Treatment Of Seizures Research Articles

Advances in understanding the pathogenesis of post-traumatic epilepsy: a literature review.

Severe head trauma can lead to seizures. Persistent epileptic seizures and their progression are associated with the severity of trauma. Although case reports have revealed that early use of anti-seizure drugs after trauma can prevent epilepsy, clinical case-control studies have failed to confirm this phenomenon. To date, many brain trauma models have been used to study the correlation between post-traumatic seizures and related changes in neural circuit function. According to these studies, neuronal and glial responses are activated immediately after brain trauma, usually leading to significant cell loss in injured brain regions. Over time, long-term changes in neural circuit tissues, especially in the neocortex and hippocampus, lead to an imbalance between excitatory and inhibitory neurotransmission and an increased risk of spontaneous seizures. These changes include alterations in inhibitory interneurons and the formation of new, over-recurrent excitatory synaptic connections. In this study, we review the progress of research related to post-traumatic epilepsy to better understand the mechanisms underlying the initiation and development of post-traumatic seizures and to provide theoretical references for the clinical treatment of post-traumatic seizures.

Antiseizure Medications in Alzheimer's Disease from Preclinical to Clinical Evidence.

Alzheimer's disease (AD) and epilepsy are common neurological disorders in the elderly. A bi-directional link between these neurological diseases has been reported, with patients with either condition carrying almost a two-fold risk of contracting the other compared to healthy subjects. AD/epilepsy adversely affects patients' quality of life and represents a severe public health problem. Thus, identifying the relationship between epilepsy and AD represents an ongoing challenge and continuing need. Seizures in AD patients are often unrecognized because they are often nonconvulsive and sometimes mimic some behavioral symptoms of AD. Regarding this, it has been hypothesized that epileptogenesis and neurodegeneration share common underlying mechanisms. Targeted treatment to decrease epileptiform activity could represent a valuable strategy for delaying the neurodegenerative process and related cognitive impairment. Several preclinical studies have shown that some antiseizure medications (ASMs) targeting abnormal network hyperexcitability may change the natural progression of AD. However, to date, no guidelines are available for managing seizures in AD patients because of the paucity of randomized clinical trials sufficient for answering the correlated questions. Future AD clinical studies are mandatory to update clinicians about the symptomatic treatment of seizures in AD patients and recognize whether ASM therapy could change the natural progression of the disease, thereby rescuing cognitive performance.

Implementation and impact of a point of care electroencephalography platform in a community hospital: a cohort study.

To determine the clinical and financial feasibility of implementing a poc-EEG system in a community hospital. Data from a prospective cohort displaying abnormal mentation concerning for NCSE or rhythmic movements due to potential underlying seizure necessitating EEG was collected and compared to a control group containing patient data from 2020. A teaching community hospital with limited EEG support. The study group consisted of patients requiring emergent EEG during hours when conventional EEG was unavailable. Control group is made up of patients who were emergently transferred for EEG during the historical period. Application and interpretation of Ceribell®, a poc-EEG system. 88 patients were eligible with indications for poc-EEG including hyperkinetic movements post-cardiac arrest (19%), abnormal mentation after possible seizure (46%), and unresponsive patients with concern for NCSE (35%). 21% had seizure burden on poc-EEG and 4.5% had seizure activity on follow-up EEG. A mean of 1.1 patients per month required transfer to a tertiary care center for continuous EEG. For the control period, a total of 22 patients or a mean of 2 patients per month were transferred for emergent EEG. Annually, we observed a decrease in the number of transferred patients in the post-implementation period by 10.8 (95% CI: -2.17-23.64, p = 0.1). Financial analysis of the control found the hospital system incurred a loss of $3,463.11 per patient transferred for an annual loss of $83,114.64. In the study group, this would compute to an annual loss of $45,713.05 for an overall decrease in amount lost of $37,401.59. We compared amount lost per patient between historical controls and study patients. Implementation of poc-EEG resulted in an overall decrease in annual amount lost of $37,401.59 by avoidance of transfer fees. We calculated the amount gained per patient in the study group to be $13,936.44. To cover the cost of the poc-EEG system, 8.59 patients would need to avoid transfer annually. A poc-EEG system can be safely implemented in a community hospital leading to an absolute decrease in transfers to tertiary hospital. This decrease in patient transfers can cover the cost of implementing the poc-EEG system. The additional benefits from transfer avoidance include clinical benefits such as rapid appropriate treatment of seizures and avoidance of unnecessary treatment as well as negating transfer risk and keeping the patient at their local hospital.

Treatment of Seizures in the Neonate: Special Report From the ILAE Task Force on Neonatal Seizures, 2022

Treatment of Seizures in the Neonate: Special Report From the ILAE Task Force on Neonatal Seizures, 2022

Epileptic Prodromal Alzheimer's Disease Treated with Antiseizure Medications: Medium-Term Outcome of Seizures and Cognition.

The medium term outcome (over more than one year) of epileptic prodromal AD (epAD) patients treated with antiseizure medications (ASMs) is unknown in terms of seizure response, treatment tolerability, and cognitive and functional progression. To describe such medium term outcome over a mean of 5.1±2.1 years. We retrospectively compared 19 epAD patients with 16 non-epileptic prodromal AD (nepAD) patients: 1) at baseline for demographics, medical history, cognitive fluctuations (CFs), psychotropic medications, MMSE scores, visually rated hippocampal atrophy, CSF neurodegenerative biomarkers, and standard EEG recordings; 2) during follow-up (FU) for psychotropic medications, MMSE progression, and conversion to dementia. In the epAD group, we analyzed baseline and FU types of seizures as well as each line of ASM with the corresponding efficacy and tolerability. At baseline, the epAD group had more CFs than the nepAD group (58% versus 20%, p = 0.03); focal impaired awareness seizures were the most common type (n = 12, 63.1%), occurring at a monthly to quarterly frequency (89.5%), and were well controlled with monotherapy in 89.5% of cases (including 63.1% seizure-free individuals). During FU, treated epAD patients did not differ significantly from nepAD patients in MMSE progression or in conversion to dementia. Epilepsy is commonly controlled with ASMs over the medium term in epAD patients, with similar functional and cognitive outcomes to nepAD patients. Pathophysiologically, epilepsy is likely to be an ASM-modifiable cognitive aggravating factor at this stage of AD.

Acute Abortive Therapies for Seizure Clusters in Long-Term Care.

To describe acute seizure treatment for the long-term care setting, emphasizing rescue (acute abortive) medications for on-site management of acute unexpected seizures and seizure clusters. Narrative review. People with seizures in long-term care, including group residences. PubMed was searched using keywords that pertained to rescue medications, seizure emergencies/epilepsy, seizure action plans, and long-term care. Seizure disorder, including epilepsy, is prevalent in long-term care residences, and rescue medications can be used for on-site treatment. Diazepam rectal gel, intranasal midazolam, and diazepam nasal spray are US Food and Drug Administration (FDA)-approved seizure-cluster rescue medications, and intravenous diazepam and lorazepam are approved for status epilepticus. Benzodiazepines differ by formulation, route of administration, absorption, and metabolism. Intranasal formulations are easy and ideal for public use and when rectal treatment is challenging (eg, wheelchair). Intranasal, intrabuccal, and rectal formulations do not require specialized training to administer and are easier for staff at all levels of training compared with intravenous treatment. Off-label rescue medications may have anecdotal support; however, potential disadvantages include variable absorption and onset of action as well as potential risks to patients and caregivers or care partners. Delivery of intravenous-administered rescue medications is delayed by the time needed to set up and deliver the medication and is subject to dosing errors. Seizure action plans that include management of acute seizures can optimize the quality and timing of treatment, which may reduce emergency service needs and prevent progression to status epilepticus. Seizure disorder is prevalent across all ages but is increased in older adults and in those with intellectual and developmental disabilities. Prompt intervention may reduce negative outcomes associated with acute unexpected seizures and seizure clusters. Seizure action plans that include acute seizures can improve the treatment response by detailing the necessary information for staff to provide immediate treatment.

Assessing liver effects of Cannabidiol and Valproate alone and in Combination using Quantitative Systems Toxicology.

In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) >3× the upper limit of normal (ULN) were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym®, a quantitative systems toxicology (QST) model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic (PBPK) models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of two weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.

GastroPlus- and HSPiP-Oriented Predictive Parameters as the Basis of Valproic Acid-Loaded Mucoadhesive Cationic Nanoemulsion Gel for Improved Nose-to-Brain Delivery to Control Convulsion in Humans.

Oral and parenteral delivery routes of valproic acid (VA) are associated with serious adverse effects, high hepatic metabolism, high clearance, and low bioavailability in the brain. A GastroPlus program was used to predict in vivo performance of immediate (IR) and sustained release (SR) products in humans. HSPiP software 5.4.08 predicted excipients with maximum possible miscibility of the drug. Based on the GastroPlus and HSPiP program, various excipients were screened for experimental solubility, nanoemulsions, and respective gel studies intended for nasal-to-brain delivery. These were characterized by size, size distribution, polydispersity index, zeta potential, morphology, pH, % transmittance, drug content, and viscosity. In vitro drug release, ex vivo permeation profile (goat nasal mucosa), and penetration studies were conducted. Results showed that in vivo oral drug dissolution and absorption were predicted as 98.6 mg and 18.8 mg, respectively, from both tablets (IR and SR) at 8 h using GastroPlus. The predicted drug access to the portal vein was substantially higher in IR (115 mg) compared to SR (82.6 mg). The plasma drug concentration-time profile predicted was in good agreement with published reports. The program predicted duodenum and jejunum as the prime sites of the drug absorption and no effect of nanonization on Tmax for sustained release formulation. Hansen parameters suggested a suitable selection of excipients. The program recommended nasal-to-brain delivery of the drug using a cationic mucoadhesive nanoemulsion. The optimized CVE6 was associated with the optimal size (113 nm), low PDI (polydispersity index) (0.26), high zeta potential (+34.7 mV), high transmittance (97.8%), and high strength (0.7% w/w). In vitro release and ex vivo permeation of CVE6 were found to be substantially high as compared to anionic AVE6 and respective gels. A penetration study using confocal laser scanning microscopy (CLSM) executed high fluorescence intensity with CVE6 and CVE6-gel as compared to suspension and ANE6. This might be attributed to the electrostatic interaction existing between the mucosal membrane and nanoglobules. Thus, cationic nanoemulsions and respective mucoadhesive gels are promising strategies for the delivery of VA to the brain through intransal administration for the treatment of seizures and convulsions.

Observers for Phenomenological Models of Epileptic Seizures.

Progress towards effective treatment of epileptic seizures has seen much improvement in the past decade. In particular, the emergence of phenomenological models of epileptic seizures specifically designed to capture the electrical seizure dynamics in the Epileptor model is inspiring new approaches to predicting and controlling seizures. These new models present in various forms and contain important but unmeasurable variables that control the occurrence of seizures. These models have been used mostly as nodes in large networks to study the complex brain behaviour of seizures. In order to use this model for the purposes of seizure forecasting or to control seizures through deep brain stimulation, the states of the model will need to be estimated. Although devices such as EEG electrodes can be related to some of the states of the model, most remain unmeasured and would require an observer (as defined in control theory) for their estimation. Additionally, we would like to consider the case for large nodes of systems where the number of electrodes is far smaller than the number of nodes being estimated. In this paper, we provide methods towards obtaining the full states of these phenomenological models using nonlinear observers. In particular, we explore the effectiveness of the Extended Kalman Filter for small networks of nodes of a smoothed sixth order Epileptor model. We show that observer design is possible for this family of systems and identify the difficulties in doing so.Clinical relevance-The methods presented here can be applied with an individual epileptic patient's EEG to reveal previously hidden biomarkers of epilepsy for seizure forecasting.

Age-Related Changes in Epilepsy Characteristics and Response to Antiepileptic Treatment in Autism Spectrum Disorders.

Despite the high prevalence of epilepsy in individuals with autism spectrum disorder (ASD), there is little information regarding whether seizure characteristics and treatment effectiveness change across age. Using an online survey, seizure characteristics, effectiveness of antiepileptic treatments, comorbidities, potential etiologies, and ASD diagnosis were collected from individuals with ASD and seizures. We previously reported overall general patterns of treatment effectiveness but did not examine the effect of seizure characteristics or age on antiepileptic treatment effectiveness. Such information would improve the personalized medicine approach to the treatment of seizures in ASD. Survey data from 570 individuals with ASD and clinical seizures were analyzed. Seizure severity (seizure/week) decreased with age of onset of seizures, plateauing in adolescence, with a greater reduction in generalized tonic-clonic (GTC) seizures with age. Seizure severity was worse in those with genetic disorders, neurodevelopmental regression (NDR) and poor sleep maintenance. Carbamazepine and oxcarbazepine were reported to be more effective when seizures started in later childhood, while surgery and the Atkins/modified Atkins Diet (A/MAD) were reported to be more effective when seizures started early in life. A/MAD and the ketogenic diet were reported to be more effective in those with NDR. Interestingly, atypical Landau-Kleffner syndrome was associated with mitochondrial dysfunction and NDR, suggesting a novel syndrome. These interesting findings need to be verified in independent, prospectively collected cohorts, but nonetheless, these data provide insights into novel relationships that may assist in a better understanding of epilepsy in ASD and provide insight into personalizing epilepsy care in ASD.

Value contribution of cenobamate for the treatment of Focal-Onset Seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through reflective Multi-Criteria Decision Analysis (MCDA)

IntroductionEpilepsy is one of the most common neurological conditions worldwide. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, despite the availability of many anti-seizure medications, including the latest options, called third-generation anti-seizure medications (ASMs), approximately 40% of people with epilepsy present drug-resistant epilepsy (DRE). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. In a chronic disease with a portfolio of available ASMs, the decision to introduce a new therapeutic alternative must follow a holistic evaluation of value provided. Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine the value contribution of a treatment in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. PurposeThe aim of this study was to determine the relative value contribution of cenobamate in the treatment of FOS in patients with DRE compared with third-generation ASMs using reflective MCDA-based methodology. MethodsA systematic literature review (combining biomedical databases and grey literature sources) was performed to populate the Evidence and Value: Impact on DEcisionMaking (EVIDEM) MCDA framework adapted to determine what represents value in the management of FOS in patients with DRE in Spain. The study was conducted in two phases. The first took place in 2021 with a multi-stakeholder group of eight participants. The second phase was conducted in 2022 with a multi-stakeholder group of 32 participants. Participants were trained in MCDA methodology and scored four evidence matrices (cenobamate vs. brivaracetam, vs. perampanel, vs. lacosamide and vs. eslicarbazepine acetate). Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. ResultsDRE is considered a very severe condition associated with many important unmet needs, mainly with regard to the lack of more effective treatments to achieve the ultimate goal of treatment. Compared to third-generation ASMs, cenobamate is perceived to have a better efficacy profile based on improvements in responder rate and seizure freedom. Regarding safety, it is considered to have a similar profile to alternatives and a positive quality-of-life profile. Cenobamate results in lower direct medical costs (excluding pharmacological) and indirect costs. Overall, cenobamate is regarded as providing a high therapeutic impact and supported by high-quality evidence. ConclusionsBased on reflective MCDA methodology and stakeholders’ experience in clinical management of epilepsy in Spain, cenobamate is perceived as a value-added option for the treatment of patients with DRE when compared with third-generation ASMs.

A Retrospective Matched Comparison Study of Prolonged Seizures in ECT.

This study assessed the incidence of and risk factors for prolonged seizures (>180 sec) in electroconvulsive therapy (ECT). In 611 adult patients undergoing 6697 ECT treatments administered over a 2.5-year study period, 29 individuals experienced 42 prolonged seizures. A comparison sample (n = 29) was matched on sex, age, and treatment, and compared on psychiatric and medical diagnoses, as well as current medications. To examine the association between the characteristics and prolonged seizure, conditional logistic regression models or exact McNemar tests were conducted. Prolonged seizures occurred on average in 1 of every 167 treatments. No specific psychiatric disorders or medical conditions were associated with the prolonged seizure group. Antipsychotic drugs were used in a higher proportion of the comparison group than in the prolonged seizure group, suggesting a protective effect. Atropine was used in a lower proportion of the long seizure group than in the comparison group. No untoward sequelae occurred, and no progression to status epilepticus was observed. Prolonged seizures appear to be an uncommon complication of ECT in adults. The characteristics examined in this study suggest limited association of psychotropic medications with prolonged seizures. Treatment of prolonged seizures was straightforward. Prolonged seizures had no impact on the course of treatment. Further exploration of prolonged seizures would enhance the generalizability of the findings from this single site study.

Modified Atkins diet in children with epilepsy with eyelid myoclonia (Jeavons syndrome)

BackgroundEpilepsy with eyelid myoclonia(EEM) or Jeavons syndrome is considered a genetic generalized epilepsy with a typical age of onset in childhood. Many types of seizures can be observed, including eyelid myoclonia, absence, generalized tonic-clonic, and myoclonic seizures. Seizures tend to be difficult to control requiring polypharmacy treatment or become drug-resistant. Dietary therapy, particularly with Modified Atkins Diet (MAD), as a treatment of seizures in this syndrome has rarely been studied. We report efficacy and tolerability of MAD in children with epilepsy with eyelid myoclonia. MethodsWe reviewed medical records of children with EEM treated at the University of Chicago Ketogenic Diet program from 2017 to 2022. Patient’s demography, seizure characteristics, EEG findings, response to treatment, and adverse effects were reviewed. ResultSix patients with EEM were identified. Average age of seizure onset was 6 (2–11) years and an average age when the MAD started was 10.7 (6–15) years. All patients were started on MAD and completed at least 6 months on the diet at the time of report. An average of 4 (0–9) anti-seizure medications (ASM) had been tried prior to the MAD. All patients achieved ketosis with an average level of serum beta-hydroxybutyrate of 1.9 (1.03–3.61) mmol/L. At the 6-month follow-up visit, all patients (100%) experienced a greater than 50% seizure reduction, 3/6 patients (50%) had more than 90% seizure reduction, 1/6 patients (17%) became seizure-free. All seizure types demonstrated a greater than 80% reduction in frequency.Absence and myoclonic seizures showed the greatest reduction with 100% seizure reduction. Eyelid myoclonia and generalized tonic-clonic seizures showed more than 80% seizure reduction.Moreover, all patients reported improvement in alertness, mood, and concentration. Initial weight loss and mild gastrointestinal disturbances were reported in 2/6 patients (33%) and corrected with dietary adjustment. ConclusionThe Modified Atkins Diet has shown to be effective and welltolerated for children with EEM in our study. Cognitive improvement has also been subjectively reported in all patients. Adverse effects are tolerable and correctable. The MAD, therefore, may be considered as a treatment option for patients with epilepsy with eyelid myoclonia.

Tetrastigma hemsleyanum suppresses neuroinflammation in febrile seizures rats via regulating PKC-δ/caspase-1 signaling pathway

Ethnopharmacological relevanceTetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum, Sanyeqing) has been used in the prevention and treatment of repetitive Febrile seizures (FS) over the centuries in China. Aim of the studyT. hemsleyanum exerts wide pharmacological action, which has been widely used for treating various diseases, including infantile febrile seizure. However, the systematic study on this herb's material basis and the functional mechanism is lacking. This study intended to systematically elucidate the mechanism of T. hemsleyanum against febrile seizures. Materials and methodsThe efficacy of T. hemsleyanum was estimated by using a hot bath as a model of FS, the onset and duration of seizure, morphological structure changes of hippocampal neurons as well as magnetoencephalography were applied to evaluate the effects. Meanwhile, the bioactive components of T. hemsleyanum responsible for the therapeutic effect of T. hemsleyanum on FS were identified by UPLC-MS/MS. Then we systematically elucidated the mechanism of T. hemsleyanum based on metabonomics, transcriptomics, network pharmacological and experimental validation. ResultsIn a hyperthermia-induced FS model of rats, T. hemsleyanum significantly increased the seizure latency and decreased seizure duration, alleviating the abnormal delta and gamma band activity during epileptic discharge. Furthermore, ten chemical components of ethanol extracts from T. hemsleyanum were identified by UPLC-MS/MS, including quercetin, kaempferol, and procyanidin B1 and so on, which was consistent with the network pharmacology prediction. The serum metabolomics indicated that T. hemsleyanum mainly acts on inflammation regulation and neuroprotection by the glycerophospholipid metabolism pathway. Ninety-two potential targets of T. hemsleyanum on FS were identified by network pharmacology, and TNF, IL-6, and IL-1β were considered the pivotal targets. In the hippocampus transcriptomics, 17 KEGG pathways were identified after T. hemsleyanum treatment compared with the FS model group, among which 15 pathways overlapped with those identified by network pharmacology, and the PKC-δ/caspase-1 signaling pathway was a critical node. Finally, in vivo experiments also verified T. hemsleyanum inhibited the activation of microglia and resulted in a significant reduction in the level of PKCδ, NLRC4, caspase-1, IL-1β, IL-6 and TNF-α in hippocampus of FS rats. ConclusionsOur study suggested that the therapeutic effect of T. hemsleyanum on FS might be regulated by inhibiting the neuroinflammation, thus exerting an anticonvulsant effect in vivo, and the mechanism might be related to regulating the PKC-δ/caspase-1 signaling pathway.

Pharmacokinetics of cenobamate as monotherapy compared with adjunctive therapy

ObjectiveCenobamate was approved by the US Food and Drug Administration (FDA) based on studies of adjunctive therapy in patients with focal epilepsy. To support the use of cenobamate monotherapy, this pharmacokinetic (PK)-based simulation analysis evaluated the predicted PK exposure of cenobamate when used as monotherapy versus adjunctive therapy. MethodsA population pharmacokinetic (PopPK) model of cenobamate was developed using pooled human data from eight phase 1 studies in healthy subjects or special populations, and three phase 2 and 3 studies in patients with focal seizures (N = 960). Concomitant antiseizure medications (ASMs) with a statistically significant effect on the apparent systemic clearance (CL/F) of cenobamate in the PopPK model were used to compare simulated patient plasma exposures (area under the plasma concentration vs time curve [AUC]) following monotherapy versus adjunctive therapy. Treatment equivalence between monotherapy and adjunctive therapy was concluded if the 90% confidence interval (CI) of the geometric mean AUC ratio was within 0.8–1.25. ResultsIn the PopPK model, statistically significant effects on cenobamate CL/F were shown for clobazam (decreased cenobamate CL/F by 19%) and carbamazepine (increased cenobamate CL/F by 15%); these differences were not considered clinically meaningful. Other ASMs (lacosamide, lamotrigine, levetiracetam, oxcarbazepine, topiramate, and valproate) when coadministered with cenobamate did not have significant effects on the disposition (ie, PK or efficacy) of cenobamate. The geometric mean ratio (90% CIs) of cenobamate AUC for adjunctive therapy/monotherapy was 0.87 (0.816–0.925) for adjunctive carbamazepine and 1.24 (1.147–1.339) for adjunctive clobazam. The 90% CI was within the no-effect limits (90% CIs 0.8–1.25) for adjunctive carbamazepine and partially exceeding no-effect limits for adjunctive clobazam. ConclusionsBased on the results from this PopPK analysis, cenobamate monotherapy can be expected to result in comparable exposures to those that have been demonstrated to be safe and effective when used as adjunctive therapy for the treatment of focal seizures, supporting the use of cenobamate as monotherapy in these patients.

Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures:A real-world experience in eastern China

ObjectiveTo assess the effectiveness and tolerability of perampanel (PER) monotherapy in real-world practice for the treatment of focal-onset seizures (FOS) in eastern China. MethodThis is a single-center, retrospective study of patients with FOS, aged ≥ 4 years, who had been prescribed PER as monotherapy. Outcomes included retention, seizure-free, and responder rates at 3, 6 and 12 months and adverse events (AEs) throughout the follow-up period. The efficacy and AEs of PER monotherapy in patients with aged < 14 years old and ≥ 14 years old were also compared. ResultsSixty-seven patients with FOS who received PER monotherapy and completed a one-year follow-up were included in the analysis. The median maintenance dose was 4 mg. Modified intent-to-treat analysis demonstrated that the retention rates of PER monotherapy at follow-up of 3, 6 and 12months were 75%, 70% and 63%, respectively. At the same points, seizure-free rates of PER monotherapy were 69%, 63% and 52%, and responder rates were 69%, 66% and 61%, respectively. Patients with sleep-related seizures had higher seizure-free rates at 12 months of follow-up. No significant difference in seizure-free and responder rates was found between the aged < 14 years old and the aged ≥ 14 years old. Twenty-one patients (31.3%) had AEs and five patients discontinued using PER because of intolerant AEs. Common AEs were dizziness, irritability and somnolence. The AEs rate in patients < 14 years was 17.9%, significantly lower than patients ≥ 14 years. ConclusionsOur findings revealed the real-world data of patients in eastern China with FOS using PER as monotherapy. Patients had good retention, seizure-free and responder rates, and relatively low AEs rate at a low dose of PER treatment.

Real-world safety of Lacosamide: A pharmacovigilance study based on spontaneous reports in the FDA adverse event reporting system

IntroductionLacosamide is licensed for the treatment of focal seizures in both adults and children, however there is little information available on its adverse reactions. Using the FDA Adverse Event Reporting System (FAERS), we seek to assess adverse occurrences that may be related to Lacosamide. MethodsOn the basis of the FAERS database from the fourth quarter of 2008 to the second quarter of 2022, disproportionality analysis was carried out using the reporting odds ratio (ROR) method, the United Kingdom Medicines and Healthcare Products Regulatory Agency omnbius standard (MHRA) method, and the bayesian confidence propagation neural network (BCPNN) method. We extracted valuable positive signals for designated medical event (DME) screening, focused on the evaluation and comparison of safety signals appearing in DME with system organ classification (SOC) analysis. ResultsA total of 10,226 adverse reaction reports with Lacosamide as the primary suspect drug were obtained, with 30,960 reported cases, detecting 232 valuable positive signals, involving a total of 20 SOCs, of which the most frequently reported SOCs were nervous system disorders (6537 cases, 55.21%), psychiatric disorders (1530 cases, 12.92%), injury poisoning and procedural complications (1059 cases, 8.94%). According to 232 valuable positive signals with DME screening results, two signals of stevens-johnson syndrome and ventricular fibrillation were consistent with PT signals on the DME list, with the two SOCs focusing on skin and subcutaneous tissue disorders and cardiac disorders, respectively. ConclusionsOur research demonstrates that the clinical use of Lacosamide should be noticed and avoided in relation to ADRs since it raises the risk of cardiac arrest, ventricular fibrillation, stevens-johnson syndrome, and rhabdomyolysis.

Disentangling the cascade of seizure precipitants: A prospective observational study

BackgroundThe management of epilepsy includes appropriate antiseizure medication (ASM) treatment and careful avoidance of seizure precipitating factors. Seizure precipitants may be multiple occurring with low intensity adding to each other, thus leaving essential elements unrecognized. The aim of this study was to reveal the patients’ subjective perceptions of the most important factors and to compare them with standardized measurements. MethodsThe study included 152 acute hospital admissions for seizures. The patients were asked to score the impact of various seizure precipitants as perceived by themselves on a visual analogue scale (VAS). The following items related to seizure occurrence were quantified: sleep deprivation by sleep diaries, ASM adherence by therapeutic drug monitoring, the Alcohol Use Identification Test, and the Hospital Anxiety and Depression Scale. Statistical analyses, including multiple regression, were performed to discover relationships between various parameters. ResultsThe interaction of the various factors was high. The association between lack of sleep and hazardous drinking and anxiety was highly significant. Perceived stress correlated well with anxiety and depression. Relatively low VAS scores for missed medication in patients with identified non-adherence suggest that insufficient patient awareness is common. Low VAS-scores for alcohol in patients with harmful drinking also suggest low acknowledgment of alcohol-related seizures. High alcohol scores were associated with sleep deprivation, anxiety and depression. ConclusionThe circumstances leading to an epileptic seizure are complex. Stress, sleep loss, alcohol intake, and missed medication are among the most commonly reported seizure precipitants. They are often combined, and various facets of the same underlying cause may be at play. Their sequence and relative impact are often difficult to establish. Improved understanding of the cascade of events preceding a seizure can improve comprehensive personalized management of uncontrolled epilepsy.

Sublingual lorazepam as rescue therapy for seizure emergencies in adults

ObjectiveLimited acute home treatments are available for patients with prolonged (>5 minutes) or repetitive (≥2 in 24 hours) seizures. While this early seizure treatment may reduce the need for emergency care, intermittent intranasal benzodiazepine formulations are expensive and rectal diazepam administration is often socially unacceptable. We determined whether caregivers could use sublingual lorazepam oral concentrate solution effectively as acute treatment for adults with prolonged and repetitive seizures. MethodsPatients prescribed sublingual lorazepam solution at the Johns Hopkins Epilepsy Center for acute seizure treatment during a 5-year period (2012–2017) were screened. We determined clinical history of seizure patterns and number of antiseizure medications (ASMs) through patient and caregiver surveys, and we verified this history in patients’ medical records and charts. During a 2-year span (2017–2018), patients and caregivers were surveyed on responses to their most recent use of sublingual lorazepam solution, including seizure cessation (prolonged seizure stopping <5 minutes or ≤1 repetitive seizure), presence of sedation and adverse events within 24 hours of administration, and whether refrigeration limited use. ResultsIn total, 52 patients used sublingual lorazepam for treatment of acute seizures during the study period (median dose 1 mg, range 0.5 to 2 mg). Of them, 48 patients participated in treatment survey interviews. Family caregivers usually administered lorazepam (88%); 3 self-administered. Patients were surveyed on responses to their most recent use of sublingual lorazepam treatment: 66% (23/35) of patients with repetitive seizures reported no further seizure activity after administering treatment; 70% (7/10) with prolonged seizures reported seizure activity ceased within 5 minutes of treatment. Three patients treated auras and had no seizures. There were no serious adverse events during most recent use: 31% of patients developed moderate/severe sedation. Of note, 98% refrigerated lorazepam, often with coolers; 44%, however, said this limited treatment access. There was high treatment satisfaction; 79% reported that having the emergency treatment available made them feel safer. SignificanceThis patient survey and retrospective chart review demonstrates that home treatment with sublingual lorazepam solution may be effective for interrupting prolonged and repetitive seizures. No patients had sedation complications with home doses of 0.5 to 2 mg, and patients report high satisfaction with the treatment.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.