Standard Antiepileptic Drugs Research Articles

EXTH-35. REPURPOSING OF CLINICALLY APPROVED GLUTAMATE ANTAGONISTS TO TREAT GLIOBLASTOMA

Abstract The neurotransmitter glutamate plays a fundamental role in promoting epilepsy and tumor progression in glioblastoma. Glioblastoma cells secrete glutamate into the tumor microenvironment via the cystine-glutamate antiporter system Xc, leading to neuronal hyperexcitability, excitotoxicity, and tumor cell invasion. Additionally, glutamatergic neuroglioma synapses drive glioma progression in preclinical tumor models. To pharmacologically counteract effects of glutamate in glioblastoma, we employed a triple combination of anti-glutamatergic drugs: gabapentin, sulfasalazine, and memantine, which target glutamate synthesis, release, and post-synaptic signaling, respectively. In genetically engineered murine glioblastoma models, daily treatment with this triple combination prolonged median survival. This survival benefit was not observed with single or double drug combinations, nor with the standard antiepileptic drug levetiracetam, indicating the potential synergy and efficacy of this drug combination beyond merely treating epilepsy. Importantly, these preliminary results support the rationale for the ongoing phase Ib/II randomized clinical trial GLUGLIO, which explores the efficacy of combined gabapentin, sulfasalazine, and memantine in conjunction with standard chemoradiotherapy in patients with newly diagnosed glioblastoma (NCT05664464).

Effects of acute administration of 4-allyl-2,6-dimethoxyphenol in mouse models of seizures

Epilepsy, a chronic neurological disorder characterized by recurrent unprovoked seizures, presents a substantial challenge in approximately one-third of cases exhibiting resistance to conventional pharmacological treatments. This study investigated the effect of 4-allyl-2,6-dimethoxyphenol, a phenolic compound derived from various natural sources, in different models of induced seizures and its impact on animal electroencephalographic (EEG) recordings. Adult male Swiss albino mice were pre-treated (i.p.) with a dose curve of 4-allyl-2,6-dimethoxyphenol (50, 100, or 200 mg/kg), its vehicle (Tween), or standard antiepileptic drug (Diazepam; or Phenytoin). Subsequently, the mice were subjected to different seizure-inducing models – pentylenetetrazole (PTZ), 3-mercaptopropionic acid (3-MPA), pilocarpine (PILO), or maximal electroshock seizure (MES). EEG analysis was performed on other animals surgically implanted with electrodes to evaluate brain activity. Significant results revealed that animals treated with 4-allyl-2,6-dimethoxyphenol exhibited increased latency to the first myoclonic jerk in the PTZ and PILO models; prolonged latency to the first tonic-clonic seizure in the PTZ, 3-MPA, and PILO models; reduced total duration of tonic-clonic seizures in the PTZ and PILO models; decreased intensity of convulsive seizures in the PTZ and 3-MPA models; and diminished mortality in the 3-MPA, PILO, and MES models. EEG analysis indicated an increase in the percentage of total power attributed to beta waves following 4-allyl-2,6-dimethoxyphenol administration. Notably, the substance protected from behavioral and electrographic seizures in the PTZ model, preventing increases in the average amplitude of recording signals while also inducing an increase in the participation of theta and gamma waves. These findings suggest promising outcomes for the tested phenolic compound across diverse pre-clinical seizure models, highlighting the need for further comprehensive studies to elucidate its underlying mechanisms and validate its clinical relevance in epilepsy management.

Potential neuroprotective and autophagy-enhancing effects of alogliptin on lithium/pilocarpine-induced seizures in rats: Targeting the AMPK/SIRT1/Nrf2 axis

BackgroundStatus epilepticus (SE) as a severe neurodegenerative disease, greatly negatively affects people's health, and there is an urgent need for innovative treatments. The valuable neuroprotective effects of glucagon-like peptide-1 (GLP-1) in several neurodegenerative diseases have raised motivation to investigate the dipeptidyl peptidase-4 (DPP-4) inhibitor; alogliptin (ALO), an oral antidiabetic drug as a potential treatment for SE. ALO has shown promising neuroprotective effects in Alzheimer's and Parkinson's diseases, but its impact on SE has not yet been studied. AimThe present study aimed to explore the repurposing potential for ALO in a lithium/pilocarpine (Li/Pil)-induced SE model in rats. Main methodsALO (30 mg/kg/day) was administered via gavage for 14 days, and SE was subsequently induced in the rats using a single dose of Li/Pil (127/60 mg/kg), while levetiracetam was used as a standard antiepileptic drug. Key findingsThe results showed that ALO reduced seizure severity and associated hippocampal neurodegeneration. ALO also increased γ-aminobutyric acid (GABA) levels, diminished glutamate spikes, and corrected glial fibrillary acidic protein (GFAP) changes. At the molecular level, ALO increased GLP-1 levels and activated its downstream signaling pathway, AMP-activated protein kinase (AMPK)/sirtuin-1 (SIRT1). ALO also dampened the brain's pro-oxidant response, curbed neuroinflammation, and counteracted hippocampal apoptosis affording neuroprotection. In addition, it activated autophagy as indicated by Beclin1 elevation. SignificanceThis study suggested that the neuroprotective properties and autophagy-enhancing effects of ALO make it a promising treatment for SE and can potentially be used as a management approach for this condition.

CoQ10 targeted hippocampal ferroptosis in a status epilepticus rat model

Status epilepticus (SE), the most severe form of epilepsy, leads to brain damage. Uncertainty persists about the mechanisms that lead to the pathophysiology of epilepsy and the death of neurons. Overloading of intracellular iron ions has recently been identified as the cause of a newly recognized form of controlled cell death called ferroptosis. Inhibiting ferroptosis has shown promise as a treatment for epilepsy, according to recent studies. So, the current study aimed to assess the possible antiepileptic impact of CoQ10 either alone or with the standard antiepileptic drug sodium valproate (SVP) and to evaluate the targeted effect of COQ10 on hippocampal oxidative stress and ferroptosis in a SE rat model. Using a lithium-pilocarpine rat model of epilepsy, we evaluated the effect of SVP, CoQ10, or both on seizure severity, histological, and immunohistochemical of the hippocampus. Furthermore, due to the essential role of oxidative stress and lipid peroxidation in inducing ferroptosis, we evaluated malonaldehyde (MDA), reduced glutathione (GSH), glutathione peroxidase 4 (GPX4), and ferritin in tissue homogenate. Our work illustrated that ferroptosis occurs in murine models of lithium-pilocarpine-induced seizures (epileptic group). Nissl staining revealed significant neurodegeneration. A significant increase in the number of astrocytes stained with an astrocyte-specific marker was observed in the hippocampus. Effective seizure relief can be achieved in the seizure model by administering CoQ10 alone compared to SVP. This was accomplished by lowering ferritin levels and increasing GPX4, reducing MDA, and increasing GSH in the hippocampus tissue homogenate. In addition, the benefits of SVP therapy for regulating iron stores, GPX4, and oxidative stress markers were amplified by incorporating CoQ10 as compared to SVP alone. It was concluded that CoQ10 alone has a more beneficial effect than SVP alone in restoring histological structures and has a targeted effect on hippocampal oxidative stress and ferroptosis. In addition, COQ10 could be useful as an adjuvant to SVP in protecting against oxidative damage and ferroptosis-related damage that result from epileptic seizures.

Modern treatment of epileptic encephalopathies in young children: improvement of precision medicine

Background. Treatment of epileptic seizures in young children, especially with epileptic encephalopathies (EE), is a difficult task, which is impossible in modern conditions without the use of a personified (precision) therapy. The diagnostic algorithm for EE must include genetic examination by the next-generation sequencing, which makes it possible to prescribe targeted therapy depending on the genetic etiology of the disorder. The article presents the results of own research on the effectiveness and approaches to targeted therapy of genetic epileptic encephalopathies in young children. Materials and methods. Fifty-eight children aged 0–3 years with clinical manifestations of epileptic encephalopathies, onset of seizures in the first year of life and diagnosed genetic etiology were included in the study. Pathogenic variants in genes associated with the development of epileptic seizures were identified in all children using the next-generation sequencing. The study included assessment of neurological status, history collection, evaluation of semiology and seizure type, development and screening for autism spectrum disorders at the age of 18 and 24 months, video-electroencephalography during night sleep, magnetic resonance imaging of the brain, assessment of antiepileptic treatment received by the child. Results. Of 58 children with EE who were prescribed antie­pileptic drugs, 10 (17.2 %) received monotherapy, 40 patients (69 %) received combined therapy with two anticonvulsants, and 8 children (13.8 %) — combined therapy with three or more anticonvulsants. Levetiracetam (31 patients), valproic acid salt preparations (20 cases), topiramate (11 children) and vigabatrin (10 cases) were most used antiepileptic drugs. In all examined patients with EE, we used schemes of targeted (persona­lized) antiepileptic therapy focused on the genetic etiology of the disorder. In children with tuberous sclerosis caused by mutations in the TSC1 and TSC2 genes, vigabatrin (50–150 mg/kg per day) was included in the antiepileptic therapy and showed efficacy in 75.0 % (9/12) of children with infantile spasms. Corticosteroids (adrenocorticotropic hormone or prednisone) were additionally included in the treatment regimen and showed effectiveness in 66.7 % of cases (4/6). In children with mutations in SCN1A gene, combined therapy including valproic acid, topiramate and clobazam, or valproic acid with levetiracetam and corticosteroids was used, which showed effectiveness in reducing the frequency of seizures in 100 % of cases. Conclusions. Epileptic encephalopathies are a heterogeneous group of genetic disorders in young children that are difficult to treat and often have a malignant course. Since standard antiepileptic drugs are often insufficiently effective in epileptic encephalopathies, the use of targeted therapy drugs and alternative treatments such as hormone therapy are extremely important. The goal of treatment for epileptic encephalopathies is not only to control seizures, but also to prevent the development of neurological and cognitive deficits and restore lost functions.

Subgroup analysis for longitudinal data based on a partial linear varying coefficient model with a change plane.

Subgroup analysis has become an important tool to characterize the treatment effect heterogeneity, and finally towards precision medicine. On the other hand, longitudinal study is widespread in many fields, but subgroup analysis for this data type is still limited. In this article, we study a partial linear varying coefficient model with a change plane, in which the subgroups are defined based on linear combination of grouping variables, and the time-varying effects in different subgroups are estimated to capture the dynamic association between predictors and response. The varying coefficients are approximated by basis functions and the group indicator function is smoothed by kernel function, which are included in the generalized estimating equation for estimation. Asymptotic properties of the estimators for the varying coefficients, the constant coefficients and the change plane coefficients are established. Simulations are conducted to demonstrate the flexibility, efficiency and robustness of the proposed method. Based on the Standard and New Antiepileptic Drugs study, we successfully identify a subgroup in which patients are sensitive to the newer drug in a specific period of time.

Efficacy of Acetazolamide in Refractory Epilepsy Management: A Quasi-Experimental Study

Objective: To assess the efficacy of Acetazolamide in refractory epilepsy management.
 Study Design: Quasi-experimental study.
 Place and Duration of Study: Outpatient Neurology Department, Allied Hospital, Faisalabad Pakistan, from Sep 2020 to Feb 2021.
 Methodology: Using a non-probability consecutive sampling technique, 260 patients of either gender aged 18 to 60 years who met the criteria of refractory epilepsy were included in the study. Group-A (n=130) received oral Acetazolamide (250 mg twice a day) plus standard antiepileptic drugs, and Group-B (n=130) received a placebo plus standard antiepileptic drugs. Patients were assessed every four weeks for a six-month response to treatment. The outcome was assessed in terms of control of refractory epilepsy.
 Results: Acetazolamide was effective in 88(68.2%) patients compared to Placebo Group, which showed efficacy in 41(31.8%) patients (p-value was <0.001). In addition, the mean change in the number of attacks after treatment was significantly different between Group-A (2.9±1.5) versus Group-B (1.6±1.6) (p-value <0.001).Conclusion: Acetazolamide is effective in treating refractory epilepsy.

Role of EEG as a monitoring tool in patients with glucose transporter type I deficiency syndrome (GLUT1-DS) on ketogenic diet.

Glucose transporter type I deficiency syndrome (GLUT1-DS) is the fourth most frequent single-gene epilepsy refractory to standard antiepileptic drugs. Multiple seizure types and variable electrographic findings are reported. Ketogenic diet is expected to result in the complete resolution of the epileptiform activity. A retrospective chart review of patients with GLUT1-DS on ketogenic diet between December 2012 and February 2022 was done. Analysis of the EEGs prior to and during the ketogenic diet was done. 34 patients on ketogenic diet were reviewed. Ten had clinical diagnosis of GLUT1-DS, and seven of them had genetic confirmation. 71% were female. The average age at seizure onset was 13.85 m.o. (range: 3-60, SD ±20.52), at diagnosis was 44.57 m.o (range: 19-79), and at the onset of ketogenic diet was 46.43 m.o. (range: 20-83). 29 months (range: 13-38) delay between symptoms onset until diagnosis was noticed. At the diagnosis 100% reported seizures: 71% myoclonic, 57% generalized motor, 57% absence, 28% atonic, and 14% focal motor. Also, 71% abnormal eye movements, 57% ataxia, and 28% intolerance to fasting. 86% had normal brain MRI. 71% had abnormal EEG. All were on ketogenic diet, and four on classical (1.75:1-2.25:1 ratio). Six were clinically seizure-free after the ketogenic diet. EEG features included notch delta, focal spike and wave, and generalized spike/polyspike and wave. One patient had bilateral independent centrotemporal spikes. Spikes showed high and very high amplitude in all of them (>200 μV). The variation of the spike index decreased in three patients but increased in two. Ketogenic diet is the choice treatment for patients with GLUT1-DS. Electrographic features could show worsening after initiation of the ketogenic diet even with seizure control. EEG did not prove to be a reliable tool for adjusting KD in our cohort. Centrotemporal spikes have not been reported in patients with GLUT-1 DS.

Seizures and chronic kidney disease: An in-depth review

Seizures are not uncommon in patients with chronic kidney disease (CKD), with an approximate incidence of roughly 10%. There are two primary groups: Patients who develop acute provoked seizures in the setting of CKD and patients with pre-existing epilepsy who then develop CKD. The recognition of potential etiology and management of seizures in this patient population may be challenging for clinicians, particularly non-neurologists. Standard antiepileptic drug (AED) treatment is indicated for those with pre-existing epilepsy. The prescription of AED in CKD population requires careful consideration, due to potentially altered pharmacokinetics. Clinicians frequently encounter challenges in the selection, loading, titration, and maintenance of AEDs. There are few internationally recognized consensus recommendations for AED prescription in CKD and dialysis. Non-AED management aims at addressing factors that may have provoked the seizure. In this article, we provide an in-depth review of the potential etiologies and pathophysiological pathways of provoked seizures in CKD. We discuss strategies, including non-AED treatment options, which aim to prevent, and/or manage provoked seizures in the setting of CKD. We discuss the AEDs used in contemporary clinical practice and how their metabolism is affected by CKD, concurrent AED prescriptions, and dialysis.

Clinical side-effects based drug repositioning for anti-epileptic activity

Several generations of anti-epileptic drugs (AEDs) are available but have several associated side effects apart from a limited success rate. Drug repositioning strategies have gained importance in the last two decades owing to lower failure rates and economic burden. Drugs with similar side effect profiles may share a common mechanism of action and thus can be linked to other disease treatments. The present study was carried out to identify the newly approved drug candidate(s) as AEDs using clinical side-effects drug repositioning strategy. The clinical side effect similarity of drugs available in the SIDER v4.1 database was estimated against common side effects of 5 major marketed AEDs, using the ‘dplyr’ package library in the R. Further drugs were filtered based on Blood Brain Barrier permeability prediction and FDA-approval status. Molecular docking studies were performed for selected 26 hits (drugs) against previously identified epilepsy target receptors: Voltage-gated sodium channel α2 (Nav1.2), GABA receptor α1-β1 (GABAr α1-β1), and Voltage-gated calcium channel α-1 G (Cav3.1). Only 2 drugs (Ziprasidone and Paroxetine) showed better binding affinities against studied epilepsy receptors Nav1.2, GABAr α1-β1, and Cav3.1, than their corresponding standard AEDs, i.e. Carbamazepine, Clonazepam, and Pregabalin, respectively. Ziprasidone reportedly showed seizure-like symptoms in ∼3% of patients and was hence omitted from further study. The MDS study of docked complexes of Paroxetine with selected epilepsy target receptors showed stable RMSD values and better interaction energies. The study reveals Paroxetine as a potential candidate to be repurposed for 1st line epileptic seizure medication. Communicated by Ramaswamy H. Sarma

Effect of digoxin, sodium valproate, and celecoxib on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice

Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvuls

The blockade of transient receptor potential ankyrin 1 (TRPA1) protects against PTZ-induced seizure.

Treatment of epilepsy remains a major problem as some epileptic patients do not respond to the current therapeutics. Transient receptor potential ankyrin 1 (TRPA1) belongs to the TRP channels and has diverse physiological functions in the body. Considering its physiological properties, we aimed to evaluate its role in two experimental models of epilepsy, including pentylenetetrazol (PTZ)-induced acute seizure and PTZ-evoked kindling. Furthermore, the TRPA1 protein levels were assessed in the cerebral cortex, hippocampus, and cerebellum after seizure induction. Three groups of Wistar rats received acute intraperitoneal injection of pentylenetetrazol (PTZ, 85mg/kg). The groups received intraventricular injections of vehicle (dimethyl sulfoxide, Tween 80, and sterile 0.9% saline), valproate (30µg/rat), or HC030031 (TRPA1 antagonist, 14µg/rat) before PTZ injection. In the PTZ-induced kindling model, PTZ was administrated 35mg/kg every other day for 24 days. PTZ gradually provoked seizure-related behaviors. After experiments, the TRPA1 levels in the brain were assessed using western blot. The results showed that HC030031 reduced the median of seizure scores and S5 duration while increasing S2 and S5 latencies in acute and kindling models. The anticonvulsant effect of HC030031 was comparable with valproate as a standard anticonvulsant drug. Furthermore, induction of seizure, either acute or kindling, enhanced TRPA1 levels in the cerebral cortex, hippocampus, and cerebellum that were prevented by HC030031 or valproate administration. The results of this study showed that HC030031 as a TRPA1 receptor antagonist promoted a significant anticonvulsant effect comparable with valproate. Both drugs prevented TRPA1 upregulation during seizures. These findings imply that TRPA1 is a potential target in treating epilepsy.

Aqueous extract of Parkia biglobosa (Jacq.) R. Br. (Fabaceae) exerts antiepileptogenic, anti-amnesic, and anxiolytic-like effects in mice via mechanisms involving antioxidant and anti-inflammatory pathways.

Parkia biglobosa (Jacq.) R. Br. (Fabaceae) is a widely distributed tree, used in traditional medicine to treat amebiasis, hookworm infection, ascariasis, asthma, sterility, dental pain, headaches, cardiac disorders, and epilepsy. To date, no study on the effect of an aqueous extract of P. biglobosa on epileptogenesis and associated neuropsychiatric disorders has been undertaken. Therefore, this study aimed to investigate antiepileptogenic-, antiamnesic-, and anxiolytic-like effects of an aqueous extract of P. biglobosa using pentylenetetrazole (PTZ)-induced kindling in mice. Animals were divided into six groups of eight mice each. Thus, a PTZ group received distilled water (10ml/kg, per os), a positive control group received sodium valproate (300mg/kg, p.o.), and three test groups received the aqueous extract of P. biglobosa (80, 160, and 320mg/kg, p.o.).In addition, a control group of eight mice receiving distilled water (10ml/kg, p.o.) was formed. The treatments were administered to mice, 60min before administration of PTZ (20mg/kg, i.p.). These co-administrations were performed once daily, for 22days. The number and duration of seizures (stages 1, 2, 3, and 4 of seizures) exhibited by each mouse were assessed for 30min during the treatment period. Twenty-four hours following the last administration of the treatments and PTZ, novel object recognition and T-maze tests were performed to assess working memory impairment in mice, while the open field test was performed to assess anxiety-like behavior. After these tests, the animals were sacrificed, and the hippocampi were collected for biochemical and histological analysis. During the period of PTZ-kindling, the extract at all doses completely (p < 0.001) protected all mice against stages 3 and 4 of seizures when compared to sodium valproate, a standard antiepileptic drug. The extract also significantly (p < 0.001) attenuated working memory impairment and anxiety-like behavior. In post-mortem brain analyses, the extract significantly (p < 0.001) increased γ-aminobutyric acid (GABA) level and reduced oxidative stress and inflammation. Histological analysis showed that the aqueous extract attenuated neuronal degeneration/necrosis in the hippocampus. These results suggest that the extract is endowed with antiepileptogenic-, anti-amnesic-, and anxiolytic-like effects. These effects seem to be mediated in part by GABAergic, antioxidant, and anti-inflammatory mechanisms. These results suggest the merit of further studies to isolate the bioactive molecules responsible for these potentially therapeutically relevant effects of the extract.

Case Report: Acute isoniazid intoxication after intentional ingestion

Isoniazid is an anti-tuberculosis medication that is extensively used for treatment and prevention of tuberculosis. Acute isoniazid poisoning is characterized by a clinical triad of recurrent seizures, raised anion gap metabolic acidosis and coma. The seizures are unresponsive to standard anticonvulsant drugs, instead requiring pyridoxine administered in a dose equal to the amount of isoniazid consumed. Due to the high incidence of tuberculosis in low-income countries like Nepal, isoniazid intoxication should be considered in any patient who present with such unresponsive seizures and coma. We report a case of a 31 years old woman from Nepal, who intentionally ingested 12 grams of isoniazid and presented with generalized tonic-clonic seizures. She was successfully managed with 10 grams of pyridoxine along with other supportive management, including sodium bicarbonate for metabolic acidosis and mechanical ventilation. Doctors working in low-income countries, like Nepal, where tuberculosis is endemic, should be well acquainted with presentations and management of isoniazid intoxication.

Doubly robust estimation of optimal dynamic treatmentregimes with multicategory treatments andsurvival outcomes.

Patients with chronic diseases, such as cancer or epilepsy, are often followed through multiple stages of clinical interventions. Dynamic treatment regimes (DTRs) are sequences of decision rules that assign treatments at each stage based on measured covariates for each patient. A DTR is said to be optimal if the expectation of the desirable clinical benefit reaches a maximum when applied to a population. When there are three or more options for treatments at each decision point and the clinical outcome of interest is a time-to-event variable, estimating an optimal DTR can be complicated. We propose a doubly robust method to estimate optimal DTRs with multicategory treatments and survival outcomes. A novel blip function is defined to measure the difference in expected outcomes among treatments, and a doubly robust weighted least squares algorithm is designed for parameter estimation. Simulations using various weight functions and scenarios support the advantages of the proposed method in estimating optimal DTRs over existing approaches. We further illustrate the practical value of our method by applying it to data from the Standard and New Antiepileptic Drugs study. In this analysis, the proposed method supports the use of the new drug lamotrigine over the standard option carbamazepine. When the actual treatments match the estimated optimal treatments, survival outcomes tend to be better. The newly developed method provides a practical approach for clinicians that is not limited to cases of binary treatment options.

Felbamate add-on therapy for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Evaluation of the anticonvulsant properties of the ethanol extract of Detarium senegalense leaves in mice

Detarium senegalense, J.F. Gmelin (Fabaceae) is used in Nigerian folk medicine to treat different diseases including epilepsy, microbial infections, gastrointestinal diseases and inflammation; its efficacy is widely acclaimed among communities in South Eastern Nigeria. The leaf extract (100 mg/kg, 200 mg/kg and 400 mg/kg) was evaluated for its anticonvulsant activity in mice. Three different study models were used; pentylenetetrazole (PTZ), brucine and isoniazid (INH) convulsion methods. The acute toxicity study and the phytochemical analysis of the extract were also determined. The extract produced significant (p&lt;0.05 and p&lt;0.01) dose-dependent delay in onset, frequency and duration of seizures in mice in the three models of convulsion which is comparable to the standard anticonvulsant drug. The oral acute toxicity test was greater than 5000 mg/kg in mice. The phytochemical screening revealed that D. senegalense leaf extract contains bioactive principles that are relevant in the management of seizure disorders. These findings suggest that D. senegalense leaf extract possesses anticonvulsant properties and justifies its use in traditional medicine.

An aqueous extract of Khaya senegalensis (Desv.) A. Juss. (Meliaceae) prevents seizures and reduces anxiety in kainate-treated rats: modulation of GABA neurotransmission, oxidative stress, and neuronal loss in the hippocampus

Ethnopharmacological relevanceTemporal lobe epilepsy is the most common form of drug-resistant epilepsy. Therefore, medicinal plants provide an alternative source for the discovery of new antiepileptic drugs. Aim of the studyThis study was aimed at investigating the antiepileptic- and anxiolytic-like effects of an aqueous extract of Khaya senegalensis (K. senegalensis) in kainate-treated rats. MethodsSeventy-two rats received a single dose of kainate (12 mg/kg) intraperitoneally. Those that exhibited two hours of status epilepticus were selected and monitored for the first spontaneous seizure. Then, animals that developed seizures were divided into 6 groups of 8 rats each and treated twice daily for 14 days as follows: negative control group received per os (p.o.) distilled water (10 ml/kg); two positive control groups received either sodium valproate (300 mg/kg, p.o.) or phenobarbital (20 mg/kg, p.o.); and three test groups received different doses of the extract (50, 100, and 200 mg/kg, p.o.). In addition, a group of 8 normal rats (normal control group) received distilled water (10 ml/kg, p.o.). During the treatment period, the animals were video-monitored 12 h/day for behavioral seizures. At the end of the treatment period, animals were subjected to elevated plus-maze and open field tests. Thereafter, rats were euthanized for the analysis of γ-aminobutyric acid (GABA) concentration, oxidative stress status, and neuronal loss in the hippocampus. ResultsThe aqueous extract of K. senegalensis significantly reduced spontaneous recurrent seizures (generalized tonic-clonic seizures) and anxiety-like behavior compared to the negative control group. These effects were more marked than those of sodium valproate or phenobarbital. Furthermore, the extract significantly increased GABA concentration, alleviated oxidative stress, and mitigated neuronal loss in the dentate gyrus of the hippocampus. ConclusionThese findings suggest that the aqueous extract of K. senegalensis possesses antiepileptic- and anxiolytic-like effects. These effects were greater than those of sodium valproate or phenobarbital, standard antiepileptic drugs. Furthermore, these effects are accompanied by neuromodulatory and antioxidant activities that may be related to their behavioral effects. These data justify further studies to identify the bioactive molecules present in the extract for possible future therapeutic development and to unravel their mechanisms of action.

Efficacy of levetiracetam, lamotrigine and sodium valproate on seizure attacks and EEG disorders in patients with juvenile myoclonic epilepsy: A double blind randomized clinical trial.

Background:Juvenile myoclonic epilepsy (JME) is one of the most important types of generalized idiopathic epilepsy. Patients generally respond quickly and perfectly to standard antiepileptic drugs but lifelong medication is necessary. Sodium valproate is the drug of choice in most references but it has some adverse reactions and some patients cannot tolerate the complications. Because of the need for life long treatment in this young aged group particularly child bearing women, we aimed to analyze the efficacy of these drugs to determine which has better efficacy with lower adverse effects.Methods:In this double-blind clinical trial 102 patients suffering from juvenile myoclonic epilepsy were randomly divided to three groups and treated with valproate, levetiracetam or lamotrigine and followed for 12 months at specified intervals.Results:Patients' mean age was 22.8 years and 28.4% of them were males and 71.6% were females. Effective terminal dose of sodium valproate, levetiracetam and lamotrigine were 1000, 1000 and 250mg, respectively. The rate of failure in controlling seizures and myoclonic jerks in lamotrigine group was meaningfully more than levetiracetam and sodium valproate (P=0.037).The general side effects of sodium valproate were much more; but there was not any significant difference between their effects on electroencephalogram (EEG) findings (P=0.81).Conclusion: Levetiracetam and sodium valproate have similar efficacy. But in the group of lamotrigine, rate of failure, myoclonus and drug adverse reactions were meaningfully more than sodium valproate and levetiracetam. According to our study, lamotrigine could not be a suitable treatment option for JME patients as a mono therapy. Levetiracetam can be a good alternative to sodium valproate, especially in women of childbearing age.

Evaluation of Antiepileptic activity of Mosapride in Albino wistar rats

Serotonin causes a significant shift in the excitability of neurons and endogenous serotonin and drugs acting on serotonergic receptors play a role in pathogenesis of epilepsy. This study was done to study the effect of Mosapride, a serotonin receptor 5HT4 agonist, in animal models of epilepsy. Albino Wistar rats were divided into 5 groups with six animals in each group. Group 1 was control group, group 2 was standard group and group 3, 4 and 5 received test drug mosapride in low dose (3mg/kg), high dose (6mg/kg) and mosapride plus standard antiepileptic drug respectively. The antiepileptic efficacy was evaluated using Maximal Electroshock Seizure model (MES) and Pentylenetetrazole (PTZ) induced convulsions. Data was analysed using ANOVA followed by post hoc Tukeys test. Mosapride treated animals showed statistically significant decrease (p&lt;0.001) in the duration of flexion, hind limb extension and post ictal depression in MES model which was comparable to phenytoin group. In PTZ model, mosapride alone did not show any significant difference as compared to control group in terms of latency and duration of seizures (p&gt;0.05). The antiepileptic efficacy of mosapride is similar to phenytoin in MES model. However, in PTZ model mosapride did not show any beneficial antiepileptic effect