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Pregnancy and the postpartum period are potentially high-risk periods for women with epilepsy and their babies. All women with epilepsy should have the opportunity for preconception counselling with the aim of reducing risk, optimising outcomes for the potentially developing fetus and enabling informed decision-making. This article provides an evidence-based framework for preconception counselling discussion, including the review of diagnosis and of current antiseizure medication, the risk to the fetus in relation to antiseizure medication and maternal seizures, maternal morbidity, SUDEP risk, folic acid supplements, contraception, breastfeeding and safety advice., Competing Interests: Competing interests: RB has provided consultancy to a women’s health initiative funded by UCB Pharma with the fee going to her institution., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Drug-resistant epilepsy has a cumulative incidence between 14 and 20% of patients with epilepsy. It is associated with more comorbidities and with higher healthcare expenditure and impact on quality of life., Patients and Methods: A retrospective longitudinal descriptive study was performed covering the period from 01/01/2010 to 02/28/2024. All patients with epilepsy seen in the Pediatric Neurology unit of our center were collected and a review of medical records was carried out to collect the characteristics and evolution during the study period. The classification and definitions used were those established by the International League Against Epilepsy., Results: A total of 325 patients with epilepsy were identified, with a cumulative incidence of DRE of 29%. The most frequent etiology was structural both in all patients with epilepsy (22%), and in drug-resistant epilepsy (36%). A statistically significant association was established between refractoriness and genetic and structural causes, and between having status epilepticus and the development of drug-resistant epilepsy. Seventy-nine percent of patients with drug-resistant epilepsy developed epileptic encephalopathy. The most commonly used antiseizure drug was valproic acid (90%), 19% received a ketogenic diet and 4.2% received epilepsy surgery., Conclusions: In our setting the incidence of drug-resistant epilepsy is high, more so than previously described. Genetic and structural etiologies are associated with a higher incidence. Having suffered status epilepticus is associated with refractoriness. A higher incidence was observed in patients with defined electroclinical syndromes, probably influenced by epileptic and developmental encephalopathies.

Background: To systematically review the efficacy and safety of second-line medications for status epilepticus (SE)., Methods: Electronic searches were conducted in PubMed, Embase, and The Cochrane Library for randomized controlled trials of second-line medications for SE from inception to January 2024. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Network meta-analysis was performed using R 4.2.2 software., Results: A total of 23 randomized controlled trials were analyzed, examining the efficacy of 5 different treatment regimens: levetiracetam (LEV), phenytoin (PHT), fosphenytoin (FPHT), valproate (VPA), and phenobarbital (PHB). The results of the network meta-analysis indicated that the seizure control rate ranking was as follows: PHB (98.1%) > LEV (60.7%) > FPHT (40.3%) > PHT (33.0%) > VPA (17.8%). The surface under the cumulative ranking (SUCRA) values revealed that PHB had the highest ranking (SUCRA, 91.8%), followed by VPA (SUCRA, 69.3%), PHT (SUCRA, 56.1%), and FPHT (SUCRA, 5.9%) for the recurrence of seizures within 24 hours. Subgroup analysis revealed that PHB was most effective for seizure control in both pediatric and adult populations, VPA demonstrated superior efficacy in children across various indicators, LEV was deemed the safest option for children and elderly individuals, and VPA was identified as the safest choice for adult patients., Conclusions: PHB continues to be a prominent option for managing SE, although its safety profile warrants careful consideration. Meanwhile, both VPA and LEV offer distinctive advantages in the treatment of SE, with each demonstrating commendable safety profiles., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The teratogenic potential of valproate in pregnancy is well established; however, evidence regarding the long-term safety of other antiseizure medications (ASMs) during pregnancy remains limited. Using routinely collected primary care data from the UK and nationwide Swedish registries to create a cohort of 3,182,773 children, of which 17,495 were exposed to ASMs in pregnancy, we show that those exposed to valproate were more likely to receive a diagnosis of autism, intellectual disability, and ADHD, when compared to children not exposed to ASMs. Additionally, children exposed to topiramate were 2.5 times more likely to be diagnosed with intellectual disability (95% CI: 1.23-4.98), and those exposed to carbamazepine were 1.25 times more likely to be diagnosed with autism (95% CI: 1.05-1.48) and 1.30 times more likely to be diagnosed with intellectual disability (95% CI: 1.01-1.69). There was little evidence that children exposed to lamotrigine in pregnancy were more likely to receive neurodevelopmental diagnoses. While further research is needed, these findings may support considering safer treatment alternatives well before conception when clinically appropriate., Competing Interests: Competing interests T.T. has received support to the EURAP pregnancy registry from Accord, Eisai, GSK, UCB, Bial, Sanofi, GW Pharma, Teva, Angelini Pharma, Zentiva, SF Group, Glenmark and personal fees from Eisai, Sanofi, UCB and Angelini Pharma outside the submitted work. BL reports receiving consulting fees from Beasley Allen Law Firm, Patterson Belknap Webb & Tyler LLP and AlphaSights. None of the above entities had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The remaining authors have no conflicts of interest., (© 2024. The Author(s).)

Background: Pyridoxamine 5'-phosphate oxidase deficiency is a rare inborn error of vitamin B 6 metabolism that presents with drug-resistant epileptic seizures. However, the condition is responsive to supplementation with the active vitamin B 6 metabolite pyridoxal 5'-phosphate and, in some cases, pyridoxine., Case Presentation: In this case report, a 10-year-old Iranian male of Fars ethnicity came to a regional hospital in Tehran, Iran with a chief complaint of tic-like movement. He had a history of unintentional, repetitive, and stereotypic movements of both arms since the age of 4 years. The physical examination depicted facial dimorphism. During admission, the patient experienced habitual hypermotor seizures and generalized tonic-clonic seizures. Ictal electroencephalography demonstrated a generalized background attenuation and bursts of generalized, predominantly left-sided, biphasic spike-wave complexes. Whole-genome sequencing revealed a pyridoxamine 5'-phosphate oxidase deficiency as the underlying cause of the drug-resistant seizures, resulting in a low serum level of pyridoxal 5'-phosphate. The patient underwent pyridoxine supplementation therapy, which ultimately resolved his seizures. At 6 months, he was seizure free., Conclusion: Physicians ought to be aware of manifestations of vitamin B6 deficiency such as mimicking tic and consider it in the differential for drug-resistant epilepsy., Competing Interests: Declarations Ethics approval and consent to participate Informed consent was obtained from the participant and the parents of the patient included in the study. Consent for publication Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Preeclampsia is the second leading cause of maternal death in Uganda. WHO recommends using magnesium sulphate (MgSO4) to prevent and treat preeclampsia with severe features (PEC) and eclampsia. MgSO4 is used to prevent eclampsia and treat women who experience an eclamptic convulsion to avoid severe maternal/infant illnesses and death. We set out to assess MgSO4 administration patterns in women with PEC or eclampsia and the immediate newborn outcomes of neonates., Methods: This was an analytical observational cohort study at Kawempe National Referral Hospital in Uganda. Two hundred ten pregnant mothers with PEC or eclampsia were recruited in the study after receiving the loading dose of MgSO4 and then followed through labour and delivery to observe MgSO4 administration patterns and immediate newborn outcomes using Apgar and Thompson scores. SPSS version 23 was used to analyse data, and both bivariate and multivariate logistic regressions were used to determine factors associated with the low Apgar score at five minutes., Results: Overall, majority of the patients received more than one dose with 33.3% received a sixth dose of MgSO4. The majority, 84.8%, of the mothers delivered live babies, 31.0% babies had complications, and were admitted to the neonatal intensive care unit (NICU). NICU admissions were mostly due to respiratory distress21.4%, preterm delivery21.0%, and 5.5% died within seven days. Majority 93.3% of the newborns had an Apgar score of seven and above at five minutes, of the newborns who were Thompson scored, 70.4% scored between 1 to 10 which is mild HIE. Initiation of MgSO4 treatment within one hour from prescription (AOR = 0.49, CI: 0.01-1.94), 4-hourly timing of the first maintenance dose (AOR = 0.22, CI: 0.06-0.79) and having complete doses of MgSO4 treatment (AOR = 0.89, CI: 0.03-3.05) decreased the likelihood of having low Apgar scores at five minutes., Conclusions: Timely administration of the first maintenance dose of MgSO4 decreases the likelihood of low Apgar score at 5 min and NICU admission in newborns, and most NICU admissions were due to respiratory distress and preterm delivery., Competing Interests: Declarations Ethics approval and consent to participate Ethical review and approval were obtained from the Research Ethics Committee (REC) of the School of Health Sciences, College of Health Sciences at Makerere University under REC number MAKSHSREC-2022–330. Administrative clearance and permission to collect data were obtained from the management of Kawempe National Referral hospital. All participants gave written informed consent to participate voluntarily in the study prior to data collection and were informed that there would be no consequences if they withdraw from the study at any given point of the study if they wished not to continue. Participants who could not read or write were asked to provide informed verbal consent after the script was read to them by the research assistant in order to assist in the comprehension of the research and informed verbal consent process, and these participants signed the written consent form by putting a thumb print. Information collected from the respondents was held with confidentiality through the use of anonymous questionnaires which were filed and kept under lock and key throughout the whole data collection and analysis process. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Gain-of-function (GOF) mutations of the sodium-activated potassium channel K Na 1.1 (Slack, Slo2.2, or K Ca 4.1) induce severe, drug-resistant forms of epilepsy in infants and children. Although quinidine has shown promise in treating KCNT1-related epilepsies compared to other drugs, its limited efficacy and substantial side effects necessitate the development of new K Na 1.1 channel inhibitors. In this study, we developed a novel class of K Na 1.1 inhibitors using combined silico approaches and structural optimization. Among these inhibitors, compound Z05 was identified as a selective potential K Na 1.1 inhibitor, especially against the hERG channel. Moreover, its binding site and potential counteraction to a GOF mutant Y796H were identified by the mutation studies. Our data also showed that Z05 had significant pharmacological profiles, including high brain penetration and moderate oral bioavailability, offering a valuable in vitro tool compound for further drug development in treating KCNT1-related epilepsies.

Objectives: There is no report on the initial antiepileptic drug (AED) treatment of older Thai epileptic patients. This study aimed to determine the trends, prescribing patterns, and determinants of initial AED treatment., Methods: This cross-sectional study used data on older (≥60 years) epileptic patients gathered from one tertiary-care hospital's database from 2012 to 2022. We evaluated the trends and prescribing patterns for starting AED treatment. We used logistic regression to identify the determinants of the initial treatment with new-generation AEDs., Key Findings: This study comprised 919 participants (59.19% men, 70.99 ± 8.00 years old). Between 2012 and 2022, we observed a decreasing trend in starting therapy with old-generation AEDs, from 89.16% to 64.58%. In contrast, there was an increasing trend in initiating treatment with new-generation AEDs, from 10.84% to 35.72% (P for trend <0.001 for both). Each assessment year, the most prescribed treatment pattern was monotherapy. The determinants of initial therapy with new-generation AEDs included the year treatment began (adjusted odds ratios [AOR] = 1.0006; 95% confidence intervals [CI] 1.0003-1.0008), non-Universal Coverage Scheme (AOR = 1.94; 95% CI 1.26-3.00), liver disease (AOR = 6.44; 95% CI 2.30-18.08), opioid use (AOR = 2.79; 95% CI 1.28-6.09), and statin use (AOR = 0.59; 95% CI 0.36-0.95)., Conclusions: There is a growing trend of initiating treatment with new-generation AEDs in older Thai patients with epilepsy. Factors positively associated with starting new-generation AEDs include the year treatment began, non-Universal Coverage Scheme, liver disease, and opioid use, while statin use is a negatively associated factor., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A pregnant woman in her late 20s with a history of epilepsy since childhood presented with recurrent loss of consciousness and witnessed twitching and involuntary muscle contractions. She had hyperemesis during pregnancy reporting four previous miscarriages attributed to seizures. During evaluation in cardiac telemetry and while suffering from severe nausea, the patient experienced prolonged ventricular asystole resulting in convulsive syncope and was diagnosed with cardioinhibitory malignant vasovagal syncope (CMVS). Initiation of levetiracetam was recommended for 6 months, and after undergoing dual-chamber pacemaker placement, her neurological symptoms resolved despite persistent hyperemesis during the first trimester, leading to a successful vaginal delivery. 4 years later, the patient remains asymptomatic. This case emphasises the importance of conducting a thorough differential diagnosis in patients with atypical seizure presentations, the multidisciplinary approach required to assure optimal outcomes in cardio-obstetric cases and the role of selective pacemaker placement in patients with documented prolonged ventricular asystole associated with CMVS., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

This study introduces a novel in vitro model for intractable temporal lobe epilepsy (TLE) utilizing 3D bioprinting technology, aiming to replicate the complex neurobiological characteristics of TLE more accurately. Primary neural cell constructs were fabricated and subjected to epileptiform-inducing conditions, fostering synaptic proliferation and neuronal loss. Systematically electrophysiological and immunofluorescent analyses indicated that significant synaptic connectivity and sustained epileptiform activities within the constructs akin to those observed in human epilepsy models. Notably, the model responded to treatments with phenytoin and tetrodotoxin, illustrating its potential utility in drug response kinetics studies. Furthermore, we performed drug permeability simulations using COMSOL Multiphysics to analyze the diffusion characteristics of these drugs within the constructs. These results confirm that our 3D bioprinted neural model provides a physiologically relevant and ethically sustainable platform, which is beneficial for studying TLE mechanisms and developing therapeutic strategies with high accuracy and clinical relevance., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Valproic acid (VPA) is a commonly used anti-seizure medication, owing to its efficacy and cost-effectiveness. However, maintaining appropriate serum levels is crucial due to the narrow therapeutic window, as subtherapeutic levels can lead to treatment failure or adverse outcomes. This study aimed to identify the factors associated with subtherapeutic serum levels of valproic acid in patients undergoing treatment. This retrospective cohort study was performed at a tertiary care hospital and involved inpatients aged ≥ 18 years who were receiving valproic acid for epilepsy treatment. Data were obtained through chart reviews and a Therapeutic Drug Monitoring database. Subtherapeutic VPA levels were defined as < 50 mg/L. Logistic regression was used to identify risk factors for subtherapeutic levels. Of the 152 patients, 96 (63.2%) had subtherapeutic VPA levels (<50 mg/L). Males were more likely than females to have subtherapeutic levels (OR 2.45, 95% CI: 1.15-5.22; P = .02). Previous use of phenytoin significantly increased the risk of subtherapeutic VPA levels (OR 2.58, 95% CI: 1.16-5.71; P = .02). VPA administration by syrup and doses below 15 mg/kg/day were associated with subtherapeutic levels (OR 3.28 and 2.34, respectively). Additionally, co-medications, such as topiramate and meropenem, also increased this risk (OR 5.09 and 4.64, respectively). This study identified several factors significantly associated with subtherapeutic levels of valproic acid, including males, prior phenytoin use, co-medications, such as topiramate and meropenem, and lower VPA dosages. These findings underscore the importance of careful monitoring and individualized treatment plans to maintain therapeutic VPA levels in clinical practice. Further research is needed to explore the clinical implications and to develop strategies to minimize the risk of subtherapeutic levels in patients receiving VPA., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Sodium valproate is used for the management of seizures, status epilepticus, chronic pain syndrome, bipolar, and other affective disorders. Even with an acceptable safety profile, severe idiosyncratic reactions can occur with valproate use. A rare, serious, and life-threatening side effect of valproate is valproate-induced hyperammonemic encephalopathy (VHE). We intend to analyze the clinical presentation, diagnosis, treatment options, and outcome of VHE in neurosurgical patients and review the pertinent literature on this rare sequelae. We retrospectively reviewed patients who developed VHE following valproate use, either for the treatment of epilepsy or for seizure prophylaxis in our centre. We analyzed the demographic details, clinical presentation, diagnosis, management, and outcomes. A total of four patients with a mean age of 26.3 ± 5.1 (range 19 - 32 years). Valproate was prescribed for primary seizure prophylaxis in 2 patients (50%). The commonest etiology for valproate prescription was for brain tumors (3, 75%) followed by drug-refractory epilepsy (DRE) (1, 25%). None of the patients were documented to have urea cycle disorder. The mean daily prescribed dosage of valproate was 1250 ± 559 mg and the mean duration of administration was 13 ± 13.3 months (range 4 months - 36 months). The mean serum NH3 level was 136,5 ± 44.2 µmol/L (range 107 - 212.8) and all patients (4, 100%) had hyperammonemia with a mortality rate of 50% (2 patients). The hyperammonemia was treated by stopping the valproate use (4, 100%) and dialysis (2, 50%). Normalization of ammonia levels led to clinical improvement in 50% (2 patients). Neurological deterioration in the postoperative period is a diagnostic challenge. VHE is a rare and life-threatening sequelae of Valproate-associated Hyperammonemia (VAH) in neurosurgical patients. A high index of suspicion is required due to its ambiguous presentation. Early diagnosis and prompt treatment can change the course of this life-threatening sequelae., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: Around 30% of patients with epilepsy show drug-resistant epilepsy (DRE). While cannabidiol has demonstrated efficacy as an adjunctive treatment in Dravet syndrome (DS), Lennox-Gastaut Syndrome (LGS), and epilepsy related to tuberous sclerosis complex (TSC), its more global effectiveness in adult patients with DRE apart from these three specific contexts needs to be clarified., Methods: We conducted a retrospective study at the epilepsy unit of Pitié Salpêtrière Hospital. Patients initiating pharmaceutical cannabidiol treatment and followed for at least 1 year were included. Patients were categorized into "authorized" (LGS, DS, or TSC) and "off-label" groups. Cannabidiol effectiveness and tolerance were compared between groups, and characteristics of responders (patients with >50% reduction in seizure frequency) in the off-label group were examined., Results: Ninety-one patients, followed by a median duration of 24 months, were included. A total of 35.2% of the patients were in the authorized group. No significant differences were observed in responder rates between groups (31.3% vs. 35.6%, p = 0.85) and retention rates at 1 year (75.0% vs. 74.6%, p = 0.97). Sleepiness was more commonly reported in the authorized group (50.0% vs. 22.0%, p = 0.01), with no other significant differences. Among off-label patients (n = 59), clobazam co-prescription was more prevalent in responders (71.4% vs. 28.9%, p = 0.002)., Conclusion: Our findings suggest that cannabidiol may benefit all adult patients with DRE, particularly those already receiving clobazam. Randomized controlled trials are warranted in off-label patients to validate these observational findings., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Objective: To investigate the clinical outcomes and safety of surgery in infants (< 12 months of age) with drug-resistant epilepsy, clarify surgical indications, and select appropriate surgical methods., Methods: This was a retrospective analysis of infants with drug-resistant epilepsy who underwent epilepsy surgery and were followed up for > 6 months at the Epilepsy Center of Shenzhen Children's Hospital. Clinical data included etiology, seizure type, surgical procedure, preoperative auxiliary examinations, pathological findings, and intraoperative and postoperative complications. Clinical outcomes were assessed based on postoperative seizure frequency, antiseizure medicines (ASMs) use, and neurocognitive development. Intraoperative blood loss, operative duration, postoperative complications, and duration of intensive care were evaluated to assess the safety of epilepsy surgery. Univariate and logistic analyses were performed to explore the factors influencing prognosis., Results: Epilepsy surgery was performed on 44 infants with drug-resistant epilepsy, including 7 patients who underwent two operations. The age of seizure onset ranged from 1 day to 11 months (median: 1 month, interquartile range (IQR): 0.1-3.8), the disease course was 1-11 months (median: 4 months, IQR: 2-7), and the age at surgery was 6.9 ± 3.6 months. Twenty-three patients underwent hemispherectomy (52.3 %), and two underwent subtotal hemispherectomy. Five patients underwent multilobar disconnection, five underwent frontal lobotomy, and the remaining nine underwent focal resection. The surgical duration was 7.5 ± 2 h. Intraoperative blood loss ranged from 50 to 1800 ml (median: 275 ml, IQR: 200-500), with all patients receiving an intraoperative blood transfusion of 0.5-6 U (median: 1.5 U, IQR: 1.5-3). The intensive care unit stay was 1-4 days (median: 1 day, IQR: 1-2). The postoperative complication rate was 13.6 % (6/44; two cases of hydrocephalus with intracranial infection, two isolated hydrocephalus, and two subdural hematomas). Excluding one child who died of severe lung infection approximately one year after surgery and one child lost to follow-up after surgery, all other cases were regularly followed up for 10 -49 months (median: 30 months, IQR: 16.5-36). After surgery, patients were treated with 0-3 ASMs (median: 1 ASM, IQR: 0-2); 27.9 % (12/43) stopped taking ASMs and 51.2 % (22/43) had reduced number of ASMs. Engel I was achieved in 76.7 % (33/43) of the patients at the last follow-up. In 17 cases with complete developmental quotient follow-up data, the preoperative and postoperative developmental quotient means were 28.8 ± 21 and 43.2 ± 20.1, showing statistically significant differences (p<0.05) SIGNIFICANCE: Epilepsy surgery in infants under 12 months of age is safe and effective. Early preoperative evaluation is crucial for identifying structural lesions and suitable candidates for surgery among infants with drug-resistant epilepsy. The timeliness of surgery is essential for achieving favorable clinical outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Cannabidiol oil (CBD) has been approved as an antiseizure medication for the treatment of drug -resistant epilepsy in pediatric patients in 2018 for some special types of epilepsy. Since this time its use was extended to other forms of epilepsy. However, to date, there are few publications on the use of CBD in adult patients with drug-resistant focal epilepsy and psychiatric comorbidities. We conducted a prospective, observational, open cohort study, with a before-after design, in adult patients, we assessed the effectiveness, dosage, and tolerance of adjunctive CBD treatment. Our study concluded that CBD was effective and safe.Our study in line with others examining CBD use in adult patients with drug-resistant epilepsy, omits consideration of psychiatric aspects. The aim of this study was to evaluate, in the same patient population that was part of a previous observational study, depression, quality of life, anxious symptoms and daytime sleepiness before and after CBD treatment. RESULTS: Forty-four patients were enrolled in the study. Prior to CBD treatment, 50 % of participants exhibited symptoms of depression. Following CBD treatment, 95.4 % of these individuals demonstrated a marked improvement (p = 0.001). Among this cohort, 71.5 % of patients reported minimal or no depressive symptoms post-treatment. Moreover, 68 % of patients experienced an enhancement in their overall quality of life. Comparative analysis of BDI-II and QOLIE-10 scores before and after CBD treatment revealed a statistically significant positive correlation (p < 0.036 and < 0.001, respectively). Improvements in depressive symptoms were found to correspond with enhancements in quality of life. In terms of anxiety symptoms, 54.5 % of patients exhibited such symptoms prior to CBD treatment, with 71 % showing improvement post-treatment. Adjunctive CBD treatment in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated and associated with significant improvement in depressive symptoms, anxiety and quality of life., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Data for the use of ketamine (Ket) in treatment of refractory and super-refractory status epilepticus (RSE, SRSE) is lacking despite its widespread growing use. We examined the efficacy of ketamine plus midazolam (MDZ) infusions for treating RSE versus midazolam alone. We hypothesized that ketamine initiation would result in earlier seizure termination., Methods: Data was obtained from electronic health records (EHR) of adult patients who received intravenous anesthetic agents for RSE in our neurointensive care unit. Two cohorts were identified. The MDZ cohort received midazolam as the only intravenous anesthetic agent for RSE. The Ket+MDZ cohort received midazolam infusion followed by ketamine infusion. The primary outcomes were time from midazolam infusion start to SE end in both cohorts, and time from ketamine infusion start (Ket Start) to SE end in the Ket+MDZ cohort versus midazolam infusion start (MDZ start) to SE end in the MDZ cohort., Results: 73 patients were included (MDZ cohort n=17, Ket + MDZ cohort n=56). Cohorts did not differ significantly in age, sex, race, RSE etiology, or GCS on admission. Mean APACHE II score was higher in the Ket +MDZ cohort (26 ± 7.32 SD) versus the MDZ cohort (22 ± 5.89 SD)(P=.015). In survival analyses, cohorts did not differ significantly in time from midazolam start to SE end (HR=0.965, 95 % CI=0.556-1.673, P=.899; median [IQR]: MDZ: 25 h [4.5-58]; Ket+MDZ: 21.5 h [IQR 13.5-49]). Time from Ket start (Ket+MDZ group) versus time from MDZ start (MDZ group) to SE end was significantly shorter in the Ket+MDZ cohort (HR=1.895, 95 % CI=1.083-3.314, P=.025). The pattern of results was similar when including APACHE II and MDZ maximum dosage as covariates., Conclusion: Time to SE end was significantly shorter after addition of ketamine infusion to midazolam infusion, versus after initiation of midazolam infusion monotherapy. Patients with higher disease severity favored Ket+MDZ. Randomized controlled trials are warranted in determining optimal anesthetics in RSE and SRSE., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: We aimed to assess the effectiveness of vigabatrin (VGB) in patients diagnosed with infantile epileptic spasm syndrome (IESS) and categorize these patients based on their etiologies., Methods: This retrospective study included patients diagnosed with IESS who exhibited epileptic spasms before the age of 2 years between January 1, 2015, and October 31, 2023 at Saitama Children's Medical Center. Patients with tuberous sclerosis as the identified etiology were excluded. The effectiveness of VGB was assessed based on the resolution of ES for three months with the absence of hypsarrhythmia on interictal electroencephalogram., Results: This study analyzed 41 patients (26 boys). The etiologies included genetic, congenital structural, acquired structural, and unknown in 12, 11, 10, and 8 patients, respectively. Patient characteristics did not significantly differ among the four groups. The overall effectiveness of VGB for IESS was 39.0 % (16/41). Categorized based on etiology, VGB was effective in 41.7 % (5/12), 9.1 % (1/11), 50 % (5/10), and 75 % (6/8) in the genetic, congenital structural, acquired structural, and unknown groups, respectively. Statistical analysis revealed a significant difference in effectiveness among the four groups (p = 0.03). Categorized based on diseases, VGB was effective in 28.6 % (2/7) and 50 % (4/8) in trisomy 21 and perinatal brain injury, respectively., Conclusion: The effectiveness of VGB in patients with IESS varied with etiology. Further investigations into the effectiveness of VGB in etiological subtypes of IESS could facilitate the development of tailored treatment algorithms for each etiology, representing valuable guidelines for future medical practice., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Epileptic encephalopathies are generally considered to be functional disruptions in the balance between neural excitation and inhibition. Excitatory and inhibitory voltage-gated ion channels are key targets of antiepileptic drugs, playing a critical role in regulating neuronal excitation and synaptic transmission. Recent research has highlighted the significance of ion channels in various aspects of epilepsy, including presynaptic neurotransmitter release, intrinsic neuronal excitability, and neural synchrony. Genetic alterations in excitatory and inhibitory ion channels within principal neurons and in inhibitory interneurons have also been identified as key contributors to the development of epilepsies. We review these recent studies and shed light on the bidirectional relationship between epilepsy and neuronal excitability and the latest advancements in pharmacological therapeutics targeting ion channels for epilepsy treatment., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glioblastoma multiforme (GBM) is a malignant tumor of the brain that is considered to be incurable. Currently, surgical removal of tumors, chemotherapy with temozolomide, and radiation treatment remain established options for treatment. Nevertheless, the prognosis of those with GBM continues to be poor owing to the inherent characteristics of tumor growth and spread, as well as the resistance to treatment. To effectively deal with the present circumstances, it is vital to do extensive study to understand GBM thoroughly. The following piece provides a concise overview of the most recent advancements in using valproic acid, an antiseizure medication licensed by the FDA, for treating GBM. In this review, we outline the most recent developments of valproic acid in treating GBM, as well as its fundamental mechanisms and practical consequences. Our goal is to provide a greater understanding of the clinical use of valproic acid as a potential therapeutic agent for GBM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Epilepsy stands as one of the prevalent and significant neurological disorders, representing a critical healthcare challenge. Recently, machine learning techniques have emerged as versatile tools across various healthcare domains, encompassing diagnostics, treatment assessment, and prognosis. We compared 11 machine learning model to find the best ML model to predict drug treatment outcomes for our cohort, which we previously evaluated using classical statistical methods., Methods: In our study, we evaluated patients who presented to the pediatric neurology department of our university hospital with seizures at the age of 1 to 24 months and were diagnosed with epilepsy. We utilized 11 different machine learning techniques namely Decision Tree, Bagging, K-Nearest Neighbour, Linear Discriminant Analysis, Logistic Regression, Neural Networks, Deep Neural Networks, Support Vector Machine. Besides, we compared these techniques using various performance metrics to identify anti-seizure medicine response. We also utilized the chi-square feature selection methods to enhance performance in machine learning algorithms., Results: Two hundred and twenty-nine patients (110 male and 119 female) who were diagnosed between the ages of 1-24 months were included in the study. Support Vector Machine algorithm was found to be effective in drug resistant epilepsy detection, with the highest aure under curve value (0.9934) and achieving a test accuracy of 97.06 %., Conclusion: This study can shed light on future studies by showing that the Support Vector Machine algorithm can effectively determine the drug resistant epilepsy. The pediatric neurologist and experts should be referred to non-medical treatment (epilepsy surgery, ketogenic diet) at the early stages and multidisciplinary approach should be provided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Epilepsy, a common neurological disorder, is characterized by paroxysmal, short-term, repetitive, and stereotypical features, significantly impacting patients' quality of life. Currently, the pathogenesis of epilepsy remains incompletely understood. Changes in neuronal excitability, imbalances in glutamate and gamma-aminobutyric acid (GABA) levels, alterations in the activity of GABA receptors, and dysfunction of GABA receptors are considered closely related to its occurrence. Thyroid hormones, vital for human growth and development, also play a crucial role in the nervous system. They mediate oxidative stress, influence reactive oxygen species production, affect mitochondrial function and neuronal excitability, and modulate glutamate and GABA levels. Also, they combine with thyroid hormone receptors and exert genomic effects by regulating the expression of numerous genes. However, once there are defects in thyroid hormone signaling, these defects may lead to severe neurodevelopmental disorders that are associated with an increased frequency of seizures. The impact of antiseizure medications (ASMs) on serum thyroid hormone levels, particularly traditional ASMs, has been extensively studied. It is reported that conventional ASMs such as phenobarbital, phenytoin sodium, carbamazepine, and valproate sodium were more likely to induce subclinical hypothyroidism (elevated TSH with normal FT4) or isolated hypothyroidism (decreased FT4 with normal TSH). However, the new ASMs, such as levetiracetam, have no effect on thyroid hormone levels. Together, seizures not only affect thyroid hormone levels, but abnormal thyroid hormone levels can also influence seizures. However, the precise mechanism underlying the interaction between serum thyroid hormone levels and seizures remains unclear. This review aims to explore the relationship between thyroid hormone levels and seizures, along with the underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The outcomes of patients who experience status epilepticus during the post-cardiac arrest period, or post-anoxic status epilepticus (PASE), remain dismal despite advances in resuscitation. The combination of therapeutic nihilism and the refractoriness of seizures in a setting where pessimistic prognostic impressions prevail is likely the main driver of such poor outcomes. The resulting pervasive vicious cycle perpetuates this knowledge gap, whereby hypoxic-ischemic insults as the etiology for seizures remain a ubiquitous exclusion criterion for clinal trials in status epilepticus. Effective therapies targeting hyperexcitability resulting from hypoxic-ischemic brain injury are urgently needed. Early inhibition of gamma-aminobutyric acid (GABA) transaminase with vigabatrin holds potential as an effective adjunctive therapy for PASE. This scientific premise is based on the resulting halted GABA catabolism thereby promoting synergistic augmentation of GABAergic pathway when used in combination with positive GABAergic allosteric modulators. This paper is based on a lecture presented at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in London 8-10 April 2024., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carolina Barbosa Maciel reports financial support was provided by American Heart Association. Carolina Barbosa Maciel reports a relationship with National Institute of Neurological Disorders and Stroke that includes: funding grants. Katharina Maria Busl reports a relationship with National Institute of Neurological Disorders and Stroke that includes: funding grants. Lawrence J Hirsch reports a relationship with Daniel Raymond Wong Neurology Research Fund that includes: funding grants. Lawrence J Hirsch reports a relationship with Ceribell, Inc that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Accure that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Marinus Pharmaceuticals Inc that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Natus that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Neurelis Inc that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with NeuroPace Inc that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with Rapport Therapeutics, Inc. that includes: consulting or advisory. Lawrence J Hirsch reports a relationship with UCB Pharma SA that includes: consulting or advisory. Royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for co-authoring the book “Atlas of EEG in Critical Care”, 1st and 2nd editions for co-author Lawrence J Hirsch. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this epidemiological study was to assess the prevalence, comorbidities, and real-world management of childhood epilepsy to provide insights for enhancing epilepsy management and medical resource planning., Materials and Methods: The study encompassed insured individuals aged 0-17 years as of December 2018 who were registered at any point in 2018, for at least part of the year, in a Japanese health claims database spanning January-December 2018. Epilepsy was defined as a diagnosis of epilepsy based on the International Classification of Diseases, 10th Revision codes, and a claimed management fee for epilepsy or an anti-seizure medication (ASM) prescription for longer than 4 weeks. The prevalence of epilepsy, patient characteristics, including comorbidities, and management status, such as prescription of ASMs, were evaluated., Results: Among 1528,905 registered children, 9279 were identified as having epilepsy. The prevalence of epilepsy was the lowest at 1.97 per 1000 population (95 % confidence interval [CI] 1.80-2.15) in the 0-2-year age group and increased with age to 9.34 per 1000 population (95 % CI 8.98-9.72) in the 15-17-year age group, with a significantly higher prevalence in boys than in girls in the ≥12-year age group. ASMs were prescribed to 88.3 %-91.9 % of the patients. Moreover, 27 (0.29 %) patients underwent epilepsy surgery. The frequency of claiming intravenous ASMs and long-term electroencephalogram fees increased with a decrease in age., Conclusions: Our findings indicate that young children receive more medical resources than adolescents and that epilepsy surgery is underutilized. Further investigations will help improve the management of and develop measures against epilepsy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Perampanel, the first third-generation anti-seizure medication targeting the AMPA receptor, has been used in the treatment of patients with focal seizures, with or without secondary generalized seizures, and primary generalized tonic-clonic seizures. This study focused on the effectiveness and safety of perampanel for pediatric patients with at least 1-year follow-up in real-world settings., Methods: We systematically searched PubMed, EMBASE, and Web of Science for real-world studies published before April 27, 2024. The data of interest were extracted and analyzed using the R software (version 4.2.1)., Results: From 1181 retrieved citations, 25 records involved a total of 2985 individuals were included in the meta-analysis. The 50 % responder rate pooled from the 22 studies yielded an overall 55.0 % (95 % CI: 46.1-63.8 %), with significant evidence of between-study heterogeneity (I 2 = 93 %, P < 0.01, τ 2 = 0.038). The seizure-free rate pooled from 22 studies yielded an overall rate of 28.9 % (95 % CI: 19.6-39.1 %). Twenty studies reported the retention rate of perampanel treatment with a pooled proportion was 71.1 % (95 % CI: 61.1-80.2 %). The estimate of the adverse events incidence rate pooled from the 23 studies yielded an overall 29.0 % (95 % CI: 23.4-34.9 %). Subgroup analyses were conducted based on follow-up time (12 months or ≥ 24 months)., Conclusion: Perampanel is generally well tolerated and effective in the treatment of epilepsy in children and adolescents with mid-long-term follow-up. The 50 % responder rate in children and adolescents improved with time. The retention rate and the seizure-free rate during at least 24 months of follow-up were not as sustained as those in 12 months of follow-up. Adverse events, particularly psychiatric and behavioral, should be monitored during clinical practice administration., Competing Interests: Declarations of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Epilepsy, a widespread neurological disorder, affects approximately 50 million people worldwide. This disorder is typified by recurring seizures due to abnormal neuron communication in the brain. The seizures can lead to severe ischemia and hypoxia, potentially threatening patients' lives. However, with proper diagnosis and treatment, up to 70 % of patients can live without seizures. The causes of epilepsy are complex and multifactorial, encompassing genetic abnormalities, structural brain anomalies, ion channel dysfunctions, neurotransmitter imbalances, neuroinflammation, and immune system involvement. These factors collectively disrupt the crucial balance between excitation and inhibition within the brain, leading to epileptic seizures. The management of treatment-resistant epilepsy remains a considerable challenge, necessitating innovative therapeutic approaches. Among emerging potential treatments, ketamine-a drug traditionally employed for anesthesia and depression-has demonstrated efficacy in reducing seizures. It is noteworthy that, independent of its anti-epileptic effects, ketamine has been found to improve the balance between excitatory and inhibitory (E/I) activities in the brain. The balance is crucial for maintaining normal neural function, and its disruption is widely considered a key driver of epileptic seizures. By acting on N-methyl-D-aspartate (NMDA) receptors and other potential mechanisms, ketamine may regulate neuronal excitability, reduce excessive synchronized neural activity, and counteract epileptic seizures. This positive impact on E/I balance reinforces the potential of ketamine as a promising drug for treating epilepsy, especially in patients who are insensitive to traditional anti-epileptic drugs. This review aims to consolidate the current understanding of ketamine's therapeutic role in epilepsy. It will focus its impact on neuronal excitability and synaptic plasticity, its neuroprotective qualities, and elucidate the drug's potential mechanisms of action in treating epilepsy. By scrutinizing ketamine's impact and mechanisms in various types of epilepsy, we aspire to contribute to a more comprehensive and holistic approach to epilepsy management., Competing Interests: Declaration of Competing Interest Dr. Tan declares no conflict of interest. Dr. Hashimoto is the inventor of filed patent applications on “The use of R-Ketamine in the treatment of psychiatric diseases”, “(S)-norketamine and salt thereof as pharmaceutical”, “R-Ketamine and derivative thereof as prophylactic or therapeutic agent for neurodegeneration disease or recognition function disorder”, “Preventive or therapeutic agent and pharmaceutical composition for inflammatory diseases or bone diseases”, and “R-Ketamine and its derivatives as a preventive or therapeutic agent for a neurodevelopmental disorder” by the Chiba University. Dr. Hashimoto has also received speakers’ honoraria, consultant fee, or research support from Abbott, Boehringer-Ingelheim, Daiichi-Sankyo, Meiji Seika Pharma, Seikagaku Corporation, Dainippon-Sumitomo, Taisho, Otsuka, Murakami Farm and Perception Neuroscience., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: Information on self-limited epilepsy with centrotemporal spikes (SeLECTS) epidemiology is limited. We aimed to determine the incidence of SeLECTS in children, its association with socioeconomic deprivation and the prevalence of neurodevelopmental comorbidities., Method: We performed a retrospective cohort study (2004-2017) using anonymised, linked, routinely collected, primary care and demographic data for children in Wales. We used primary care diagnosis codes to identify children (aged 0-16 years) with SeLECTS and other epilepsies and to record antiseizure medication (ASM) prescriptions and neurodevelopmental comorbidities. We used a mixed effects Poisson regression model to determine temporal trends of SeLECTS incidence and its association with socioeconomic deprivation., Results: We identified 6,732 children with epilepsy, 186 (3%) with SeLECTS. In 2017, epilepsy and SeLECTS prevalence was 0.55% and 0.02% respectively with corresponding crude incidence of 51.2/100,000/year and 1.1/100,000/year. The incidence of epilepsy in children decreased with decreasing deprivation with an adjusted incidence rate ratio (AIRR) of 0.72 (95% CI 0.64-0.82) in the least deprived compared with the most deprived quintile. The corresponding AIRR for children with SeLECTS was 1.35 (95% CI 0.46-1.99). 34% of children with epilepsy, 18% of children with SeLECTS and 3% of all children in Wales had a neurodevelopmental disorder and or school problems. Half of children with SeLECTS were treated with ASM., Conclusions: We identified a lower than previously reported incidence of SeLECTS, which may be due to under-recording of SeLECTS. There was no change in the incidence of SeLECTS over time, whilst the incidence of childhood epilepsy overall was decreasing. There was no significant association between incidence of SeLECTS and deprivation but the modest sample size needs to be considered. Children with SeLECTS should be screened for neurodevelopmental and or learning comorbidities. Treatment for SeLECTS remains debatable., Competing Interests: Declaration of competing interest The authors do not note any conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures. The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants., Methods: We used online gene-matching tools to identify 13 patients with de novo POLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas., Results: All 13 patients had novel POLR3B variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic-atonic, atypical absence, or tonic-clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic-atonic seizures (EMAtS) in seven patients and "probable EMAtS" in two more. Seizures were treatment resistant in all cases. Three patients became seizure-free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset. Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5/9) who tried it; rufinamide (2/3); and ketogenic diet (2/3). Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13)., Significance: POLR3B is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose: Epileptic spasms are the primary symptom of infantile epileptic spasms syndrome (IESS); however, their direct impact on blood-brain barrier (BBB) function is unknown. Matrix metallopeptidase-9 (MMP-9), degrades type IV collagen, a key component of the blood-brain barrier, while tissue inhibitor of metalloproteinase-1 (TIMP-1) suppresses its activity, protecting BBB integrity. This study aimed to assess serum MMP-9 and TIMP-1 levels in patients with IESS of unknown etiology., Methods: We prospectively assessed serum MMP-9 and TIMP-1 levels prior to administering vigabatrin or adrenocorticotropic hormone therapy in patients with IESS of unknown etiology at Saitama Children's Medical Center between February 2012 and December 2023. We compared these biomarkers between patients with epileptic spasms and age-matched controls and performed a curve regression analysis between the biomarkers and the frequency of epileptic spasms. Additionally, we assessed whether MMP-9 and TIMP-1 levels were diagnostic predictors of IESS., Results: This study included 22 patients with IESS (11 males) and 12 controls. Serum MMP-9 and MMP-9/TIMP-1 ratios were higher in patients with IESS than in controls (p < 0.001 and p = 0.002, respectively). A high frequency of epileptic spasms also led to higher serum MMP-9 levels (y = 0.0871x 2 + 0.195x + 195.15, R² = 0.77, p < 0.001). Using MMP >188 ng/mL as the cutoff level, the sensitivity for diagnosing IESS was 95.5 %, the specificity was 75.0 %, the positive likelihood ratio was 3.82 (95 % confidence interval (CI) 1.43-10.22), and the relative risk was 8.75 (95 % CI 1.36-56.5)., Conclusion: Patients with IESS had elevated serum MMP-9 levels, suggesting an association between epileptic spasms and blood-brain barrier dysfunction. MMP-9 level measurement may be useful for diagnosing suspected patients., Competing Interests: Declaration of Competing Interest Shin-ichiro Hamano received funding from Daiichi Sankyo Co. Ltd., UCB Japan Co. Ltd., and Eisai Co. Ltd. Kenjiro Kikuchi received research funding from Syneos Health Clinical Co. Ltd. and Janssen Pharmaceutical K.K. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Epilepsy is primarily treated with antiseizure medications (ASMs). The recommendations for first ASM in newly diagnosed epilepsy are inconsistently followed, and we sought to examine whether nonrecommended first ASM was associated with acute care utilization., Methods: We conducted a retrospective cohort study of adults (≥18 years old) with newly diagnosed epilepsy (identified using validated epilepsy/convulsion International Classification of Diseases, Clinical Modification codes) in 2015-2019, sampled from Marketscan's Commercial and Medicare Databases. Exposure of interest was receipt of a non-guideline-recommended ASM, and the primary outcome was acute care utilization (an emergency department visit or hospitalization after the first ASM claim). Descriptive statistics characterized covariates, and multivariable negative binominal regression models were built adjusting for age, sex, Elixhauser Comorbidity Index, comorbid neurologic disease (e.g., stroke), and ASM polypharmacy., Results: Approximately 14 681 people with new epilepsy were prescribed an ASM within 1 year. The three most prescribed medications were levetiracetam (54%, n = 7912), gabapentin (10%, n = 1462), and topiramate (7%, n = 1022). Approximately 4% (n = 648) were prescribed an ASM that should be avoided, and ~74% of people with new epilepsy had an acute care visit during the follow-up period. Mean number of acute care visits during follow-up was 3.34 for "recommended" ASMs and 4.42 for ASMs that "should be avoided." Prescription of a recommended/neutral ASM as compared to an ASM that should be avoided was associated with reduced likelihood of acute care utilization (incidence rate ratio [IRR] = .85, 95% confidence interval [CI] = .77-.94). The recommended/neutral category of ASMs was not statistically significantly associated with seizure- or epilepsy-specific acute care utilization (IRR = .93, 95% CI = .79-1.09)., Significance: Adults with new epilepsy are frequent users of acute care. There remain a proportion of persons with epilepsy prescribed ASMs that guidelines suggest avoiding, and these ASMs are associated with increased likelihood of emergency department visit or hospitalization. These findings reinforce the importance of optimizing the choice of first ASM in epilepsy., (© 2024 International League Against Epilepsy.)

Purpose: Although generic drugs are essential in reducing medical costs, their use in epilepsy therapy remains a subject of ongoing debate. In this study, we analysed prescription trends of generic drugs using data from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan., Methods: The number of generic drug prescriptions from 2017-2021 was extracted from the NDB Open Data Japan, with data for each medication stratified by prefectural region, sex, and age, allowing for the analysis of the impact of each factor. We analysed the correlation between the prescription volumes of generic antiseizure medications (ASMs) and the number of clinical epileptologists registered with the Japan Epilepsy Society per 100,000 population., Results: In 2021, the prescription volume of generic ASMs was 49 %, whereas that for other pharmacological agents was between 70-80 %. Notably, for children < 15 years of age, generics made up approximately 20 % of prescriptions, which was significantly less than that in other age groups. Analysis by prefecture revealed a negative correlation between prescription volumes of ASMs and the number of clinical epileptologists across prefectural regions in Japan (R = -0.47, p < 0.01)., Conclusion: Our findings indicate that the higher the proportion of clinical epileptologists in each prefecture, the lower the number of prescribed generic ASMs. Clinical epileptologists in Japan therefore prescribe antiseizure agents in accordance with the Japanese epilepsy treatment guidelines that do not recommend the use of generic agents., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objective: Antiseizure medications (ASMs) can potentially trigger psychobehavioral adverse events associated with the onset or exacerbation of psychiatric symptoms such as irritability, aggression, and hyperactivity. The objective of this study was to evaluate the effects of levetiracetam and valproic acid on changes in clinical features of anger, attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD). The purpose was to furnish guidance on rational drug selection in children and adolescents with epilepsy to minimize psychiatric comorbidity in the treatment of epilepsy., Method: This was a prospective, observational, cohort study involving treatment-naïve children aged 7-18 years with newly diagnosed generalized or focal epilepsy who were prescribed levetiracetam or valproic acid as monotherapy for a 6-month period and regularly followed up. Psychiatric assessment was conducted at the time of the new epilepsy diagnosis and at the six-month follow-up. These assessments were performed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children Current and Lifetime Version (DSM-5), a structured psychiatric interview, as well as the State-Trait Anger Expression Style Inventory and Turgay DSM-IV Based Disruptive Behaviour Disorders Screening and Rating Scale. Anger subscores, ADHD symptoms, change in diagnosis, focal and generalized epilepsy groups, continuous seizures and seizure-free periods before and 6 months after treatment with valproic acid and levetiracetam were compared., Results: A total of 50 children, 25 in the valproic acid group and 25 in the levetiracetam group, with a mean age of 11.92 ± 3.08 years, were included in the study. There was a statistically significant increase in the ADHD subscale score post-treatment among patients receiving levetiracetam (p = 0.045) and valproic acid (p = 0.034) compared with pre-treatment. The change in both anger-in and anger-out expression scores with treatment was significantly higher in patients receiving levetiracetam (p = 0.035) compared with those receiving valproic acid (p = 0.026). Statistically, there was a significant difference in the diagnostic criteria of the levetiracetam group pre- and post-treatment (p = 0.026). The proportion of patients in whom the diagnostic criteria for ADHD+ODD were fulfilled increased from 16% before treatment to 48% after treatment, a statistically significant increase (p = 0.026)., Conclusion: This study found an increase in internalized anger features and ADHD symptom severity in children with epilepsy treated with valproic acid and levetiracetam. In those prescribed levetiracetam, there was a statistically significant rise in the proportion meeting the diagnostic criteria for ADHD + ODD. Our research is one of the first to prospectively examine the psychiatric assessment of children diagnosed with epilepsy. The remarkable results demonstrate changes in psychiatric diagnoses associated with the treatment of levetiracetam and valproic acid. Furthermore, a considerable rise in ADHD symptoms was observed in those treated with valproic acid., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Buccal midazolam (buc MDL) is the first buccal mucosal delivery formulation applied for status epilepticus in Japan. Herein, we aimed to investigate the effectiveness and adverse events of buc MDL as a pre-hospital treatment for epileptic seizures in real-world clinical practice., Methods: This study involved a retrospective review based on medical records. We included children who received buc MDL as pre-hospital treatment for epileptic seizures and were subsequently transported to the emergency department between April 2021 and November 2023., Results: This study included 26 patients (136 episodes). The overall efficacy rate, which was defined as seizure cessation within 10 min after buc MDL administration with no recurrence within 30 min, was 43 %. Moreover, 70 % of the episodes did not require additional medications. None of the episodes required bag-mask ventilation or intubation following seizure cessation with buc MDL alone. The efficacy was decreased when buc MDL was administered longer than 15 min from seizure onset. Furthermore, the efficacy did not decrease as long as it was within 0.2-0.5 mg/kg, even if the dose was smaller than the appropriate dose for the specific age., Conclusions: The response rate was significantly higher in episodes where buc MDL was administered within 15 min. Additionally, there was no concern regarding respiratory depression with buc MDL alone., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Bipolar Disorder (BD) is associated with alterations of circadian rhythms of activity (CRA). Experimental research suggests that lithium (Li) modifies CRA, but this has been rarely explored in BD using actigraphy., Methods: The sample comprised 88 euthymic BD-I cases with 3 weeks of actigraphy. We used a Principal Component Analysis (PCA) to generate CRA dimensions. We then used linear regression analyses to compare these dimensions between groups of individuals defined according to prescribed mood stabilizers: Li monotherapy ("Li" group, n = 28), anticonvulsant or atypical antipsychotic monotherapy ("AC or AAP" group, n = 27) or combined treatments ("Li+AC or Li+AAP" group, n = 33). Analyses were adjusted for potential confounders (gender, age, body mass index, depressive symptoms, co-prescribed benzodiazepines and antidepressants, smoking status and past alcohol use disorder)., Results: The PCA identified two dimensions: "robust CRA" (high amplitude and interdaily stability, with low intradaily variability) and "late chronotype". Univariate analyses showed higher scores for "robust CRA" in the "Li" versus the "AC or AAP" (p = 0.021) or "Li+AC or Li+AAP" groups (p = 0.047). These findings remained significant after adjustments (respectively p = 0.010 and p = 0.019). Post-hoc analyses suggested lower variability, higher stability and higher amplitude of CRA in the "Li" group. Medication groups were similar for the "late chronotype" dimension (p = 0.92)., Conclusions: This actigraphy study is the first to show more favorable CRA in BD-I individuals receiving a Li monotherapy when compared with those receiving other classes or combinations of mood stabilizers. Replications in larger samples are required. Prospective studies are also warranted to elucidate whether the introduction of Li or other mood stabilizers might influence CRA in BD-I., Competing Interests: Declaration of competing interest B.E. has received honoraria for consulting from Sanofi. F.B. is an advisor on mental health to the French government. All other authors have no conflict of interest regarding this work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The median cost of anti-seizure medications (ASM) in the United States (U.S.) nearly doubled per person between 2006 and 2021. This increase, combined with shifts in ASM usage and the impact of the COVID-19 pandemic on drug supply chains amid rising inflation, underscored the urgent need to scrutinize ASM pricing dynamics. This study aimed to analyze the complex dynamics of ASM pricing in the U.S. over the past decade (2013-2023); this included how the entry of generic ASMs influenced the pricing of brand-name counterparts and what impacted price variations across different ASM formulations (e.g., significant inflation, the COVID-19 pandemic)., Methods: This study utilized National Average Drug Acquisition Cost (NADAC) data from November 2013 to July 2023. We adjusted ASM prices for inflation using the Consumer Price Index for Medicinal Drugs - Seasonally Adjusted (CPI-MDS). Statistical analyses included fixed effects regressions and multivariable regression analysis to evaluate the impact of inflation, the number of medication labelers, and the COVID-19 pandemic on ASM prices., Results: Our study analyzed 23 ASMs approved by the U.S. Food and Drug Administration (FDA), which encompassed 223 oral formulations:112 brand-name and 111 generics. From 2013-2016 to 2020-2023, accounting for standard deviations (SD), the average price of brand-name ASMs increased from $8.71 (SD 5.9) to $15.43 (SD 10.7), while generic ASMs saw a slight decrease from $1.39 (SD 1.8) to $1.26 (SD 1.6). Consequently, the price gap between brand-name and generic ASMs surged from 1452.39 % to 3399.26 %. The proportion of matched brand-name and generic ASMs with a price difference of 1000 %-9999 % increased from 32.88 % (2013-2016) to 41.43 % (2020-2023), while those exceeding 10,000 % rose from 16.44 % to 20 % in the same period. Generic immediate-release (IR) formulations were significantly less expensive than extended-release (ER) or delayed-release (DR) counterparts, with cost differences reaching up to 7751.20 %. The number of medication labelers was inversely related to generic ASM prices, which decreased by 5.45 % (p = 0.001) with each additional generic labeler, while brand-name ASM prices increased by 2.46 % (p < 0.001) with each additional generic labeler. The COVID-19 pandemic led to a 24.4 % increase in brand-name ASM prices and a 23.1 % decrease in generic ASM prices., Conclusions: The findings reveal an expanding price disparity between brand-name and generic oral ASMs. An inverse relationship was observed between the number of medication labelers and generic ASM prices, with additional labelers driving down generic prices. However, introducing more generic labelers led to a significant increase in brand-name ASM prices. Furthermore, following patent expirations, brand-name ASM prices rose-a trend explained by the "generics paradox," where, contrary to expectations, brand prices do not decrease and may even increase when generics enter the market. These findings underscore the need for targeted interventions in drug pricing policies to manage the rising costs associated with epilepsy treatment. To ensure equitable access to ASMs, stakeholders must understand and address the factors driving these pricing dynamics., Competing Interests: Declaration of competing interest The authors report no disclosures., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: E2730, an uncompetitive γ-aminobutyric acid (GABA) transporter-1 (GAT-1) inhibitor, has potent anti-seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function., Methods: We conducted a randomized cross-over study, incorporating 1-week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post-KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [ 18 F]Flumazenil positron emission tomography (PET) quantifying GABA A receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)-mediated motor activity, as well as continuous video-EEG recording to measure spontaneous seizures during each treatment. Age-matched, healthy control animals treated with E2730 or vehicle were also studied., Results: E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure-free. MRS revealed that E2730-treated animals had significantly reduced taurine levels. [ 18 F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS., Significance: This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To explore seizure control and offspring outcomes associated with antiseizure medication (ASM) withdrawal during the first trimester of pregnancy., Methods: Based on a prospective multicenter study in China, pregnancies followed up between 2009 and 2023 at the neurology outpatient clinic of 50 hospitals were included in this study. Information on demographics, epileptic characteristics, treatment during pregnancy, and offspring outcomes was collected. Pregnancies were categorized into an ASM withdrawal group and an ASM continuation group. Balance tests and univariate log-binomial regression analysis were conducted to identify imbalanced factors between groups and potential risk factors for seizure deterioration during pregnancy. Multivariate log-binomial regression was then used to estimate the adjusted effects of ASM withdrawal on seizure deterioration during pregnancy and fetal outcomes. In addition, exploratory subgroup analysis was conducted to identify high-risk patients who should avoid ASM withdrawal., Results: Of the 695 pregnancies enrolled, 14.2% withdrew ASMs in the first trimester of pregnancy. ASM withdrawal during this period was associated with a risk of seizure deterioration during pregnancy (adjusted risk ratio [aRR] 1.405, 95% confidence interval [CI] 1.009-1.876). Subgroup analysis revealed a significant risk of seizure deterioration in pregnancies with seizures in 9 months (aRR 1.590, 95% CI 1.079-2.344). After adjusting the folic acid dose, no evidence of protective effects on fetus after ASM withdrawal was observed compared to patients with continued treatment, whereas seizure deterioration during pregnancy increased the risk of fetal death (aRR 3.577, 95% CI 1.086-11.651)., Significance: ASM withdrawal in the first trimester of pregnancy did not show a protective effect on fetal outcomes but rather resulted in increased seizure frequency during pregnancy. However, this finding requires a larger sample for validation. Furthermore, seizure deterioration during pregnancy was associated with an increased risk of fetal death., (© 2024 International League Against Epilepsy.)

Levetiracetam (LEV) and carbamazepine (CBZ) are effective monotherapies for focal epilepsy in children. However, the best drug remains controversial. Therefore, we performed a systematic review and meta-analysis comparing LEV and CBZ monotherapy in the management of pediatric focal epilepsy (PFE). We searched PubMed, Embase, and Cochrane databases for randomized controlled trials (RCTs) published until February 2024 comparing LEV and CBZ monotherapy in PFE. Statistical analysis was performed using R version 4.2.2, heterogeneity was assessed using I 2 statistics, and the risk of bias was evaluated using the RoB-2 tool. Risk Ratios (RR) with p < 0.05 were considered significant. The outcomes of interest were seizure freedom, any adverse events, adverse events leading to treatment discontinuation, dermatologic adverse events, and the frequency of at least one seizure, defined as the proportion of patients experiencing one or more seizures during the treatment period. Four RCTs comprising 381 children with a mean age of 7.32 to 9.28 years were included, of whom 186 (48.8%) received LEV monotherapy. There was no significant difference between groups (RR: 1.15; 95% CI 0.88-1.50; p = 0.31; I 2  = 90%) regarding seizure freedom. The frequency of at least one seizure (RR: 0.71; 95% CI 0.52-0.97; p = 0.03; I 2  = 8%) and dermatologic adverse events (RR: 0.24; 95% CI 0.09-0.64; p < 0.01; I 2  = 0%) were both significantly lower in the LEV group. There were no significant differences in the presence of any adverse events (RR: 0.58; 95% CI 0.33-1.01; p = 0.05; I 2  = 36%) or adverse events leading to treatment discontinuation (RR: 0.67; 95% CI 0.13-3.42; p = 0.63; I 2  = 30%).Conclusion: In monotherapy, LEV was more advantageous than CBZ for PFE, with a lower frequency of seizures and fewer dermatological adverse events. However, both drugs are equally effective in achieving seizure freedom, adverse events without specification, and those that lead to treatment discontinuation. Our findings have important implications for clinical practice and decision-making in this condition., (© 2024. The Author(s).)

Background: Status epilepticus (SE) is a neurologic emergency defined as continued seizure activity greater than five minutes or recurrent seizure activity without return to baseline. Benzodiazepine-refractory SE is continuous seizure activity despite treatment with a benzodiazepine. Treatment of benzodiazepine-refractory SE includes levetiracetam with loading doses ranging from 20 mg/kg to 60 mg/kg up to a maximum dose of 4500 mg. While levetiracetam has minimal adverse effects, there is currently a lack of studies directly comparing the safety and efficacy of various loading doses of levetiracetam., Objective: The objective of this study was to evaluate the safety and efficacy of three loading doses of levetiracetam in the setting of benzodiazepine-refractory SE., Methods: This was a single center, retrospective cohort study of adult patients with benzodiazepine-refractory SE who were treated with levetiracetam from April 1, 2016, to August 31, 2023. Patients with documented hypersensitivity to levetiracetam, those who were pregnant or incarcerated and patients who received an alternative antiepileptic drug (AED) prior to levetiracetam were excluded. Patients with other identifiable causes of SE including hyperglycemia, hypoglycemia, hyponatremia or who were post cardiac arrest were also excluded. Patients were divided into three arms based on loading dose of levetiracetam administered (≤20 mg/kg [LEVlow], 21--39 mg/kg [LEVmed] or ≥40 mg/kg [LEVhigh]). The primary endpoint was the rate of seizure termination, defined as the lack of need for an additional AED within 60 min following levetiracetam administration. Secondary outcomes included the rate of intubation, and recurrent seizure activity 60 min to 24 h post seizure termination as defined by positive EEG results or need for an additional AED. Subgroup analyses were performed to assess the influence of adequate loading doses of benzodiazepines, and outpatient levetiracetam use., Results: Overall, 740 patients were screened for inclusion, with 218 patients being included in the primary analysis. Patients were divided into three groups with an average levetiracetam loading dose of 14.5 mg/kg in the LEVlow group, 28.8 mg/kg in the LEVmed group, and 48.8 mg/kg in the LEVhigh group. There was no difference in rates of seizure termination at 60 min (92.9% LEVlow vs 89.3% LEVmed vs 84.7% LEVhigh; p = 0.377). Additionally, no difference was found in rates of recurrent seizure activity between 60 min and 24 h post levetiracetam loading dose (32.1% LEVlow vs 32.0% LEVmed vs 28.8% LEVhigh; p = 0.899). However, the LEVhigh group did have a higher rate of intubation (45.8%) compared to the LEVmed (28.2%) and LEVlow (26.8%) group (p = 0.040)., Conclusion: The loading of levetiracetam did not result in a statistically significant difference in rate of seizure termination at 60 min nor did it appear to impact the rate of recurrent seizures at 24 h. However, we did find higher rates of intubation in patients who received levetiracetam >40 mg/kg. Further research is warranted to determine the optimal loading dose of levetiracetam in benzodiazepine-refractory SE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy., Methods: We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations., Results: Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden., Significance: The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

2,4-Thiazolidinedione derivatives represent nitrogen-containing heterocyclic compounds utilized in type 2 diabetes mellitus management. Recent advances in medicinal chemistry have unveiled diverse therapeutic potentials and structural modifications of these derivatives. This review delves into novel TZD derivatives, encompassing their synthesis, structure-activity relationships, and pharmacokinetic profiles. Various therapeutic potentials of TZDs are explored, including anticancer, antimicrobial, anti-inflammatory, antioxidant, anticonvulsant, antihyperlipidemic, anticorrosive, and antitubercular activities. Additionally, it addresses mitigating side effects associated with marketed TZD derivatives such as weight gain, oedema, fractures, and congestive heart failure in type 2 diabetes mellitus management. The review elaborates on in vivo, in vitro, and ex vivo studies supporting different biological activities, alongside predicting ADME and drug-likeness properties of TZDs. Computational studies are also integrated to elucidate binding modes and affinities of novel TZD derivatives. Furthermore, a plethora of novel TZD derivatives with varied and enhanced therapeutic potentials are presented, warranting further evaluation of their biological activities., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

2-deoxy-D-glucose (2DG) has been proposed as a potential antiseizure treatment based on seizure suppressive actions in multiple acute and chronic seizure models, including models of status epilepticus (SE). Here we summarize recently completed preclinical toxicological studies of single doses of an intravenous formulation of 2DG supporting potential safety of 2DG for acute treatment of SE and acute repetitive seizures (ARS)., Competing Interests: Declaration of competing interest T.S. and N.F. hold equity interests in Hexokine Therapeutics, Inc. which is developing 2DG for potential human use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no conflict of interest to declare.

Objective: Following hypoxic-ischemic (HI) brain injury, neuronal cytoplasmic chloride concentration ([Cl - ] i ) increases, potentially contributing to depolarizing γ-aminobutyric acid (GABA) responses, onset of seizures, and the failure of antiepileptic drugs that target inhibitory chloride-permeable GABA A receptors. Post-HI seizures characteristically begin hours after injury, by which time substantial accumulation of [Cl - ] i may have already occurred. In immature neurons, a major pathway for Cl - influx is the reversible Na + -K + -2Cl - cotransporter NKCC1., Methods: Spontaneous neuronal network, neuronal [Cl - ] i , and GABA activity were determined in hippocampal preparations from neonatal Clomeleon and SuperClomeleon/DLX-cre mice to test whether blocking NKCC1 earlier after oxygen-glucose deprivation (OGD) injury would more effectively ameliorate the increase in [Cl - ] i , ictallike epileptiform discharges (ILDs), and the failure of the GABAergic anticonvulsant phenobarbital., Results: In vitro, murine intact hippocampi were free of ILDs for 12 h after preparation. Transient OGD resulted in a gradual increase in [Cl - ] i , depolarizing action of GABA, and facilitation of neuronal network activity. Spontaneous ILDs began 3-5 h after injury. Blocking NKCC1 with 2-10 μmol·L -1 bumetanide reduced [Cl - ] i equally well when applied up to 10 h after injury. Whereas phenobarbital or bumetanide applied separately were less effective when applied later after injury, ILDs were successfully suppressed by the combination of phenobarbital and bumetanide regardless of the number of prior ILDs or delay in application., Significance: The present age-specific group studies demonstrate that after OGD, NKCC1 transport activity significantly contributes to progressive [Cl - ] i accumulation, depolarizing action of GABA, and delayed onset of ILDs. In this neonatal model of neuronal injury and ILDs, earlier treatment with bumetanide alone more efficiently recovered control baseline [Cl - ] i and depressed epileptiform discharges. However, there was no time dependency to the anti-ictal efficacy of the combination of phenobarbital and bumetanide. These in vitro results suggest that after perinatal injury, early pre-emptive treatment with phenobarbital plus bumetanide would be as efficacious as late treatment after seizures are manifest., (© 2024 International League Against Epilepsy.)

Purpose: This study aims to assess the predictive performance of published valproic acid (VPA) population pharmacokinetic (PPK) models using an external data set in Chinese adults with epilepsy or after neurosurgery., Methods: A total of 384 concentrations from 290 Chinese adults with epilepsy or after neurosurgery were used for external validation. Data on published VPA PPK models were extracted from the literature. Prediction-based diagnostics (such as F20 and F30), simulation-based diagnostics, and Bayesian forecasting were used to evaluate the predictability of models., Results: The results of prediction-based diagnostics of all models were unsatisfactory. Models B, F, and H showed the best prediction performance in simulation-based diagnostics and Bayesian forecasting, demonstrating superior precision and accuracy. Bayesian forecasting demonstrated significant improvements in the model predictability., Conclusion: The published PPK models showed extensive variation in predictive performance for extrapolation among Chinese adults with epilepsy or after neurosurgery patients. Fixed parameters of Vd and Ka in the PPK modeling of VPA might be the reason for the unsatisfied predictive performance. Bayesian forecasting significantly improved model predictability and may help to individualize VPA dosing., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: There is increased focus on the negative impact of the overprescribing of medication, specifically psychotropic medication, including anti-seizure medications (ASM), in people with Intellectual Disability (ID). This is particularly important for the older adult population, where multi-morbidity and polypharmacy are more common. ASMs are associated with psychiatric and behavioral adverse effects. Furthermore, there is growing awareness of the anticholinergic burden for older adults with epilepsy and ID and the relationship with behaviors that challenge (BtC)., Areas Covered: This review defines the older adult population and outlines the relationship between epilepsy and ID. BtC is outlined in the context of the population and the relationship with ASMs. The evidence base to guide prescribing and de-prescribing for newer ASMs is also presented, including pragmatic data., Expert Opinion: Polypharmacy, particularly psychotropics, are a mortality risk factor for older adults with epilepsy and ID. Therefore, any BtC requires a holistic assessment with a multi-disciplinary approach. This includes specific consideration of all prescribed medicines in the context of polypharmacy. There should be routine reviews, at least annually, for those aged 40 years and over particularly focused on anticholinergic burden and/or polypharmacy.

Background: There is not a preferred medication for treating refractory status epilepticus (RSE) and intravenous ketamine is increasingly used. Ketamine efficacy, safety, dosage, and influence of other variables on seizure cessation while on ketamine infusions are not well studied. We aimed to characterize ketamine effect on RSE, including interictal activity on electroencephalogram (EEG) and when done by Teleneurocritical care (TNCC)., Methods: We conducted a multicenter, retrospective study from August 2017 to October 2022. Patients 18 years or older who had RSE and received ketamine were included. The primary outcome was effect of ketamine on RSE including interictal activity; secondary outcomes were effect of other variables on RSE, care by TNCC, ketamine infusion dynamics, adverse events, and discharge outcomes. Logistic regression was used., Results: Fifty-one patients from five hospitals met inclusion criteria; 30 patients had RSE and interictal activity on EEG. Median age was 56.8 years (IQR 18.2) and 26% had previously diagnosed epilepsy. Sixteen (31%) patients were treated virtually by TNCC. In those with RSE on EEG, ketamine was added as the fourth antiseizure medication (mean 4.4, SD 1.6). An initial bolus of ketamine was used in 24% of patients (95 mg, IQR 47.5), the median infusion rate was 30.8 mcg/kg/min (IQR 40.4), and median infusion duration was 40 h (IQR 37). Ketamine was associated with 50% cessation of RSE and interictal activity at 24 h in 84% of patients, and complete seizure cessation in 43% of patients. In linear regression, ASMs prior to ketamine were associated with seizure cessation (OR 2.6, 95% CI 0.9-6.9, p = 0.05), while the inverse was seen with propofol infusions (OR 0.02, 95% CI 0.001-0.43, p = 0.01). RSE management by in-person NCC versus virtual by TNCC did not affect rates of seizure cessation., Conclusions: Ketamine infusions for RSE were associated with reduced seizure burden at 24 h, with 84% of patients having 50% seizure reduction. Similar efficacy and safety was observed irrespective of underlying RSE etiology or when done via TNCC vs in-person NCC., (© 2024. Fondazione Società Italiana di Neurologia.)

Background. The effect of antiseizure medications (ASMs) on cognition varies depending on the type of ASM. We aimed to investigate the effects of ASMs on patients with epilepsy based on the conflicting findings in the literature. Methods. Patients diagnosed with epilepsy who were taking ASMs were included. All patients underwent a neuropsychiatric assessment, Beck Depression and Anxiety Inventories, Positive and Negative Syndrome Scale, and general psychopathological tests. The patients were divided into polytherapy and monotherapy groups. Subgroups were categorized according to the type of ASMs, dosage, and duration of monotherapy. Results. Ninety-seven patients were included in this study. The polytherapy group showed a significant decrease in attention, total learning, and interpretation of proverbs compared to the monotherapy group. In the monotherapy group, carbamazepine use had a moderate positive correlation with working memory ( r  = .669; P  = .034), and a strong negative correlation with maintaining attention ( r  = -.740; P  = .014). The duration of levetiracetam monotherapy was negatively correlated with verbal memory (immediate recall r  = -.436, P  = .038; free recall r  = .426, P  = .043) and negatively weakly correlated with naming performance ( r  = -.488, P  = .025). Conclusion. The study showed polytherapy may affect verbal and working memory. Carbamazepine may affect working memory and the maintenance of attention in a dose-dependent manner. Levetiracetam may cause impairments in verbal memory and naming, depending on the duration of usage., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent severe manifestations of a potentially life-threatening spectrum defined by a desquamating rash of the skin and mucous membranes. This study was prompted by the observed increase in the off-label use of lamotrigine as a causal agent in SJS/TEN in our regional burn center., Methods: A retrospective cohort of 48 patients presenting to the Connecticut Burn Center from 2015-2022 with suspicion for SJS/TEN were reviewed for age, sex, causative drug, presenting symptoms, hospital course, biopsy confirmation, length of stay, comorbidities, and 30-day mortality. Descriptive statistical analysis was conducted to identify trends in causative agent, clinical presentation, and mortality., Results: Thirty patients in our cohort received a final diagnosis of SJS/TEN. While antibiotics remain the most frequent cause of SJS/TEN across the study period (33.3 %, n = 10), the incidence of cases attributable to lamotrigine increased from 1 case between 2015 and 2018 (6.7 %) to 6 cases between 2019 and 2022 (40 %). In 2020 alone, 50 % of all cases were attributable to lamotrigine (n = 4). Of the patients where lamotrigine was implicated, 71.4 % (n = 5) were prescribed lamotrigine for off-label use in the treatment of non-bipolar mood disorders. The average lamotrigine-associated SJS/TEN patient was younger (p < 0.001), had fewer comorbidities, and was more likely to be female than the general SJS/TEN population., Conclusion: Off-label use of lamotrigine is emerging as a major driver of SJS/TEN with notable changes in patient demographics. Further research is necessary to understand how changing trends in the patient population will impact clinical course and optimal management., Competing Interests: Declaration of Competing Interest The authors report no funding sources or conflict of interest concerning the materials or methods used in this study or the findings specified in this study., (Copyright © 2024 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

West syndrome is an epileptic disease that seriously affects the normal growth and development of infants in early childhood. Based on the methods of brain topological network and graph theory, this article focuses on three clinical states of patients before and after treatment. In addition to discussing bidirectional and unidirectional global networks from the perspective of computational principles, a more in-depth analysis of local intra-network and inter-network characteristics of multi-partitioned networks is also performed. The spatial feature distribution based on feature path length is introduced for the first time. The results show that the bidirectional network has better significant differentiation. The rhythmic feature change trend and spatial characteristic distribution of this network can be used as a measure of the impact on global information processing in the brain after treatment. And localized brain regions variability in features and differences in the ability to interact with information between brain regions have potential as biomarkers for medication assessment in WEST syndrome. The above shows specific conclusions on the interaction relationship and consistency of macro-network and micro-network, which may have a positive effect on patients' treatment and prognosis management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Despite various treatment approaches, a significant number of patients continue to experience uncontrolled seizures, leading to refractory epilepsy. The emergence of novel anti-epileptic drugs, such as perampanel (PER), has provided promising options for effective epilepsy treatment. However, the specific mechanisms underlying the therapeutic effects of PER remain unclear. This study aimed to investigate the intrinsic molecular regulatory mechanisms involved in the downregulation of GluA2, a key subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, following epileptic seizures. Primary mouse hippocampal neurons were cultured and subjected to an epilepsy cell model. The expression levels of GluA2 and autophagy-related proteins were assessed using Western blotting and real-time fluorescent quantitative PCR. Immunofluorescence and immunohistochemistry techniques were employed to investigate the nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1). Additionally, status epilepticus animal models were established to further validate the findings. The epilepsy cell model exhibited a significant decrease in GluA2 expression, accompanied by elevated levels of autophagy-related proteins. Immunofluorescence analysis revealed the nuclear translocation of CRTC1, which correlated with the expression of autophagy-related genes. Treatment with an autophagy inhibitor reversed the decreased expression of GluA2 in the epilepsy cell model. Furthermore, the calcium/calmodulin-dependent protein phosphatase inhibitor FK506 and CaN overexpression affected the dephosphorylation and nuclear translocation of CRTC1, consequently influencing GluA2 expression. Animal model results further supported the involvement of these molecular mechanisms in epilepsy. Our findings suggest that the downregulation of GluA2 following epileptic seizures involves the activation of autophagy and the regulation of CRTC1 nuclear translocation. These intrinsic molecular regulatory mechanisms provide potential targets for developing novel therapeutic strategies to alleviate refractory epilepsy and preserve cognitive functions in patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)