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Resumen Objetivo La estereoelectroencefalografia (E-EEG) es una tecnica de evaluacion prequirurgica en pacientes con epilepsia focal refractaria de dificil localizacion (EFRDL) que permite explorar con electrodos profundos regiones cerebrales de dificil acceso y la profundidad de la corteza. Esta tecnica, en auge en centros internacionales, apenas se ha desarrollado en Espana. Describimos nuestra experiencia con la E-EEG en la evaluacion de pacientes con EFRDL. Material y metodos En los ultimos 8 anos, 71 pacientes con EFRDL fueron evaluados con E-EEG en nuestro centro. Analizamos prospectivamente los resultados obtenidos en la localizacion, los resultados quirurgicos y las complicaciones asociadas a la tecnica. Resultados La mediana de edad fue de 30 anos (rango 4-59 anos), 27 pacientes eran mujeres (38%). La RM cerebral fue negativa en 45 pacientes (63,4%). Se implantaron 627 electrodos (mediana de 9 electrodos por paciente, rango 1-17), con un 50% de implantaciones multilobares. En 64 (90,1%) pacientes se localizo la zona epileptogena (ZE), siendo extratemporal o temporal plus en el 66% de los casos. En 55 pacientes de los 61 intervenidos el seguimiento fue superior al ano: en el ultimo ano de seguimiento 32/55 pacientes (58,2%) estaban libres de crisis (Engel I) siendo los resultados favorables (Engel I-II) en el 76,4% de las intervenciones. Tres pacientes (4,2%) presentaron una hemorragia cerebral. Conclusion La E-EEG permite localizar la ZE en pacientes en quienes anteriormente no era posible, ofreciendo unos resultados quirurgicos superiores a otras tecnicas invasivas y una tasa de complicaciones relativamente baja.

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Background and objectives: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. Methods: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. Results: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. Discussion: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. Classification of evidence: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy., The MORE registry was sponsored and funded by Medtronic, plc.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms. ispartof: BRAIN vol:146 issue:4 ispartof: location:England status: Published online

PURPOSE: To assess the impact of fenfluramine (FFA) on the expected mortality incidence, including sudden unexpected death in epilepsy (SUDEP), in persons with Dravet syndrome (DS). METHODS: In this pooled analysis, total time of exposure for persons with DS who were treated with FFA in phase 3 clinical trials, in United States and European Early Access Programs, and in two long-term open-label observational studies in Belgium was calculated. Literature was searched for reports of SUDEP mortality in DS, which were utilized as a comparison. Mortality rates were expressed per 1000 person-years. RESULTS: A total of 732 persons with DS were treated with FFA, representing a total of 1185.3 person-years of exposure. Three deaths occurred, all in the phase 3 program: one during placebo treatment (probable SUDEP) and two during treatment with FFA (one probable SUDEP and one definite SUDEP). The all-cause and SUDEP mortality rates during treatment with FFA was 1.7 per 1000 person-years (95% CI, 0.4 to 6.7), a value lower than the all-cause estimate of 15.8 per 1000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported by Cooper et al. (Epilepsy Res 2016;128:43-7) for persons with DS receiving standard-of-care. CONCLUSION: All-cause and SUDEP mortality rates in DS patients treated with FFA were substantially lower than in literature reports. Further studies are warranted to confirm that FFA reduces SUDEP risk in DS patients and to better understand the potential mechanism(s) by which FFA lowers SUDEP risk. CLINICAL TRIAL REGISTRATION: NCT02926898, NCT02682927, NCT02826863, NCT02823145, NCT03780127. ispartof: SEIZURE-EUROPEAN JOURNAL OF EPILEPSY vol:93 pages:154-159 ispartof: location:England status: published

IntroductionPattern separation (PS) is a fundamental aspect of memory creation that defines the ability to transform similar memory representations into distinct ones, so they do not overlap when storing and retrieving them. Experimental evidence in animal models and the study of other human pathologies have demonstrated the role of the hippocampus in PS, in particular of the dentate gyrus (DG) and CA3. Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HE) commonly report mnemonic deficits that have been associated with failures in PS. However, the link between these impairments and the integrity of the hippocampal subfields in these patients has not yet been determined. The aim of this work is to explore the association between the ability to perform mnemonic functions and the integrity of hippocampal CA1, CA3, and DG in patients with unilateral MTLE-HE.MethodTo reach this goal we evaluated the memory of patients with an improved object mnemonic similarity test. We then analyzed the hippocampal complex structural and microstructural integrity using diffusion weighted imaging.ResultsOur results indicate that patients with unilateral MTLE-HE present alterations in both volume and microstructural properties at the level of the hippocampal subfields DG, CA1, CA3, and the subiculum, that sometimes depend on the lateralization of their epileptic focus. However, none of the specific changes was found to be directly related to the performance of the patients in a pattern separation task, which might indicate a contribution of various alterations to the mnemonic deficits or the key contribution of other structures to the function.Discussionwe established for the first time the alterations in both the volume and the microstructure at the level of the hippocampal subfields in a group of unilateral MTLE patients. We observed that these changes are greater in the DG and CA1 at the macrostructural level, and in CA3 and CA1 in the microstructural level. None of these changes had a direct relation to the performance of the patients in a pattern separation task, which suggests a contribution of various alterations to the loss of function.

OBJECTIVE The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life (QOL) for patients, caregivers, and families. Metrics are needed to assess whether patients with residual seizures have moved meaningfully toward seizure freedom after treatment with new antiseizure medications. METHODS We evaluated the time required postrandomization for each patient to experience the same number of seizures experienced during baseline (i.e., time-to-nth seizure), using a post hoc time-to-event (TTE) analysis of data from two Phase 3 placebo-controlled trials of adjunctive fenfluramine for DS (Study 1, N = 119; Study 2, N = 87). Patients aged 2-19 years were randomized to placebo or adjunctive fenfluramine (Study 1: .7 mg/kg/day or .2 mg/kg/day; Study 2: .4 mg/kg/day with stiripentol). Data were analyzed by Kaplan-Meier TTE curves and waterfall plots. RESULTS The proportion of patients who never reached baseline seizure frequency was greater with fenfluramine than with placebo (Study 1: fenfluramine .7 mg/kg/day, 60%; fenfluramine .2 mg/kg/day, 31%; placebo, 13%; Study 2: fenfluramine .4 mg/kg/day, 58%; placebo, 2%). Median time-to-nth seizure was longer after fenfluramine than after placebo (Study 1: fenfluramine .7 mg/kg/day, 13 weeks; .2 mg/kg/day, 10 weeks; placebo, 7 weeks; Study 2: fenfluramine .4 mg/kg/day, 13 weeks; placebo, 5 weeks; p

Objective Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. Methods Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. Results Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

To evaluate the effectiveness and tolerability of cannabidiol (CBD) in patients with developmental and epileptic encephalopathies, including Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS), in a Spanish Expanded Access Program (EAP).This was a multicenter, retrospective, observational study of patients treated with purified CBD in 14 hospitals across Spain. Patients with (1) written informed consent and (2) at least 6 months follow-up before the closure of the database were included. Primary effectiveness endpoints included reductions (100 %, ≥75 %, ≥50 %, ≥25 %, or 0 %) or worsening in seizure frequency (all seizure types and most disabling seizures) at 1-, 3-, 6-, and 12-month visits and at the last visit, and median relative seizure reduction between baseline and last visit. Secondary effectiveness endpoints included retention rate, reduction in seizure severity, status epilepticus, healthcare utilization, and quality of life. Primary safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation.One hundred and two patients (DS 12 %; LGS 59 %; other epilepsy syndromes 29 %) with a mean age of 15.9 years were enrolled. Patients were highly refractory to antiseizure medications (ASMs); mean number of prior failed ASMs was 7.5 (SD 3.7). The mean CBD dose was 13.0 mg/kg/day at the last visit. The proportion of patients with ≥50 % reduction in the total number of seizures from baseline was 44.9 % at 6 months and 38.9 % at 12 months. The median number of total seizures per month reduced by 47.6 % from baseline to the last visit. At 12 months, seizure severity was lower in 33/54 patients (61.1 %) and unchanged in 17/54 patients (31.5 %). Quality of life, based on the CAVE scale, increased from a mean score of 17.9 ± 4.7 (n = 54) at baseline to 21.7 ± 5.5 (n = 51) at the last patient visit (21.2 % improvement). The mean treatment retention time was 10.3 months. There were no statistically significant changes in the number of status epilepticus episodes, but lower healthcare utilization was observed. Adverse events occurred in sixty-eight patients (66.7 %), and the most common were somnolence (34.3 %) and diarrhea (12.7 %). Cannabidiol was discontinued exclusively due to AEs in 7.8 % of patients, increasing to 25.5 % when both lack of efficacy and AEs were considered together.Cannabidiol demonstrated promising effectiveness and tolerability in patients with developmental and epileptic encephalopathies taking part in a Spanish EAP.

Objective: \ud To examine the efficacy and safety of fenfluramine in patients with Dravet syndrome (DS) in three age groups

Aim: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. Method: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20–30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20–30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. Results: Seven participants (one female, six males; age range 5–23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. Interpretation: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. What this paper adds: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B 6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.

Over the last few decades the ILAE classifications for seizures and epilepsies (ILAE-EC) have been updated repeatedly to reflect the substantial progress that has been made in diagnosis and understanding of the etiology of epilepsies and seizures and to correct some of the shortcomings of the terminology used by the original taxonomy from the 1980s. However, these proposals have not been universally accepted or used in routine clinical practice. During the same period, a separate classification known as the "Four-dimensional epilepsy classification" (4D-EC) was developed which includes a seizure classification based exclusively on ictal symptomatology, which has been tested and adapted over the years. The extensive arguments for and against these two classification systems made in the past have mainly focused on the shortcomings of each system, presuming that they are incompatible. As a further more detailed discussion of the differences seemed relatively unproductive, we here review and assess the concordance between these two approaches that has evolved over time, to consider whether a classification incorporating the best aspects of the two approaches is feasible. To facilitate further discussion in this direction we outline a concrete proposal showing how such a compromise could be accomplished, the "Integrated Epilepsy Classification". This consists of five categories derived to different degrees from both of the classification systems: 1) a "Headline" summarizing localization and etiology for the less specialized users, 2) "Seizure type(s)", 3) "Epilepsy type" (focal, generalized or unknown allowing to add the epilepsy syndrome if available), 4) "Etiology", and 5) "Comorbidities & patient preferences".

IMPORTANCE: New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. OBJECTIVE: To evaluate the efficacy and safety of fenfluramine in patients with LGS. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. INTERVENTIONS: Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. MAIN OUTCOMES AND MEASURES: Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. RESULTS: A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. CONCLUSIONS AND RELEVANCE: Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03355209. ispartof: JAMA NEUROLOGY vol:79 issue:6 pages:554-564 ispartof: location:United States status: published

SCN8A-developmental and epileptic encephalopathy is caused by pathogenic variants in the SCN8A gene encoding the Na

This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

Perampanel, a selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, is a once-daily oral anti-seizure medication (ASM) for focal-onset seizures (FOS) and generalized tonic-clonic seizures (GTCS). In the US, perampanel is approved for the treatment of FOS (adjunctive and monotherapy), with or without focal to bilateral tonic-clonic seizures (FBTCS), in patients aged ≥4 years, and as adjunctive treatment of GTCS in patients aged ≥12 years. The monotherapy approvals in the US were based on the Food and Drug Administration's (FDA's) policy allowing extrapolation of adjunctive data to the monotherapy setting in the absence of randomized controlled monotherapy trials; since then, perampanel monotherapy has received approvals in approximately 48 countries. As there are key differences in clinical evidence of perampanel as adjunctive therapy vs monotherapy, we review the clinical outcomes of perampanel when administered as primary or secondary monotherapy. Eight publications reporting the efficacy and safety outcomes of perampanel monotherapy in clinical trial and real-world settings were selected during our literature search and are included; these comprise three Eisai-sponsored studies in patients with epilepsy: one prospective, open-label, Phase III clinical trial of patients with newly diagnosed epilepsy (Study 342 [FREEDOM]) and two retrospective, real-world Phase IV studies of patients with epilepsy who received perampanel during routine clinical care (Studies 504 and 506 [PROVE]); and five retrospective, real-world studies in patients with epilepsy who were prescribed perampanel during routine clinical care. Results from these studies demonstrated that seizure freedom may be achieved following treatment with perampanel monotherapy (either primary or secondary), with favorable retention rates and safety profiles. Overall, the clinical evidence supports the use of perampanel monotherapy both in newly diagnosed patients and in those who have been unable to control their seizures with other ASMs.

Purpose: There is scarce evidence of effective treatments for the chronic phase of Febrile infection-related epilepsy syndrome (FIRES). This study aimed to analyze the outcomes of treatment with anakinra and tocilizumab. Methods: Retrospective study including patients receiving either anti-interleukin-1 (anti-IL-1, anakinra) or anti IL-6 (tocilizumab) during the chronic phase of FIRES. We evaluated seizure outcomes, non-seizure comorbidities, and adverse events. Additionally, an indirect control group including patients during the chronic phase of FIRES non-treated with-IL therapies was evaluated. Results: Five patients were included; three females. Median age at FIRES: 8 years (IQR: 6???10). Five patients received anakinra; one patient switched to tocilizumab after ineffectiveness. Median treatment duration was 9months (IQR: 7???20). While no patients became seizure-free, 20???50% reduction in seizure frequency was reported in 3/5 patients after 6 months with anakinra. Retention rate was 100% at 6 months and 40% at 12months. Three patients reported reduced seizure intensity and rescue medication needed, and better behavior/communication. Similar improvement was reported for the patient switching to tocilizumab. Patients with the best response received anti-IL a median of 9 years after acute phase. All discontinuations were due to ineffectiveness. There were none relevant adverse events apart from one patient presenting transient seizure aggravation. Nine patients were included in the control group; none of them showed relevant improvement in seizure outcomes or cognitive/behavioral comorbidities. Only one presented mild improvement in seizure frequency during the 6 months follow-up. Conclusion: This study provides promising data on effectiveness/safety of anakinra and tocilizumab in the chronic phase of FIRES. These findings warrant prospective/larger studies.

ObjectiveThe appropriate management of patients with Dravet Syndrome (DS) is challenging, given the severity of symptoms and the burden of the disease for patients and caregivers. This study aimed to identify, through a qualitative methodology and a Delphi consensus-driven process, a set of recommendations for the management of DS to guide clinicians in the assessment of the clinical condition and quality of life (QoL) of DS patients, with a special focus on patient- and caregiver-reported outcomes (PROs).MethodsThis study was conducted in five phases, led by a multidisciplinary scientific committee (SC) including pediatric neurologists, epileptologists, a neuropsychologist, an epilepsy nurse, and members of DS patient advocates. In phases 1 and 2, a questionnaire related to patients' QoL was prepared and answered by caregivers and the SC. In phase 3, the SC generated, based on these answers and on a focus group discussion, a 70-item Delphi questionnaire, covering six topic categories on a nine-point Likert scale. In phase 4, 32 panelists, from different Spanish institutions and with a multidisciplinary background, answered the questionnaire. Consensus was obtained and defined as strong or moderate if ≥80% and 67–79% of panelists, respectively, rated the statement with ≥7. Phase 5 consisted of the preparation of the manuscript.ResultsThe panelists agreed on a total of 69 items (98.6%), 54 (77.14%), and 15 (21.43%) with strong and moderate consensus, respectively. The experts' recommendations included the need for frequent assessment of patient and caregivers QoL parameters. The experts agreed that QoL should be assessed through specific questionnaires covering different domains. Likewise, the results showed consensus regarding the regular evaluation of several clinical parameters related to neurodevelopment, attention, behavior, other comorbidities, and sudden unexpected death in epilepsy (SUDEP). A consensus was also reached on the instruments, specific parameters, and caregivers' education in the routine clinical management of patients with DS.ConclusionsThis consensus resulted in a set of recommendations for the assessment of clinical and QoL parameters, including PROs, related to the general evaluation of QoL, neurodevelopment, attention, behavior, other comorbidities affecting QoL, SUDEP, and QoL of caregivers/relatives and patients with DS.

Dr Fisher and colleagues have recently provided a commentary on our critique of the 2017 International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsies. The commentary was disappointing in that it did not depart from their original views and suggests a lack of engagement to consider an alternative framework that might improve the ILAE classifications of epileptic seizures and the epilepsies. Epileptologists actively dealing with people with epilepsy must provide feedback and express their views on any official ILAE position, as the latter would only be valid if it succeeds in striking a balance between the perspectives of any ILAE commission and that of the practitioners. It is evident that thoughtful critiques of ILAE position papers can only be forwarded once a text is published and their directions put into use, which is what we did in our critique, in an effort to achieve the best synthesis of accumulated knowledge that could result in a practical, useful, and forward-looking classification of epileptic seizures and the epilepsies.

Introduction Epilepsy is a serious neurological disease, ranking high in the top causes of disability. Approximately 40% of patients with epilepsy are pharmacoresistant after their seizures failed at least two antiseizure medications (ASMs). Adult patients experiencing focal-onset seizures (FOS) account for approximately 60% of all patients with epilepsy and they are more likely to become drug-resistant epilepsy (DRE) than those with generalized onset. Drug-resistant epilepsy is associated with mortality, morbidity, and reduced quality of life. The information available on the clinical management, health outcomes, and unmet needs of the disease within the Spanish healthcare environment is very limited. Multi-Criteria Decision Analysis (MCDA) allows determination of what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner and from the perspective of relevant stakeholders. Purpose The aim of this study was to identify the burden of DRE (clinical, quality of life, and economic) and the unmet needs in Spain and to determine what represents value in the treatment of FOS in DRE patients from the perspective of Spanish epileptologists. Methods The steps taken to carry out the MCDA were based on previously published good methodological practices. A systematic literature review (combining biomedical databases and gray literature sources) was performed between March and April 2020. Results were reviewed and validated with three epileptologists in June 2020 and used to develop a MCDA value framework, adapted for FOS in DRE, composed of 12 quantitative criteria and 3 contextual criteria. A group of six Spanish epileptologists from four Spanish regions were trained in MCDA methodology before individually validating value criteria (and their definitions based on literature review findings) and assigned relative weights using an ordinal 6-points scale. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results Drug-resistant epilepsy is considered a very severe health problem with important unmet needs affecting a considerably sized population. While safety and impact on quality of life of available ASMs are considered adequate, efficacy remains insufficient for patients to achieve seizure freedom and maintain it over time. Hence, the therapeutic benefit of pharmacological treatments currently used is regarded as suboptimal. Drug-resistant epilepsy management is associated with moderate pharmacological, relevant direct medical and high indirect costs. Quality of evidence available for current treatments is moderate. It is considered that DRE does not currently stand as a key priority for the Spanish healthcare system. Conclusions Drug-resistant epilepsy is considered a very severe health problem associated with relevant unmet needs. These include the lack of availability of specific treatment protocols, the need to improve early diagnosis by increasing the number of referrals to specialized epilepsy units and the availability of specific ASMs with improved efficacy and safety profiles, allowing to reach treatment objectives. Reflective MCDA provided a standardized, transparent approach to evaluate multiple criteria ascertaining what represents value from a holistic point of view and from the perspective of clinical experts, facilitating decision-making.

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 effi-cacy, safety and QoL when compared with available ASMs.(c) 2022 The Authors. Published by Elsevier Inc.

Objective To evaluate the impact of the coronavirus disease 2019 (COVID-19) measures on the lives and psychosocial well-being of persons with epilepsy (PWE) during the third trimester of the COVID-19 pandemic. Methods A structured questionnaire investigating different aspects of the lives and psychosocial well-being of PWE during the COVID-19 pandemic was developed. Persons with epilepsy were invited via social media to anonymously respond to a secure web-based online questionnaire ( www.icpcovid.com ). Responses were collected between July 26th and December 3rd, 2020. Hospital anxiety and depression scales (HADS) were used to screen respondents for depression (HADS-D) and anxiety (HADS-A). Results Responses of 407 PWE were included in the analysis; 304 (74.7%) respondents were female and 245 (60.2%) living in Europe, 157 (38.6%) in South America, and 5 (1.2%) in Canada. Seventy-six (18.7%) reported a decrease of income during the COVID-19 lockdown, and 122 (30.0%) experienced difficulties in obtaining anti-seizure medication (ASM), mostly (72/122, 59.0%) due to unavailability. Seizure frequency increased in 122 (30.0%); 295 (72.5%) screened positive for anxiety, and 159 (39.1%) for depression. Hundred eighty-eight (46.2%) reported reluctance to seek medical care; 27.3% believed that epilepsy was associated with an increased risk of COVID-19 disease. Forty-six (74.2%) of 62 PWE who were followed up by telephone or video consult were satisfied with this consult. Fifty-five respondents, most (89.1%) of whom were from Europe, had also participated in a previous survey during the early months of the pandemic. In this subgroup, although there was no difference in prevalence of a positive screening for depression or anxiety, mean scores on HADS-A and HADS-D increased from 6.65 ± 3.99 to 7.27 ± 4.01 (p = 0.418), and from 5.84 ± 4.43 to 6.60 ± 4.45 (p = 0.371), respectively. Conclusions The COVID-19 pandemic continues to impact the psychosocial and somatic well-being of PWE. To minimize this impact, ensuring uninterrupted access to ASM is essential. Teleconsultations are valid alternatives for continued follow-up, but should include attention to psychosocial well-being. Persons with epilepsy should be more actively informed that epilepsy is not a risk factor for developing (more severe) COVID-19 disease.

Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for >12 months or >24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of -0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117-22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2-18 y/o; fenfluramine dose: 0.2-0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2-12 months; 128 were treated for >24 months. Relative to the reference population with DS, fenfluramine treatment for >12 months or for >24 months had minimal impact on height or weight over time as assessed by Zscore analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for >12 months (N = 262) had an estimated change in Z-score per year of -0.056 for height and -0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were -0.025 for height and -0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. Methods: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. Results: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 (+/- 19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 +/- 7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. Conclusion: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES. (C) 2020 Elsevier Inc. All rights reserved.

Teleneurology in Spain had not been implemented so far in clinical practice, except in urgent patients with stroke. Telemedicine was hardly used in epilepsy, and patients and neurologists usually preferred onsite visits. Our goal was to study impressions of adult and pediatric epileptologists about the use of telemedicine after emergent implementation during the new coronavirus 2019 (COVID-19) pandemic. Methods An online survey was sent to the members of the Spanish Epilepsy Society and the members of the Epilepsy Study Group of the Catalan Neurological Society, inquiring about different aspects of telemedicine in epilepsy during the pandemic lockdown. Results A total of 66 neurologists responded, mostly adult neurologists (80.3%), the majority with a monographic epilepsy clinic (4 out of 5). Of all respondents, 59.1% reported to attend more than 20 patients with epilepsy (PWE) a week. During the pandemic, respondents handled their epilepsy clinics mainly with telephone calls (88%); only 4.5% used videoconference. Changes in antiseizure medications were performed less frequently than during onsite visits by 66.6% of the epileptologists. Scales were not administered during these visits, and certain types of information such as sudden expected unrelated death in epilepsy (SUDEP) were felt to be more appropriate to discuss in person. More than 4 out of 5 of the neurologists (84.8%) stated that they would be open to perform some telematic visits in the future. Conclusions In Spain, emergent implantation of teleneurology has shown to be appropriate for the care of many PWE. Technical improvements, extended use of videoconference and patient selection may improve results and patient and physician satisfaction.

We hypothesized that epilepsy associated with temporal pole encephaloceles (ETPE) could be the consequence and an unrecognized manifestation of idiopathic intracranial hypertension (IIH). To test this hypothesis in patients with ETPEs we evaluated: 1) the frequency of two radiological signs of IIH and 2) whether these patients develop over time clinical manifestations suggestive of elevated intracranial pressure (ICP). Case-control study comparing two cardinal radiological signs of IIH pituitary gland height (PGH) and the diameter of the two optic nerve sheaths (ONS) between 29 patients with ETPEs (TPE group) and 29 patients with focal epilepsy of other etiologies (control group), adjusted by age, sex, body mass index (BMI), age at epilepsy onset and epilepsy duration. Analysis was performed using conventional and ordinal logistic regression. The measurements in both groups were compared with validated radiological criteria of IIH. Of the patients 17 (63%) in the TPE group had all three measurements over the cut-off values for IIH, while no patients in the control group had all three findings. The TPE group patients had lower PGH (3.2 ± 1.0 mm vs. 4.9 ± 1.3 mm, p

PCDH19-related epilepsy is usually refractory to current antiseizure medications (ASM), but seizures are easier to control especially after the second decade of life. Nonetheless, there is no evidence regarding the withdrawal of ASM in this clinical scenario. We aimed to evaluate the outcomes of attempts to discontinue ASM in seizure-free patients with PCDH19-related epilepsy.This survey was a cross-sectional study of patients with PCDH19-related epilepsy open between June 2019 and February 2020 and implemented in collaboration with international patient advocacy groups. Caregivers or patients were asked to fill out an anonymous questionnaire of clinical data about the attempts of ASM reduction.The survey received 42 unique responses with collected data of 77 attempts of ASM withdrawal. Median age at the ASM reduction was 10 years and mean duration of the previous seizure-free period was 35.8 months. Overall, 88.3 % had seizure recurrence (p 0.001). After seizure recurrence, the medication had to be increased above the previous ASM dose in 36.5 % and come back to the previous one in 25.4 % cases. 5.2 % did not become seizure-free again. Only 2.6 % cases had their ASM totally withdrawn. Patients without seizure recurrence were significantly older and showed longer seizure-free period (p 0.001).This pilot study in PCDH19-related epilepsy shows that the withdrawal of ASM seems to be associated with a high risk of seizure recurrence. Despite this novel methodology is useful for rare diseases, it has some limitations and biases. Additional studies are warranted in more extensive samples.

Purpose: Epilepsy patients consider driving issues to be one of their most serious concerns. Ideally, decisions regarding fitness to drive should be based upon thorough evaluations by specialists in epilepsy care. In 2009, an EU directive was published aiming to harmonize evaluation practices within European countries, but, despite these recommendations, whether all epileptologists use the same criteria is unclear. We therefore conducted this study to investigate routine practices on how epileptologists at European epilepsy centers evaluate fitness to drive.Methods: A questionnaire was sent to 63 contact persons identified through the European Epi-Care and the E-pilepsy network. The questionnaire addressed how fitness-to-drive evaluations were conducted, the involvement of different professionals, the use and interpretation of EEG, and opinions on existing regulations and guidelines.Results: The questionnaire was completed by 35 participants (56 % response rate). Results showed considerable variation regarding test routines and the emphasis placed on the occurrence and extent of epileptiform discharges revealed by EEG. 82 % of the responders agreed that there was a need for more research on how to better evaluate fitness-to-drive in people with epilepsy, and 89 % agreed that regulations on fitness to drive evaluations should be internationally coordinated.Conclusion: Our survey showed considerable variations among European epileptologists regarding use of EEG and how findings of EEG pathology should be assessed in fitness-to-drive evaluations. There is a clear need for more research on this issue and international guidelines on how such evaluations should be carried out would be of value.

Idiopathic photosensitive occipital lobe epilepsy (IPOE) is a syndrome that should be suspected in patients with seizures with occipital semiology, photosensitivity, and normal MRI. It should be distinguished from occipital epilepsy of unknown aetiology (cryptogenic) given the differences in management. We reviewed patients with occipital seizures which were investigated in our epilepsy unit during the last three years. Three patients were identified with features of IPOE and genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, and their clinical characteristics were analysed. We propose the term "idiopathic generalized epilepsy with occipital semiology" based on the significance of managing and treating this syndrome as a GGE.

Background Ring chromosome 20 (R20) syndrome is a chromosomal disorder characterized mainly by drug-resistant frontal lobe seizures, recurrent nonconvulsive status epilepticus (NCSE), and typical EEG features. The aim of this study was to investigate if this triad is common and specific to all patients with R20. Methods In this cross-sectional study (from 2000 to 2011), we selected patients who fulfilled at least two out of three criteria: drug-resistant frontal lobe seizures, recurrent NCSE, and characteristic electroencephalography (EEG) features. In all patients, diagnosis was based on karyotype analysis of at least 100 metaphases. Results We identified 36 patients who met at least two of the selected criteria: six patients (16.7%) with R20 and 30 (83.3%) without R20 (non-R20). All patients with R20 met all three criteria. Eleven (36.7%) patients without R20, however, also displayed the full triad. In 19 patients without R20 (63.3%), one of the three clinical features was missing: frontal lobe seizures were not resistant to antiepileptic drugs (AED) in four (13.3%), recurrent NCSE was missing in six (20%), and nine (30%) patients did not have typical EEG features. Based on this data, specificity was 63.3%, positive predictive value was 35.3%, and sensitivity and negative predictive values were 100%. Additionally, a review of all publications describing the R20 phenotype revealed that 81.98% of patients with R20 display the full electroclinical triad. Conclusions In our study, all patients with R20 displayed the three electroclinical characteristics. This is in line with previous reports (presenting high sensitivity and negative predictive value). However, these features can also be observed in other epilepsies and are not specific to R20. Our findings suggest that in the presence of the full triad of symptoms, karyotype analysis focused on chromosome 20 should be conducted.

Objective This study aimed to evaluate the access to advanced diagnostic tests in patients with epilepsy and intellectual disability, with special focus on genetics. Methods Patients with epilepsy and intellectual disability evaluated between 2016 and 2018 at the Epilepsy Unit of two hospitals in Madrid, Spain were included. The main inclusion criterion was an undetermined etiological diagnosis after clinical assessment, neuroimaging, and electroencephalogram (EEG). Results Two hundred and five patients with epilepsy and intellectual disability were evaluated, with 124 fulfilling the inclusion criteria (mean age: 33.9 years). Regarding the etiological workup, advanced neuroimaging, prolonged video-EEG, and any type of genetic test had been performed in 58%, 41%, and 40%, respectively. An etiological diagnosis was reached in 18.5%. The workup was considered incomplete in 67%. Variables that showed the strongest association with an incomplete diagnostic workup in the multivariate analysis were current age and seizure freedom. Conclusions Despite the multiple implications of modern diagnostic techniques, especially genetic testing, there is a large proportion of patients with epilepsy and intellectual disability who do not have access to them. Older age and seizure freedom seem to be associated with the highest diagnostic gap.

Background Surgery is a widely accepted treatment option for drug-resistant focal epilepsy. A detailed analysis of longitudinal postoperative seizure outcomes and use of antiepileptic drugs for different brain lesions causing epilepsy is not available. We aimed to analyse the association between histopathology and seizure outcome and drug freedom up to 5 years after epilepsy surgery, to improve presurgical decision making and counselling.Methods In this retrospective, multicentre, longitudinal, cohort study, patients who had epilepsy surgery between Jan 1, 2000, and Dec 31, 2012, at 37 collaborating tertiary referral centres across 18 European countries of the European Epilepsy Brain Bank consortium were assessed. We included patients of all ages with histopathology available after epilepsy surgery. Histopathological diagnoses and a minimal dataset of clinical variables were collected from existing local databases and patient records. The primary outcomes were freedom from disabling seizures (Engel class 1) and drug freedom at 1, 2, and 5 years after surgery. Proportions of individuals who were Engel class 1 and drug-free were reported for the 11 main categories of histopathological diagnosis. We analysed the association between histopathology, duration of epilepsy, and age at surgery, and the primary outcomes using random effects multivariable logistic regression to control for confounding.Findings 9147 patients were included, of whom seizure outcomes were available for 8191 (89.5%) participants at 2 years, and for 5577 (61.0%) at 5 years. The diagnoses of low-grade epilepsy associated neuroepithelial tumour (LEAT), vascular malformation, and hippocampal sclerosis had the best seizure outcome at 2 years after surgery, with 77.5% (1027 of 1325) of patients free from disabling seizures for LEAT, 74.0% (328 of 443) for vascular malformation, and 71.5% (2108 of 2948) for hippocampal sderosis. The worst seizure outcomes at 2 years were seen for patients with focal cortical dysplasia type I or mild malformation of cortical development (50.0%, 213 of 426 free from disabling seizures), those with malformation of cortical development-other (52.3%, 212 of 405 free from disabling seizures), and for those with no histopathological lesion (53.5%, 396 of 740 free from disabling seizures). The proportion of patients being both Engel class 1 and drug-free was 0-14% at 1 year and increased to 14-51% at 5 years. Children were more often drug-free; temporal lobe surgeries had the best seizure outcomes; and a longer duration of epilepsy was associated with reduced chance of favourable seizure outcomes and drug freedom. This effect of duration was evident for all lesions, except for hippocampal sclerosis.Interpretation Histopathological diagnosis, age at surgery, and duration of epilepsy are important prognostic factors for outcomes of epilepsy surgery. In every patient with refractory focal epilepsy presumed to be lesional, evaluation for surgery should be considered. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Objective To assess the effectiveness and tolerability of perampanel (PER) monotherapy in routine clinical practice for the treatment of focal onset and generalized tonic-clonic seizures (GTCS). Methods This multicenter, retrospective, observational study was conducted in patients aged >= 12 years treated with PER as primary monotherapy or converted to PER monotherapy by progressive reduction of background antiepileptic drugs. Outcomes included retention, responder, and seizure-free rate after 3, 6, and 12 months and tolerability throughout the follow-up. Results A total of 98 patients (mean age = 49.6 +/- 21.7 years, 51% female) with focal seizures and/or GTCS were treated with PER monotherapy for a median exposure of 14 months (range = 1-57) with a median dose of 4 mg (range = 2-10). The retention rates at 3, 6, and 12 months and last follow-up were 93.8%, 89.3%, 80.9%, and 71.4%, respectively. The retention rates according to the type of monotherapy (primary vs conversion) did not differ (log-rank P value = .57). Among the 98 patients, 61.2% patients had seizures throughout the baseline period, with a median seizure frequency of 0.6 seizures per month (range = 0.3-26). Responder rates at 3, 6, and 12 months were 79.6%, 70.1%, and 52.8%, respectively, and seizure freedom rates at the same points were 62.7%, 56.1%, and 41.5%. Regarding the 33 patients who had GTCS in the baseline period, 87.8% were seizure-free at 3 months, 78.1% at 6 months, and 55.1% at 12 months. Over the entire follow-up, PER monotherapy was generally well tolerated, and only 16% of patients discontinued PER due to adverse events (AEs). Female patients were found to be at a higher risk of psychiatric AEs (female vs male odds ratio = 2.85, 95% confidence interval = 1-8.33, P = .046). Significance PER demonstrated good effectiveness and a good safety profile when used as primary therapy or conversion to monotherapy at relatively low doses, in a clinical setting with patients with focal seizures and GTCS.

IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02926898

Importance Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, Setting, and Participants This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main Outcomes and Measures The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%;P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%;P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and Relevance Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial Registration ClinicalTrials.gov Identifier:NCT02224703

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (

Patients' education is the most relevant contributor to patient self-management of epilepsy. We aimed to assess the acquisition of knowledge after a semi-structured interview.We performed a quasi-experimental prospective study with a cohort of patients with epilepsy admitted for prolonged video electroencephalogram (VEEG). We measured patients' baseline knowledge with a 10-item true-false test (test A). Then, a qualified nurse carried out a semi-structured interview. We measured acquired knowledge with another 10-item true-false exam (test B), prior to VEEG discharge and after a 3- to 5-month follow-up, and we compared the difference between the scores in test A and test B. Finally, we conducted a satisfaction and suitability survey on the interview at follow-up.Thirty-two patients participated, half were women. Their median age was 39.5, and the median length of schooling was 14 years. The median time since epilepsy onset was 13 years, 75% had suffered tonic-clonic seizures. The median score on test A was 7, while the median score on test B was 8.5 (p 0.001) both at VEEG discharge and after follow-up. After the interview, 84.4% of participants reported that they were very satisfied with the information received; 87.5% stated that they had not previously heard about SUDEP (sudden unexpected dead in epilepsy); and 93.8% considered it important to receive detailed information about SUDEP.Patient education through a semi-structured comprehensive interview improves knowledge of patients with epilepsy about their disease. The calm atmosphere and the qualified nursing working at VEEG units make them an appropriate setting for talking about epilepsy and its risks, including SUDEP.

Objective To develop recommendations for the management of patients with primary or secondary generalized tonic-clonic seizures (GTCS) based on best evidence and experience. Methods The Delphi methodology was followed. A multidisciplinary panel of 10 experts was established, who defined the scope, users and preliminary recommendations. Systematic and narrative reviews of the current literature were performed to assess data on the risk of sudden unexpected death in epilepsy and the efficacy and safety of add-on therapy in patients with GTCS. Twenty-five definitive recommendations were generated which were then graded on a scale of 1 (totally disagree) to 10 (totally agree) by the experts and 45 neurologists. Consensus was reached if at least 70% of the participants applied a score of ≥7. Each recommendation was then assigned a level of evidence, a grade of agreement and a grade of recommendation. The entire process was supervised by an expert methodologist. Results Overall, 24 out of 25 recommendations achieved consensus. These included specific recommendations on diagnosis, evaluation and treatment. The recommendations also emphasized the importance of proper psychological evaluation and effective communication between patients and health professionals, and the importance of patient and family education and support. Significance The recommendations generated by this consensus can be used as a guide for the diagnosis and management of patients with GTCS.

Objective: This study was aimed to analyze the effectiveness of sodium channel blockers (SCBs) in CDKL5 deficiency disorder (CDD)-related epilepsy. Methods: A retrospective, observational study was performed, including patients with CDD diagnosis evaluated between 2016 and 2019 at three tertiary Epilepsy Centers. Demographic, electroclinical and genetic features, as well as ASM treatments and their outcomes were analyzed, with special focus on SCBs. Results: Twenty-one patients evaluated at three tertiary Epilepsy Centers were included, of which 19 presented with epilepsy (90.5%); all had pathogenic mutations of CDKL5. Six patients (31.6%) were classified as SCB responders (more than 50% reduction), four being currently seizure free (mean seizure-free period of 8 years). Most frequent SCB drugs were oxcarbazepine (OXC), carbamazepine (CBZ), and lacosamide (LCM). None of them presented relevant adverse events. In contrast, three patients showed seizure aggravation in the non-responder group. When comparing both groups, responders had statistically significant younger age at SCB treatment and epilepsy onset, higher proportion of focal epileptiform activity and less frequent history of West syndrome. Conclusions: The results of this study indicate that treatment with SCBs might be effective and safe in a subset of patients with CDD-related epilepsy. (C) 2021 Elsevier Inc. All rights reserved.

Following publication in 2014 of the International League Against Epilepsy (ILAE) official report changing the definition of epilepsy, a number of questions remain unresolved in regard to deciding when to start treatment and to the choice of a particular antiseizure medication (ASM). This study uses a Delphi method to update consensus among a panel of experts on the initiation of epilepsy treatment in order to provide insight regarding those questions. The study was undertaken in four phases. Firstly, a multi-center steering committee met to review relevant bibliography and to draft a questionnaire. Secondly, a panel of neurologists specialized in epilepsy was selected and convened. Thirdly, an online survey was carried out in two rounds. Fourthly, the final results were discussed at a face-to-face meeting of the steering committee to draw conclusions. The final questionnaire focused on three independent sections: the decision to commence ASM in different clinical situations, the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex (including childbearing potential), and the choice of initial monotherapy depending on comorbidity. In these two latter sections, fourteen ASMs approved for monotherapy use by the EMA and available in Spain were considered. Regarding the decision as to when to commence treatment, the results show agreement exists to initiate treatment following a first generalized tonic-clonic seizure or a focal seizure if the electroencephalography (EEG) reveals epileptiform activity, if the MRI reveals a lesion, or when it occurs in elderly patients. With respect to the choice of initial monotherapy depending on the type of epilepsy and the patient's age/sex profile, it is agreed to avoid valproic acid (VPA) in women with childbearing potential, with levetiracetam (LEV) and lamotrigine (LTG) being the preferable options in generalized epilepsy. In focal epilepsy, the options are broader, particularly in men, and include the most recent ASMs approved for monotherapy. In the elderly, LEV, lacosamide (LCM), eslicarbazepine acetate (ESL) and LTG are considered the most suitable drugs for initiating treatment. With regard to comorbidities, the recommendation is to avoid enzyme inducing ASMs, with LEV, the most recent ASMs approved for monotherapy and LTG being the preferred options. In conclusion, as the ILAE definition states, there are different situations that lead to treatment initiation after a first seizure. When choosing the first ASM, the type of epilepsy, childbearing potential and drug-drug interaction are key factors.

Introduccion. El cannabidiol (CBD) es uno de los componentes principales de la planta del cannabis que ha demostrado efecto ante las crisis epilepticas. Tras su desarrollo clinico, obtuvo su aprobacion por la Agencia Europea del Medicamento en septiembre de 2019 para el tratamiento de las crisis epilepticas asociadas con el sindrome de Lennox-Gastaut (SLG) y el sindrome de Dravet (SD), en combinacion con el clobazam (CLB), en pacientes a partir de los dos anos. Objetivo. Establecer unas recomendaciones de manejo del CBD derivado de la planta altamente purificado consensuadas por expertos espanoles en el tratamiento de la epilepsia para su uso en pacientes con SD y SLG, basandose en su experiencia clinica y en la evidencia cientifica. Desarrollo. Reunion de consenso de un grupo de cuatro neurologos y neuropediatras espanoles expertos en el manejo de la epilepsia asociada al SD y el SLG y con experiencia clinica en el uso de CBD. Se debatio sobre diferentes areas, incluyendo la posologia (dosis de inicio, pauta de escalada), la eficacia (valoracion de resultados e indicaciones para la suspension del tratamiento) y la seguridad (evaluacion, interacciones entre farmacos, manejo de efectos adversos). Conclusiones. Para optimizar el tratamiento con CBD, se recomienda una pauta lenta de escalada de dosis (de cuatro semanas o mas) hasta alcanzar la dosis maxima recomendada o el efecto deseado, reducir los farmacos anticrisis epilepticas concomitantes si aparecen efectos adversos por interacciones y mantener el tratamiento al menos seis meses si se tolera. La eficacia y la seguridad del CBD deben evaluarse de forma individual, considerando el beneficio y el riesgo para cada paciente.

Introduccion. Los sindromes de Dravet (SD) y Lennox-Gastaut (SLG) son dos sindromes epilepticos graves y de inicio en la edad pediatrica, refractarios al tratamiento, asociados a un notable incremento en las tasas de mortalidad y comorbilidades respecto a la poblacion general. Suponen un fuerte impacto en la vida de los pacientes y sus familiares, ya que los pacientes estan sometidos a multiples terapias farmacologicas (muchas sin indicacion especifica), con cambios frecuentes debido a la escasa eficacia y a los efectos adversos. Los especialistas que les atienden destacan las necesidades no cubiertas y la falta de tratamientos especificos, seguros y eficaces para un mejor manejo de la enfermedad. Desarrollo. Se ha reunido un grupo formado por cuatro neurologos especialistas en epilepsia para hacer una revision de la literatura cientifica y evaluar los resultados de eficacia y seguridad de la solucion oral de cannabidiol en el tratamiento de estos sindromes, tanto en ensayos clinicos aleatorizados como en diversos estudios observacionales. Conclusiones. El cannabidiol se situa como una terapia innovadora que permite un mejor control de las crisis epilepticas y comorbilidades del SD y el SLG; ademas, su eficacia y seguridad han sido evaluadas en mas de 700 pacientes. En los ensayos clinicos redujo significativamente el porcentaje de crisis convulsivas y de caida en comparacion con placebo en los pacientes con SD y SLG, respectivamente, y puede mejorar su calidad de vida y la de sus familiares. Los efectos adversos mas frecuentes fueron la somnolencia y la disminucion del apetito. Tambien se notificaron niveles elevados de aminotransferasas hepaticas, especialmente en pacientes tratados concomitantemente con acido valproico. Esta terapia podria permitir un mejor control de las crisis epilepticas asociadas a estas patologias.