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OBJECTIVE: Monotherapy with antiepileptic drugs (AEDs) is the preferred strategy for the initial treatment of epilepsy. However, an inadequate response to the initially prescribed AED is a significant indicator of a poor long-term prognosis, emphasizing the importance of precise prediction of treatment outcomes with the initial AED regimen in patients with epilepsy. Approach: We introduce OxcarNet, an end-to-end neural network framework developed to predict treatment outcomes in patients undergoing oxcarbazepine monotherapy. The proposed predictive model adopts a Sinc Module in its initial layers for adaptive identification of discriminative frequency bands. The derived feature maps are then processed through a Spatial Module, which characterizes the scalp distribution patterns of the electroencephalography (EEG) signals. Subsequently, these features are fed into an attention-enhanced Temporal Module to capture temporal dynamics and discrepancies. A Channel Module with an attention mechanism is employed to reveal inter-channel dependencies within the output of the temporal module, ultimately achieving response prediction. OxcarNet was rigorously evaluated using a proprietary dataset of retrospectively collected EEG data from newly diagnosed epilepsy patients at Nanjing Drum Tower Hospital. This dataset included patients who underwent long-term EEG monitoring in a clinical inpatient setting. Main results: OxcarNet demonstrated exceptional accuracy in predicting treatment outcomes for patients undergoing Oxcarbazepine monotherapy. In the ten-fold cross-validation, the model achieved an accuracy of 97.27%, and in the validation involving unseen patient data, it maintained an accuracy of 89.17%, outperforming six conventional machine learning methods and three generic neural decoding networks. These findings underscore the model's effectiveness in accurately predicting the treatment responses in patients with newly diagnosed epilepsy. The analysis of features extracted by the Sinc filters revealed a predominant concentration of predictive frequencies in the high-frequency range of the gamma band. Significance: The findings of our study offer substantial support and new insights into tailoring early AED selection, enhancing the prediction accuracy for the responses of AEDs. .

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This study aimed to analyze the frequency of unexpected subclinical spikes (USCS) in pediatric patients who underwent high-density electroencephalogram (HD-EEG). Of the 4481 successful HD-EEG studies, 18.5% (829) were abnormal, and 49.7% of these abnormal studies showed SCS, of which 64.1% were USCS. USCS were found to be correlated with attention/concentration deficits and executive dysfunction, often accompanied by the dual psychiatric diagnosis of ADHD. MRI revealed abnormal findings in 32.6% of the subjects with USCS, such as abnormal signal or signal hyperintensity in brain parenchyma, temporal or arachnoid cysts, and vascular malformations. Moreover, the USCS group who received neuropsychiatric testing scored lower than the population mean on Full-Scale Intelligence Quotient, Working Memory Index, and Processing Speed Index. This study highlights the potential of USCS as biomarkers that can lead to changes in clinical management and outcomes, provide valuable information about pathophysiological mechanisms, and suggest potential treatment pathways.

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Epilepsy is a persistent neurological condition that affects 60 million individuals globally, with recurrent spontaneous seizures affecting 80% of patients. Antiepileptic drugs (AEDs) are the main course of therapy for approximately 65% of epileptic patients, and the remaining 35% develop resistance to medication, which leads to Drug-Resistant Epilepsy (DRE). DRE continues to be an important challenge in clinical epileptology. There are several theories that attempt to explain the neurological causes of pharmacoresistance in epilepsy. The theory that has been studied the most is the transporter hypothesis. Therefore, it is believed that upregulation of multidrug efflux transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp), which extrudes AEDs from their target location, is the major cause, leading to pharmacoresistance in epilepsy. The most effective strategies for managing this DRE are peripheral and central inhibition of P-gp and maintaining an effective concentration of the drug in the brain parenchyma. Presently, no medicinal product that inhibits P-gp is being used in clinical practice. In this review, several innovative and promising treatment methods, including gene therapy, intracranial injections, Pgp inhibitors, nanocarriers, and precision medicine, are discussed. The primary goal of this work is to review the P-gp transporter, its substrates, and the latest novel treatment methods for the management of DRE.

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Rhabdomyolysis is the breakdown of muscle cells secondary to both traumatic and non-traumatic causes. The lysing of the muscle cells can lead to the release of cell contents that can lead to acute injury and other life-threatening conditions. Levetiracetam is an anticonvulsant commonly used in generalized and partial tonic-clonic seizures. Well-known side effects include agitation, depression, anxiety, irritability, rash, and somnolence; however, there are an increasing number of case reports that report rhabdomyolysis secondary to antiepileptic use. We present a case of a 27-year-old male with new-onset seizures who was started on levetiracetam therapy and found to have elevated creatine kinase (CK), which decreased only with tapering of the drug. Our case displays the importance of considering levetiracetam as a cause of rhabdomyolysis, supporting this rare side effect of the antiseizure medication. Rhabdomyolysis is a potentially life-threatening condition that can lead to irreversible renal damage if not managed properly.

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INTRODUCTION: The use of anti-epileptic drugs (AEDs) in degenerative dementia (DD) remains uncertain. We aimed to evaluate the association of early AED administration with subsequent DD occurrence. METHODS: Using a large nationwide database, we enrolled patients newly diagnosed with epilepsy from 2014 to 2019 (n = 104,225), and using propensity score matching, we divided them into treatment (those prescribed AEDs in 2014) and control groups. The primary outcome was subsequent DD occurrence in 2019. RESULTS: Overall, 4489 pairs of patients (2156 women) were matched. The odds ratio (treatment/control) for DD occurrence was 0.533 (95% confidence interval: 0.459-0.617). The DD proportions significantly differed between the treatment (340/4489 = 0.076) and control (577/4489 = 0.129) groups. DISCUSSION: Among patients newly diagnosed with epilepsy, compared to non-use, early AED use was associated with a lower occurrence of subsequent DD. Further investigations into and optimization of early intervention for epilepsy in DD are warranted. Highlights: Anti-epileptic drug (AED) use before epilepsy diagnosis was linked with a lower subsequent degenerative dementia (DD) occurrence.Identifying the epileptic phenotype was crucial for justifying early AED use in DD.AED use with an epilepsy diagnosis did not pose an additional risk of DD.The potential contribution of combination drug therapy to the strategy was noted.

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BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening skin lesion triggered by hypersensitive drug reaction. They are characterized by extensive epidermal necrosis and skin exfoliation. Fulminant type 1 diabetes mellitus (FT1DM) is featured by a rapid-onset of hyperglycemia with ketoacidosis due to severely destroyed ß-cell function. Fulminant type 1 diabetes mellitus as a sequela of SJS/TEN has rarely been reported. CASE PRESENTATION: We present a 73-year-old female patient who developed SJS/TEN skin allergic reaction after taking carbamazepine and phenytoin for 35 days. Then, hyperglycemia and diabetic ketoacidosis occurred 20 days after discontinuation of antiepileptic drugs. A very low serum C-peptide level (8.79 pmol/l) and a near-normal glycosylated hemoglobin level met the diagnostic criteria for fulminant T1DM. Intravenous immunoglobulin (IVIG) and insulin were promptly administered, and the patient recovered finally. CONCLUSIONS: This rare case indicates that monitoring blood glucose is necessary in SJS/TEN drug reaction, and comprehensive therapy with rehydration, insulin, antibiotics, and IVIG may improve the prognosis.

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BACKGROUND:  Understanding the intersection of epilepsy and pregnancy, including knowledge gaps and healthcare access for women with epilepsy (WWE), is critical. This study evaluated WWE knowledge gaps and information needs concerning epilepsy's impact on their sexual and reproductive health during pregnancy and examined healthcare system factors affecting their access to information, aiming to identify areas for improvement in educational and healthcare strategies to enhance health management for WWE. METHODS:  From July 2022 to June 2023, 111 WWE aged 18 to 40 years were recruited from the family medicine and internal medicine outpatient departments at Steve Biko Academic Hospital, Tembisa Tertiary Hospital (TTH), and Kalafong Hospital. Interviews assessed various aspects related to epilepsy in pregnancy and contraceptive use. RESULTS:  The study found strong links between WWE, their demographics, and their awareness of pregnancy-related epilepsy issues. Participants from TTH showed notably higher awareness (85.5%) of risks from epilepsy and AED during pregnancy (p  0.05). Age and education significantly influenced pregnancy planning and understanding of medication risks. Younger women (20-25 years) were more inclined towards future pregnancies, and those with more education were better informed about medication risks (p  0.05); and 68.5% had received counselling on AED and contraceptive interactions, yet only 16.2% knew AED could reduce contraceptive effectiveness. CONCLUSION:  The study reveals significant knowledge gaps in WWE regarding the impact of epilepsy and AED on pregnancy, suggesting tailored educational and counselling initiatives to improve WWE health outcomes and quality of life, advancing chronic disease management and public health objectives.Contribution: The study highlights substantial knowledge gaps in epilepsy during pregnancy among WWE, urging tailored counselling and information to empower informed decisions.

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Introduction Epilepsy, a chronic neurological disorder marked by recurrent seizures, affects approximately 50 million people worldwide with a higher prevalence in developing countries. This condition challenges motor skills and coordination, leading to poor oral health maintenance. The study aimed to evaluate the effect of epilepsy on oral health outcomes in adults by contrasting South Indian epileptics with healthy controls. The primary objective was to assess the prevalence of oral health issues in patients with epilepsy compared to healthy individuals and to analyze the types and frequency of dental procedures required in epileptic patients compared to healthy controls in the South Indian population. Materials and methods A retrospective study was conducted in the Department of Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Chennai, India. Approved by the Institutional Human Ethical Committee (Registration ID: IHEC/SDC/OMED-2202/23/106), the study involved 105 epileptic patients and 105 healthy controls from records between January 2021 and December 2023. Both male and female patients within the age limit of 18-55 years were included. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 29.0 (Released 2022; IBM Corp., Armonk, New York, United States). Results The study involved 210 participants with an equal gender distribution. Valproate was the most common medication used by 39% of epileptic patients. Gingival hyperplasia was significantly more prevalent in the epileptic group (24%). The epileptic group also required more dental procedures, with 32% of teeth needing restoration, 20% root canal treatment, and 20% extraction, compared to 12%, 11%, and 5%, respectively, in the control group. Conclusion Epileptic patients exhibit poorer oral health outcomes, including higher rates of gingival hyperplasia and a greater need for dental procedures compared to healthy controls. These findings highlight the necessity for targeted dental care and regular monitoring for individuals with epilepsy to improve their oral health and overall quality of life.

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OBJECTIVE: To evaluate the experience of prescribing phenosanic acid in the practice of a neurologist/epileptologist when prescribing the second, third anticonvulsant drug (AED) as part of combination therapy for patients with manifestations of fatigue due to epilepsy. MATERIAL AND METHODS: 501 patients with focal epilepsy accompanied by asthenic disorders were included in the observational program. The observation program protocol included 5 visits, including visit 1, at which screening and inclusion in the OP took place. The observation period was 10 months. At baseline and at the end of the 10-month follow-up, the patients' condition was assessed according to the following indicators: frequency and transformation of attacks with focal onset, severity of fatigue (self-assessment scale MFI-20); quality of life (questionnaire QoLiE-10-P); frequency of attacks with focal onset. The safety of phenosanic acid (Dibufelon) was also assessed. RESULTS: In 10 months after the inclusion of Dibufelon as the 2nd, 3rd AED in the treatment regimen, a statistically significant (p<0.01) decrease in the frequency of seizures was observed: in general - in 88% of patients; by 50% or more - in 76% of patients; transition from the group with a large number of seizures to the group with a smaller number of seizures - 74% of patients. Also when taking phenosanic acid, a positive dynamics of seizure type was noted: a reliable decrease in the proportion of patients with seizures with secondary generalization from 70% to 56%; a decrease in the number of focal seizures with impaired consciousness from 65% to 53%. In addition, there was a 38% decrease in the severity of fatigue on the MFI-20 scale (the greatest decrease on the «Mental fatigue¼ scale), improvement in the quality of life - a 2.7-fold increase in the mean values of the QOLIE-10 questionnaire. CONCLUSION: The addition of phenosanic acid to antiepileptic therapy as a second or third AED allows for better control of seizures, leading to a decrease the frequency and severity of attacks and the severity of fatigue both, and an increase of the quality of life of patients with epilepsy.

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Background: Evidence of an association between maternal use of anti-seizure medication (ASM) during pregnancy and the risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children is conflicting. This systematic review and meta-analysis aimed to summarize the relationship between fetal exposure to ASM and the development of ASD or ADHD in offspring. Methods: A comprehensive literature search was conducted in PubMed and other databases to identify relevant epidemiological studies published from inception until 1 March 2024. Results: Seven cohort studies were included in the meta-analysis. The results showed that maternal exposure to ASMs during pregnancy was associated with an increased risk of ASD [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.63-2.71; p < 0.001] in the general population. This association became weaker (ASD: OR: 1.38, 95% CI: 1.11-1.73; p = 0.004) when the reference group was mothers with a psychiatric disorder or epilepsy not treated during pregnancy. Furthermore, an increased risk of ADHD was observed when the study data adjusted for drug indications were pooled (OR: 1.43, 95% CI: 1.07-1.92; p = 0.015). In subgroup analyses based on individual ASM use, only exposure to valproate preconception was significantly associated with an increased risk of ASD or ADHD. Conclusion: The significant association between maternal ASM use during pregnancy and ASD or ADHD in offspring may be partially explained by the drug indication or driven by valproate.

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Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome usually presents two to six weeks after treatment with a drug implicated in this disorder. However, in some cases, it can present more than eight weeks after the initiation of an implicated medication. This is a type 4 drug hypersensitivity reaction in which any internal organ may be involved. While the liver is commonly involved, cardiac involvement is not unheard of. Comorbidities and multiorgan involvement may obscure the diagnosis, and Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) criteria are a useful diagnostic aid. It is best treated by withdrawing the offending agent and administering systemic steroids. Oxidative stress is high in DRESS syndrome. Hepatoprotection is a priority in all patients and yields a better prognosis.

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Genetic epilepsy with febrile seizures plus (GEFS+) is a genetic epilepsy syndrome characterized by a marked hereditary tendency inherited as an autosomal dominant trait. Patients with GEFS+ may develop typical febrile seizures (FS), while generalized tonic-clonic seizures (GTCSs) with fever commonly occur between 3 months and 6 years of age, which is generally followed by febrile seizure plus (FS+), with or without absence seizures, focal seizures, or GTCSs. GEFS+ exhibits significant genetic heterogeneity, with polymerase chain reaction, exon sequencing, and single nucleotide polymorphism analyses all showing that the occurrence of GEFS+ is mainly related to mutations in the gamma-aminobutyric acid type A receptor gamma 2 subunit (GABRG2) gene. The most common mutations in GABRG2 are separated in large autosomal dominant families, but their pathogenesis remains unclear. The predominant types of GABRG2 mutations include missense (c.983A → T, c.245G → A, p.Met199Val), nonsense (R136*, Q390*, W429*), frameshift (c.1329delC, p.Val462fs*33, p.Pro59fs*12), point (P83S), and splice site (IVS6+2T → G) mutations. All of these mutations types can reduce the function of ion channels on the cell membrane; however, the degree and mechanism underlying these dysfunctions are different and could be linked to the main mechanism of epilepsy. The γ2 subunit plays a special role in receptor trafficking and is closely related to its structural specificity. This review focused on investigating the relationship between GEFS+ and GABRG2 mutation types in recent years, discussing novel aspects deemed to be great significance for clinically accurate diagnosis, anti-epileptic treatment strategies, and new drug development.

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BACKGROUND/AIM: The most commonly prescribed anti-seizures medications (ASMs) for the treatment of epilepsy are currently topiramate, zonisamide, lacosamide, carbamazepine and levetiracetam. The objective of this study was to examine the correlation between preoperative, intraoperative, and postoperative metabolic acidosis and the use of ASMs prior to craniotomy operations. MATERIALS AND METHODS: This retrospective cross-sectional study evaluated patients who underwent intracranial surgery with craniotomy under general anaesthesia between May 2020 and April 2023 and used ASMs. The patients were classified into four groups based on the pharmacological mechanisms of action of the ASMs administered before intracranial surgery (Group-I, zonisamide or topiramate; Group-II, lacosamide; Group-III, carbamazepine; Group-IV, levetiracetam). Metabolic acidosis severity was defined based on base excess (BE) levels: mild (-3 to -5), moderate (-5 to -10), and severe (below - 10). The study investigated the correlation between ASMs and the severity of metabolic acidosis in preoperative, intraoperative, and postoperative blood gas measurements. RESULTS: Out of 35 patients, 24 patients underwent intracranial surgery and 11 patients underwent epilepsy surgery. There were statistically significant differences in the severity of metabolic acidosis between preoperative (p < 0.001), intraoperative (p < 0.001) and postoperative (p = 0.01) groups. The preoperative mean BE of group-I was - 4.7, which was statistically lower than that of group-III (p = 0.01) and group-IV (p < 0.001). Intraoperatively and postoperatively, group-I had a mean BE of -7.5 and - 3.2, respectively, which was statistically lower than that of groups II (p = 0.007; p = 0.04), III (p = 0.002; p = 0.03), and IV (p < 0.001; p = 0.009). There was no statistically significant difference in BE between groups II, III and IV at all three time points. Group I had the lowest BE at all three time points. Intraoperative bicarbonate was administered to all patients in group I, whereas no intraoperative bicarbonate was required in the other groups. In group I, 50% of patients required postoperative intensive care. CONCLUSION: The use of ASMs in patients undergoing surgery is important in terms of mortality and morbidity. Topirimat and zonisamide are ASMs that can cause preoperative, intraoperative and postoperative metabolic acidosis. Patients receiving topirimat or zonisamide are particularly susceptible to metabolic acidosis. Special care should be taken in the management of anaesthesia in patients receiving these drugs, and monitoring of the perioperative metabolic status is essential.

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CONTEXT: Limited data existed on the efficacy and safety of novel antiepileptic drugs (pregabalin and gabapentin) in treating pruritus. OBJECTIVES: To assess their role in managing either acute or chronic pruritus. METHODS: A systematic search was conducted in PubMed, EMBASE, the Cochrane Library, and Web of Science databases for relevant randomized controlled trials. Pooled odd ratio (OR) with 95% CI were performed using RevMan5.4 and R4.3.1. RESULTS: Analysis of 27 articles involving 2,016 patients showed significant reduction in pruritus incidence (OR, 0.30 [CI, 0.22-0.4]; I2=1%) and improvements in VAS (MD, 2.76 [CI, 0.95-4.57]; I2=98%) and 5-D scores (MD, 3.42 [CI, 2.10-4.75]; I2=92%) with pregabalin/gabapentin compared to controls. Adverse effects mainly included dizziness, somnolence, nausea and vomiting, dry mouth, constipation, and anxiety, with no significant difference between the groups (OR, 1.08 [CI, 0.32-3.59]; I2=76%). CONCLUSION: The novel antiepileptic drugs pregabalin and gabapentin demonstrated significant therapeutic value in the treatment of pruritus, with a favorable safety profile. Compared to commonly used pruritus treatments such as antihistamines and antidepressants, these medications offered a promising alternative.

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Epilepsy, a neurological disorder characterized by excessive neuronal activity and synchronized electrical discharges, ranks among the most prevalent global neurological conditions. Despite common use, antiepileptic drugs often result in adverse effects and lack effectiveness in controlling seizures in temporal lobe epilepsy (TLE) patients. Recent research explored the potential of occidentalin-1202, a peptide inspired by Polybia occidentalis venom, in safeguarding Wistar rats from chemically induced seizures. The present study evaluated the new analog from occidentalin-1202 named NOR-1202 using acute and chronic pilocarpine-induced models and an acute kainic acid (KA) male mice model. NOR-1202 was administered through the intracerebroventricular (i.c.v.), subcutaneous, or intraperitoneal routes, with stereotaxic procedures for the i.c.v. injection. In the acute pilocarpine-induced model, NOR-1202 (i.c.v.) protected against generalized seizures and mortality but lacked systemic antiepileptic activity. In the KA model, it did not prevent generalized seizures but improved survival. In the chronic TLE model, NOR-1202's ED50 did not differ significantly from the epileptic or healthy groups regarding time spent in spontaneous recurrent seizures during the five-day treatment. However, the NOR-1202 group exhibited more seizures than the healthy group on the second day of treatment. In summary, NOR-1202 exhibits antiepileptic effects against chemoconvulsant-induced seizures, but no effect was observed when administered systemically.

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OBJECTIVE: To compare the effects of levetiracetam（LEV）, lamotrigine(LTG), oxcarbazepine(OXC), topiramate(TPM) and valproate (VPA) on postictal state (PIS). METHODS: A total of 187 epilepsy patients undergoing monotherapy were enrolled in a long-term follow-up study at the Affiliated Hospital of Yangzhou College. This included 30 patients on levetiracetam, 41 on valproate, 30 on oxcarbazepine, 28 on topiramate, and 31 on lamotrigine. A control group of 28 newly diagnosed or previously untreated epilepsy patients was also included. The Liverpool Seizure Severity Scale 2.0 (LSSS2.0) and the Seizure Severity Questionnaire (SSQ) were utilized to evaluate the patients' condition, with comparison based on the results of the postictal status items. EEG during PIS termination was assessed using the Grand Total EEG score (GTE) as an objective tool to measure the impact of Antiseizure medications (ASMs) on the post-seizure state. RESULTS: The LSSS2.0 score indicated a statistically significant difference in post-seizure status score among the 5 groups (p < 0.05). The difference between the 5 groups and the control group was statistically significant (p < 0.05). Results of the SSQ demonstrated that all 5 drugs significantly reduced the post-seizure status score compared to the control group (p < 0.05). The GTE score revealed that, in the later stage of the seizure, the GTE score of the levetiracetam group, valproate group, oxcarbazepine group, and lamotrigine group significantly decreased compared to the control group (P < 0.05). There was no significant decrease in the GTE score in the topiramate group (P < 0.05). CONCLUSION: Levetiracetam, lamotrigine, oxcarbazepine, topiramate, and valproate demonstrate favorable efficacy in ameliorating the severity of post-seizure condition. Further investigations are warranted to assess the potential of other widely employed anti-seizure medications in enhancing post-seizure status.

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The growing interest in Kv7.2/7.3 agonists originates from the involvement of these channels in several brain hyperexcitability disorders. In particular, Kv7.2/7.3 mutants have been clearly associated with epileptic encephalopathies (DEEs) as well as with a spectrum of focal epilepsy disorders, often associated with developmental plateauing or regression. Nevertheless, there is a lack of available therapeutic options, considering that retigabine, the only molecule used in clinic as a broad-spectrum Kv7 agonist, has been withdrawn from the market in late 2016. This is why several efforts have been made both by both academia and industry in the search for suitable chemotypes acting as Kv7.2/7.3 agonists. In this context, in silico methods have played a major role, since the precise structures of different Kv7 homotetramers have been only recently disclosed. In the present review, the computational methods used for the design of Kv.7.2/7.3 small molecule agonists and the underlying medicinal chemistry are discussed in the context of their biological and structure-function properties.

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INTRODUCTION AND AIM: Seizures due to epilepsy in any form cause a wide range of problems in a patient's physical, psychological, and social health. This study aimed to investigate piperine's anti-seizure and antiepileptic effects and mechanisms. METHODS: In this systematic review study, which was conducted according to the principles of PRISMA 2020, the initial search was conducted on November 2, 2023, using EndNote software. Various databases such as PubMed, Cochrane Library, Web of Science, Embase, and Scopus were searched using specific keywords. After screening the articles, a form was designed according to the objectives of the study, and the information related to the included articles was entered in the form, and the studies were reviewed. RESULTS: Piperine showed its antiepileptic activity by affecting the brain's antioxidant, anti-inflammatory, and anti-apoptotic activity. It also, by modulating brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA)ergic activity, can control seizures. In addition, piperine can help treat seizures and epilepsy by elevating 5-HT levels in the brain, modulating astrocyte and microglia function, modulatory effects on Ca2+ and NA+ channels, increasing antiepileptic drugs bioavailability and influencing protein and gene expression. CONCLUSION: In vivo and in vitro studies showed beneficial effects on treating epilepsy. Although clinical studies also showed similar results, these needed to be increased, and more clinical studies needed to be designed in this field.

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BACKGROUND: Padsevonil (PSL) is a rationally designed anti-seizure medication (ASM) which has overlapping mechanisms of action with the two most common ASMs used for neonatal seizures, phenobarbital (PB) and levetiracetam (LEV). Here we evaluated the anti-seizure properties of PSL across the neonatal and adolescent period in rats in the pentlyenetetrazole (PTZ) induced seizures model. METHODS: Postnatal day (P)7, P14 and P21 Sprague-Dawley rat pups were pre-treated with PSL (1-30 mg/kg), and assessed for seizure latency and severity 30 min later following injection of PTZ. A separate cohort of P7 pups were treated with neonatal ASMs and euthanized 24 h later (on P8) to assess induction of cell death, a feature common to many ASMs when given to P7 rodents. This effect has been extensively reported with PB, but not with LEV. Cell death was assessed by PathoGreen staining. RESULTS: PSL suppressed PTZ-evoked seizures across multiple age groups, particularly at higher doses, without producing increased cell death compared to vehicle. The effects of PSL were particularly notable at suppressing tonic-clonic seizure manifestations (82% of P7 and 100% of P14 and P21 animals were protected from tonic-clonic seizures with the 30 mg/kg dose). CONCLUSIONS: PSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures.

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