Maternal exposure to folate antagonists and susceptibility to congenital heart disease in offspring: A systematic review and meta-analysis.

AIMS: The objective of this meta-analysis was to determine whether maternal exposure to folate antagonists is associated with increased rates of congenital heart disease in offspring. METHODS: A comprehensive search for articles in the MEDLINE (PubMed) and EMBASE databases published up to 21 August 2023 was performed. The search strategy was not limited by study design but only for articles in the English language. RESULTS: Analysis of 6 cohort studies and 5 cross-sectional studies, published between 1976 and 2020, showed significant increase in rate of congenital heart disease (odds ratio 1.55, 95% confidence interval, 1.28-1.87) when exposed to folate antagonists compared with the control. Further subgroup analysis showed the increased rate for exposure to both dihydrofolate reductase inhibitors and antiepileptic drugs separately. No differences were observed when analyses were stratified by timing of study. CONCLUSION: Administration of folate antagonists within the 12-week period preceding conception and throughout the second and third months of gestation exhibited a statistically significant elevation in the susceptibility to congenital heart diseases. Notably, the protective effect of folic acid supplementation was reported in cases of congenital heart disease linked to dihydrofolate reductase inhibitors but not that associated with antiepileptic drugs.

[Amino acid metabolism characteristics of Banxia Baizhu Tianma Decoction in realizing drug withdrawal based on transcriptomic analysis].

This study aimed to demonstrate the effect of Banxia Baizhu Tianma Decoction(BBTD) on realizing withdrawal of anti-epileptic drugs and explore the relationship between BBTD and the amino acid metabolism by transcriptomic analysis in the rat model of epilepsy induced by lithium chloride-pilocarpine. The rats with epilepsy were divided into a control group(Ctrl), an epilepsy group(Ep), a BBTD & antiepileptic drug integrative group(BADIG), and an antiepileptic drug withdrawal group(ADWG). The Ctrl and Ep were given ultrapure water by gavage for 12 weeks. The BADIG was given BBTD extract and carbamazepine solution by gavage for 12 weeks. The ADWG was given carbamazepine solution and BBTD extract by gavage for the former 6 weeks, and then only given BBTD extract for the latter 6 weeks. The therapeutic effect was evaluated by behavioral observation, electroencephalogram(EEG), and hippocampal neuronal morphological changes. High-throughput sequencing was used to obtain amino acid metabolism-related differen-tial genes in the hippocampus, and the mRNA expression in the hippocampus of each group was verified by real-time quantitative polymerase chain reaction(RT-qPCR). The hub genes were screened out through protein-protein interaction(PPI) network, and Gene Ontology(GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed. Two ceRNA networks, namely circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA, were constructed for ADWG vs BADIG. The experimental results showed that compared with those in Ep, rats in ADWG were significantly improved in the behavioral observation, EEG, and hippocampal neuronal impairment. Thirty-four amino acid metabolism-related differential genes were obtained by transcriptomic analysis, and the sequencing results were confirmed by RT-qPCR. Eight hub genes were obtained through PPI network, involving several biological processes, molecular functions, and signal pathways related to amino acid metabolism. Finally, the circRNA-miRNA-mRNA ternary transcription network of 17 circRNA, 5 miRNA, and 2 mRNA, and a lncRNA-miRNA-mRNA ternary network of 10 lncRNA, 5 miRNA, and 2 mRNA were constructed in ADWG vs BADIG. In conclusion, BBTD can effectively achieve the withdrawal of antiepileptic drugs, which may be related to the transcriptomic regulation of amino acid metabolism.

A narrative review on traditional Chinese medicine prescriptions and bioactive components in epilepsy treatment.

Background and Objective: In traditional Chinese medicine (TCM), natural drugs and their bioactive components have been widely used to treat epilepsy. Epilepsy is a chronic disease caused by abnormal discharge of brain neurons that leads to brain dysfunction and cognitive impairment. Several factors are involved in the mechanisms of epilepsy, and the current treatments do not seem promising. The potential efficacy of natural drugs with lower toxicity and less side effects have attracted increasing attention. Methods: We used the terms, "TCM", "traditional Chinese medicine", "herbal", "epilepsy", "seizure", and the name of each prescription and bioactive components in the review to collect papers about application of TCM in epilepsy treatment from PubMed online database and Chinese database including Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Key Content and Findings: We summarized some common TCM prescriptions and related active components used for the treatment of epilepsy. Six prescriptions (Chaihu Shugan decoction, Tianma Gouteng decoction, Kangxian capsules, Taohong Siwu decoction, Liujunzi decoction, Compound Danshen dropping pills) and nine main bioactive compounds (Saikosaponin A, Rhynchophylline, Tetramethylpyrazine, Gastrodin, Baicalin and baicalein, α-Asarone, Ginsenoside, Tanshinone, Paeoniflorin) were reviewed to provide a scientific basis for the development of potential antiepileptic drugs (AEDs). Conclusions: The pharmacological effects and molecular mechanisms of TCM in the treatment of epilepsy are complex, targeting several pathological aspects of epilepsy. However, the limitations of TCM, such as the lack of standardized treatments, have prevented its clinical application in epilepsy treatment. Thus, additional clinical trials are required to further evaluate the effectiveness and safety of TCM prescriptions and their bioactive components in the future.

Narrative review of brivaracetam for genetic generalized epilepsies.

BACKGROUND: The licensed treatment options for genetic generalized epilepsies are limited although many patients with these conditions require chronic pharmacological management with antiseizure medications and there are no curative surgical treatment options. Brivaracetam is being studied as a new therapeutic option for genetic generalized epilepsies. METHOD: In order to carry out a narrative review on the efficacy and safety of brivaracetam in genetic generalized epilepsies, a literature research was performed in Pubmed, EMBASE, Cochrane and Clinical Trials.gov databases. RESULTS: Promising results were found with doses ranging from 50 to 200 mg/day in terms of efficacy (with > 50% responder rates between 36 and 84%), tolerability, and short and long-term safety (24-57% drug-associated adverse effects), with most studies reporting adequate retention rates and an absence of serious adverse effects, in monotherapy or as adjuvant therapy, even in refractory epilepsies, special populations and in patients with previous use and/or therapeutic failure with levetiracetam. CONCLUSION: According to our review, brivaracetam is a valid treatment alternative in patients with genetic generalized epilepsies capable of improving patients' quality of life by reducing seizure frequency with minimal adverse effects.

From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

Epilepsy in Pregnancy-Management Principles and Focus on Valproate.

An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20-40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy.

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs.

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 min after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.

Chinese Herbal Medicine Combined With Antiepileptic Drugs for Intractable Epilepsy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Intractable epilepsy (IE) is still a major concern in neurology, and existing therapies do not adequately control symptoms. Chinese Herbal Medicine (CHM) has been widely used as an adjunct to antiepileptic drugs (AEDs) for IE. However, because of the contradictory findings reported in previous studies, it is uncertain if the present evidence is robust enough to warrant its usage. The purpose of this meta-analysis was to systematically evaluate the efficacy of the combination of CHM and AEDs for IE. Methods: From inception to September 2021, Medline, Ovid, Embase, Cochrane Library, Chinese Biomedical Database, China National Knowledge Infrastructure, VIP Database, and Wanfang Database were searched. Only randomized controlled trials (RCTs) that assessed the efficacy of the combination of CHM and AEDs for IE were included. We defined monthly seizure frequency as the primary outcome. The secondary outcomes included the abnormal rate of electroencephalogram (EEG), seizure duration, quality of life (QoL), and adverse events (AEs). Results: Twenty studies with 1,830 patients were enrolled. Most trials had poor methodological quality. The meta-analysis showed that the combination of CHM and AEDs was more efficient than AEDs alone in reducing monthly seizure frequency [MD = -1.26%, 95% CI (-1.62, -0.91); p < 0.00001], the abnormal rate of EEG [RR = 0.66%, 95% CI (0.53, 0.82); p = 0.0002], and improving the QoL [MD = 6.96%, 95% CI (3.44, 10.49); p = 0.0001]. There was no significant difference in seizure duration between groups. Moreover, the combination of CHM and AEDs significantly reduced the AEs [RR = 0.45%, 95% CI (0.32, 0.64); p < 0.00001]. Conclusion: The combination of CHM and AEDs could improve seizure control by reducing monthly seizure frequency and abnormal rate of EEG with a decreased risk of adverse events in patients with IE. However, these findings must be interpreted carefully due to the high or uncertain risk of bias in the included trials. To provide stronger evidence for the use of CHM combined with AEDs in IE, high-quality RCTs will be urgently warranted in the future.

Long-term music adjuvant therapy enhances the efficacy of sub-dose antiepileptic drugs in temporal lobe epilepsy.

AIMS: Noninvasive music adjuvant therapy shows great potential in improving seizure control when combined with routine antiepileptic drugs. However, the diversity of previous music protocols has resulted in disparate outcomes. The optimized protocol and features for music adjuvant therapy are still not fully understood which limits its feasibility. METHODS: By applying different regimens of music therapy in various temporal lobe epilepsy models, we evaluated the effect of music in combination with sub-dose drugs on epileptic seizures to determine the optimized protocol. RESULTS: A subgroup of kindled mice that were responsive to music adjuvant therapy was screened. In those mice, sub-dose drugs which were noneffective on kindled seizures, alleviated seizure severity after 12 h/day Mozart K.448 for 14 days. Shorter durations of music therapy (2 and 6 h/day) were ineffective. Furthermore, only full-length Mozart K.448, not its episodes or other music varieties, was capable of enhancing the efficacy of sub-dose drugs. This music therapeutic effect was not due to increasing cerebral drug concentration, but instead was related with the modulation of seizure electroencephalogram (EEG) spectral powers in the hippocampus. CONCLUSION: These results indicate that long-term full-length Mozart K.448 could enhance the anti-seizure efficacy of sub-dose drugs and may be a promising noninvasive adjuvant therapy for temporal lobe epilepsy.

The role of vagus nerve stimulation in the treatment of refractory epilepsy: clinical outcomes and impact on quality of life.

BACKGROUND: Vagus nerve stimulation (VNS) is used as a complementary therapy to pharmacological treatment in patients with refractory epilepsy. This study aims to evaluate the efficacy of VNS in reducing seizure frequency, severity, and duration; reducing the number of antiepileptic drugs administered; and improving patients' quality of life. MATERIAL AND METHODS: We analysed the clinical progression of 70 patients with refractory epilepsy treated with VNS at Hospital Universitario de Alicante and Hospital Clínico de Valencia. Data were collected before and after the procedure. The difference in seizure frequency pre- and post-VNS was classified using the McHugh scale. Data were also collected on seizure duration and severity, the number of drugs administered, and quality of life. RESULTS: According to the McHugh classification, 12.86% of the patients were Class I, 44.29% were Class II, 40% were Class III, and the remaining 2.86% of patients were Class IV-V. A ≥ 50% reduction in seizure frequency was observed in 57.15% of patients. Improvements were observed in seizure duration in 88% of patients and in seizure severity in 68%; the number of drugs administered was reduced in 66% of patients, and 93% reported better quality of life. CONCLUSIONS: VNS is effective for reducing seizure frequency, duration, and severity and the number of antiepileptic drugs administered. It also enables an improvement in patients' quality of life.

Association of Anemia With Epilepsy and Antiepileptic Drugs.

Epilepsy is a disorder that causes unprovoked seizures regularly. It affects between 1% and 3% of the population. After the first seizure, the chances of having another one are almost 40%-52%. The etiology of febrile seizures in children with sickle cell disease is still unknown. In some groups, iron deficiency anemia has been linked to an increased risk of seizures. Although the reason and process are uncertain, some people believe that taking iron supplements can help prevent seizures. This literature covers haptene, non-haptene immune-related hemolysis, and oxidative processes activated by anti-seizure medications (ASMs). In epileptic patients, ASMs can cause anemia. Folic acid can be given to carbamazepine-treated anemic patients. There is growing evidence that it improves hemoglobin and leukocytes in individuals who take it. Therefore, one of the most efficient strategies to avoid future seizures is to take ASMs daily to maintain an even level of anticonvulsant in the body. To prevent further seizures, lifestyle changes are essential. Further studies and clinical trials are warranted to prove a clear association between epilepsy and hematologic disease, which will improve quality of life in the future.

Selected Molecular Targets for Antiepileptogenesis.

The term epileptogenesis defines the usually durable process of converting normal brain into an epileptic one. The resistance of a significant proportion of patients with epilepsy to the available pharmacotherapy prompted the concept of a causative treatment option consisting in stopping or modifying the progress of epileptogenesis. Most antiepileptic drugs possess only a weak or no antiepileptogenic potential at all, but a few of them appear promising in this regard; these include, for example, eslicarbazepine (a sodium and T-type channel blocker), lamotrigine (a sodium channel blocker and glutamate antagonist) or levetiracetam (a ligand of synaptic vehicle protein SV2A). Among the approved non-antiepileptic drugs, antiepileptogenic potential seems to reside in losartan (a blocker of angiotensin II type 1 receptors), biperiden (an antiparkinsonian drug), nonsteroidal anti-inflammatory drugs, antioxidative drugs and minocycline (a second-generation tetracycline with anti-inflammatory and antioxidant properties). Among other possible antiepileptogenic compounds, antisense nucleotides have been considered, among these an antagomir targeting microRNA-134. The drugs and agents mentioned above have been evaluated in post-status epilepticus models of epileptogenesis, so their preventive efficacy must be verified. Limited clinical data indicate that biperiden in patients with brain injuries is well-tolerated and seems to reduce the incidence of post-traumatic epilepsy. Exceptionally, in this regard, our own original data presented here point to c-Fos as an early seizure duration, but not seizure intensity-related, marker of early epileptogenesis. Further research of reliable markers of early epileptogenesis is definitely needed to improve the process of designing adequate antiepileptogenic therapies.

Bone mineral density and fractures in institutionalised children with epilepsy and intellectual disability.

BACKGROUND: Long-term use of antiseizure drugs is associated with a low bone mineral density (BMD) and an increased fracture risk. The literature regarding institutionalised children on chronic antiseizure drugs is limited. Therefore, the aim of this cross-sectional study is to evaluate the prevalence of low BMD and the history of fractures in institutionalised children with epilepsy and intellectual disability (ID). METHODS: A dual-energy X-ray absorptiometry of lumbar spine (L1-L4) and hip was performed in 24 children, residing in a long-stay care facility in the Netherlands. Additionally, serum concentrations of albumin, calcium and 25-hydroxyvitamin D were determined. Data on fractures were retrospectively extracted from the medical files. RESULTS: Ages of the children (14 male and 10 female) ranged from 5 to 17 years with a mean age of 13.0 (±3.2). The criteria of the International Society for Clinical Densitometry (ISCD) were used for classification of bone mineral disorders. Eight (33.3%) children had a normal BMD (Z-score > - 2.0). Of the 16 children with a low BMD (Z-score ≤ - 2.0), three were diagnosed as osteoporotic, based on their fracture history. Ten children (41.7%) were reported to have at least one fracture in their medical history. Serum concentrations of albumin-corrected calcium (2.28-2.50 mmol/L) and (supplemented) vitamin D (16-137 nmol/L) were within the normal range. CONCLUSIONS: This study demonstrated that 67% of institutionalised children with epilepsy and ID had low BMD and 42% had a history of at least one fracture, despite supplementation of calcium and vitamin D in accordance with the Dutch guidelines.

Efficacy and tolerability of hydroalcoholic extract of Paeonia officinalis in children with intractable epilepsy: An open-label pilot study.

Despite a wide range of medications available to control epilepsy, seizures in more than 30 % of patients remain uncontrolled. However, in traditional medicine, Paeonia officinalis (P. officinalis), a native perennial herb of Southern Europe and Western Asia, has been used for an anticonvulsant effect for over 2000 years globally. In an open-label pilot study implemented on 30 children with intractable epilepsy aged 1-14 years, the hydroalcoholic extract of P. officinalis was administered. This study's purpose was to assess the efficacy and tolerability of the P. officinalis extract as an adjunct therapy to a patient's antiseizure medications in reducing the frequency and duration of the seizures in childhood intractable epilepsy. The mean frequency of seizures decreased significantly during treatment with the P. officinalis extract (P < 0.05). At the end of the intervention, 62.5 % and 36.7 % of the patients showed a≥50 % and a≥75 % reduction in seizure frequency, respectively. Regarding safety and tolerability, no serious adverse events occurred during the trial, although restlessness was reported in one child and the other children who experienced constipation, stopped treatment. The results show that the P. officinalis root extract was well tolerated and has contributed to a significant improvement in seizure control in children with medically intractable epilepsy. This trial was registered with the Iranian Registry of Clinical Trials (www.irct.ir; registration number: IRCT20131125015533N2.

Management of bone metabolism in epilepsy.

BACKGROUND AND PURPOSE: Many systemic problems arise due to the side effects of antiepileptic drugs (AEDs) used in epilepsy patients. Among these adverse effects are low bone mineral density and increased fracture risk due to long-term AED use. Although various studies have supported this association with increased risk in recent years, the length of this process has not been precisely defined and there is no clear consensus on bone density scanning, intervals of screening, and the subject of calcium and vitamin D supplementation. In this study, in accordance with the most current recommendations, our applications and data, including the detection of possible bone mineralization disorders, treatment methods, and recommendations to prevent bone mineralization disorders, were evaluated in epilepsy patients who were followed up at our outpatient clinic. It was aimed to draw attention to the significance of management of bone metabolism carried out with appropriate protocols. METHODS: Epilepsy patients were followed up at the Antalya Training and Research Hospital Department of Neurology, Epilepsy Outpatient Clinic who were at high risk for osteoporosis (use of valproic acid [VPA] and enzyme-inducing drugs, using any AED for over 5 years, and postmenopausal women) and were evaluated using a screening protocol. According to this protocol, a total of 190 patients suspected of osteoporosis risk were retrospectively evaluated. Four patients were excluded from the study due to secondary osteoporosis. RESULTS: Of the 186 patients who were included in the study, 97 (52.2%) were women and 89 (47.8%) were men. Prevalence of low bone mineral density (BMD) was 42%, in which osteoporosis was detected in 11.8% and osteopenia in 30.6% of the patients. Osteoporosis rate was higher at the young age group (18-45) and this difference was statistically significant (p=0.018). There was no significant difference between male and female sexes according to osteoporosis and osteopenia rates. Patients receiving polytherapy had higher osteoporosis rate and lower BMD compared to patients receiving monotherapy. Comparison of separate drug groups according to osteoporosis rate revealed that osteoporosis rate was highest in patient groups using VPA+ carbamazepine (CBZ) (29.4%) and VPA polytherapy (19.4%). Total of osteopenia and osteoporosis, or low BMD, was highest in VPA polytherapy (VPA+ non-enzyme-inducing AED [NEID]) and CBZ polytherapy (CBZ+NEID) groups, with rates of 58.3% and 55.1%, respectively. In addition, there was no significant difference between drug groups according to bone metabolism markers, vitamin D levels, and osteopenia-osteoporosis rates. CONCLUSION: Assuming bone health will be affected at an early age in epilepsy patients, providing lifestyle and diet recommendations, avoiding polytherapy including VPA and CBZ when possible, and evaluating bone metabolism at regular intervals are actions that should be applied in routine practice.

Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice.

Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.

Effects of antiepileptic drugs' administration during pregnancy on the nerve cell proliferation and axonal outgrowth of human neuroblastoma SH-SY5Y nerve cells.

It has been suggested that the intelligence quotient of children born to pregnant women taking 1000 mg or more of valproic acid per day is lower than that of children born to pregnant women taking other antiepileptic drugs. However, the mechanism whereby intelligence quotient is decreased in children exposed to valproic acid during the fetal period has not yet been elucidated. Therefore, we used the human neuroblastoma cell line SH-SY5Y to evaluate the effects of antiepileptic drugs containing valproic acid on nerve cells. We assessed the anti-proliferative effects of drugs in these cells via WST-8 colorimetric assay, using the Cell Counting Kit-8. We also quantified drug effects on axonal elongation from images using ImageJ software. We also evaluated drug effects on mRNA expression levels on molecules implicated in nervous system development and folic acid uptake using real-time PCR. We observed that carbamazepine and lamotrigen were toxic to SH-SY5Y cells at concentrations >500 µM. In contrast, phenytoin and valproic acid were not toxic to these cells. Carbamazepine, lamotrigen, phenytoin, and valproic acid did not affect axonal outgrowth in SH-SY5Y cells. Sodium channel neuronal type 1a (SCN1A) mRNA expression-level ratios increased when valproic acid was supplemented to cells. The overexpression of SCN1A mRNA due to high valproic acid concentrations during the fetal period may affect neurodevelopment. However, since detailed mechanisms have not yet been elucidated, it is necessary to evaluate it by comparing cell axon elongation and SCN1A protein expression due to high-concentration valproic acid exposure.

Epilepsy in Morocco: Realities, pitfalls and prospects.

The World Health Organization (WHO) estimates that about 50 million people of all ages have epilepsy and nearly 85% of whom live in low- and middle-income (LMICs) countries. In Morocco, epilepsy is one of the major neurological health conditions, with an estimated prevalence of 1.1%. The management of patients is difficult due to multiple factors. The lack of neurologists whose number is currently 180, the uneven distribution of neurologists who are concentrated in large cities, 43% of whom are in Rabat and Casablanca alone; the low involvement of general practitioners in the management of epilepsy; the frequent consultation of traditional healers; and the low coverage of social security all contribute to the treatment gap. The management of epilepsy has advanced considerably since the early nineties. Several factors contributed to this progress: the increasing number of neurologists compared to previous years, the creation of well-equipped new academic centers, and small units of general neurology, in addition to the disuse of several antiepileptic drugs. However, much work remains to be done against the use of many forms of traditional practices and the low involvement of general practitioners in the management of epilepsy. This is the first study on epilepsy conducted in Morocco.

Folate fortification of food: Insufficient for women with epilepsy.

OBJECTIVE: Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking anti-seizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folic acid, but no data exist on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluated the effect of dietary folate from natural folates plus folic acid fortification, separate from folic acid vitamin supplements, on age-6 year IQ in children with fetal-ASM exposure. METHODS: Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study were retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of the present study was to assess association of maternal prepregnancy nutrient levels to child age-6 IQ. RESULTS: Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: -11.7-2.3, p = 0.187). Periconceptual folate supplement use was associated with a 10.1-point higher age-6 IQ (95% CI: 5.2-15.0, p < .001). Total combined folate from food plus supplement also showed that higher intake of folate was associated with higher age-6 IQ (Coefficient: 4.5, 95% CI: 2.0-6.9, p < .001). Six other nutrients from food and supplements were analyzed (Vitamin C, Vitamin D, Vitamin E, Omega 3, Gamma Tocopherol, and Vitamin B12) and had no significant association with age 6-IQ. SIGNIFICANCE: Dietary content of folate, even in a country where food is fortified with folic acid, is not sufficient to provide improved cognitive outcomes for children of women taking ASMs during pregnancy. Folate supplementation is needed for significant improvement in cognitive outcomes, specifically age-6 IQ.

Effects of long-term antiepileptic polytherapy on bone biochemical markers in ambulatory children and adolescents and possible benefits of vitamin D supplementation: a prospective interventional study.

PURPOSE: Our aim was to investigate any adverse effects of long-term polytherapy (VPA and add-on-therapy) on bone biochemical markers in ambulatory children and adolescents with epilepsy and the possible benefits of vitamin D supplementation on the same markers. METHODS: In this prospective interventional study, the levels of 25(OH)D and the bone turnover markers of CrossLaps (CTX), total alkaline phosphatase (tALP), osteoprotegerin (OPG), and the receptor activator for nuclear factor kB (RANK) ligand (sRANKL) were determined in forty-two ambulatory children with epilepsy on polytherapy (valproic acid + one or more other from levetiracetam, topiramate, lamotrigine, or rufinamide). The same markers were assessed after a year's supplementation of vitamin D (400 IU/d) and were compared with those of clinically healthy controls. The respective mean (±SD) ages were 11.9 ±â€¯4.6 and 11.4 ±â€¯4.4 yrs. RESULTS: The basal mean 25(OH)D levels in the patients did not differ from controls (23.9 ±â€¯11.5 vs 27.4 ±â€¯13.3 ng/ml), but increased significantly after the vitamin D intake (31.1 ±â€¯13.3 ng/ml, p < 0.01). In parallel, basal serum CTX levels were found to be significantly lower in the patients than controls (0.89 ±â€¯0.63 vs 1.22 ±â€¯0.58 ng/ml, p < 0.02), but not tALP. Osteoprotegerin was higher in the patients (5.7 ±â€¯7.7 pmol/L vs 2.6 ±â€¯1.0 pmol/L, p < 0.03), while sRANKL did not differ. After vitamin D, the CTX levels increased to comparable levels in controls (0.99 ±â€¯0.57 ng/ml), and those of OPG decreased to levels that did not differ from controls (4.9 ±â€¯5.1 pmol/L). The ratio of OPG/sRANKL was higher in patients than controls before treatment (0.030 ±â€¯0.045 vs 0.009 ±â€¯0.005, p < 0.03), but decreased (0.026 ±â€¯0.038) to comparable values in controls later. CONCLUSIONS: These findings imply a lower bone turnover in the young patients on long-term polytherapy (VPA and add-on-therapy), but after one year's vitamin D intake, bone biochemical markers improved.