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Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities.

Background Several studies found that patients with new‐onset epilepsy (NOE) have higher seizure recurrence rates if they presented already prior seizures. These observations suggest that timing of antiseizure medication (ASM) is crucial and should be offered immediately after the first seizure. Here, we wanted to assess whether immediate ASM is associated with improved outcome. Methods Single‐center study of 1010 patients (≥16 years) who presented with a possible first seizure in the emergency department between 1 March 2010 and 1 March 2017. A comprehensive workup was launched upon arrival, including routine electroencephalography (EEG), brain computed tomography/magnetic resonance imaging, long‐term overnight EEG and specialized consultations. We followed patients for 5 years comparing the relapse rate in patients treated within 48 h to those with treatment >48 h. Results A total of 487 patients were diagnosed with NOE. Of the 416 patients (162 female, age: 54.6 ± 21.1 years) for whom the treatment start could be retrieved, 80% (333/416) were treated within 48 h. The recurrence rate after immediate treatment (32%; 107/333) was significantly lower than in patients treated later (56.6%; 47/83; p < 0.001). For patients for whom a complete 5‐year‐follow‐up was available (N = 297, 123 female), those treated ≤48 h (N = 228; 76.8%) had a significantly higher chance of remaining seizure‐free compared with patients treated later (N = 69; 23.2%; p < 0.001). Conclusions In this retrospective study, immediate ASM therapy (i.e., within 48 h) was associated with better prognosis up to 5 years after the index event. Prospective studies are required to determine the value of immediate workup and drug therapy in NOE patients.

Summary The mainstay of therapy for epilepsy is anti‐seizure drugs (ASDs, also referred to as anticonvulsants and anti‐epileptic medications). Through much of the past century, only a handful for ASDs were available for clinical use. However, with the creation of the U.S. National Institutes of Health/National Institute of Neurological Disorders and Stroke (NINDS)–sponsored Anticonvulsant Screening Program (ASP), coupled with the emergence of high‐throughput screening platforms and methodologies, and advances in our understanding of the fundamental neurobiology of epilepsy, ASD development has greatly accelerated over the past 25 years. More than 18 new ASDs have been approved for clinical use since the inception of the ASP. Despite this remarkable success and the emergence of drugs possessing more favorable pharmacokinetic profiles that act on novel molecular targets, there has been increasing recognition that the paradigms for drug discovery have not yielded significant improvements in therapeutic efficacy, and that disease modification (i.e., anti‐epileptogenesis), among other challenges, must be addressed. Thus, with the renewed framework and mission of improving the lives of people with epilepsy, the name of the ASP was changed to the Epilepsy Therapy Screening Program (ETSP). This review briefly summarizes the history of ASD development and outlines some of the challenges and opportunities for the next generation of drug therapies for the epilepsy field.

Pediatric epilepsy is a neurological condition that causes repeated and unprovoked seizures and is more common in 1–5-year-old children. Drug resistance has been indicated as a key challenge in improving the clinical outcomes of patients with pediatric epilepsy. In the present study, we aimed to identify plasma small extracellular vesicles (sEVs) derived microRNAs (miRNAs) from the plasma samples of children for predicting the prognosis in patients with epilepsy and drug-resistant epilepsy. A total of 90 children clinically diagnosed with epilepsy [46 antiepileptic drug (AED)-responsive epilepsy and 44 drug-resistant epilepsy] and 37 healthy controls (HCs) were enrolled in this study. RNA sequencing was performed to identify plasma sEVs derived miRNAs isolated from the children’s plasma samples. Differentially expressed plasma sEVs derived miRNAs were identified using bioinformatics tools and were further validated by reverse transcription-polymerase chain reaction and receiver operator characteristic (ROC) curve analysis. In the present study, 6 miRNAs (hsa-miR-125b-5p, hsa-miR-150-3p, hsa-miR-199a-3p, hsa-miR-584-5p hsa-miR-199a-5p, and hsa-miR-342-5p) were selected for further validation. hsa-miR-584-5p, hsa-miR-342-5p, and hsa-miR-150-5p with area under curve (AUC) values of 0.846, 0.835, and 0.826, respectively, were identified as promising biomarkers of epilepsy. A logistic model combining three miRNAs (hsa-miR-584-5p, hsa-miR-342-5p, and hsa-miR-199a-3p) could achieve an AUC of 0.883 and a six miRNAs model (hsa-miR-342-5p, hsa-miR-584-5p, hsa-miR-150-5p, hsa-miR-125b-5p, hsa-miR-199a-3p, and hsa-miR-199a-5p) could attain an AUC of 0.888. The predicted probability of multiple miRNA panels was evaluated for differentiating between drug-resistant children and drug-responsive children. The AUC of a six-miRNA panel (hsa-miR-342-5p, hsa-miR-584-5p, hsa-miR-150-5p, hsa-miR-125b-5p, hsa-miR-199a-3p, and hsa-miR-199a-5p) reached 0.823. We identified and confirmed plasma sEVs derived miRNA biomarkers that could be considered as potential therapeutic targets for pediatric epilepsy and drug-resistant epilepsy.

Aims Previous studies suggest potential associations between epilepsy, anti‐epileptic drugs (AEDs), and levels of vitamin D and vitamin D‐binding protein (VDBP). This study aims to investigate the causal relationships among these variables using Mendelian Randomization (MR) methods. Methods Using summary data from genome‐wide association studies on serum 25‐hydroxyvitamin D [25(OH)D] levels (N = 417,580), VDBP concentrations (N = 65,589), and various types of epilepsy (Ncases = 27,559), MR analyses were conducted to determine bidirectional causal relationships among these variables. Additionally, eQTL data from eQTLGen (N = 31,684) were employed to model the effects of AEDs and evaluate their causal impact on both biomarkers. Results No causal relationships were found between serum 25(OH)D or VDBP levels and epilepsy. Although genetically predicted focal epilepsy risk was potentially associated with increased serum 25(OH)D levels (OR 1.031, 95% CI: 1.006–1.058, p = 0.017), and a higher genetic risk of juvenile myoclonic epilepsy was linked to lower VDBP levels (OR 0.977, 95% CI: 0.961–0.993, p = 0.004), both associations lost significance after multiple correction. Furthermore, significant associations were observed between serum 25(OH)D levels and AED target genes SCN4A, GABBR1, CA13, ALDH5A1, and CA8. No significant associations were found between AED target genes and VDBP levels after correction. Conclusion No causal relationships were found between genetically determined serum 25(OH)D levels, VDBP, and epilepsy or its subtypes. Furthermore, the use of AEDs, such as Carbamazepine, Oxcarbazepine, Progabide, and Valproic Acid, reduces serum 25(OH)D levels, while not affect VDBP levels. The study utilized single nucleotide polymorphisms from genome‐wide association studies as instrumental variables and employed Mendelian Randomization to uncover causal relationships between epilepsy and both vitamin D and vitamin D‐binding protein. Additionally, the findings support that anti‐epileptic drugs reduce serum vitamin D levels without affecting vitamin D‐binding protein.

Background Meningioma is the most common primary intracranial tumor and surgery is the main treatment modality. As death from lack of tumor control is rare, other outcome measures like anxiety, depression and post‐operative epilepsy are becoming increasingly relevant. In this nationwide registry‐based study we aimed to describe the use of antiepileptic drugs (AED), antidepressants and sedatives before and after surgical treatment of an intracranial meningioma compared to a control population, and to provide predictors for continued use of each drug‐group two years after surgery. Methods All adult patients with histopathologically verified intracranial meningiomas were identified in the Swedish Brain Tumor Registry and their data were linked to relevant national registries after assigning five matched controls to each patient. We analyzed the prescription patterns of antiepileptic drugs (AED), antidepressants and sedative drugs in the two years before and the two years following surgery. Results For the 2070 patients and 10312 controls identified the use of AED, antidepressants and sedatives was comparable two years before surgery. AED use at time of surgery was higher for patients than for controls (22.2% vs. 1.9%, p < 0.01), as was antidepressant use (12.9% vs. 9.4%, p < 0.01). Both AED and antidepressant use remained elevated after surgery, with patients having a higher AED use (19.7% vs. 2.3%, p < 0.01) and antidepressant use (14.8% vs. 10.6%, p < 0.01) at 2 years post‐surgery. Use of sedatives peaked for patients at the time of surgery (14.4% vs. 6.1%, p < 0.01) and remained elevated at two years after surgery with 9.9% versus 6.6% (p < 0.01). For all the studied drugs, previous drug use was the strongest predictor for use 2 years after surgery. Conclusion This nationwide study shows that increased use of AED, antidepressants and sedatives in patients with meningioma started perioperatively, and remained elevated two years following surgery. By coupling a nationwide cancer registry of 2070 patients with data on purchased drugs and diagnoses, it was shown that after meningioma surgery the use of antiepileptics, antidepressants and sedatives was distinctly increased compared to controls. As this may be an often‐overlooked factor in deciding whether to perform surgery, predictors for identifying especially vulnerable patients are explored.

The aim of this study was to investigate the possible effects of single-nucleotide polymorphisms (SNPs) within SLC1A1, SLC6A1, FAM131B, GPLD1, F2, GABRG2, GABRA1, and CACNG5 genes on response to anti-epileptic drugs (AEDs) and the genetic predisposition of epilepsy in Jordanian patients. A total of 299 healthy individuals and 296 pediatric patients from the Jordanian population were recruited. Blood samples are collected, and genotyping was performed using a custom platform array analysis. The SLC1A1 rs10815018 and FAM131B rs4236482 polymorphisms found to be associated with epilepsy susceptibility. Moreover, SLC1A1 rs10815018 and GPLD1 rs1126617 polymorphisms were associated with generalized epilepsy (GE), while FAM131B rs4236482 is associated with the focal phenotype. Regarding the therapeutic response, the genetic polymorphisms of FAM131B rs4236482, GABRA1 rs2279020, and CACNG5 rs740805 are conferred poor response (resistance) to AEDs. There was no linkage of GLPD1 haplotypes to epilepsy, its subtypes, and treatment responsiveness. Our findings suggested that SLC1A1, FAM131B, and GPLD1 polymorphisms increasing the risk of generating epilepsy, while FAM131B, GABRA1, and CACNG5 variants may play a role in predicting drug response in patients with epilepsy (PWE).

The purpose of the present study was to quantitatively elucidate the levels of protein expression of anti-epileptic-drug (AED) transporters, metabolizing enzymes and tight junction molecules at the blood–brain barrier (BBB) in the focal site of epilepsy patients using accurate SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Brain capillaries were isolated from focal sites in six epilepsy patients and five normal brains; tryptic digests were produced and subjected to SWATH analysis. MDR1 and BCRP were significantly downregulated in the epilepsy group compared to the normal group. Out of 16 AED-metabolizing enzymes detected, the protein expression levels of GSTP1, GSTO1, CYP2E1, ALDH1A1, ALDH6A1, ALDH7A1, ALDH9A1 and ADH5 were significantly 2.13-, 6.23-, 2.16-, 2.80-, 1.73-, 1.67-, 2.47- and 2.23-fold greater in the brain capillaries of epileptic patients than those of normal brains, respectively. The protein expression levels of Claudin-5, ZO-1, Catenin alpha-1, beta-1 and delta-1 were significantly lower, 1.97-, 2.51-, 2.44-, 1.90- and 1.63-fold, in the brain capillaries of epileptic patients compared to those of normal brains, respectively. Consistent with these observations, leakage of blood proteins was also observed. These results provide for a better understanding of the therapeutic effect of AEDs and molecular mechanisms of AED resistance in epileptic patients.

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.

Background Repeated PO dosing of anti‐epileptic drugs may contribute to poor compliance in treated cats. Intermediate‐release levetiracetam has been used safely in cats, but must be given q8h to maintain serum concentrations in the therapeutic interval for humans (5–45 μg/mL). Approved extended‐release levetiracetam (XRL) for human use may require less frequent dosing, but the large dosing unit has limited its use in cats. Hypotheses In healthy cats, serum levetiracetam concentration will remain above 5 μg/mL for at least 24 hours after administration of a single dose of XRL PO and will be well tolerated. Animals 7 healthy cats. Methods Extended‐release levetiracetam (500 mg) was administered PO. Blood was collected and neurologic examination findings recorded at scheduled times over 30 hours. Serum levetiracetam concentration was quantitated by an immunoassay validated in cats. Data were subjected to noncompartmental analysis. Descriptive statistics were reported. Results The median dosage of 86.2 mg/kg, (range, 80–94.3) achieved a mean maximum concentration (Cmax) of 89.8 ± 25.8 μg/mL at 4.9 ±1.57 hours. Serum levetiracetam was >5 μg/mL in all cats by 90 minutes. Mean concentrations were 43.7 ± 18.4 and 4.9 ± 3.4 μg/mL at 12 and 24 hours, respectively. The half‐life was 4.1 ± 1.0 hours. The drug was well tolerated. Conclusions and Clinical Importance A single 500 mg PO dose of XRL safely maintained serum levetiracetam concentration ≥5 μg/mL in healthy cats for at least 21 hours. Clinical efficacy studies in epileptic cats receiving XRL are indicated; however, monitoring should be implemented for individual cats.