046). Regarding safety, a profile study shows LEV has fewer and less severe side effects compared to Phenytoin. Conclusion: Levetiracetam is a safe, well-tolerated, and effective treatment as a second-line antiepileptic drug in the management of status epilepticus. [ABSTRACT FROM AUTHOR]

Although many anti-seizure medications (ASMs) are available, treatment failure, known as drug-resistant epilepsy (DRE), still occurs in around 30% of children with epilepsy. Second-line ASMs are usually used as substitution therapy in DRE to control seizures, although international consensus is not available yet. Previous studies focus on comparing the ASMs, whether as add-on or substitution therapy, mainly conducted in newly diagnosed epilepsy. However, the study that investigated first-line ASMs as substitution therapy compared to second-line ones, particularly among DRE children, is still lacking. A randomized controlled trial (RCT) enrolling 102 participants, aged 1–18, at three referral hospitals in Indonesia will be conducted, dividing them into intervention and control groups. The intervention group will be treated with first-line ASMs as the substitution therapy, while the other in the control group will get second-line ASMs. The primary outcome measure is the proportion difference of responders between groups who get first-line and second-line ASMs in 14 weeks of intervention.Clinical trial registration: ClinicalTrials.gov, identifier NCT05697614.

Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated NaC currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated NaC (INa) and hyperpolarization-activated cation currents (Ih) intrinsically in electrically excitable cells (GH3 cells). The effective IC50 values of CRS for the differential suppression of transient (INa.T/) and late INa (INa.L/) were 56.4 and 11.4 mM, respectively. However, CRS strongly decreased the strength (i.e., 1area) of the nonlinear window component of INa (INa.W/), which was activated by a short ascending ramp voltage (Vramp); the subsequent addition of deltamethrin (DLT, 10 mM) counteracted the ability of CRS (100 mM, continuous exposure) to suppress INa.W/. CRS strikingly decreased the decay time constant of INa.T/evoked during pulse train stimulation; however, the addition of telmisartan (10 mM) effectively attenuated the CRS (30 mM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 mM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of INa.T/and INa.L/. The amplitude of Ih activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC50 value of 38 mM. For Ih, CRS altered the steady-state I-V relationship and attenuated the strength of voltage-dependent hysteresis (Hys.V/) activated by an inverted isoscelestriangular Vramp. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys.V/. The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNaV1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNaV1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify INa.T/and INa.L/differentially and to effectively suppress the magnitude of Ih. INa and Ih are thus potential targets of the actions of CRS in terms of modulating cellular excitability. [ABSTRACT FROM AUTHOR]

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one‐third of epilepsy patients experience seizures despite therapy. Drug‐resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3–13.4 times higher mortality rate than in seizure‐free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic–clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long‐term, open‐label studies, 10%–36% of patients were seizure‐free for a median duration of ~30–45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open‐label extension studies. Mortality was reduced 5‐fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post‐launch information about the efficacy and safety of these ASMs. [ABSTRACT FROM AUTHOR]

Epilepsy is a common chronic neurological disease. The International League Against Epilepsy (ILAE) defines seizures as: the transient occurrence of signs or symptoms due to abnormally excessive or synchronous neuronal activity in the brain. About 70% of patients achieve seizure⁃free with appropriate medical treatment, but nearly one⁃third of patients still do not respond to current antiepileptic drugs (AED). The alpha subunits of voltage⁃gated sodium channels (VGSC) are encoded by a highly conserved gene family, of which mutations in SCN1A, SCN2A, and SCN8A genes are important causes of central nervous system diseases. Previous studies have shown that voltage⁃gated sodium channels play an important role in the pathological process of treatment⁃resistant epilepsy (TRE). In this review, the concept, pathogenesis and drug resistance mechanism of TRE were introduced in detail, meanwhile the role and mechanisms of VGSC in TRE were reviewed. [ABSTRACT FROM AUTHOR]

Selection criteria for clinical trials for medication‐resistant epilepsy are used to limit variability and to ensure safety. However, it has become more challenging to recruit subjects for trials. This study investigated the impact of each inclusion and exclusion criterion on medication‐resistant epilepsy clinical trial recruitment at a large academic epilepsy center. We retrospectively identified all patients with medication‐resistant focal or generalized onset epilepsy who attended an outpatient clinic over a consecutive 3‐month period. We assessed each patient's eligibility for trials with commonly required inclusion and exclusion criteria to evaluate the proportion of eligible patients and the most common reasons for exclusion. Among 212 patients with medication‐resistant epilepsy, 144 and 28 patients met the criteria for focal or generalized onset epilepsy, respectively. Overall, 9.4% (n = 20) patients were eligible for trials (19 focal onset and one generalized onset). Most patients were excluded from the study due to insufficient seizure frequency (58% of focal onset, 55% of generalized onset). A small proportion of patients with medication‐resistant epilepsy were eligible for trials based on common selection criteria. These eligible patients may not be representative of the general population of patients with medication‐resistant epilepsy. Insufficient seizure frequency was the most common reason for exclusion. [ABSTRACT FROM AUTHOR]

Active substances detected in surface water in Hungary today include pain and anti-inflammatory agents and antiepileptics, as wastewater treatment mechanisms cannot remove these micropollutants. The aim of our research is to detect residues of four pain-killer drugs—naproxen, nimesulide, diclofenac, and ibuprofen—and an anti-epileptic drug—carbamazepine—in water samples we collected (n = 8) from the Danube. Our samples were concentrated using solid-phase extraction and then detected with HPLC. During the evaluation, we looked for a significant difference in the concentration of the active substances. Naproxen was detectable in the largest amount in one sampling point, with an average concentration of 12,029.337 ± 1772.957 ng/L, while ibuprofen was present in the second highest concentration in another sampling site, which reached an average concentration of 4048.112 ± 2086.789 ng/L. We examined water samples taken from the same sampling sites but at different distances from the riverbank, and we found a significant difference regarding the active substance naproxen at the sampling site in Budapest District XX. The analytes were detected in varying amounts in all the water samples, so the contamination in the examined section is significant. Examining the turnover data on medicines and our results, we concluded that pharmaceutical consumption significantly contributes to the pollution of the Danube. In order to protect water quality, further research would be advisable in the field of mechanisms for wastewater treatment in order to achieve the complete removal of drug residues from wastewater. [ABSTRACT FROM AUTHOR]

Introduction: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe and life-threatening mucocutaneous conditions characterized by fever and necrosis of the epidermis. Up to 90% of cases are drug-induced. Antiseizure drugs (ASD) are known to cause SJS, but only a very few ethosuximide-induced SJS cases have been reported in the literature. Case presentation: We report a case of ethosuximide-induced SJS/TEN overlap in a 4-year-old boy, confirmed by patch tests, with improvement with intravenous immunoglobulin (IVIG) and systemic corticosteroid therapy cycle. Conclusion: This case highlights the need to expand knowledge about the optimal treatment strategy for these rare conditions, in addition to supportive treatment. [ABSTRACT FROM AUTHOR]

• Levetiracetam broad-spectrum and drug features led to a "one-for-all" overprescription. • Levetiracetam seems to be an optimal choice in some clinical scenarios, such as childbearing-aged and pregnant female patients with idiopathic generalized epilepsies and in Alzheimer's and down Syndrome-related epilepsies, as well as in some genetic epilepsies. • Levetiracetam is scarcely effective or even harmful in other clinical scenarios, such as in epilepsies related to malformations of cortical development, or patients with variants in PRRT2 or SV2A, as well as SCN8A with gain-of-function. Levetiracetam (LEV) is an antiseizure medication (ASM) whose mechanism of action involves the modulation of neurotransmitters release through binding to the synaptic vesicle glycoprotein 2A. It is a broad-spectrum ASM displaying favorable pharmacokinetic and tolerability profiles. Since its introduction in 1999, it has been widely prescribed, becoming the first-line treatment for numerous epilepsy syndromes and clinical scenarios. However, this might have resulted in overuse. Increasing evidence, including the recently published SANAD II trials, suggests that other ASMs are reasonable therapeutic options for generalized and focal epilepsies. Not infrequently, these ASMs show better safety and effectiveness profiles compared to LEV (partially due to the latter's well-known cognitive and behavioral adverse effects, present in up to 20% of patients). Moreover, it has been shown that the underlying etiology of epilepsy is significantly linked to ASMs response in particular scenarios, highlighting the importance of an etiology-based ASM choice. In the case of LEV, it has demonstrated an optimal effectiveness in Alzheimer's disease, Down syndrome, and PCDH19-related epilepsies whereas, in other etiologies such as malformations of cortical development, it may show negligible effects. This narrative review analyzes the current evidence related to the use of LEV for the treatment of seizures. Illustrative clinical scenarios and practical decision-making approaches are also addressed, therefore aiming to define a rational use of this ASM. [ABSTRACT FROM AUTHOR]

Background and Objectives: After failed epilepsy surgery, patients often revert to an antiseizure medication (ASM) ASM regimen, which can be adjusted or optimized in three ways: increasing the dose, alternative therapy, and combination therapy. It is unclear which type of antiseizure medication adjustment method can improve outcomes. Materials and Methods: Children who underwent failed epileptic resection surgery at the Department of Neurosurgery, Children's Hospital of Chongqing Medical University between January 2015 and December 2021 were included in this cohort, who were reviewed for whether they underwent adjustment of ASM with increased dose, alternative therapy, or combination therapy. The seizure outcome and quality of life (QoL) were assessed. Two-tailed Fisher exact test and Mann–Whitney U test were used for statistical analysis. Results: Sixty-three children with failed surgery were included for further analysis, with a median follow-up time of 53 months. The median seizure recurrence time was 4 months. At the last follow-up, 36.5% (n = 23) of patients achieved seizure freedom, 41.3% (n = 26) achieved seizure remission, and 61.9% (n = 39) had a good QoL. None of the three types of ASM adjustment improved children's outcomes, whether considered in terms of seizure-free rate, seizure remission rate, or QoL. Early recurrences were significantly associated with decreased probability of seizure freedom (p = 0.02), seizure remission (p = 0.02), and a good QoL (p = 0.01). Conclusions: Children who underwent failed epilepsy surgery remains some potential for late seizure remission from ASM. Yet adjusting ASM regimen does not increase the probability of seizure remission nor does it improve the QoL. Clinicians should complete evaluations and consider the need for other antiepileptic treatment as soon as possible after surgery failed, especially when dealing with children with an early recurrence. [ABSTRACT FROM AUTHOR]

Abstract We sought to assess the anti‐seizure efficacy of carbamazepine (CBZ) and retention rate (RR) in randomized, controlled trials (RCTs) in epilepsy. Our analysis was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. Inclusion criteria were monotherapy of CBZ in adequate dosage for epilepsy treatment and RCT duration of ≥3 months. Outcome measures were seizure freedom rate (SFR) and RR. Random‐effects meta‐analyses were performed to allow for comparison with other anti‐seizure medications (ASMs). Thirty RCTs of 734 were included. SFR at last follow‐up ranged from 11% at 36 months to 85% at 3 months. The aggregated SFR at 6 months was 58% (CI 49–66%) and 48% (CI 40–57%) at 12 months. The 6‐month SFR among blinded studies was 55% (CI 43–66%), compared with 61% (CI 50–71%) in unblinded studies. The 12‐month SFR was not significantly linked to the age of study participants. RR varied from 36% at 24 months to 81% at 6 months. When adjusting for blinding, the aggregated 6‐month RR in blinded studies was 59% (CI 52–66%) vs 76% (CI 71–81%) in unblinded studies. The point estimates of SFR of all RCTs showed an upward time trend, with an increase of approximately 15% between the years 1981 and 2018. In conclusion, the SFR and RR of CBZ were highly variable in RCTs and especially affected by study duration and blinding. These results underscore the impact of the design of RCTs investigating ASM and may challenge the wide use of CBZ as a comparator.

Abstract Objective To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug‐resistant epilepsy in two multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group trials. Methods The phase 2b dose‐finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic–clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4‐week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. Results In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12‐week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p‐values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: −5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). Significance In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.

Background. Epilepsy is a common disease in children and adults, requiring long-term or lifelong use of antiepileptic drugs (AEDs) in 60% of cases. Enzyme-inducing and enzyme-inhibiting AEDs may have a negative effect on vitamin D metabolism. However, at present, standard treatment protocols for patients with epilepsy include no nutrients and vitamin-mineral vitamin D containing complexes.Objective: to analyze studies on the prevalence of vitamin D deficiency induced by AEDs intake in patients with epilepsy.Material and methods. The search for full-text publications in Russian and English was carried out in еLibrary, PubMed/ MEDLINE, ClinicalKey, Google Scholar databases, covering the last five years. The analysis included 9 domestic and 54 foreign epidemiological studies assessing prevalence of AED-induced vitamin D deficiency and, consequently, altered bone mineralization and osteomalacia/osteoporosis.Results. Both in children and adults, the prevalence of AED-induced vitamin D deficiency reaches 40% and even higher. The region of residence of patients with epilepsy does not significantly affect this indicator. Impaired bone mineralization is associated with AED-induced vitamin D deficiency and requires the inclusion of vitamin D in the protocols of disease-modifying epilepsy therapy in children and adults.Conclusion. The results of the review showed high relevance of the discussed interdisciplinary problem and need to introduce laboratory screening of vitamin D deficiency among pediatric and adult patients with epilepsy.

Abstract Background Epileptogenesis can be defined as the process by which a previously healthy brain develops a tendency toward recurrent electrical activity, occurring in three phases: first as an initial trigger (such as stroke, infections, and traumatic brain injury); followed by the latency period and the onset of spontaneous and recurrent seizures which characterizes epilepsy. Main body The mechanisms that may be involved in epileptogenesis are inflammation, neurogenesis, migration of neurons to different regions of the brain, neural reorganization, and neuroplasticity.In recent years, experimental studies have enabled the discovery of several mechanisms involved in the process of epileptogenesis, mainly neuroinflammation, that involves the activation of glial cells and an increase in specific inflammatory mediators. The lack of an experimental animal model protocol for epileptogenic compounds contributes to the difficulty in understanding disease development and the creation of new drugs. Conclusion To solve these difficulties, a new approach is needed in the development of new AEDs that focus on the process of epileptogenesis and the consolidation of animal models for studies of antiepileptogenic compounds, aiming to reach the clinical phases of the study. Some examples of these compounds are rapamycin, which inhibits mTOR signaling, and losartan, that potentiates the antiepileptogenic effect of some AEDs. Based on this, this review discusses the main mechanisms involved in epileptogenesis, as well as its pharmacological approach.

Background: The aim of this study was to analyze whether prescriptions of antiepileptic drugs (AEDs) are significantly associated with an increased incidence of Parkinson's disease (PD) in the German population. Methods: This study used data from German primary care practices found in the Disease Analyzer database (IQVIA) and included all patients aged ≥18 years who were diagnosed with PD between January 2010 and December 2021 (index date). The controls were patients without PD matched (1:1) by age, sex, and pre-diagnostic observation time in years. Associations between AED prescriptions (any AED as well as separate evaluations for carbamazepine, lamotrigine, levetiracetam, sodium valproate, gabapentin, and pregabalin) and subsequent diagnosis of PD were examined using a logistic regression model adjusted for epilepsy, restless legs syndrome, and neuropathy diagnoses. Results: We identified 24,950 cases that were matched with 24,950 controls (mean age 75.2 years, 47.3% women). Diagnoses of epilepsy, restless legs syndrome, and neuropathy as well as AED prescription were significantly associated with an increased incidence of PD. In the multivariate analysis, incidence of PD was significantly associated with epilepsy (OR: 1.91; 95% CI: 1.69–2.15), restless legs syndrome (OR: 3.02; 95% CI: 2.73–3.34), and neuropathy (OR: 1.53; 95% CI: 1.44–1.62)), as well as the prescription of any AED (OR: 1.43; 95% CI: 1.33–1.53), sodium valproate (OR: 2.39; 95% CI: 1.84–3.11), gabapentin (OR: 1.36; 95% CI: 1.22–1.52), and pregabalin (OR: 1.28; 95% CI: 1.15–1.41). Conclusion: Prescriptions of AEDs, including sodium valproate, gabapentin, and pregabalin, were associated with an increased risk of subsequent PD, even after adjustment for underlying diagnoses. Further studies are needed to confirm the present results. [ABSTRACT FROM AUTHOR]

Introduction: A rapidly increasing number of patients with dementia present a serious social problem. Recently, the incidence of epilepsy in patients with Alzheimer's disease (AD) is increasing, drawing attention to the pathological relationship between the two conditions. Clinical studies have suggested the protective action of antiepileptic agents on dementia; however, the underlying mechanism remains unknown. We evaluated the effects of multiple antiepileptic drugs using tau aggregation assay systems to determine the effects of antiepileptic agents on tau aggregation, a major neuropathological finding associated with AD. Methods: We evaluated the effects of seven antiepileptic agents on intracellular tau aggregation using a tau-biosensor cell-based high-throughput assay. Next, we tested these agents in a cell-free tau aggregation assay using thioflavin T (ThT). Results: The assay results revealed that phenobarbital inhibited tau aggregation, whereas sodium valproate, gabapentin, and piracetam promoted tau aggregation. In the cell-free tau aggregation assay using ThT, we confirmed that phenobarbital significantly inhibited tau aggregation. Conclusion: Antiepileptic drugs may modify the tau pathology in AD in a neural activity-independent manner. Our finding may provide an important insight into the optimization of antiepileptic drug therapy in older adults with dementia. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients' quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience. The present review summarizes emerging cooperative mechanisms in oncogenesis and epileptogenesis, focusing on the neuron-to-glioma interface. The main effects and efficacy of selected AEDs used in the management of GRE are discussed in this paper, as well as their potential beneficial activity as antitumor treatment. Overall, although still many unclear processes overlapping in GBM growth and seizure onset need to be elucidated, this review focuses on the intriguing targeting of GBM-neuron mutual interactions to improve the outcome of the so challenging to treat GBM. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to directly compare the effectiveness of first‐line monotherapy levetiracetam (LEV) versus enzyme‐inducing antiseizure medications (EIASMs) in glioma patients. Methods: In this nationwide retrospective observational cohort study, Grade 2–4 glioma patients were included, with a maximum duration of follow‐up of 36 months. Primary outcome was antiseizure medication (ASM) treatment failure for any reason, and secondary outcomes were treatment failure due to uncontrolled seizures and due to adverse effects. For estimation of the association between ASM treatment and ASM treatment failure, multivariate cause‐specific cox proportional hazard models were estimated, adjusting for potential confounders. Results: In the original cohort, a total of 808 brain tumor patients with epilepsy were included, of whom 109 glioma patients were prescribed first‐line LEV and 183 glioma patients first‐line EIASMs. The EIASM group had a significantly higher risk of treatment failure for any reason compared to LEV (adjusted hazard ratio [aHR] = 1.82, 95% confidence interval [CI] = 1.20–2.75, p =.005). Treatment failure due to uncontrolled seizures did not differ significantly between EIASMs and LEV (aHR = 1.32, 95% CI =.78–2.25, p =.300), but treatment failure due to adverse effects differed significantly (aHR = 4.87, 95% CI = 1.89–12.55, p =.001). Significance: In this study, it was demonstrated that LEV had a significantly better effectiveness (i.e., less ASM treatment failure for any reason or due to adverse effects) compared to EIASMs, supporting the current neuro‐oncology guideline recommendations to avoid EIASMs in glioma patients. [ABSTRACT FROM AUTHOR]

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.

Objective:To evaluate the effect of short- and long-term treatment on laboratory parameters in patients diagnosed with epilepsy in childhood and receiving monotherapy (carbamazepine, valproic acid, phenobarbital, levetiracetam).Methods:This study included a total of 258 patients who were admitted to Adiyaman University pediatric neurology clinic between 1 October 2017 and 1 June 2019, diagnosed with epilepsy, and received monotherapy. Hematological, biochemical, and hormonal profiles were compared in the third and nine months following the initiation of monotherapy.Results:Of the patients, 115 (44.57%) were female and 143 (55.43%) were male. The mean age was 8.33 ± 3.51 (0-17) years. Examination of biochemical parameters showed that there was a statistically significant difference in creatinine levels in patients using levetiracetam and phenobarbital (p = 0.009, p = 0.031); calcium levels in patients using valproic acid (p = 0.002); and alanine aminotransferase levels in patients using carbamazepine (p = 0.045). Considering hematological parameters, a statistically significant difference was observed in white blood cell count levels in patients receiving valproic acid (p = 0.005); hemoglobin and hematocrit levels in those receiving carbamazepine (p = 0.010, p = 0.042); and platelet levels in patients receiving phenobarbital (p = 0.037). In all patients receiving monotherapy, there was no statistically significant difference between hormonal parameters (folate, 25-OH D3, vitamin B12, free t4, and TSH) measured in the third and ninth months.Conclusions:We recommend that AED therapy should be checked routinely to investigate the effects of treatment on hormonal, biochemical, and hematological parameters.

Background: The decision to continue or discontinue antiepileptic drug (AED) treatment in patients who are seizure free for a prolonged time is critical. Studies have used certain risk factors or electroencephalogram (EEG) findings to predict seizure recurrence after the withdrawal of AEDs. However, applicable biomarkers to guide the withdrawal of AEDs are lacking. Methods: In this study, we used EEG analysis based on multiscale deep neural networks (MSDNN) to establish a method for predicting seizure recurrence after the withdrawal of AEDs. A total of 60 patients with epilepsy were divided into two groups (30 in the recurrence group and 30 in the non-recurrence group). All patients were seizure free for at least 2 years. Before AED withdrawal, an EEG was performed for each patient, which showed no epileptiform discharges. These EEG recordings were classified using MSDNN. Results: We found that the performance indices of classification between recurrence and non-recurrence groups had a mean sensitivity, mean specificity, mean accuracy, and mean area under the receiver operating characteristic curve of 74.23%, 75.83%, 74.66%, and 82.66%, respectively. Conclusion: Our proposed method is a promising tool to help physicians to predict seizure recurrence after AED withdrawal among seizure-free patients.

The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden.A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0–1 occasion, and non-adherent if they forgot at 2–10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher’s test and a logistic regression model was used to find risk factors for non-adherence.In the cohort of 416 PWE aged median 43, IQR 29–62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects.The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence.

Background: Safety information of antiseizure medication (ASM) during breastfeeding is scarce and conflicting. We aimed to identify characteristic traits of safety concerns among healthcare professionals by reviewing enquiries to the Norwegian Regional Medicines Information and Pharmacovigilance Centres (RELIS). Method: Enquiries related to breastfeeding, epilepsy, and ASM identified by their ATC-numbers were retrieved from the RELIS database of question-and-answer pairs (QAPs) by combining indexed and Boolean database searches and manual inspection. 112 QAPs were analyzed retrospectively using descriptive statistics. Results: Hospital-employed physicians and nurses were puzzled by ambiguous or conflicting drug information advice and called for general information about the compatibility of an ASM with breastfeeding, mainly related to lamotrigine and levetiracetam. Other enquiries were related to co-medication with other drugs, mainly antidepressants. Half of the enquiries were posed after birth, 12 of these motivated by suspected adverse events in the infants. Conclusion: Healthcare professionals with acknowledged high competence in the topic were uncertain about the prevailing safety information of ASM during breastfeeding. The fear to harm the infant may lead to the decision not to recommend breastfeeding. Future information strategies should aim to reach these professions, and support their information need on this topic.