Epilepsy Research

BackgroundLevetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy. ObjectiveThe aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore the identified influencing covariates. MethodsWe systematically searched the PubMed and Embase databases from inception to 30 June, 2020. The information on study designs, target population, model characteristics, and identified covariates was summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults. ResultsFourteen studies were included, among which 2 involved neonates, 4 involved children, 2 involved both children and adults, and 6 involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038-0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039-0.061] L/h/kg). Body weight was found to significantly influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9%-22%, whereas co-administration with valproate acid decreased it by 18.8%. ConclusionLevetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women. Key pointsO_LIThis review identifies weight, renal function, daily dose, and postmenstrual age as the covariates that most likely influence the levetiracetam (LEV) pharmacokinetics. C_LIO_LIChildren showed higher clearance per kilogram body weight than adults, indicating that a higher dosage is required for children per kilogram body weight. C_LIO_LIFurther PPK studies are needed to evaluate LEV pharmacokinetics in special populations such as pregnant women and neonates. C_LI

BackgroundUp to 35% of individuals diagnosed with epilepsy proceed to develop pharmacoresistant epilepsy, leading to persistent uncontrolled seizure activity that can directly, or indirectly, significantly degrade an individuals quality of life. The factors underlying pharmacoresistance are unclear, but it has been hypothesised that repeated ictogenic activity is conducive to the development of a more robust epileptogenic network. To ensure that the most effective treatment choices are made and ictogenic activity is minimised, accurate outcome modelling at the point of diagnosis is key. ObjectivesThis review therefore aims to identify demographic, clinical, physiological (e.g. EEG), and imaging (e.g. MRI) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). Data sources, study eligibility criteria, participants, and interventionsMEDLINE and EMBASE were searched for prediction models of treatment outcomes in patients with newly diagnosed epilepsy and any non-surgical treatment plan. Study appraisal and synthesis methodsStudy characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST tool. Prognostic factors associated with treatment outcomes are reported. ResultsAfter screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally high for susceptibility to bias. Outcomes reported were heterogenous, but fit broadly into four categories: pharmacoresistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics (semiology), epilepsy history, and age at onset. ASM response was often included as a prognostic factor, potentially obscuring factor relationships at baseline. ConclusionsCurrently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD practices, and by avoiding including response to treatment as a prognostic factor. Implications of key findingsThis review identified semiology, epilepsy history, and age at onset as factors associated with treatment outcome prognosis, suggesting that future prediction model studies should focus on these factors in their models. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE. Key PointsO_LIThis paper presents a systematic literature search for treatment outcome prediction models in newly diagnosed epilepsy. C_LIO_LIThe risk of bias in the included models were evaluated using the PROBAST framework, finding a universally high risk level. C_LIO_LIThe relationship between semiology, epilepsy history, and age at onset with seizure remission should be examined in future prediction model studies. C_LIO_LITo improve the overall quality of prediction model development in NDE, prospective authors are advised to adhere to TRIPOD guidelines, and to avoid including response to treatment as a prognostic variable. C_LI

Epilepsy, characterised by a predisposition towards unprovoked seizures, is one of the most common neurological disorders globally. Whilst 60-70% of individuals diagnosed with epilepsy will gain seizure control through anti-seizure medication, the mechanisms underlying seizure persistence are unclear. Intractability can significantly degrade a patients quality of life amongst other things; the use of predictive modelling of epilepsy outcomes in deciding on treatment therefore offers a tangible benefit to the patient. Early indicators of pharmacoresistance may discourage certain treatment options, and save time in what has been indicated to be a critical stage for newly-diagnosed epilepsy. Primarily, this paper aims to evaluate existing predictive models to identify demographic, clinical, physiological (e.g. EEG), and neuroimaging (e.g. MRI) factors that may be predictive of treatment outcomes in newly-diagnosed epilepsy. Two electronic databases, MEDLINE and EMBASE, will be searched with terms related to prognosis in newly-diagnosed epilepsy, and identified studies will be included for review if they have combined at least two demographic, clinical, neuroimaging, and/or physiological factors to predict treatment outcome in people with newly-diagnosed epilepsy. Papers will be screened by two independent reviewers via titles, abstracts and then full text against the inclusion criteria for eligibility. Data will be extracted by reviewers using standardised forms, assessed for risk of bias using the PROBAST tool and synthesised narratively. If considered appropriate the authors will carry out a meta-analysis on the available data. Prospero registration number- CRD42022329936

BackgroundCarbamazepine (CBZ) and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics and maturation of drug metabolizing enzymes further complicates personalized dosing. Physiologically-based pharmacokinetic (PBPK) modeling includes these mechanisms and is hence a promising tool to optimize dosing. Our aim is to better support pediatric drug dosing of CBZ and VPA. MethodsAll CBZ and VPA dosing simulations were conducted with Simcyp, using available CBZ and VPA compound models linked with adult and pediatric population models. Current Dutch national dosing strategies were simulated to evaluate their appropriateness to achieve therapeutic levels. Where doses could be optimized, alternative dosing strategies were proposed based on simulations. ResultsTherapeutic levels of CBZ and VPA will be reached after 1 or 2 weeks of treatment with the current dosing strategies. Simulations suggest a CBZ starting dose of 7 mg/kg/day for neonates rather than 10 mg/kg/day. In contrast, children aged 12 to 18 years may receive a higher starting dose (e.g., 400 mg/day instead of 200 mg/day), to reach therapeutic levels more quickly. For VPA, when higher doses are needed (i.e., [≥]30 mg/kg/day), measuring unbound VPA concentrations are advised to guide dosing. ConclusionWe demonstrate that PBPK modeling is a valuable tool to confirm and further optimize dosing recommendations in children. The use of PBPK modeling offers a practical, cost-effective, and swift method to provide valuable comprehensive evidence for guiding clinical practice and potentially informing pediatric drug labeling, thus eliminating the necessity for clinical studies.

Cannabidiol is a non-psychoactive phytocannabinoid that has been implicated as a potential therapeutic in numerous neurological diseases. Perhaps the most widespread therapeutic use of CBD has been in the form of Epidiolex, which is used to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome and tuberous sclerosis. Whilst the effectiveness of CBD in seizure reduction is clear, its mechanism of action is complex, and reflects the wide range of pharmacodynamic targets that includes receptors, ion channels and enzymes. This study investigated the effects of action of cannabidiol (CBD) on GABAergic transmission in layer II of the medial entorhinal cortex in animals that had previously undergone a period of status epilepticus (SE). Spontaneous post-synaptic currents were recorded from medial entorhinal cortex layer II pyramidal cells in animals 1-7 after SE and in age matched controls as well as in tissue resected from children with temporal lobe epilepsy (TLE). CBD enhanced GABAAR-mediated inhibition by increasing decay times and inhibitory charge transfer across the postsynaptic membrane in status epilepticus (SE) but did not alter GABAergic transmission in age-matched control rats. The SE-induced effects of CBD were blocked by ligands acting as inverse agonists at the benzodiazepine site of the GABAAR receptor and the effects of CBD were additive to low-doses of benzodiazepine and barbiturate agonists, consistent with allosteric actions on the GABAAR. Similar effects were observed in both SE rat and human layer II neurons. Overall, these data suggest CBD may act as a positive allosteric modulator (PAM) at postsynaptic GABAARs and this action appears to develop following SE. Key pointsO_LICBD increases inhibition only post status epilepticus. C_LIO_LIThis effect is blocked by benzodiazepine site inverse agonists C_LIO_LICBD is additive to low-dose zolpidem, suggesting an allosteric effect on the GABAAR C_LIO_LICBD was similarly effective in ex vivo human epileptic tissue C_LIO_LIThese results suggest CBD is a positive allosteric modulator at the GABAAR C_LI

Background and PurposeRepetitive epileptic seizures trigger massive neuronal death. Therefore, neuroprotection plays a role in preventing neuronal death and inversely suppresses seizure generation. Additionally, some studies have shown ferroptosis, featured by lipid peroxidation (a dominant form of oxidative stress in the brain), is of paramount importance in epileptic seizures. Lapatinib can play a first-line anti-tumor role by targeting oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. We hypothesize whether lapatinib can protect against ferroptosis in epileptic seizures via regulating lipid peroxidation. Experimental ApproachThe epileptic behavior of the mice was recorded after intracranial injection of KA. Western blot and RT-qPCR were used to detect the protein expression of 4-hydroxynonenal (4-HNE) and glutathione peroxidase 4 (GPX4) and the mRNA expression of prostaglandin endoperoxide synthase 2 (PTGS2) in vivo and in vitro. The level of lipid reactive oxygen species (lipid ROS) in cells pretreated with lapatinib was analyzed by flow cytometry. Key ResultsLapatinib remarkably prevented KA-induced epileptic seizures in mice and ferroptosis was involved in the neuroprotection of lapatinib. Compared with the model group, western blot showed that lapatinib significantly upregulated the levels of GPX4. In the ferroptotic cell death model, lapatinib exerted neuroprotection via up-regulating GPX4. Treatment with Ras-selective lethal small molecule 3 (RSL3), a selective GPX4 inhibitor abrogated its anti-ferroptotic potential. Conclusions and ImplicationsThese results illustrated that lapatinib has neuroprotective potential against KA-triggered epileptic seizures via suppressing GPX4-dependent ferroptosis. What is already knownO_LIActivation of ferroptosis occurs in epileptic seizures. C_LI What this study addsO_LILapatinib protects brain against epileptic seizures via blocking ferroptosis. C_LIO_LIGPX4-dependent ferroptosis is involved in the neuroprotection of lapatinib. C_LI What is the clinical significanceO_LIInhibition of ferroptosis by lapatinib represents a potential neuroprotective strategy for epileptic patients. C_LI

BackgroundTransient pentylenetetrazol (PTZ) treatment on zebrafish larvae has been widely accepted a promising animal model for human epilepsy. However, this model is not ideal due to its acuteness and lack of recurrent seizures, which are the key feature of epilepsy in human disease. It is important to develop a more sensitive zebrafish model for epilepsy with well-controlled, predictable, recurrent seizures.\n\nNew MethodThe new method includes an experimental setup and a treatment protocol. The setup tracks the locomotion activity of up to 48 larvae simultaneously, while a visual stimulus can be presented to each of the 48 animals individually. The protocol treated the larvae through a water bath in 5 mM PTZ while being stimulated with rotating grating stimuli for 1 hour/day from 5 to 7 days postfertilization.\n\nResultsThe setup captured the locomotion activity of zebrafish larvae during visual stimulation. The new protocol generated recurrent responses after flashing lights 4 hours post PTZ treatment. The effects could be suppressed by the anti-epileptic drug valproic acid. The characteristics of the visual stimulus play a major role in this kindling model.\n\nComparisons with Existing MethodsWe compared the proposed method with the transient PTZ model and confirmed that the flashing-light-evoked recurrent seizure is a new feature in addition to the transient changes.\n\nConclusionsThe new method generated non-drug-triggered predictable recurrent seizures in response to intermittent photic stimulation in zebrafish larvae and may serve as a sensitive method for anti-epileptic drug screening or a new research protocol in epilepsy research.

ObjectiveSudden unexpected death in epilepsy (SUDEP) has been recognized as an important cause of death in patients with epilepsy. In order to inform patients with epilepsy and their relatives correctly, it is necessary to increase the awareness of students about SUDEP from the early stages of medical education. The aim of this study was to identify the level of knowledge and awareness of medical students in Turkey about SUDEP. MethodsMedical students (23{+/-}7 years old; n=793) in Turkey participated in the online SUDEP awareness survey. The survey included demographic evidence, followed by questions about their awareness of epilepsy, seizure knowledge and about the definition, awareness of SUDEP. ResultsThe majority of medical students (95%) claimed that they had heard about epileptic seizures. Half of the participants (49.9%) mentioned that they had heard about tonic-clonic seizures. However, two-thirds of the students (67%) have never heard about SUDEP, while 85% of the students stated that they did not have sufficient knowledge about SUDEP. Concerning the potential prevention of SUDEP, 80.8% of the students did not know about this topic. Furthermore, most participants (82%) expressed their interest and willingness to learn about SUDEP. ConclusionKnowledge about SUDEP plays a key role in identifying patients at risk and informing patients and their relatives. The limited awareness of SUDEP in medical education may pose risks for patients diagnosed with epilepsy and their relatives, and the effective incorporation of lectures and training in SUDEP into the curriculum of medical school is of paramount importance.

ObjectiveThe aim of this study was to investigate the clinical trials of Perampanel (PER) at the First Affiliated Hospital of Xiamen University (FAHXU). Recommendations have been developed for the use of Perampanel in clinical practice. DesignA retrospective single-center validation study. SettingA tertiary general hospital in Xiamen, a city located on the southeastern coast of China. ParticipantsA total of 831 prescriptions were included for 188 patients were treated with Perampanel. Outcome measuresRecord the patients medication, including the diagnosis of the patients disease, the dose, course of medication, and the combination of medication, analyze the characteristics of the drug population and the medication unreasonableness by comparing the drug instructions and referring to relevant literature and guidelines. ResultsPER was mainly used in Neurology. Epilepsy is the most common conditions prescribed. There were 119 cases of inconsistent drug indications, 56 inappropriate dosing frequency, 3 inconsistent dose, and 6 inconsistent dose adjustment intervals. ConclusionThere is an improper use of PER within the FAHXU. Greater attention should be paid to changes in patients condition and observation of discomfort following medication administration. Monitoring of PER use should be further enhanced. A rational drug evaluation system should be established to promote the rational use of PER. Article SummaryOur study was one of the few studies on the clinical use of Perampanel, especially in Southeast China. As a third-generation antiepileptic drug, data on the clinical rational drug use of Perampanel is limited in China. There were several limitations worth noting. Firstly, the data in our study were collected at only one institution, thus not covering a broader population from other regions. Clinical outcomes, including medication efficacy and adverse events, were not tracked in patients with irrational medication use. Strengths and limitationsOur study was one of the few studies on the clinical use of Perampanel, especially in Southeast China. As a third-generation antiepileptic drug, data on the clinical rational drug use of Perampanel is limited in China. There were several limitations worth noting. Firstly, the data in our study were collected at only two institutions, thus not covering a broader population from other regions. Clinical outcomes, including medication efficacy and adverse events, were not tracked in patients with irrational medication use.

BackgroundHow different thalamic sites are recruited during seizure propagation remains poorly understood. Simultaneous recordings from multiple thalamic sites in patients with focal seizures provide a rare opportunity to investigate the spatiotemporal pattern of thalamic involvement during human epilepsy. ObjectiveTo characterize the recruitment patterns of mediodorsal (MD) thalamic subregion during seizures and their generalization to the contralateral hemisphere. MethodsWe analyzed 119 seizures from 23 patients (12 male, age range: 20-57y) undergoing multisite thalamic recordings. In accordance with current clinical standards, we determined the spatial and temporal features of thalamic seizure activity by visually reviewing intracranial EEG recordings from different seizure types in each individual patient. ResultsThe procedure of multisite thalamic recordings had no complications. In total, we captured seizures originating from temporal lobes (63%), orbitofrontal (11%), frontotemporal (8%), occipital (8%), lateral frontal (4%), parietal (3%), and cingulate (2%) regions. Seizures were focal (76% in 21 patients), focal-to-bilateral tonic-clonic (FBTC, 9% in nine patients), or only electrographic (15% in six patients). Thalamic engagement was seen in 100% of patients occurring typically early during seizure evolution (83% within 15 seconds of seizure onset). Majority of FBTC seizures (73%) had faster thalamic recruitment, often within the first 5 seconds. The pulvinar (PLV) subregion was the most common first-activated thalamic site, particularly in temporal lobe seizures. Although the MD was involved in most seizures (88.2%), it was rarely the initial or sole thalamic structure engaged and more often followed anterior (ANT) and/or PLV sites. Contralateral propagation occurred in 66% of seizures and was strongly linked to MD involvement: the ipsilateral and contralateral MDs were engaged in about 95% of these cases. When ipsilateral MD engagement was absent, contralateral spread of seizures was uncommon. In majority of seizures (60%) that generalized to the contralateral hemisphere, the ipsilateral MD was involved before or simultaneously with the contralateral cortical sites. Importantly, seizures that first activated the MD originated mainly from the medial temporal lobes, whereas those spreading primarily to the contralateral cortex were mostly neocortical in onset. ConclusionsThe thalamic MD subregion was often involved after the other thalamic sites, but the MD sites, along with the massa intermedia connecting the two thalami, were significantly involved when seizures spread to contralateral hemisphere. Our findings suggest that a single thalamic lead capturing both MD subregions may yield important clinical information about laterality, origin, and generalization of seizures.

BackgroundThe goal of this systematic review is to assess the published literature for seizure risk with chloroquine therapy in persons with and without epilepsy. With the COVID-19 pandemic, there is a desperate need for therapy against the SARS CoV-2 virus. Chloroquine is one proposed medication that has received substantial public attention. However, drug labeling in the package insertion states that persons with epilepsy have the risk of chloroquine provoking seizures, and this has increased questions and anxiety in the epilepsy community. MethodsPubMed (1970 to March 27, 2020) and the Embase (1970 to March 27, 2020) were searched with the terms chloroquine and seizure or epilepsy. Selected studies were reviewed, and the adverse drug reaction was classified. ResultsOnly nine out of 27 studies were deemed eligible for systematic analysis. Out of the nine studies, only one was a prospective study (N=109), two were case series (N=6), and the remaining 6 were case reports. The dose of chloroquine ranged between 100-500 mg/day, except in one patient, the seizure was after taking 1000 mg. The strength of causality for the drug causing seizures in healthy and persons with epilepsy was mostly possible or unlikely, and none were certain. The only clinical trial that evaluated seizure risk with chloroquine failed to find any significant relation. ConclusionAlthough the drug insertion label states an increased risk of seizure, the systematic review highlights that such a statement is not supported by any class I studies but by anecdotal case reports. The only randomized clinical study revealed that seizures were not associated with an increased blood level of chloroquine or its metabolite. The present systematic review should provide reassurance to busy clinicians and persons with epilepsy that chloroquine, if prescribed to treat COVID-19, lacks any substantial evidence to suggest that the medication increases the risk of seizure.

Key points1. Antiseizure medications may change how strongly seizures synchronise with seizure cycles estimated from seizure diaries. 2. One seizure rate can be produced by different seizure cycles, suggesting a one-to-many relationship between seizure rate and cycles. 3. Using seizure cycles to time medication and assess efficacy could prove challenging with paper-based monitoring due to the complexity of cycles and potential drug effects. A seizure cycle tracking algorithm combined with an electronic seizure diary might support this task. Evaluating effectiveness of anti-seizure medications in epilepsy often relies on seizure frequency, reported through seizure diaries before and after treatment initiation. Measuring efficacy with seizure frequency can be challenging and unreliable as seizures tend to occur in cyclical patterns-- seizure cycles--making it difficult to distinguish drug effects from natural fluctuations. Incorporating cycle information could aid treatment evaluation, but antiseizure medications (ASMs) may alter seizure cycles, warranting further study. We conducted an observational study using seizure and ASM tracking app data (Feb. 2023) from 86 individuals with epilepsy. Participants were grouped based on ASM regimen and [&ge;]50% seizure rate reduction at 4 months after a drug change (drug-switching-responders, n=7/45; drug-switching-non-responders, n=38/45) or random timepoint (drug-sustained-responders, n=8/41; drug-sustained-non-responders, n=33/41). We compared groups on three seizure cycle variables detected via diaries: 1. how strongly seizures synchronise with a cycle, measured by the Synchronisation Index (SI), 2. cycle period, and 3. number of detected cycles. Permutation tests (=0.05, p<0.004 with Bonferroni correction) assessed significance, and regression models examined correlations with seizure rate. Across an average 612-day study period, 22,976 seizures were reported. Following an ASM change, the SI of the seizure cycle was more likely to change (p<0.004). This was pronounced in drug-switching-responders (median absolute SI difference: 0.37 [IQR=0.26] vs. 0.11 [IQR=0.11] in the drug-sustained-responders, p<0.004, permutation test). Changes in cycle length and number of detected cycles were similar across groups, possibly due to a non-linear relationship between seizure rate and cycles, suggested by weak linear correlations and poorly fitting models. These findings suggest ASMs may influence how strongly seizures synchronise with diary-detected seizure cycles. However, this relationship is complex and not yet well understood, complicating clinical interpretation. Ongoing research into real-time seizure cycle tracking may support the use of seizure cycles in aiding treatment monitoring.

Newer antiepileptic drugs (AEDs) offer favourable safety profiles than the previously used AEDs. Despite the introduction of many AEDs, a large number of patients continue to suffer from uncontrolled partial-onset seizures which have considerable impact on a patients quality of life. Lacosamide (LCM) is a third generation AED approved for adjunctive use in partial-onset seizures. Patients with epilepsy frequently experience cognitive dysfunctions due to a variety of factors. Because AEDs are the major therapeutic modality for epilepsy, the adverse effects of AEDs on cognition are important. ObjectivesTo assess the adverse effects of lacosamide on cognition among patients with localization related epilepsy to whom lacosamide is given as adjuvant therapy. METHODOLOGYAn open labelled prospective observational study in 22 patients who suffered from localization related epilepsy. ResultsAverage Initial seizure frequency per month was 3.56 (SD 2.58) and median frequency 2.5 seizures per month. Range being 1-8 per month. At the final followup at 6months, only 2 persons experienced seizure and that too only single episodes. The difference in frequency is statistically significant (Wilcoxon Signed Ranks TestP <0.001). All the pre and post lacosamide cognition scores showed statistically significant positive correlation in this study. ConclusionExcellent seizure control is observed in patients with refractory localization related epilepsy treated with lacosamide. Also, lacosamide has no serious adverse effects or drug interactions. In this study, it is observed that unlike many AEDs, lacosamide contributed to significant improvement in cognition and can improve the quality of life in such patients.

PurposeFenfluramine and cannabidiol are licensed as add-on therapies for the treatment of seizures in Dravet syndrome (DS); however, there are no comparative trials of these therapies. We assessed the comparative effectiveness of fenfluramine (with/without concomitant stiripentol) versus cannabidiol (with/irrespective of concomitant clobazam, using robust indirect comparison methods. MethodsWe systematically searched for randomised controlled trials (RCTs) of licensed regimens published up to 30 November 2021. Outcomes of interest were placebo-adjusted reductions from baseline in monthly convulsive seizure frequency (MCSF), the odds of achieving [&ge;]25%, [&ge;]50%, [&ge;]75% and 100% reductions from baseline in MCSF, and the odds of experiencing serious treatment-emergent adverse events (TEAEs). Comparative efficacy and safety were assessed using Bayesian network meta-analysis (NMA). PROSPERO registration: CRD42021296141. ResultsWe identified five relevant placebo-controlled RCTs (three for fenfluramine; two for cannabidiol; N=667). All licensed regimens of fenfluramine and cannabidiol significantly reduced MCSF compared with standard of care. When indirectly comparing fenfluramine 0.7mg/kg/day (without concomitant stiripentol) and fenfluramine 0.4mg/kg/day (with concomitant stiripentol) versus cannabidiol 10mg/kg/day, irrespective of clobazam use, the mean differences in placebo-adjusted reduction from baseline in MCSF were 47.3% (95%CrI: 18.9, 64.7) and 35.1% (1.0, 57.5), respectively, and versus cannabidiol 10mg/kg/day plus clobazam were 37.2% (2.0, 59.7) and 23.5% (-20.2, 51.3), respectively. For these outcomes, and for the proportion of patients achieving [&ge;]25%, [&ge;]50% and [&ge;]75% reductions in MCSF, Bayesian treatment ranking indicated [&ge;]99% probability that fenfluramine is the most effective therapy versus <1% probability for cannabidiol 10 or 20mg/kg/day (maximum recommended dose), with/irrespective of concomitant clobazam. Fenfluramine regimens had lower odds of serious TEAEs. ConclusionNMA using RCT data indicates fenfluramine provides superior convulsive seizure control compared to cannabidiol across all licensed dose regimens and is comparatively well-tolerated. Fenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in DS. O_TEXTBOXWhat is already known on this topicO_LIFenfluramine (Fintepla(R)) is a recently licensed add-on therapy to standard of care antiepileptic drugs for the treatment of seizures in Dravet syndrome. C_LIO_LICannabidiol (Epidiolex(R)/Epidyolex(R)) is also licensed for this use. In Europe cannabidiol is only licensed for use with concomitant clobazam. C_LIO_LIThere are no direct comparative data to inform on the relative efficacy and safety of these therapies in the management of seizures in Dravet syndrome. No indirect comparisons have been conducted across the full licensed dose regimens of these therapies. C_LI What this study addsO_LIBased on NMA using RCT data, fenfluramine provides superior convulsive seizure control in Dravet syndrome compared with cannabidiol across all licensed dose regimens, and is comparatively well tolerated. C_LIO_LIFenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in Dravet syndrome C_LI C_TEXTBOX

ObjectiveThere continue to be concerns regarding exposure during pregnancy to anti-epilepsy drugs (AEDs). The study aims were to determine the suspected adverse drug reactions (ADRs) associated with AEDs and potential mechanistic hypotheses. MethodsSuspected ADR profiles for 8 AEDs were data-mined from the MHRA Yellow Card scheme (January 2018-August 2022) together with prescribing data from OpenPrescribing (August 2017-July 2022). The physicochemical, pharmacokinetic, and pharmacology of the AEDs were data-mined from public databases. ResultsThe suspected ADRs per 1,000,000 Rx identified across all AEDs are statistically significant ({chi}2 test, P < .05). Pregnancy, puerperium & perinatal conditions associated with lamotrigine (1.51 per 1,000,000 Rx, {chi}2 test, P < .05, d = 2.720, 95% CI [1.656, 4.469]) had a larger size effect than valproic acid (2.28 per 1,000,000 Rx, {chi}2 test, P < .05, d = 1.846, 95% CI [1.150, 2.964]). The large size effect associated with valproic acid for congenital and hereditary disorders (d = 9.069, 95% CI [5.807, 14.163]) and foetal exposure during pregnancy (d = 6.632, 95% CI [4.894, 8.988]) were notable amongst the AEDs. Valproic acid, a known teratogen, had the unique and clinically achievable targeting of histone deacetylase (HDAC 1 IC50 = 54.4, HDAC2 IC50 = 82.4 micromolar, HDAC3 IC50 = 148 micromolar, HDAC8 IC50 = 144 micromolar, Cmax = 184.3 micromolar) associated with teratogenicity. SignificanceThere is renewed discussion about the management of epilepsy in pregnancy, and the risks of different AEDs. Whilst 1 in 250 women have epilepsy, they account for 1 in 10 of women who die in childbirth or postpartum. Fears about ADRs impact on adherence to medication, whilst pregnancy itself reduces the serum level of AEDs. As a result of this women are at increased risk of seizures during pregnancy and childbirth. There has been a doubling of Sudden and Unexpected Death in Epilepsy (SUDEP) in mothers between 2013-2015 and 2019-2021 in the UK and Ireland. The AEDs studied have diverse modes of action, and the unique polypharmacology of AEDs influences their ADR profiles. Lamotrigine had a larger size effect than valproic acid (d =2.720 vs 1.846) for suspected pregnancy, puerperium and perinatal ADRs. As noted in other studies, there is a suspected association between valproic acid exposure and 1) congenital and hereditary disorders (d = 9.069), and 2) foetal exposure during pregnancy (d = 6.632) compared to other studied AEDs. Pregnancy-related ADRs with levetiracetam and topiramate did not reach statistical significance, however neurological ADRs in children who were exposed to lamotrigine and levetiracetam continue to be the subject of scrutiny. Key PointsO_LIThere are ongoing concerns regarding exposure to all anti-epilepsy drugs (AEDs) during pregnancy. Poor seizure control in pregnancy is a cause of maternal death, valproic acid continues to be used by women despite it being a known teratogen, and other AEDs also carry risks of significant ADRs. C_LIO_LIAEDs have diverse modes of action, and the unique polypharmacology of AEDs influences their ADR profiles. C_LIO_LILamotrigine had a larger size effect than valproic acid (d =2.720 vs 1.846) for suspected pregnancy, puerperium and perinatal ADRs. C_LIO_LIThere is a strong association between valproic acid exposure and congenital and hereditary disorders including foetal valproate spectrum disorder (FVSD), autism spectrum disorder (ASD), spina bifida, polydactyly and cleft palate (d = 9.069). C_LIO_LIThere is an association between valproic acid and foetal exposure during pregnancy (d = 6.632). C_LI

PurposeTo investigate the real-world adverse event signals associated with zonisamide and provide a foundation for its safe clinical use. MethodsAdverse event reports involving zonisamide as the primary suspected drug were collected from the FDA Adverse Event Reporting System (FAERS) database, covering the period from the first quarter of 2004 to the fourth quarter of 2023. The data were analyzed utilizing the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods of the proportional imbalance technique. ResultsA total of 3205 adverse event reports involving zonisamide as the primary suspected drug were identified, resulting in 260 positive signals for preferred terms (PTs). These signals, derived from both the ROR and BCPNN methods, encompassed 27 systems and organs (SOCs), with a predominant focus on nervous system disorders and skin and subcutaneous tissue disorders. The most frequently reported PTs included seizures, drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, rash, and dizziness. Notably, the top PTs in terms of signal intensity included perinephritis, epilepsy with myoclonic-atonic, ocular mucocutaneous syndrome, ocular choroidal leakage, tonsillar exudate, and ovarian granulosa vesicular cell tumor. Interestingly, ten of the top 30 risk signals for adverse events, based on signal strength, were not detailed in the package inserts. Thses included perinephritis, myoclonic dystonic epilepsy, ovarian granulosa vesicular cell tumor, positive human herpesvirus 6 serology, and positive lymphocyte stimulation test. ConclusionCommon adverse reactions to zonisamide in real-world settings are generally in line with the established specification, with the most frequently observer signals related to neurological, skin, and subcutaneous tissue disorders. However, several newly suspected adverse reactions have been identified, including perinephritis, infectious pneumonitis, ovarian granulosa vesicular cell tumor, positive serology for human herpesvirus 6, and positive lymphocyte stimulation test. These findings indicate that these potential adverse reactions should be closely monitored in clinical practice.

Epilepsy is a prevalent neurological disorder, affecting approximately 1 to 2% of the global population. The hallmark of epilepsy is the occurrence of epileptic seizures, which are characterized by predictable behavioral changes reflecting the underlying neural mechanisms of the disease. Unfortunately, around 30% of patients do not respond to the current available pharmacological treatments. Consequently, it is crucial to explore alternative therapeutic options for managing these seizures. Two potential candidates for attenuating seizures are N-acetylcysteine (NAC) and Acetyl-L-carnitine (ALC), as they have shown promising neuroprotective effects through the modulation of the neurotransmitter glutamate. Therefore, this study aims to assess the effects of varying concentrations (0.1, 1.0, and 10 mg/L) of NAC and ALC on acute PTZ-induced seizures in zebrafish, in both adult and larval stages. The evaluation of behavioral parameters such as seizure intensity and latency to the crisis can provide insights into the efficacy of these substances. However, our results indicate that both drugs at any of the tested concentrations were not able to reduce PTZ-induced epileptic seizures. On the other hand, the administration of diazepam demonstrated a notable reduction in seizure intensity and an increase in latencies to higher scores of epileptic seizures. Consequently, we conclude that, under the conditions employed in this study, NAC and ALC do not exhibit any significant effects on acute seizures in zebrafish.

Epilepsy is among the most common neurological diseases, affecting more than 50 million people worldwide. Unfortunately, one-third of people with epilepsy fail to respond to any current treatment and present a decreased quality of life. Nevertheless, different studies suggest that epilepsies acquired from an initial insult as status epilepticus (SE) followed by epileptogenesis can be prevented. Therefore, it is necessary to establish animal models of epileptogenesis induced by SE. Thus, here we proposed an animal model of epileptogenesis triggered by SE that occurred during the neurodevelopment of zebrafish (Danio rerio). Zebrafish larvae at the 7th day post-fertilization (dpf) were randomly assigned to two experimental groups. One group was exposed to embryo medium. The other group was exposed to pentylenetetrazol (15 mM PTZ) to induce SE. At the 8th dpf, each larva was subjected to the open tank test (OTT) to analyze locomotion and behavioral parameters. After the OTT, each initial group was divided into two groups: animals maintained in embryo medium and animals exposed to PTZ (3 mM), and the susceptibility to PTZ-induced seizure-like behavior was analyzed. Data showed that animals submitted to SE on the 7th dpf showed altered locomotion and behavior 24 hours later. Interestingly, zebrafish larvae submitted to SE on the 7th dpf showed decreased latency to reach seizure-like behavioral stages when exposed to a low concentration of PTZ on the 8th dpf. Concluding, our results show that SE during neurodevelopment increases the susceptibility of zebrafish larvae to present PTZ-induced seizure-like behavior. Our study contributes to the establishment of a model of epileptogenesis in developing zebrafish. Finally, the next step is to improve this model by characterizing molecular, biochemical and physiological markers.

Impaired consciousness is a serious clinical manifestation of epilepsy with negative consequences on quality of life. Little work has investigated impaired consciousness in frontal lobe seizures, a common form of focal epilepsy. In temporal lobe seizures, previous studies showed widespread cortical slow waves associated with depressed subcortical arousal and impaired consciousness. However, in frontal lobe epilepsy, it is not known whether cortical slow waves are present, or whether a very different cortical activity pattern may be related to impaired consciousness. We used intracranial EEG recordings of 65 frontal lobe seizures in 30 patients for quantitative analysis of ictal cortical activity and its relationship to impaired consciousness. Behavioral changes based on blinded review of seizure videos were used to classify focal aware, focal impaired awareness, and focal to bilateral tonic-clonic seizures. Changes in intracranial EEG power from preictal baseline were analyzed in different cortical regions and across frequency ranges in these three categories. We found that frontal lobe focal aware seizures showed approximately 40% increases in intracranial EEG power localized to the frontal lobe of seizure onset across frequency ranges, with relatively smaller changes in other cortical regions. Frontal lobe focal impaired awareness seizures showed approximately 50% increases in intracranial EEG power, not significantly different from focal aware seizures in the frontal lobe of seizure onset (P = 1.038), but significantly greater than focal aware seizures in other broad cortical regions (P < 0.001). Importantly, the widespread cortical increases in EEG power observed in focal impaired awareness versus focal aware seizures were seen not just in the frequency range of slow waves, but were also observed across other frequencies including fast activity. However, the widespread cortical increases in focal impaired awareness seizures differed from focal to bilateral tonic-clonic seizures where intracranial EEG power increased to a much higher level by approximately 600%. The large power increases in focal to bilateral tonic-clonic were significantly greater than in focal impaired awareness seizures both in the frontal lobe of seizure onset and in other cortical regions (P < 0.001). Our findings contrast with focal temporal lobe epilepsy, where impaired consciousness is associated with cortical slow waves. We can speculate that different focal seizure types produce impaired consciousness by impacting widespread cortical regions but through different physiological mechanisms. Insights gained by studying mechanisms of impaired consciousness may be the first step towards developing novel treatments to prevent this important negative consequence of epilepsy.

Low power is a problem in many fields, as underpowered studies that find a statistically significant result will exaggerate the magnitude of the observed effect size. We quantified the statistical power and magnitude error of studies of epilepsy surgery outcomes. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4 (median odds ratio 9.3 vs. median true odds ratio 1.7), while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6 (2.7 vs. 1.7). We conclude that Bayesian estimation of odds ratio attenuates the exaggeration of significant effect sizes in underpowered studies. This approach could help improve patient counseling about the chance of seizure freedom after epilepsy surgery. SHORT SUMMARYWe estimated the statistical power of studies predicting seizure freedom after epilepsy surgery. We exacted data from a Cochrane meta-analysis. The median power across all studies was 14%. Studies with a median sample size or less (n<=56) and a statistically significant result exaggerated the true effect size by a factor of 5.4, while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6. We conclude that Bayesian estimation of odds ratios attenuates the exaggeration of significant effect sizes in underpowered studies. This result could improve patient counseling regarding epilepsy surgery.