Search

Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy., Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses., Results: A total of 236 subjects with a median age of 38 (Q 1 -Q 3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q 1 -Q 3  = 2.50-4.47) at baseline to 2.50 (Q 1 -Q 3  = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel., Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: Despite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile., Methods: The Italian BLESS ("Cenobamate in Adults With Focal-Onset Seizures") study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available., Results: Forty participants with a median age of 36.5 (interquartile range [IQR] 26.0-47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5-17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1-80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2-3) at baseline to 2 (IQR 2-3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate., Conclusion: In adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs., Trial Registration Number: NCT05859854 (ClinicalTrials.gov Identifier)., (© 2024. The Author(s).)

Introduction: High-density EEG (hdEEG) is a validated tool in presurgical evaluation of people with epilepsy. The aim of this national survey is to estimate diffusion and knowledge of hdEEG to develop a network among Italian epilepsy centers., Methods: A survey of 16 items (and 15 additional items) was distributed nationwide by email to all members of the Italian League Against Epilepsy and the Italian Society of Clinical Neurophysiology. The data obtained were analyzed using descriptive statistics., Results: A total of 104 respondents were collected from 85 centers, 82% from the Centre-North of Italy; 27% of the respondents had a hdEEG. The main applications were for epileptogenic focus characterization in the pre-surgical evaluation (35%), biomarker research (35%) and scientific activity (30%). The greatest obstacles to hdEEG were economic resources (35%), acquisition of dedicated personnel (30%) and finding expertise (17%). Dissemination was limited by difficulties in finding expertise and dedicated personnel (74%) more than buying devices (9%); 43% of the respondents have already published hdEEG data, and 91% of centers were available to participate in multicenter hdEEG studies, helping in both pre-processing and analysis. Eighty-nine percent of respondents would be interested in referring patients to centers with established experience for clinical and research purposes., Conclusions: In Italy, hdEEG is mainly used in third-level epilepsy centers for research and clinical purposes. HdEEG diffusion is limited not only by costs but also by lack of trained personnel. Italian centers demonstrated a high interest in educational initiatives on hdEEG as well as in clinical and research collaborations., (© 2023. Fondazione Società Italiana di Neurologia.)

The objective of this study was to validate a novel assay using the volumetric absorptive microsampling (VAMS) technique combined with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of the antiseizure medication perampanel in saliva and its clinical applicability in patients with epilepsy. VAMS tips were loaded with 30 μL of saliva and dried for 60 min. Analytes were extracted with methanol. The supernatant was evaporated under a gentle stream of nitrogen and reconstituted with 60 μL of methanol. Separation and quantification were achieved on a monolithic column connected to a mass spectrometer. Calibration curves were linear between 0.5 and 300 ng/mL. Intra- and inter-day accuracy was within 85.6-103.2% and intra-day and inter-day precision did not exceed 12.1%. Perampanel was stable in samples collected by VAMS and stored under different storage conditions. The VAMS-LC-MS/MS method was validated according to internationally accepted criteria and tested in patients with epilepsy who were receiving a combination of perampanel and other antiseizure medications. The method showed adequate bioanalytical performances, holding great potential as an alternative strategy to support domiciliary TDM in patients with epilepsy treated with perampanel according to the simplicity of sample collection.

The primary anatomical defect leading to periventricular nodular heterotopia occurs within the neural progenitors along the neuroepithelial lining of the lateral ventricles and results from a defect in the initiation of neuronal migration, following disruption of the neuroependyma and impaired neuronal motility. Growing evidence indicates that the FLNA -dependent actin dynamics and regulation of vesicle formation and trafficking by activation of ADP-ribosylation factors (ARFs) can play an important role in this cortical malformation. We report the first inherited variant of ARF1 in a girl with intellectual disability and periventricular nodular heterotopia who inherited the variant from the father with previously undiagnosed single nodular heterotopia and mild clinical expression. Additionally, both patients presented some features suggestive of hypohidrotic ectodermal dysplasia. These clinical features showed similarities to those of three previously reported cases with ARF1 missense variants, confirming that haploinsufficiency of this gene causes a recognisable neurological disorder with abnormal neuronal migration and variable clinical expressivity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study was to describe the electroclinical and prognostic characteristics, and to investigate the role of leukoaraiosis in outpatients with new-onset elderly focal epilepsy aged ≥60 years, referred to a tertiary epilepsy center between 2005 and December 31, 2020. Among the 720 patients who were referred to the center, we retrospectively selected 162 consecutive outpatients, with a first referral for recent-onset focal epilepsy of unknown cause (UC) or structural cause (SC), and collected a clinical and standard-Electroencephalogram (S-EEG), 24-h ambulatory EEG (A-EEG), and neuroimaging data. We also analyzed the seizure prognosis after titration of the first antiseizure medication (ASM). One hundred and four UC and 58 SC patients, followed up for 5.8 ± 5.3 years (mean ± SD), were included. Compared with the SC group, the patients with UC showed a predominance of focal seizures with impaired awareness (51.9% of cases) and focal to bilateral tonic-clonic seizures during sleep (25%); conversely, the SC group, more frequently, had focal to bilateral tonic-clonic seizures during wakefulness (39.6%) and focal aware seizures (25.8%) ( p < 0.0001). Oral or gestural automatisms were prevalent in UC epilepsy (20.2 vs. 6.9% in the SC group, p = 0.04). In UC compared to patients with SC, interictal epileptiform discharges showed a preferential temporal lobe localization ( p = 0.0007), low expression on S-EEG, and marked activation during deep Non-Rapid Eye Movement (NREM) sleep ( p = 0.003). An overall good treatment response was found in the whole sample, with a probability of seizure freedom of 68.9% for 1 year. The cumulative probability of seizure freedom was significantly higher in the UC compared with the SC group ( p < 0.0001). The prognosis was worsened by leukoaraiosis ( p = 0.012). In the late-onset focal epilepsy of unknown cause, electroclinical findings suggest a temporal lobe origin of the seizures. This group showed a better prognosis compared with the patients with structural epilepsy. Leukoaraiosis, per se , negatively impacted on seizure prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tartara, Micalizzi, Scanziani, Ballante, Paoletti and Galimberti.)

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by dominant variants in the Glial Fibrillary Acidic Protein gene. Three main classifications are currently used, the traditional one defined by the age of onset, and two more recent ones based on both clinical features at onset and brain MRI findings. In this study, we retrospectively included patients with genetically confirmed pediatric-onset AxD. Twenty-one Italian patients were enrolled, and we revised all their clinical and radiological data. Participants were divided according to the current classification systems. We qualitatively analyzed data on neurodevelopment and neurologic decline in order to identify the possible trajectories of the evolution of the disease over time. One patient suffered from a Neonatal presentation and showed a rapidly evolving course which led to death within the second year of life (Type Ia). 16 patients suffered from the Infantile presentation: 5 of them (here defined Type Ib) presented developmental delay and began to deteriorate by the age of 5. A second group (Type Ic) included patients who presented a delay in neuromotor development and started deteriorating after 6 years of age. A third group (Type Id) included patients who presented developmental delay and remained clinically stable beyond adolescence. In 4 patients, the age at last evaluation made it not possible to ascertain whether they belonged to Type Ic or Id, as they were too young to evaluate their neurologic decline. 4 patients suffered from the Juvenile presentation: they had normal neuromotor development with no or only mild cognitive impairment; the subsequent clinical evolution was similar to Type Ic AxD in 2 patients, to Id group in the other 2. In conclusion, our results confirm previously described findings about clinical features at onset; based on follow-up data we might classify patients with Type I AxD into four subgroups (Ia, Ib, Ic, Id). Further studies will be needed to confirm our results and to better highlight the existence of clinical and neuroradiological prognostic factors able to predict disease progression., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To develop and validate a pragmatic algorithm that classifies seizure types, to facilitate therapeutic decision-making., Methods: Using a modified Delphi method, five experts developed a pragmatic classification of nine types of epileptic seizures or combinations of seizures that influence choice of medication, and constructed a simple algorithm, freely available on the internet. The algorithm consists of seven questions applicable to patients with seizure onset at the age of 10 years or older. Questions to screen for nonepileptic attacks were added. Junior physicians, nurses, and physician assistants applied the algorithm to consecutive patients in a multicenter prospective validation study (ClinicalTrials.gov identifier: NCT03796520). The reference standard was the seizure classification by expert epileptologists, based on all available data, including electroencephalogram (EEG), video-EEG monitoring, and neuroimaging. In addition, physicians working in underserved areas assessed the feasibility of using the web-based algorithm in their clinical setting., Results: A total of 262 patients were assessed, of whom 157 had focal, 51 had generalized, and 10 had unknown onset epileptic seizures, and 44 had nonepileptic paroxysmal events. Agreement between the algorithm and the expert classification was 83.2% (95% confidence interval = 78.6%-87.8%), with an agreement coefficient (AC1) of .82 (95% confidence interval = .77-.87), indicating almost perfect agreement. Thirty-two health care professionals from 14 countries evaluated the feasibility of the web-based algorithm in their clinical setting, and found it applicable and useful for their practice (median = 6.5 on 7-point Likert scale)., Significance: The web-based algorithm provides an accurate classification of seizure types, which can be used for selecting antiseizure medications in adolescents and adults., (© 2021 International League Against Epilepsy.)

Background: The advent of next-generation sequencing (NGS) techniques in clinical practice led to a significant advance in gene discovery. We aimed to describe diagnostic yields of a "dynamic" exome-based approach in a cohort of patients with epilepsy associated with neurodevelopmental disorders., Methods: We conducted a retrospective, observational study on 72 probands. All patients underwent a first diagnostic level of a 135 gene panel, a second of 297 genes for inconclusive cases, and finally, a whole-exome sequencing for negative cases. Diagnostic yields at each step and cost-effectiveness were the objects of statistical analysis., Results: Overall diagnostic yield in our cohort was 37.5%: 29% of diagnoses derived from the first step analysis, 5.5% from the second step, and 3% from the third. A significant difference emerged between the three diagnostic steps ( p < 0.01), between the first and second ( p = 0.001), and the first and third ( p << 0.001). The cost-effectiveness plane indicated that our exome-based "dynamic" approach was better in terms of cost savings and higher diagnostic rate., Conclusions: Our findings suggested that "dynamic" NGS techniques applied to well-phenotyped individuals can save both time and resources. In patients with unexplained epilepsy comorbid with NDDs, our approach might maximize the number of diagnoses achieved.

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort., Competing Interests: FB has participated in clinical trials for GW Pharmaceuticals; received research grants, speaker fees or participated to advisory boards for Eisai, Cyberonics, UCB Pharma and Bial. MPC Canevini has participated advisory boards and/or received research fundings from UCB Pharma, Eisai, Italfarmaco, Cyberonics, Novartis, and the European Union. AC has received speaker fees by Eisai. CB has received speaker fees from Eisai, UCB Pharma, FB Health and Sandoz. Gd'O has served on the advisory board of Eisai. CG has received research grants and/or speaker fees from UCB Pharma, Eisai and Bial. TG received a speaker fee from GW Pharmaceuticals. RG has received consulting fees and speaker honoraria from Zogenix, Biomarin, UCB, Eisai, Novartis, GW Pharma, and Biocodex. OM has received consulting fees and speaker honoraria by Bial, Eisai, GW Pharmaceuticals and UCB Pharma. AL has received speaker's or consultancy fees from Eisai, Mylan, Sanofi, Bial, GW Pharmaceuticals and UCB Pharma. PP received speaker's fees from Eisai and UCB Pharma. AR received consulting fees from GW Pharmaceuticals. ER has received speaker fees and/or fundings and has participated in advisory boards for Eisai, Pfizer, GW Pharmaceuticals, UCB Pharma, Arvelle Therapeutics. NS has received grant support and fees for advisory board participation from GW Pharmaceuticals. PS developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016) and received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, Neuraxpharma; he also received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. ET has received speaker's fees from Eisai and Sandoz. AV received speaker's fees from Eisai, Italfarmaco, and GW Pharmaceuticals. MV received speaker's fees from Eisai and GW Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Iannone, Arena, Battaglia, Bisulli, Bonanni, Boni, Canevini, Cantalupo, Cesaroni, Contin, Coppola, Cordelli, Cricchiuti, De Giorgis, De Leva, De Rinaldis, d'Orsi, Elia, Galimberti, Morano, Granata, Guerrini, Lodi, La Neve, Marchese, Masnada, Michelucci, Nosadini, Pilolli, Pruna, Ragona, Rosati, Santucci, Spalice, Pietrafusa, Striano, Tartara, Tassi, Papa, Zucca, Russo, Mecarelli and The CBD LICE Italy Study Group.)

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies., Methods: Members of the European Reference Network for rare and complex epilepsies ( EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease., Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers., Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers., Competing Interests: Sameer M Zuberi has conducted randomized controlled trials for GW Pharma and Zogenix Ltd in patients with Dravet syndrome. He has participated in advisory boards for Zogenix, GW Pharma, Biocodex, and Encoded Genomics. Katarzyna Kotulska was supported by the 7th Framework Programme of European Commission within the Large‐scale Integrating Project EPISTOP (Proposal No: 602 391‐2; Proposal title: “Long term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex”; www.EPISTOP.eu) and the Polish Ministerial funds for science (years 2014‐2018) for the implementation of international co‐financed project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. All other authors have no conflict of interest related to this survey to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The study assessed the clinical response to add-on brivaracetam (BRV) in real-world practice by means of time-to-baseline seizure count methodology. Patients with focal epilepsy who were prescribed add-on BRV were identified. Primary endpoint was the time-to-baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three-hundred eighty-seven patients were included. The overall median time-to-baseline seizure count was 150 (95% confidence interval [CI] = 130-175) days. The median time-to-baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV-naive patients, 126 (95% CI = 105-150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128-291) days for patients who discontinued LEV due to adverse events (P = .002). The number of prior antiseizure medications (adjusted hazard ratio [ adj HR] = 1.07, 95% CI = 1.02-1.13, P = .009) and baseline monthly seizure frequency ( adj HR = 1.004, 95% CI = 1.001-1.008, P = .028) were independently associated with the primary endpoint. Add-on BRV improved seizure control in LEV-naive and LEV-prior patients. The time-to-baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs., (© 2020 International League Against Epilepsy.)

Background: Although therapeutic drug monitoring of antiepileptic drugs is typically based on the analysis of plasma samples, alternative matrices, such as dried plasma spots (DPSs), may offer specific advantages. The aims of this work were to (1) develop and validate a bioanalytical method for the quantitative determination of the second-generation antiepileptic drug perampanel in DPSs; (2) assess short- and long-term stability of perampanel in DPSs; and (3) test the clinical applicability of the developed method., Methods: Two hundred microliters of plasma were dispensed on a glass paper filter and dried. Glass paper filter discs were then inserted into clean tubes. After addition of the internal standard (ie, promethazine), the analytes were extracted with 5-mL methanol, dried at room temperature (23 ± 2°C), and reconstituted. Separation and quantification were achieved on 2 serial reverse-phase monolithic columns connected to an UV detector (λ = 320 nm)., Results: Calibration curves were linear in the validated concentration range (25-1000 ng/mL). Intraday and interday accuracy were in the range of 99.2%-111.4%, whereas intraday and interday precision (coefficient of variation) ranged from 2.8% to 8.6%. The lowest limit of quantitation was 25 ng/mL. The stability of the analyte in DPSs was assessed and confirmed under different storage conditions. Perampanel concentrations estimated in DPS samples from patients receiving therapeutic doses were equivalent to those measured in plasma samples., Conclusions: This simple method enables the quantitation of perampanel in DPSs with adequate accuracy, precision, specificity, and sensitivity. The short- and long-term stabilities of perampanel in DPSs are highly beneficial for sample shipment or storage at ambient temperature. Moreover, DPSs decreases the costs associated with storage and transportation compared with conventional wet samples.

Background: Perampanel, a new specific non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor antagonist, has been recently approved in the United States and the European Union for the adjunctive treatment of focal seizures and primary generalized tonic-clonic seizures associated with idiopathic generalized epilepsy. A positive relationship between plasma perampanel concentration and improvement in seizure control has been identified in regulatory trials, suggesting that therapeutic drug monitoring could be useful in optimizing clinical response in patients with epilepsy treated with perampanel. The development of a simple and broadly applicable method for measuring plasma perampanel concentrations is desirable to permit the use of TDM for this drug in clinical practice., Methods: A high-performance liquid chromatographic method with ultraviolet detection for the quantitative determination of perampanel in small aliquots of human plasma (200 μL) has been developed and validated. Sample preparation involves a simple precipitation step followed by solvent evaporation. High-performance liquid chromatographic separation is achieved on 2 reverse-phase monolithic columns in sequence connected to an ultraviolet detector (320 nm), using as mobile phase water/acetonitrile (60:40 vol/vol) mixed with 1 mL/L phosphoric acid, at a flow rate of 1.5 mL/min. Promethazine hydrochloride is used as internal standard., Results: Calibration curves were linear over a perampanel concentration range of 25-1000 ng/mL, with correlation coefficients equal or greater than 0.998 ± 0.001 and a limit of quantitation set at 25 ng/mL. Intra- and inter-day coefficients of variation did not exceed 7.4%, and the accuracy ranged from 96.4% to 113.3%. No interference was observed from commonly coprescribed drugs., Conclusions: The present assay is simple, specific, and cost effective with performance characteristics suitable for TDM use.

Purpose: To assess the prevalence of epileptic seizures, and antiepileptic drug (AED) use among nursing home elderly residents; to evaluate demographics, seizure characteristics, and seizure-related comorbidities associated with institutionalization; and to compare findings with a previous survey conducted 12 years earlier., Methods: Data on demographics, age at institutionalization, diagnoses, functional and cognitive status (Barthel Index and Mini Mental State Examination) and drug treatment were obtained by review of medical records of all individuals aged ≥ 60 years at 21 nursing homes. Data from individuals with a diagnosis of epileptic seizures and AED users were compared with non-seizure, non-AED individuals., Results: Among the 2163 individuals surveyed (79% females, age at observation 84.9 ± 7.8 years, mean ± SD), 278 (12.8%, vs 4.3% in the previous survey) received chronic AED treatment, including 174 who did not have a diagnosis of seizures. Of the 116 residents with a diagnosis of seizures (5.4%, vs 2.9% in the previous study), 104 were on AED treatment and were younger and had lower cognitive abilities, and a higher number of comorbidities and co-medications compared with non-AED-users. The most commonly prescribed AEDs in seizure individuals were phenobarbital (43.3%, vs 70% in the previous survey) and levetiracetam (27.9%, not available at the time of previous survey). At multivariate analysis, a diagnosis of seizures was found to be associated with younger age at the time of the survey, a history of neurological (cerebrovascular events, meningiomas) and non-neurological conditions (psoriasis and chronic bronchitis), and a lower MMSE score., Conclusions: The prevalence of seizures and AED use was higher than in our previous survey and more aligned with data from other countries. Seizures, AED use and co-morbidities were associated with earlier institutionalization. There were indicators of treatment being suboptimal in many cases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To assess the yield of interictal EEG spiking in standard and whole-night sleep EEGs in elderly subjects with recent-onset focal seizures compared to younger patients., Methods: Detection of interictal epileptiform abnormalities (IEAs) and rating of mean spike index (number of interictal discharges/minute) values for different sleep stages (NREM stages 1-2 and 3-4 and REM sleep) in standard EEG (S-EEG) and 24-h ambulatory EEG (A-EEG) at first referral in three groups of thirty consecutive outpatients [aged 20-39 (young), 40-59 (adults) and ⩾60years (elderly)], retrospectively selected according to a subsequent diagnosis of focal epilepsy of unknown cause, no sleep disorders or drugs or comorbidities affecting sleep and EEG., Results: Elderly subjects showed a lower rate of IEAs on S-EEG (p<0.01) but a higher propensity for spiking during deep NREM sleep, 11/30 showing IEAs exclusively during stages 3-4. Mean spike index showed a significant increase in IEAs between sleep stages 1-2 and 3-4 in the elderly subjects (p<0.001)., Conclusions: A significant association emerged between IEAs during deep sleep and age (p<0.001)., Significance: EEG recordings covering deep NREM sleep should be recommended when IEAs detection is needed to support a diagnosis of epilepsy in elderly subjects., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings.