Assessment of the Novel Anti-Seizure Potential of Validamycin A Using Zebrafish Epilepsy Model.

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures. Validamycin A (VA) is an antibiotic fungicide that inhibits trehalase activity and is widely used for crop protection in agriculture. In this study, we identified a novel function of VA as a potential anti-seizure medication in a zebrafish epilepsy model. Electroencephalogram (EEG) analysis demonstrated that VA reduced pentylenetetrazol (PTZ)-induced seizures in the brains of larval and adult zebrafish. Moreover, VA reduced PTZ-induced irregular movement in a behavioral assessment of adult zebrafish. The developmental toxicity test showed no observable anatomical alteration when the zebrafish larvae were treated with VA up to 10 µM within the effective range. The median lethal dose of VA in adult zebrafish was > 14,000 mg/kg. These results imply that VA does not demonstrate observable toxicity in zebrafish at concentrations effective for generating anti-seizure activity in the EEG and alleviating abnormal behavior in the PTZ-induced epileptic model. Furthermore, the effectiveness of VA was comparable to that of valproic acid. These results indicate that VA may have a potentially safer anti-seizure profile than valproic acid, thus offering promising prospects for its application in agriculture and medicine.

Ketogenic diet in pharmacoresistant epilepsies: a clinical nutritional assessment.

BACKGROUND: Epilepsies are among the most prevalent chronic neurological diseases, usually beginning in childhood. About 30% of children with epilepsies develop seizures that are difficult to control with medication. Recurrent epileptic seizures hinder diet intake, impairing the nutritional status. Although non-pharmacological interventions (e.g., ketogenic diet therapy) can improve epileptic seizure frequency, few studies analyzed their impact on the nutritional status of children and adolescents with epilepsies. OBJECTIVE: The aim was to evaluate the effects of a ketogenic diet on the nutritional status and clinical course of patients with pharmacoresistant epilepsies. METHODS: This cross-sectional study included patients under 18 years of age followed up at the Ketogenic Diet Ambulatory Clinic of the Instituto de Medicina Integral Prof. Fernando Figueira between December 2015 and December 2021. Socioeconomic, clinical, nutritional, and laboratory data were collected from medical records at different time points during the ketogenic diet. RESULTS: The sample comprised 49 patients aged between 5 months and 17 years (median = 4.4 years), mostly male (62.1%), and from Recife and the metropolitan region (51%). Underweight patients (BMI-for-age) improved their nutritional status in six months. However, patients who were normal weight and overweight maintained their nutritional status. Dyslipidemia was a common and short-term adverse effect. Moreover, the treatment decreased epileptic seizure frequency and antiseizure medication intake. CONCLUSION: The ketogenic diet prevented malnutrition from worsening and reduced epileptic seizures and antiseizure medication intake.

ANTECEDENTES: A epilepsia, uma das doenças neurológicas crônicas mais prevalentes, tem geralmente início na infância. Cerca de 30% das crianças com epilepsia desenvolvem crises de difícil controle medicamentoso. As crises epilépticas recorrentes dificultam a ingestão alimentar, prejudicando o estado nutricional. Intervenções não farmacológicas, como a terapia com dieta cetogênica, podem melhorar a frequência das crises epilépticas, mas existem poucos estudos sobre a repercussão no estado nutricional da criança/adolescente. OBJETIVO: Avaliar o efeito da terapia cetogênica sobre o estado nutricional e a evolução clínica da epilepsia fármaco-resistente. MéTODOS: Estudo tipo corte transversal envolvendo menores de 18 anos acompanhados no Ambulatório de Dieta Cetogênica do Instituto de Medicina Integral Prof. Fernando Figueira entre dezembro de 2015 e dezembro de 2021. Dados socioeconômicos, clínicos, nutricionais e laboratoriais foram coletados nos prontuários dos pacientes em vários momentos da terapia cetogênica. RESULTADOS: A amostra foi composta por 49 pacientes com idades entre cinco meses e 17 anos (mediana = 4,4 anos), a maioria do sexo masculino (62,1%) e procedentes de Recife e região metropolitana (51%). Pacientes com baixo peso (de acordo com o IMC para idade) melhoraram seu estado nutricional em seis meses. No entanto, os pacientes com peso adequado e com sobrepeso mantiveram seu estado nutricional. A dislipidemia foi um efeito adverso frequente e de curta duração. Além disso, o tratamento reduziu a frequência de crises epilépticas e a dose de fármacos anticrises. CONCLUSãO: A dieta cetogênica preveniu o agravamento da desnutrição e reduziu as crises epilépticas e a dosagem de fármacos anticrises.

Treatment guidelines for rare, early-onset conditions associated with epileptic seizures: a literature review on Rett syndrome and tuberous sclerosis complex.

BACKGROUND: Rett syndrome (RTT) and tuberous sclerosis complex (TSC) are two rare disorders presenting with a range of different epileptic seizures. Seizure management requires careful therapy selection, thereby necessitating development of high-quality treatment guidelines. This targeted literature review (TLR) aimed to characterise country-specific and international treatment guidelines available for pharmacological management of seizures in RTT and TSC. METHODS: A TLR was performed between 25-Jan and 11-Mar 2021. Manual searches of online rare disease and guideline databases, and websites of national heath technology assessment bodies were conducted for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK, and US as defined by pre-specified eligibility criteria. Search terms were developed for each condition and translated into local languages where appropriate. Eligible publications were defined as guidelines/guidance reporting pharmacological management of seizures in patients with RTT and TSC. Guideline development methodology, geographical focus, author information and treatment recommendations were extracted from guidelines. An author map was generated using R version 3.5.1 to visualise extent of collaboration between authors. RESULTS: 24 total guidelines were included, of which three and six contained only recommendations for RTT and TSC, respectively (some provided recommendations for ≥ 1 condition). Guideline development processes were poorly described (50% [12 guidelines] had unclear/absent literature review methodologies); reported methodologies were variable, including systematic literature reviews (SLRs)/TLRs and varying levels of expert consultation. Most (83% [20/24]) were country-specific, with guideline authors predominantly publishing in contained national groups; four guidelines were classified as 'International,' linking author groups in the US, UK, Italy and France. High levels of heterogeneity were observed in the availability of treatment recommendations across indications, with 13 and 67 recommendations found for RTT and TSC, respectively. For RTT, all treatment recommendations were positive and sodium valproate had the highest number of positive recommendations (Khwaja, Sahin (2011) Curr Opin Pediatr 23(6):633-9). All TSC treatments (21 medications) received either exclusively negative (National Organization for Rare Disorders (2019)) or positive (Chu-Shore et al. (2010) Epilepsia 51(7):1236-41) recommendations; vigabatrin received the highest number of positive recommendations (Kaur, Christodoulou (2019)). CONCLUSIONS: This review highlights the need for the development of international high-quality and comprehensive consensus-based guidance for the management of seizures with pharmacological therapy in RTT and TSC. TRIAL REGISTRATION: Not applicable.

A comprehensive assessment of palmatine as anticonvulsant agent - In vivo and in silico studies.

Previously, we demonstrated that palmatine (PALM) - an isoquinoline alkaloid from Berberis sibrica radix, exerted antiseizure activity in the pentylenetetrazole (PTZ)-induced seizure assay in larval zebrafish. The aim of the present study was to more precisely characterize PALM as a potential anticonvulsant drug candidate. A range of zebrafish and mouse seizure/epilepsy models were applied in the investigation. Immunostaining analysis was conducted to assess the changes in mouse brains, while in silico molecular modelling was performed to determine potential targets for PALM. Accordingly, PALM had anticonvulsant effect in ethyl 2-ketopent-4-enoate (EKP)-induced seizure assay in zebrafish larvae as well as in the 6 Hz-induced psychomotor seizure threshold and timed infusion PTZ tests in mice. The protective effect in the EKP-induced seizure assay was confirmed in the local field potential recordings. PALM did not affect seizures in the gabra1a knockout line of zebrafish larvae. In the scn1Lab-/- zebrafish line, pretreatment with PALM potentiated seizure-like behaviour of larvae. Repetitive treatment with PALM, however, did not reduce development of PTZ-induced seizure activity nor prevent the loss of parvalbumin-interneurons in the hippocampus of the PTZ kindled mice. In silico molecular modelling revealed that the noted anticonvulsant effect of PALM in EKP-induced seizure assay might result from its interactions with glutamic acid decarboxylase and/or via AMPA receptor non-competitive antagonism. Our study has demonstrated the anticonvulsant activity of PALM in some experimental models of seizures, including a model of pharmacoresistant seizures induced by EKP. These results indicate that PALM might be a suitable new drug candidate but the precise mechanism of its anticonvulsant activity has to be determined.

E = mc2 : Education (E), medication (m), and conditional cash (c2 ) to improve uptake of antiseizure medications in a low-resource population: Protocol for randomized trial.

OBJECTIVE: Most people with epilepsy (PWE) could live seizure-free if treated with one or more antiseizure medications (ASMs). The World Health Organization (WHO) estimates that 75% of PWE in low-resource settings lack adequate antiseizure treatment. Limited education surrounding epilepsy and the out-of-pocket costs of ASMs in particular pose barriers to managing epilepsy in resource-poor, low-income settings. The aim of this study is to implement and test a novel strategy to improve outcomes across the epilepsy care cascade marked by (1) retention in epilepsy care, (2) adherence to ASMs, and (3) seizure reduction, with the measured goal of seizure freedom. METHODS: A randomized, double-blinded clinical trial will be performed, centered at the Ignace Deen Hospital in Conakry, Republic of Guinea, in Western Sub-Saharan Africa. Two hundred people with clinically diagnosed epilepsy, ages 18 years and above, will receive education on epilepsy and then be randomized to (i) free ASMs versus (ii) conditional cash, conditioned upon return to the epilepsy clinic. Participants will be followed for 360 days with study visits every 90 days following enrollment. SIGNIFICANCE: We design a randomized trial for PWE in Guinea, a low-resource setting with a high proportion of untreated PWE and a nearly completely privatized healthcare system. The trial includes a conditional cash transfer intervention, which has yet to be tested as a targeted means to improve outcomes for people with a chronic neurological disorder. The trial aims to provide an evidence base for the treatment of epilepsy in such settings. PLAIN LANGUAGE SUMMARY: We present a clinical trial protocol for a randomized, blinded study of 200 people with epilepsy in the low-resource African Republic of Guinea, providing an educational intervention (E), and then randomizing in a 1:1 allocation to either free antiseizure medication (m) or conditional cash (c2 ) for 360 days. Measured outcomes include (1) returning to outpatient epilepsy care, (2) adherence to antiseizure medications (ASMs), and (3) reducing the number of seizures. This study is an initial look at giving small amounts of cash for desired results (or "nudges") for improving epilepsy outcomes in the sub-Saharan African and brain disorder contexts.

Psychiatric and psychological assessment of Spanish patients with drug-resistant epilepsy and psychogenic nonepileptic seizures (PNES) with no response to previous treatments.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are common imitators of epileptic seizures. Refractoriness to antiseizure medication hinders the differential diagnosis between ES and PNES, carrying deleterious consequences in patients with PNES. Psychiatric and psychological characteristics may assist in the differential diagnosis between drug-resistant epilepsy (DRE) and PNES. Nevertheless, current comprehensive psychiatric and psychological descriptive studies on both patient groups are scarce and with several study limitations. This study provides a comprehensive psychiatric and psychological characterization of Spanish patients with DRE and PNES. METHOD: A cross-sectional and comparative study was completed with 104 patients with DRE and 21 with PNES. Psychiatric and psychological characteristics were assessed with the HADS, SCL-90-R, NEO-FFI-R, PDQ-4+, COPE, and QOLIE-31 tests. Parametric and non-parametric tests were used, and regression models were fit to further explore factors affecting patients' life quality. RESULTS: Patients with PNES had greater levels of somatization and extraversion and were associated with benzodiazepine intake. Patients with DRE showed greater narcissistic personality disorder symptoms than those with PNES. In patients with DRE, difficulty in performing basic needs-related tasks and greater psychological distress severity and seizure frequency were associated with poorer life quality. In contrast, being a woman, having a psychiatric disorder history, and greater psychiatric symptoms' intensity were associated with poorer life quality in patients with PNES. CONCLUSION: Patients with DRE and PNES share similar psychiatric and psychological characteristics, with only very few being significantly different.

Assessment of First-line Therapy With Midazolam for Prehospital Seizures in Children.

This cohort study assesses the effectiveness of midazolam treatment in terminating pediatric seizures in the prehospital setting.

Quantitative assessment of burst suppression as a predictor of seizure recurrence in refractory status epilepticus.

OBJECTIVE: To determine whether quantitative EEG analysis of burst suppression can predict seizure recurrence in patients with refractory status epilepticus (RSE) being treated with anesthetic doses of continuous IV antiseizure medications (cIVASM). METHODS: Quantitative assessment of burst suppression (including epileptiform discharges [EDs] and evolution) in 31 occasions (from 27 patients), and correlation with seizure recurrence up to 48 hours post sedative wean. RESULTS: Occasions resulting in seizure recurrence (vs. no seizure recurrence) had lower burst (8.4 vs. 10.6 µV) and interburst interval (IBI) (4.2 vs. 4.8 µV) average amplitude, duration (bursts 2.8 vs. 3.6 s: IBIs 3.6 vs. 4.4 s); and burst total power (0.4 vs. 0.7 µV2). Bursts (0.86 vs. 0.60) and IBIs (0.28 vs. 0.07) with EDs, higher number of EDs within bursts (mean 2.1 vs. 1.4) and IBIs (0.6 vs. 0.2), and positive evolution measures all predicted seizure recurrence, although EDs had the greatest adjusted odds ratio on multivariate analysis. CONCLUSIONS: For patients in burst suppression, successful wean of cIVASM was not determined by classical burst suppression measures, but instead how "epileptiform" bursts and IBIs were, as determined by EDs in both bursts and IBIs and surrogates for evolution within bursts. SIGNIFICANCE: If confirmed, these objective measures could be used during clinical care to help determine when to wean cIVASM in patients with RSE.

Seizure severity assessment tools for adult epilepsy patients: A systematic review.

INTRODUCTION: Seizure outcomes from antiseizure medication (ASM) therapy can be measured across various domains using assessment tools. The available tools may contain an array of different components or items. Seizure severity assessment, as opposed to seizure frequency count may have been a more accurate measurement in determining the effectiveness of ASM therapy. This study aimed to review studies developing seizure severity assessment tools for adults with epilepsy, describe the development methods and validation, and compare the list of items in these tools. METHODS: The systematic search utilized established databases such as Scopus, Ovid, Web of Science, Medline, Wiley Online, and Cochrane Library. Studies published from inception to December 15, 2022, were selected. Publications describing the development of tools to measure seizure severity among adult epilepsy patients were included. Outcome measures including the tool's content, development methods, validity, and reliability assessments were compared. RESULTS: The search produced eight publications describing the development of eight seizure severity assessment tools. One of these tools is part of a multidimensional assessment of the overall impact of epilepsy. The frequently used method in the initial development was the qualitative method (n = 6) where two publications reanalyzed the items from previous studies. Face validity was the most common validation test conducted (n = 4). At least one reliability assessment was conducted for each of the tools, most commonly by the test-retest method (n = 6) and inter-rater reliability (n = 5). All of these tools cover the components of pre-ictal (warning/aura), ictal, and postictal (recovery) events. CONCLUSION: The identified tools described the assessment of seizure severity using various subscales. The emergence of new methods in quantifying seizure severity unfolds opportunities in discovering more comprehensive assessments of seizure severity in both clinical trials and daily clinical practice.

Cost-effectiveness of cenobamate for focal seizures in people with drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively. METHODS: We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses. RESULTS: In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators. SIGNIFICANCE: Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Status of epilepsy in the tropics: An overlooked perspective.

Epilepsy is one of the most common serious chronic neurological diseases affecting people of all ages globally. It is characterized by recurrent seizures. About 50 million people worldwide have epilepsy. Indubitably, people with epilepsy (PWE) may be without access to appropriate treatment. Many studies have examined the molecular mechanisms and clinical aspects of epilepsy; nonetheless, the treatment gap exists in some special areas. In the tropics, the specific geographical and ecological conditions and a lack of medical resources result in neglect or delay of diagnosis for PWE. Herein, we summarized the epidemiology of epilepsy in the tropics and discussed the disease burden and existing problems, aiming to offer a medical environment for patients in need and highlight the importance of reducing the epileptic disease burden in tropical countries.

miR-9a-5p expression is decreased in the hippocampus of rats resistant to lamotrigine: A behavioural, molecular and bioinformatics assessment.

The major obstacle in developing new treatment strategies for refractory epilepsy is the complexity and poor understanding of its mechanisms. Utilizing the model of lamotrigine-resistant seizures, we evaluated whether changes in the expression of sodium channel subunits are responsible for the diminished responsiveness to lamotrigine (LTG) and if miRNAs, may also be associated. Male rats were administered LTG (5 mg/kg) before each stimulation during kindling acquisition. Challenge stimulation following LTG exposure (30 mg/kg) was performed to confirm resistance in fully kindled rats. RT-PCR was used to measure the mRNA levels of sodium channel subunits (SCN1A, SCN2A, and SCN3A) and miRNAs (miR-155-5p, miR-30b-5p, miR-137-3p, miR-342-5p, miR-301a-3p, miR-212-3p, miR-9a-5p, and miR-133a-3p). Western blot analysis was utilized to measure Nav1.2 protein, and bioinformatics tools were used to perform target prediction and enrichment analysis for miR-9a-5p, the only affected miRNA according to the responsiveness to LTG. Amygdala kindling seizures downregulated Nav1.2, miR-137-3p, miR-342-5p, miR-155-5p, and miR-9a-5p as well as upregulated miR-212-3p. miR-9a-5p was the only molecule decreased in rats resistant to LTG. The bioinformatic assessment and disease enrichment analysis revealed that miR-9a-5p targets expressed with high confidence in the hippocampus are the most significantly associated with epilepsy. Due to the miR-9a-5p dysregulation, major pathways affected are neurotrophic processes, neurotransmission, inflammatory response, cell proliferation and apoptosis. Interaction network analysis identified LTG target SCN2A as interacting with highest number of genes regulated by miR-9-5p. Further studies are needed to propose specific genes and miRNAs responsible for diminished responsiveness to LTG. miR-9a-5p targets, like KCNA4, KCNA2, CACNB2, SCN4B, KCNC1, should receive special attention in them.

Does the presence of a specialist doctor reduce the burden of disease in people with epilepsy in low-resource settings? A comparison of two epilepsy clinics in rural Tanzania.

BACKGROUND: With an estimated lifetime prevalence of epilepsy of 7.6 per 1,000 people, epilepsy represents one of the most common neurological disorders worldwide, with the majority of people with epilepsy (PWE) living in low-income and middle-income countries (LMICs). Adequately treated, up to 70 % of PWE will become seizure-free, however, as many as 85% of PWE worldwide, mostly from LMICs, do not receive adequate treatment. OBJECTIVE: To assess the impact of the presence of a neurologist on the management of PWE in Tanzania. METHODS: Two epilepsy clinics in rural Tanzania, one continuously attended by a neurologist, and one mainly attended by nurses with training in epilepsy and supervised intermittently by specialist doctors (neurologists/psychiatrists) were comparatively analyzed by multivariable linear and logistic regression models with regard to the outcome parameters seizure frequency, the occurrence of side effects of antiepileptic medication and days lost after a seizure. RESULTS: The presence of a neurologist significantly reduced the mean number of seizures patients experienced per month by 4.49 seizures (p < 0.01) while leading to an increase in the occurrence of reported side effects (OR: 2.15, p = 0.02). CONCLUSION: The presence of a neurologist may play a substantial role in reducing the burden of the disease of PWE in LMICs. Hence, specialist training should be encouraged, and relevant context-specific infrastructure established.

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment.

BACKGROUND: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. METHODS: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 µg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. RESULTS: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. CONCLUSIONS: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. TRIAL REGISTRATION: NCT, NCT03400917 , Registered 10 January 2018.

Comparative economic outcomes in patients with focal seizures initiating eslicarbazepine acetate versus brivaracetam in the long-term care setting in the USA.

Aim: To compare all-cause and epilepsy-specific pharmacy and total costs associated with initiation of eslicarbazepine acetate (ESL) or brivaracetam (BRV) among patients with focal seizures in long-term care (LTC) in the US. Methods: This retrospective analysis used data from IQVIA's New Data Warehouse. Results: 298 patients initiated ESL and 282 patients initiated BRV. Initiation of ESL versus BRV was associated with 33.3% lower all-cause pharmacy costs, 34.4% lower epilepsy-specific pharmacy costs, 21.3% lower all-cause total costs and 30.9% lower epilepsy-specific total costs (all p < 0.0001). Conclusion: Among patients with focal seizures in LTC in the US, initiation of ESL versus BRV was associated with significant reductions in all-cause and epilepsy-specific pharmacy and total costs compared with initiation of BRV.

Assessment of the long-term efficacy and safety of adjunctive perampanel in adolescent patients with epilepsy: Post hoc analysis of open-label extension studies.

OBJECTIVE: This post hoc analysis of four open-label extension (OLEx) studies evaluated the long-term efficacy and safety of adjunctive perampanel in adolescent patients (aged 12 to ≤17 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). METHODS: Patients who completed one of six double-blind, placebo-controlled studies could enter one of four OLEx studies comprising a blinded Conversion Period (6-16 weeks) followed by a Maintenance Phase (27 to ≤256 weeks; perampanel dose: ≤12 mg/day). Exposure, retention, seizure outcomes, and treatment-emergent adverse events (TEAEs) were analyzed. Efficacy outcomes were analyzed using observed case and last observation carried forward (LOCF) approaches; the latter was used to account for early dropouts. RESULTS: The Full Analysis Set comprised 309 adolescents with FOS (FBTCS, n = 109) and 19 with GTCS, and the Safety Analysis Set comprised 311 with FOS (FBTCS, n = 110) and 19 with GTCS. Mean (standard deviation) cumulative duration of perampanel exposure (weeks) was: FOS, 77.7 (58.7); FBTCS, 88.7 (63.8); and GTCS, 97.0 (35.5). Retention rates were maintained for ≤2 years (FOS, 50.0 %; FBTCS, 57.1 %; GTCS, 41.7 %). Seizure control (median percent reduction in seizure frequency/28 days) was sustained for up to 2 years; FOS (59.4 %, n = 113), FBTCS (64.6 %, n = 53), and GTCS (86.5 %, n = 17). At Year 2, 50 % responder rates were: FOS, 58.4 % (n = 66); FBTCS, 54.7 % (n = 29); and GTCS, 82.4 % (n = 14); seizure-freedom rates were: FOS, 5.3 % (n = 6); FBTCS, 24.5 % (n = 13); and GTCS, 35.3 % (n = 6). Long-term seizure control was observed even in LOCF analyses. The incidence of TEAEs was highest during Year 1 (FOS, n = 269 [86.5 %]; FBTCS, n = 95 [86.4 %]; GTCS, n = 15 [78.9 %]), compared with Years 2-4; the most common (≥10 % of patients) were dizziness, somnolence, and nasopharyngitis. No new safety signals emerged with long-term treatment. CONCLUSIONS: This post hoc analysis suggests that long-term (≤2 years) adjunctive perampanel (≤12 mg/day) is efficacious and generally well tolerated in adolescent patients with FOS, with or without FBTCS, or GTCS.

Economic aspects of treating seizure clusters.

Seizure clusters may initiate a chain of events that have economic as well as clinical consequences. The potential economic consequences of seizure clusters must be weighed against the cost of medication to attenuate them. This is true both for individual patients and for society. Data needed for economic analyses include the chance that a cluster will progress to an adverse outcome, such as a need for emergency care, the costs of such an outcome, the cost of a rescue medication (RM), and the effectiveness of the RM. Indirect costs, such as lost employment for patients and caregivers, must also be considered. Several types of economic analyses can be used to determine costs and benefits of a medical intervention. There are studies comparing different RMs from an economic perspective, but there is little direct information on the costs of using an RM versus allowing clusters to run their course. However, the high expense of consequences of seizure clusters makes it likely that effective RMs will make economic as well as medical sense for many patients.

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

BACKGROUND AND OBJECTIVE: Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. METHODS: Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate. RESULTS: The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. CONCLUSIONS: The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

The contribution of fenfluramine to the treatment of Dravet syndrome in Spain through Multi-Criteria Decision Analysis.

INTRODUCTION: Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles. Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL). Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA. METHOD: A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence. CONCLUSIONS: Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of efficacy, safety and QoL when compared with available ASMs.

Quality of life and mood assessment in conservatively treated cavernous malformation-related epilepsy.

BACKGROUND: To estimate the quality of life, anxiety, depression, and illness perception in patients with medically treated cerebral cavernous malformation (CCM) and associated epilepsy. METHODS: Nonsurgically treated patients with CCM-related epilepsy (CRE) were included. Demographic, radiographic, and clinical features were assessed. All participants received established questionnaires (short-form 36 health survey, SF-36; hospital anxiety and depression score, HADS-A/D; visual analogue scale score, VAS) assessing the functional and psychosocial burden of disease. To some extent, calculated values were compared with reference values from population-based studies. Test results were related to seizure control. RESULTS: A total of 37 patients were included. Mean age was 45.8 ± 14.4 years, and 54.1% were female. Diagnosis of CRE was significantly associated with attenuated quality of life and increased level of anxiety, affecting physical and psychosocial dimensions. The assessment of illness perception identified considerable burden. HADS was significantly associated with VAS and SF-36 component scores. Efficacy of antiepileptic medication had no restoring impact on quality of life, anxiety, depression, or illness perception. CONCLUSIONS: CRE negatively influences quality of life and mood, independent of seizure control due to antiepileptic medication. Screening for functional and psychosocial deficits in clinical practice might be useful for assessing individual burden and allocating surgical or drug treatment.