Search

Your search keyword '"Perucca, E."' showing total 188 results
Start Over Author "Perucca, E." Publication Year Range Last 10 years
188 results on '"Perucca, E."'

1. Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy

Author

Mula, M, Borghs, S, Ferro, B, Zaccara, G, Dainese, F, Ferlazzo, E, Romigi, A, Gambardella, A, Perucca, E, Mula, M, Borghs, S, Ferro, B, Zaccara, G, Dainese, F, Ferlazzo, E, Romigi, A, Gambardella, A, and Perucca, E

Abstract

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who scr

Published
2024

2. Pharmacokinetics of d- and l-norfenfluramine following their administration as individual enantiomers in rats

Author

Erenburg, N, Hamed, R, Shaul, C, Barasch, D, Perucca, E, Bialer, M, Erenburg, N, Hamed, R, Shaul, C, Barasch, D, Perucca, E, and Bialer, M

Abstract

The effect of fenfluramine and norfenfluramine enantiomers in rodent seizure models and their correlation with the pharmacokinetics of d- and l-fenfluramine in rats have been reported recently. To complement these findings, we investigated the pharmacokinetics of d- and l- norfenfluramine in rat plasma and brain. Sprague-Dawley rats were injected intraperitoneally with 20 mg/kg and 1 mg/kg l- norfenfluramine. A 1 mg/kg dose of d-norfenfluramine was used because higher doses caused severe toxicity. The concentration of each enantiomer in plasma and brain was determined at different time points by liquid chromatography/mass spectrometry. Pharmacokinetic parameters were compared between norfenfluramine enantiomers, and with those reported previously for fenfluramine enantiomers after a 20 mg/kg, i.p., dose. All enantiomers were absorbed rapidly and eliminated, with half-lives ranging from 0.9 h (l-fenfluramine) to 6.1 h (l- norfenfluramine, 20 mg/kg) in plasma, and from 3.6 h (d-fenfluramine) to 8.0 h (l-fenfluramine) in brain. Brain-to-plasma concentration ratios ranged from 15.4 (d-fenfluramine) to 27.6 (d-norfenfluramine), indicating extensive brain penetration. The fraction of d- and l-fenfluramine metabolized to norfenfluramine was estimated to be close to unity. This work is part of ongoing investigations to determine the potential value of developing enantiomerically pure l-fenfluramine or l-norfenfluramine as follow-up compounds to the marketed racemic fenfluramine.

Published
2024

4. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions

Author

Riney, K, Bogacz, A, Somerville, E, Hirsch, E, Nabbout, R, Scheffer, IE, Zuberi, SM, Alsaadi, T, Jain, S, French, J, Specchio, N, Trinka, E, Wiebe, S, Auvin, S, Cabral-Lim, L, Naidoo, A, Perucca, E, Moshe, SL, Wirrell, EC, Tinuper, P, Riney, K, Bogacz, A, Somerville, E, Hirsch, E, Nabbout, R, Scheffer, IE, Zuberi, SM, Alsaadi, T, Jain, S, French, J, Specchio, N, Trinka, E, Wiebe, S, Auvin, S, Cabral-Lim, L, Naidoo, A, Perucca, E, Moshe, SL, Wirrell, EC, and Tinuper, P

Abstract

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.

Published
2022

5. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions

Author

Specchio, N, Wirrell, EC, Scheffer, IE, Nabbout, R, Riney, K, Samia, P, Guerreiro, M, Gwer, S, Zuberi, SM, Wilmshurst, JM, Yozawitz, E, Pressler, R, Hirsch, E, Wiebe, S, Cross, HJ, Perucca, E, Moshe, SL, Tinuper, P, Auvin, S, Specchio, N, Wirrell, EC, Scheffer, IE, Nabbout, R, Riney, K, Samia, P, Guerreiro, M, Gwer, S, Zuberi, SM, Wilmshurst, JM, Yozawitz, E, Pressler, R, Hirsch, E, Wiebe, S, Cross, HJ, Perucca, E, Moshe, SL, Tinuper, P, and Auvin, S

Abstract

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.

Published
2022

6. Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions

Author

Wirrell, EC, Nabbout, R, Scheffer, IE, Alsaadi, T, Bogacz, A, French, JA, Hirsch, E, Jain, S, Kaneko, S, Riney, K, Samia, P, Snead, OC, Somerville, E, Specchio, N, Trinka, E, Zuberi, SM, Balestrini, S, Wiebe, S, Cross, JH, Perucca, E, Moshe, SL, Tinuper, P, Wirrell, EC, Nabbout, R, Scheffer, IE, Alsaadi, T, Bogacz, A, French, JA, Hirsch, E, Jain, S, Kaneko, S, Riney, K, Samia, P, Snead, OC, Somerville, E, Specchio, N, Trinka, E, Zuberi, SM, Balestrini, S, Wiebe, S, Cross, JH, Perucca, E, Moshe, SL, and Tinuper, P

Abstract

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.

Published
2022

7. ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions

Author

Hirsch, E, French, J, Scheffer, IE, Bogacz, A, Alsaadi, T, Sperling, MR, Abdulla, F, Zuberi, SM, Trinka, E, Specchio, N, Somerville, E, Samia, P, Riney, K, Nabbout, R, Jain, S, Wilmshurst, JM, Auvin, S, Wiebe, S, Perucca, E, Moshe, SL, Tinuper, P, Wirrell, EC, Hirsch, E, French, J, Scheffer, IE, Bogacz, A, Alsaadi, T, Sperling, MR, Abdulla, F, Zuberi, SM, Trinka, E, Specchio, N, Somerville, E, Samia, P, Riney, K, Nabbout, R, Jain, S, Wilmshurst, JM, Auvin, S, Wiebe, S, Perucca, E, Moshe, SL, Tinuper, P, and Wirrell, EC

Abstract

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

Published
2022

8. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

Author

Zuberi, SM, Wirrell, E, Yozawitz, E, Wilmshurst, JM, Specchio, N, Riney, K, Pressler, R, Auvin, S, Samia, P, Hirsch, E, Galicchio, S, Triki, C, Snead, OC, Wiebe, S, Cross, JH, Tinuper, P, Scheffer, IE, Perucca, E, Moshe, SL, Nabbout, R, Zuberi, SM, Wirrell, E, Yozawitz, E, Wilmshurst, JM, Specchio, N, Riney, K, Pressler, R, Auvin, S, Samia, P, Hirsch, E, Galicchio, S, Triki, C, Snead, OC, Wiebe, S, Cross, JH, Tinuper, P, Scheffer, IE, Perucca, E, Moshe, SL, and Nabbout, R

Abstract

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laborato

Published
2022

9. Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development

Author

Bialer, M, Johannessen, S, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, White, HS, Bialer, M, Johannessen, S, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, and White, HS

Abstract

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.

Published
2022

10. Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy.

Author

Ghosh, C, Westcott, R, Perucca, E, Hossain, M, Bingaman, W, Najm, I, Ghosh, C, Westcott, R, Perucca, E, Hossain, M, Bingaman, W, and Najm, I

Abstract

Polytherapy with antiseizure medications (ASMs) is often used to control seizures in patients suffering from epilepsy, where about 30% of patients are pharmacoresistant. While drug combinations are intended to be beneficial, the consequence of CYP-dependent drug interactions on apoptotic protein levels and mitochondrial function in the epileptic brain remains unclear. We examined the interactions of ASMs given prior to surgery in surgically resected brain tissues and of three ASMs (lacosamide, LCM; oxcarbazepine, OXC; levetiracetam LEV) in isolated brain cells from patients with drug-resistant epilepsy (n = 23). We divided the patients into groups-those who took combinations of NON-CYP + CYP substrate ASMs, NON-CYP + CYP inducer ASMs, CYP substrate + CYP substrate or CYP substrate + CYP inducer ASMs-to study the 1) pro- and anti-apoptotic protein levels and other apoptotic signaling proteins and levels of reactive oxygen species (reduced glutathione and lipid peroxidation) in brain tissues; 2) cytotoxicity at blood-brain barrier epileptic endothelial cells (EPI-ECs) and subsequent changes in mitochondrial membrane potential in normal neuronal cells, following treatment with LCM + OXC (CYP substrate + CYP inducer) or LCM + LEV (CYP substrate + NON-CYP-substrate) after blood-brain barrier penetration, and 3) apoptotic and mitochondrial protein targets in the cells, pre-and post-CYP3A4 inhibition by ketoconazole and drug treatments. We found an increased BAX (pro-apoptotic)/Bcl-XL (anti-apoptotic) protein ratio in epileptic brain tissue after treatment with CYP substrate + CYP substrate or inducer compared to NON-CYP + CYP substrate or inducer, and subsequently decreased glutathione and elevated lipid peroxidation levels. Further, increased cytotoxicity and Mito-ID levels, indicative of compromised mitochondrial membrane potential, were observed after treatment of LCM + OXC in combination compared to LCM + LEV or these ASMs alone in EPI-ECs, which was attenuated by pre

Published
2022

11. The 50th anniversary of the Italian League Against Epilepsy Italiana Contro q

Author

Tassi, L, Specchio, N, Mecarelli, O, Tinuper, P, Vigevano, F, Perucca, E, Tassi, L, Specchio, N, Mecarelli, O, Tinuper, P, Vigevano, F, and Perucca, E

Abstract

This article was prepared to outline the article collection submitted on behalf of Lega Italiana Contro l'Epilepsia, or LICE, for the 50th anniversary of the founding of the ILAE Italian Chapter, and provides a brief summary of the history, with its landmark achievements and challenges. LICE is a multidisciplinary, inclusive, educational, informative and multifaceted organization. Initially in 1955 and then formally in 1972, LICE was born in Milano, with the mission to devote itself to people suffering with epilepsy and by promoting appropriate treatment and care, integration into society, to promote and pursue all kinds of activities designed to achieve those aims. The LICE is currently composed of more than 1000 members including neurologists, pediatric neurologists, neurosurgeons, neurophysiologists, and neuropsychologists who function throughout Italy dealing mainly or exclusively with the diagnosis and treatment of people with epilepsy.

Published
2022

13. Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): II. Drugs in more advanced clinical development

Author

Bialer, M, Johannessen, S, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, White, HS, Bialer, M, Johannessen, S, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, and White, HS

Abstract

The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older.

Published
2022

14. Declining malformation rates with changed antiepileptic drug prescribing: An observational study

Author

Tomson T., Battino D., Bonizzoni E., Craig J., Lindhout D., Perucca E., Sabers A., Thomas S. V., Vajda F., Bisulli F., Tinuper P., for the EURAP Study Group, Tomson T., Battino D., Bonizzoni E., Craig J., Lindhout D., Perucca E., Sabers A., Thomas S.V., Vajda F., Bisulli F., Tinuper P., and for the EURAP Study Group

Subjects
Pediatrics, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Medicina Clínica, EURAP, Lamotrigine, Epilepsia, 03 medical and health sciences, Epilepsy, Neurologia, 0302 clinical medicine, AED, purl.org/becyt/ford/3.2 [https], medicine, 030212 general & internal medicine, Medical prescription, Prospective cohort study, Valproic Acid, Pregnancy, business.industry, Neurología Clínica, Carbamazepine, medicine.disease, epilepsy, purl.org/becyt/ford/3 [https], sense organs, pregnancy, Neurology (clinical), Levetiracetam, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Objective Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). Methods EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000–2005 (n = 4,760), 2006–2009 (n = 3,599), and 2010–2013 (n = 2,949). Results There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000–2005 to 4.4% in 2010–2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy. Conclusions There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events. Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Battino, Dina. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Thomas, Sanjeev V.. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Vajda, Frank. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Kochen, Sara Silvia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina Fil: Craig, John. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Binozzoni, Erminio. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Lindhout, Dick. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Perucca, Emilio. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Sabers, Anne. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia

Published
2019

15. Does screening for adverse effects improve health outcomes in epilepsy? A randomized trial

Author

Franco, V., Canevini, M. P., De Sarro, G., Fattore, C., Fedele, G., Galimberti, C. A., Gatti, G., La Neve, A., Rosati, E., Specchio, L. M., Striano, S., Striano, P, Tinuper, P., Perucca, E., Franco V., Canevini M.P., De Sarro G., Fattore C., Fedele G., Galimberti C.A., Gatti G., La Neve A., Rosati E., Specchio L.M., Striano S., Tinuper P., and Perucca E.

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Adolescent, Drug-Related Side Effects and Adverse Reactions, Follow-Up Studie, law.invention, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Quality of life, Randomized controlled trial, Retrospective Studie, law, Internal medicine, Anticonvulsant, medicine, Humans, Mass Screening, Prospective Studies, Adverse effect, Mass screening, Aged, Retrospective Studies, Epilepsy, business.industry, Anticonvulsants, Female, Follow-Up Studies, Middle Aged, Treatment Outcome, medicine.disease, Clinical trial, Prospective Studie, 030104 developmental biology, Observational study, Neurology (clinical), Drug-Related Side Effects and Adverse Reaction, business, 030217 neurology & neurosurgery, Adverse drug reaction, Human, Cohort study
Abstract

ObjectiveTo determine whether systematic screening for adverse effects of antiepileptic drugs (AEDs) reduces toxicity burden and improves health-related quality of life in patients with epilepsy.MethodsConsecutive patients with uncontrolled seizures aged ≥16 years and a high Adverse Event Profile (AEP) score were randomized to 2 groups and followed up for 18 months at 11 referral centers. AEP scores were made available to treating physicians at all visits in the intervention group, but not in the control group. Co–primary endpoints were changes in AEP scores and Quality of Life Inventory for Epilepsy-31 (QOLIE–31) scores.ResultsOf 809 enrolled patients able to complete the AEP questionnaire, 222 had AEP scores ≥45 and were randomized to the intervention (n = 111) or control group (n = 111). A total of 206 patients completed the 18-month follow-up. Compared with baseline, AEP scores decreased on average by 7.2% at 6 months, 12.1% at 12 months, and 13.8% at 18 months in the intervention group (p < 0.0001), and by 7.7% at 6 months, 9.2% at 12 months, and 12.0% at 18 months in controls (p < 0.0001). QOLIE-31 scores also improved from baseline to final visit, with a mean 20.7% increase in the intervention group and a mean 24.9% increase in the control group (p < 0.0001). However, there were no statistically significant differences in outcomes between groups for the 2 co–primary variables.ConclusionsContrary to findings from a previous study, systematic screening for adverse effects of AEDs using AEP scores did not lead to a reduced burden of toxicity over usual physician treatment.Italian Medicines Agency (AIFA) identifierFARM52K2WM_003.Clinicaltrials.gov identifierNCT03939507 (registered retrospectively in 2019; the study was conducted during the 2006–2009 period and registration of clinical trials was not a widely established practice when this study was initiated).Classification of evidenceThis study provides Class II evidence that the additional collection of formal questionnaires regarding adverse effects of AEDs does not reduce toxicity burden over usual physician treatment.

Published
2019

16. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Paternal Age, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), medicine, Humans, Exome, Copy-number variation, Indel, business.industry, Confounding, Infant, Newborn, Abnormalities, Drug-Induced, Genetic Variation, DNA, medicine.disease, Genetic load, Exact test, Teratogens, 030104 developmental biology, Neurology, Anticonvulsants, Female, Neurology (clinical), Genetic Load, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0-7) vs 3 (1-5), p = 0.50]. Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved.

Published
2020

17. Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

Author

Bialer, M, Johannessen, SI, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, White, HS, Bialer, M, Johannessen, SI, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, and White, HS

Abstract

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL-865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo-controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.

Published
2020

18. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

Perucca, P, Anderson, A, Jazayeri, D, Hitchcock, A, Graham, J, Todaro, M, Tomson, T, Battino, D, Perucca, E, Ferri, MM, Rochtus, A, Lagae, L, Canevini, MP, Zambrelli, E, Campbell, E, Koeleman, BPC, Scheffer, IE, Berkovic, SF, Kwan, P, Sisodiya, SM, Goldstein, DB, Petrovski, S, Craig, J, Vajda, FJE, O'Brien, TJ, Perucca, P, Anderson, A, Jazayeri, D, Hitchcock, A, Graham, J, Todaro, M, Tomson, T, Battino, D, Perucca, E, Ferri, MM, Rochtus, A, Lagae, L, Canevini, MP, Zambrelli, E, Campbell, E, Koeleman, BPC, Scheffer, IE, Berkovic, SF, Kwan, P, Sisodiya, SM, Goldstein, DB, Petrovski, S, Craig, J, Vajda, FJE, and O'Brien, TJ

Abstract

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.

Published
2020

19. Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development

Author

Bialer, M, Johannessen, SI, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, White, HS, Bialer, M, Johannessen, SI, Koepp, MJ, Levy, RH, Perucca, E, Perucca, P, Tomson, T, and White, HS

Abstract

Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID-19 pandemic, the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference on July 27-30, 2020 for the sessions on drugs and on August 3, 2020 for the sessions on devices, and was attended during the 5 days by >500 participants from 63 countries. This progress report summarizes key preclinical and initial (phase 1) clinical data on eight investigational treatments that are currently in early development, including 2-deoxy-D-glucose, GAO-3-02, JNJ-40411813, NBI-921352, NTX-001, sec-butylpropylacetamide, XEN1101, and XEN496. This report provides an overview of current scenarios in the area of treatment discovery and development. The information presented illustrates a variety of innovative strategies, including exploration of compounds with novel mechanisms of action, transplantation of interneurons into epileptogenic brain regions, and the targeting of rare, previously neglected syndromes.

Published
2020

21. Classification as autonomic versus sensory seizures

Author

Fisher, RS, Cross, H, D'Souza, C, French, JA, Haut, S, Higurashi, N, Hirsch, E, Jansen, FE, Peltola, J, Moshe, SL, Perucca, E, Lagae, L, Roulet-Perez, E, Schulze-Bonhage, A, Scheffer, IE, Somerville, E, Sperling, MR, Wiebe, S, Yacubian, EM, Zuberi, S, Fisher, RS, Cross, H, D'Souza, C, French, JA, Haut, S, Higurashi, N, Hirsch, E, Jansen, FE, Peltola, J, Moshe, SL, Perucca, E, Lagae, L, Roulet-Perez, E, Schulze-Bonhage, A, Scheffer, IE, Somerville, E, Sperling, MR, Wiebe, S, Yacubian, EM, and Zuberi, S

Published
2019

22. 2017 International League Against Epilepsy classifications of seizures and epilepsy are steps in the right direction

Author

Fisher, RS, Cross, H, D'Souza, C, French, JA, Haut, S, Higurashi, N, Hirsch, E, Jansen, FE, Peltola, J, Moshe, SL, Perucca, E, Lagae, L, Roulet-Perez, E, Schulze-Bonhage, A, Scheffer, IE, Somerville, E, Sperling, MR, Wiebe, S, Yacubian, EM, Zuberi, S, Fisher, RS, Cross, H, D'Souza, C, French, JA, Haut, S, Higurashi, N, Hirsch, E, Jansen, FE, Peltola, J, Moshe, SL, Perucca, E, Lagae, L, Roulet-Perez, E, Schulze-Bonhage, A, Scheffer, IE, Somerville, E, Sperling, MR, Wiebe, S, Yacubian, EM, and Zuberi, S

Published
2019

23. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology

Author

Scheffer, IE, Berkovic, S, Capovilla, G, Connolly, MB, French, J, Guilhoto, L, Hirsch, E, Jain, S, Mathern, GW, Moshe, SL, Nordli, DR, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, Zuberi, SM, Scheffer, IE, Berkovic, S, Capovilla, G, Connolly, MB, French, J, Guilhoto, L, Hirsch, E, Jain, S, Mathern, GW, Moshe, SL, Nordli, DR, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, and Zuberi, SM

Published
2018

26. How long for epilepsy remission in the ILAE definition?

Author

Fisher, RS, Acevedo, C, Arzimanoglou, A, Bogacz, A, Cross, JH, Elger, CE, Engel, J, Forsgren, L, French, JA, Hesdorffer, DC, Lee, B-I, Mathern, GW, Moshe, SL, Perucca, E, Scheffer, IE, Tomson, T, Watanabe, M, Wiebe, S, Fisher, RS, Acevedo, C, Arzimanoglou, A, Bogacz, A, Cross, JH, Elger, CE, Engel, J, Forsgren, L, French, JA, Hesdorffer, DC, Lee, B-I, Mathern, GW, Moshe, SL, Perucca, E, Scheffer, IE, Tomson, T, Watanabe, M, and Wiebe, S

Published
2017

27. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

Author

Scheffer, IE, Berkovic, S, Capovilla, G, Connolly, MB, French, J, Guilhoto, L, Hirsch, E, Jain, S, Mathern, GW, Moshe, SL, Nordli, DR, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, Zuberi, SM, Scheffer, IE, Berkovic, S, Capovilla, G, Connolly, MB, French, J, Guilhoto, L, Hirsch, E, Jain, S, Mathern, GW, Moshe, SL, Nordli, DR, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, and Zuberi, SM

Abstract

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Published
2017

28. Classification of the epilepsies: New concepts for discussion and debate-Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology.

Author

Scheffer, IE, French, J, Hirsch, E, Jain, S, Mathern, GW, Moshé, SL, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, Zuberi, SM, Scheffer, IE, French, J, Hirsch, E, Jain, S, Mathern, GW, Moshé, SL, Perucca, E, Tomson, T, Wiebe, S, Zhang, Y-H, and Zuberi, SM

Abstract

The ILAE Task Force on Classification presents a road map for the development of an updated, relevant classification of the epilepsies. Our objective is to explain the process to date and the plan moving forward as well as to invite further discussion about the newly proposed terms and concepts. Here, we present our response to feedback about the 2010 Organization of the Epilepsies and clarify the reintroduction of the word "classification" to map out a framework for epilepsy diagnosis. We introduce some new concepts and suggest four diagnostic levels: seizure type, epilepsy category, epilepsy syndrome, and epilepsy with (specific) etiology to denote specific levels of diagnosis. We expand the etiological categories to six, focusing on those with treatment implications. Finally, we discuss the changes in terminology originally suggested and modifications in response to comments from the epilepsy community. We welcome feedback and discussion from the global epilepsy community, particularly for the new suggested terms, so that we can cement a classification that both reflects current thinking and scientific understanding and provides a dynamic, evolving framework.

Published
2016

29. Withdrawal of valproic acid treatment during pregnancy and seizure outcome: Observations from EURAP

Author

Tomson, T, Battino, D, Bonizzoni, E, Craig, J, Lindhout, D, Perucca, E, Sabers, A, Thomas, SV, Vajda, F, Tomson, T, Battino, D, Bonizzoni, E, Craig, J, Lindhout, D, Perucca, E, Sabers, A, Thomas, SV, and Vajda, F

Abstract

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study.

Published
2016

30. Current State Of International Epilepsy Guidelines

Author

Sauro, K., Wiebe, S., Pedley, T., Dunkley, C., Kumlien, Eva, Moshe, S., Nakasato, N., Perucca, E., Senties, H., Thomas, S., Wang, Y., Wilmshurst, J., Jette, N., Sauro, K., Wiebe, S., Pedley, T., Dunkley, C., Kumlien, Eva, Moshe, S., Nakasato, N., Perucca, E., Senties, H., Thomas, S., Wang, Y., Wilmshurst, J., and Jette, N.

Published
2015

32. Selection of antiseizure medications for first add-on use: A consensus paper

Author

Paolo Bonanni, Emilio Perucca, Benedetto Acone, Paolo Tinuper, Giangennaro Coppola, Antonio Gambardella, Gambardella A., Tinuper P., Acone B., Bonanni P., Coppola G., and Perucca E.

Subjects
Adult, medicine.medical_specialty, Consensus, Computer science, Delphi method, Consensu, Likert scale, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, medicine, Humans, Medical physics, Adjunctive therapy, 030212 general & internal medicine, Drug selection, Set (psychology), Child, Selection (genetic algorithm), computer.programming_language, Statement (computer science), Epilepsy, business.industry, Usability, Preference, Treatment, Neurology, Italy, Neurology (clinical), business, computer, 030217 neurology & neurosurgery, Delphi, Antiepileptic drug, Human
Abstract

Introduction When monotherapy used alone or sequentially fails to achieve seizure control, a trial of combination therapy may be considered. Objective To define optimal criteria to guide choice of an antiseizure medication (ASM) for use as first add-on. Methods A standardized Delphi procedure was applied to produce a list of consensus statements. First, an Expert Board consisting of 5 epileptologists agreed on a set of 46 statements relevant to the objective. The statements were then finalized through an iterative process by a Delphi Panel of 84 Italian pediatric and adult neurologists with expertise in the management of epilepsy. Panel members provided anonymous ratings of their level of agreement with each statement on a 9-point Likert scale. Results Consensus, defined as agreement by at least 80% of Panel members, was reached for 36 statements. Medication-related factors considered to be important for drug selection included efficacy, tolerability and safety, interaction potential, mechanism of action, and ease of use. The need to optimize adherence and to tailor drug selection to individual characteristics was emphasized. Conclusions Choice of an ASM for first add-on requires consideration of many factors, many of which also apply to choose initial treatment. Factors more specifically relevant to add-on use include drug interaction potential and the preference for an ASM with a different mechanism of action.

Published
2021

33. Perampanel as first add-on antiseizure medication: Italian consensus clinical practice statements

Author

Paolo Bonanni, Paolo Tinuper, Giangennaro Coppola, Benedetto Acone, Antonio Gambardella, Emilio Perucca, Bonanni P., Gambardella A., Tinuper P., Acone B., Perucca E., and Coppola G.

Subjects
Adult, medicine.medical_specialty, Consensus, Pyridones, Antiepileptic drugs, Delphi method, Consensu, Delphi procedure, Pyridone, Perampanel, Likert scale, chemistry.chemical_compound, Epilepsy, Quality of life, Nitriles, medicine, Anticonvulsant, Humans, Adjunctive therapy, Intensive care medicine, Adverse effect, RC346-429, Child, business.industry, Cognition, General Medicine, medicine.disease, Treatment Outcome, Tolerability, chemistry, Italy, Quality of Life, Anticonvulsants, Neurology (clinical), Neurology. Diseases of the nervous system, business, Nitrile, Antiepileptic drug, Research Article, Human
Abstract

Background When use of a single antiseizure medication (ASM) fails to induce seizure remission, add-on therapy is justified. Perampanel (PER) is approved in Europe as adjunctive therapy for focal, focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures. Aim of the study was to establish whether PER is suitable for first add-on use. Methods A Delphi methodology was adopted to assess consensus on a list of 39 statements produced by an Expert Board of 5 epileptologists. Using an iterative process, statements were finalized by a Delphi Panel of 84 Italian pediatric and adult neurologists. Each statement was rated anonymously to determine level of agreement on a 9-point Likert scale. Consensus was established as agreement by at least 80% of the panelists. The relevance of each statement was also assessed on a 3-point scale. Results Consensus was achieved for 37 statements. Characteristics of PER considered to justify its use as first add-on include evidence of a positive impact on quality of life based on long term retention data, efficacy, tolerability, and ease of use; no worsening of cognitive functions and sleep quality; a low potential for drug interactions; a unique mechanism of action. Potential unfavorable factors are the need for a relatively slow dose titration; the potential occurrence of behavioral adverse effects; lack of information on safety when used in pregnancy; limited access to plasma PER levels. Conclusion Perampanel has many features which justify its use as a first add-on. Choice of an ASM as first add-on should be tailored to individual characteristics.

Published
2021

34. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry

Author

Birgitte Forsom Sondal, Zarouhi Hertz, Brenda Diputado, Meritxell Martinez Ferri, Odo Hildenhagen, Aldo Paggi, Gerhard Luef, Jakob Christensen, John Craig, Jana Zárubová, Gordana Kiteva-Trencevska, Raffaele Rocchi, Erik Tauboll, Lisa Gordon, Terttu Heikinheimo-Connell, Uden Navn, Ketevan Khomeriki, Iva Marečková, Erminio Bonizzoni, Michela Cecconi, Lone Rodam, Astrid Carius, Ineke Hogenesch, Katarzyna Miesczanleh, Angelo Labate, Eva Kumlien, Claus Albretsen, Torbjörn Tomson, Chiara Pantaleoni, David Sopelana Garay, Albertina Franza, Imad Halawa, Stefan Juhl, Emilio Perucca, Pia Gellert, Daniela Marino, Aline Russell, E. Kluck, Eylert Brodtkorb, Luigi Maria Specchio, Isabel Pires, Pietro Pignatta, Frank J.E. Vajda, Anette Huuse Farmen, Hans Lindsten, Boštjan Čebular, Maria Paola Canevini, Jens Arentsen, Francesca Faravelli, Bettina Schmitz, Noémi Becser Andersen, Birgit Müffelmann, Petr Bušek, T.-Y. Chang, Alma Sikiric, Judith Osseforth, Elias Zakharia, Elsebeth Bruun Christensen, Gemma Sansa Fayos, Vaiva Petrenaite, Alessandra Pistelli, Eliana Pastor, Hana Krijtová, Tim Hendgen, Leonor Cabral-Lim, Marina Trivisano, Hsiang-Yu Yu, Renata Listonova, Torleiv Svendsen, Vladimír Safcák, Nicoletta Foschi, Kristina Malmgren, Reetta Kälviäinen, Dag Aurlien, Martin J. Brodie, Maria Dolores Castro Vilanova, Anders Nilsson, Jesús Antonio Riuz Gimenez, Christian Samsonsen, Katsuyuki Fukushima, Maria Strandberg, Masaaki Kato, Giovanni De Maria, Katrine Haggag, Anna Maija Saukkonen, Maja Milovanovic, Masahiro Mizobuchi, Peter Mattsson, Bernhard Oehl, Anne Sabers, Juan Luis Becerra Cuñat, Mogens Worm, Antonio Gambardella, Miri Neufeld, Reina Roivainen, Kiyohito Terada, Janne Marit Ertresvåg, Birthe Pedersen, Gisela Rytířová, Claudia Cagnetti, Sanjeev V Thomas, Dick Lindhout, Silvia Kochen, Katherine Turner, Dieter Dennig, Luisa Antonini, Dina Battino, Laura Broglio, Aileen McGonigal, Helena Gauffin, Andrea Ortenzi, Ismael Barzinji, Hideyuki Ohtani, Rasmus Lossius, Elisabeth Robert-Gnansia, Morteza Zarifi-Oskoie, Leif Gjerstad, Barbara Tettenborn, Stephanie Hödl, Martin Kurthen, Barbara Mostacci, Alejandro De Marinis, Natalia Bohorquez Morera, Karl O. Nakken, Yushi Inoue, Germaine Kenou Van Rijckevorssel, Theresa Lasch, Iñigo Garamendi Ruiz, Silje Alvestad, Eugène van Puijenbroek, Anders Lundgren, Elena Zambrelli, Toni Escartin, Bernhard J. Steinhoff, Dominique Flügel, PharmacoTherapy, -Epidemiology and -Economics, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F, EURAP Study Group, Bisulli F, and Tinuper P

Subjects
Pediatrics, congenital heart malformation, topiramate, anticonvulsive agent, oxcarbazepine, Current Literature in Clinical Science, phenobarbital, cleft lip, neural tube defect, Epilepsy, 0302 clinical medicine, newborn, purl.org/becyt/ford/3.2 [https], fetus outcome, 030212 general & internal medicine, Prospective cohort study, Oxcarbazepine, anticonvulsant therapy, cleft palate, adult, phenytoin, article, longitudinal study, Abnormalities, Drug-Induced, polydactyly, cohort analysis, Kerala, fetus, female, priority journal, carbamazepine, monotherapy, perinatal death, purl.org/becyt/ford/3 [https], Anticonvulsants, Levetiracetam, lamotrigine, pregnancy, medicine.drug, Cohort study, prospective study, Topiramate, medicine.medical_specialty, levetiracetam, congenital malformation, prevalence, first trimester pregnancy, prenatal drug exposure, Lamotrigine, pregnancy termination, live birth, kidney malformation, TERATOGENICIDAD, Young Adult, 03 medical and health sciences, male, valproic acid, medicine, Humans, fetus disease, follow up, human, hypospadias, Dose-Response Relationship, Drug, business.industry, EPILEPSIA, Australia, EMBARAZO, multiple malformation syndrome, Carbamazepine, gastrointestinal malformation, medicine.disease, major clinical study, United Kingdom, Pregnancy Complications, Logistic Models, pregnant woman, maternal age, epilepsy, Neurology (clinical), conception, teratogenicity, business, Ireland, 030217 neurology & neurosurgery
Abstract

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p

Published
2018
Full Text
View/download PDF

35. Do neurologists agree in diagnosing drug resistance in adults with focal epilepsy?

Author

Stefano Meletti, Paolo Tinuper, Angela La Neve, Marco Mula, Maurizio Elia, Leila Zummo, Gaetano Zaccara, Domenico Consoli, Emilio Perucca, Bruno Ferrò, Alfonso Iudice, Anna Teresa Giallonardo, Zaccara G., Mula M., Ferro B., Consoli D., Elia M., Giallonardo A.T., Iudice A., La Neve A., Meletti S., Tinuper P., Zummo L., and Perucca E.

Subjects
Adult, Male, 0301 basic medicine, Drug Resistant Epilepsy, medicine.medical_specialty, Pediatrics, Neurology, Attitude of Health Personnel, Treatment outcome, antiepileptic drugs, classification, drug-resistant epilepsy, epilepsy, ILAE definition, reliability, Neurology (clinical), Drug resistance, 03 medical and health sciences, Epilepsy, antiepileptic drug, 0302 clinical medicine, medicine, Humans, Neurologists, Prospective Studies, Cooperative Behavior, business.industry, Middle Aged, medicine.disease, Confidence interval, Inter-rater reliability, 030104 developmental biology, Anticonvulsants, Female, Epilepsies, Partial, business, 030217 neurology & neurosurgery, Kappa
Abstract

Objective: To evaluate interrater agreement in categorizing treatment outcomes and drug responsiveness status according to the International League Against Epilepsy (ILAE) definition of drug-resistant epilepsy. Methods: A total of 1053 adults with focal epilepsy considered by the investigators to meet ILAE criteria for drug resistance were enrolled consecutively at 43 centers and followed up prospectively for 18-34months. Treatment outcomes for all antiepileptic drugs (AEDs) used up to enrollment (retrospective assessment), and on an AED newly introduced at enrollment, were categorized by individual investigators and by 2 rotating members of a 16-member expert panel (EP) that reviewed the patient records independently. Interrater agreement was tested by Cohen’s kappa (k) statistics and rated according to Landis and Koch’s criteria. Results: Agreement between EP members in categorizing outcomes on the newly introduced AED was almost perfect (90.1%, k=0.84, 95% confidence interval [CI] 0.80-0.87), whereas agreement between the EP and individual investigators was moderate (70.4%, k=0.57, 95% CI 0.53-0.61). Similarly, categorization of outcomes on previously used AEDs was almost perfect between EP members (91.7%, k=0.83, 95% CI 0.81-0.84) and moderate between the EP and investigators (68.2%, k=0.50, 95% CI 0.48-0.52). Disagreement was related predominantly to outcomes considered to be treatment failures by the investigators but categorized as undetermined by the EP. Overall, 19% of patients classified as having drug-resistant epilepsy by the investigators were considered by the EP to have “undefined responsiveness.”. Significance: Interrater agreement in categorizing treatment outcomes according to ILAE criteria ranges from moderate to almost perfect. Nearly 1 in 5 patients considered by enrolling neurologists to be “drug-resistant” were classified by the EP as having “undefined responsiveness.”.

Published
2019

36. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: The PuLsE (Open Prospective Randomized Long-term Effectiveness) trial

Author

Gabriella Colicchio, Lorella Minotti, Emilio Perucca, Louis Wagner, Philippe Ryvlin, Paolo Tinuper, Pradheep Raman, Hermann Stefan, Dang Khoa Nguyen, Frank Gilliam, Nelia Zamponi, Umberto Aguglia, Paolo Benna, Paul Boon, Alfonso Iudice, Mark Sadler, Ryvlin, P., Gilliam, F.G., Nguyen, D.K., Colicchio, G., Iudice, A., Tinuper, P., Zamponi, N., Aguglia, U., Wagner, L., Minotti, L., Stefan, H., Boon, P., Sadler, M., Benna, P., Raman, P., and Perucca, E.

Subjects
Adult, Male, medicine.medical_specialty, animal structures, Adolescent, Vagus Nerve Stimulation, Health-related quality of life, medicine.medical_treatment, Drug Resistance, Young Adult, Behavioral Neuroscience, Epilepsy, Quality of life, Seizures, Internal medicine, Anticonvulsant, medicine, Clinical endpoint, Humans, Epilepsy, Health-related quality of life, QOLIE-89, Seizures, Vagus nerve stimulation, Adverse effect, Depression (differential diagnoses), Aged, Full-Length Original Research, business.industry, Repeated measures design, Middle Aged, medicine.disease, Seizure, Treatment Outcome, Tolerability, Neurology, Anesthesia, embryonic structures, Quality of Life, Anticonvulsants, Female, Epilepsies, Partial, Neurology (clinical), Analysis of variance, Erratum, QOLIE-89, business, Vagus nerve stimulation, Human
Abstract

To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL).PuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel-group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (≥50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints.Significant between-group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load.VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Published
2015
Full Text
View/download PDF

37. Paternal exposure to antiseizure medications and offspring outcomes: a systematic review.

Author

Honybun E, Rayner G, Malpas CB, O'Brien TJ, Vajda FJ, Perucca P, and Perucca E

Subjects
Humans, Male, Female, Pregnancy, Prenatal Exposure Delayed Effects chemically induced, Infant, Newborn, Epilepsy drug therapy, Neurodevelopmental Disorders chemically induced, Neurodevelopmental Disorders epidemiology, Paternal Exposure adverse effects, Anticonvulsants adverse effects, Anticonvulsants therapeutic use
Abstract

Background: Concerns have recently been raised about risks to the fetus resulting from paternal exposure to antiseizure medications (ASMs). To address these concerns, we conducted a systematic review of the literature to assess neurodevelopmental and anatomical outcomes in offspring born to fathers taking ASMs at the time of conception., Methods: Electronic searches of MEDLINE, PsycINFO, and Embase were conducted to identify human studies published in English that reported on outcomes, comprising neurodevelopmental disorders, major congenital malformations, small-for-gestational age or low birth weight, in offspring of fathers taking ASMs at conception. Quality analysis of included studies was undertaken using the Newcastle-Ottawa Scale. A narrative synthesis was used to report study findings., Results: Of 923 studies identified by the search and screened by title and abstract, 26 underwent full-text review and 10 met eligibility criteria. There was limited evidence available, but there appeared to be no clear evidence for an adverse impact of paternal ASM use on offspring outcomes. Few isolated adverse findings were not replicated by other investigations. Several methodological limitations prevented meta-analysis, including failure by most studies to report outcomes separately for each individual ASM, heterogeneity in measurement and outcome reporting, and small numbers of monotherapy exposures., Conclusions: Although there were limited data available, this systematic review provides reassuring evidence that paternal exposure to ASMs at conception is unlikely to pose any major risk of adverse outcomes for the offspring. Further research is needed to examine the relationship between preconception ASM use in males and offspring outcomes at birth and postnatally., Competing Interests: Competing interests: CBM has received conference travel support and/or speaker fees from Merck, Novartis, and Biogen. He has received research support from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, the University of Melbourne, the Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. TOB has received research support from the Epilepsy Society of Australia, National Health and Medical Research Council, Royal Melbourne Hospital Neuroscience Foundation, Sanofi-Aventis, UCB Pharma, Janssen-Cilag, Novartis, and Sci-Gen. EP received speaker’s or consultancy fees from Eisai, GRIN Therapeutics, Shackelford Pharma, Sintetica, SKL Life Science, Sun Pharma, Takeda, UCB Pharma and Xenon Pharma and royalties from Wiley, Elsevier, and Wolters Kluwers. He is also on the board of EURAP-International Registry of Antiepileptic Drugs and Pregnancy, a non-profit organization which received financial support from Accord, Angelini, Bial, EcuPharma, Eisai, Glenmark, GW Pharma, GlaxoSmithKline, Sanofi, SF Group, Teva, UCB, and Zentiva. PP has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma, outside of the submitted work. He is an Associate Editor for Epilepsia Open. He is also on the board of EURAP-International Registry of Antiepileptic Drugs and Pregnancy, a non-profit organization which received financial support from Accord, Angelini, Bial, EcuPharma, Eisai, Glenmark, GW Pharma, GlaxoSmithKline, Sanofi, SF Group, Teva, UCB, and Zentiva. GR has received speaker honoraria from Liva Nova. FV has received research support for the Australian Pregnancy Register from the Epilepsy Society of Australia, National Health and Medical Research Council, Royal Melbourne Hospital Neuroscience Foundation, Epilepsy Action Australia, Sanofi-Aventis, UCB Pharma, Janssen-Cilag, Novartis, and Sci-Gen. He is also on the board of EURAP-International Registry of Antiepileptic Drugs and Pregnancy, a non-profit organization which received financial support from Accord, Angelini, Bial, EcuPharma, Eisai, Glenmark, GW Pharma, GlaxoSmithKline, Sanofi, SF Group, Teva, UCB, and Zentiva. EH does not have any conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Published
2024
Full Text
View/download PDF

38. Response to Letter on "Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol".

Author

Stjerna S, Huber-Mollema Y, Tomson T, Perucca E, Battino D, Craig J, Sabers A, Thomas S, Vajda F, and Gaily E

Abstract

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Published
2024
Full Text
View/download PDF

39. N-of-1 trials in epilepsy: A systematic review and lessons paving the way forward.

Author

Defelippe VM, Brilstra EH, Otte WM, Cross HJ, O'Callaghan F, De Giorgis V, Poduri A, Lerche H, Sisodiya S, Braun KPJ, Jansen FE, and Perucca E

Subjects
Humans, Anticonvulsants therapeutic use, Clinical Trials as Topic methods, Randomized Controlled Trials as Topic methods, Research Design, Epilepsy drug therapy, Epilepsy therapy, Cross-Over Studies
Abstract

Objective: Defined as prospective single-patient crossover studies with repeated paired cycles of active and control intervention, N-of-1 trials have gained attention as an option to obtain high-quality evidence of efficacy, particularly for patients with rare epilepsies in whom conduction of well-powered randomized controlled trials can be challenging. The objective of this systematic review is to provide an appraisal of the literature on N-of-1 trials in individuals with epilepsy., Methods: We searched PubMed and Embase on January 12, 2024, for studies meeting the following criteria: prospectively planned, within-patient, multiple-crossover design in individuals with epilepsy and outcomes related to comorbidities. Information on design, outcome measurements, intervention, and analyses was retrieved. Risk of bias assessment was performed using the Risk of Bias in N-of-1 Trials (RoBiNT) scale. We highlighted methodological aspects of the N-of-1 trials identified and discuss future recommendations., Results: Five studies met our inclusion criteria. An additional multiple-crossover trial that evaluated treatment effects exclusively at group level was also included because of its relevance to N-of-1 study methodology. The studies enrolled individuals with focal seizures, absences or cognitive impairement and electrographic discharges. Treatments included established or investigational antiseizure medications, off-label medications, neurostimulation or lifestyle intervention. Three of the five N-of-1 trials reported on individual cases. The studies' strengths were the use of individualized treatment dosages and symptom-specific patient-reported outcomes. Limitations were related to minimal reporting of baseline characteristics and seizure burden., Significance: The trials identified by our search exemplify how the N-of-1 design can be applied to assess interventions in individuals with epilepsy-related disorders. Future N-of-1 trials of antiseizure interventions should take into account baseline seizure frequency, should apply statistical models suited to capture seizure frequency changes reliably and make predefined interim assessments. Non-seizure outcome measures evaluable over short periods should be considered. Tailored N-of-1 methodology could pave the way to evidence-based, treatment selection for patients with rare epilepsies., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

40. Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

Author

Stjerna S, Huber-Mollema Y, Tomson T, Perucca E, Battino D, Craig J, Sabers A, Thomas S, Vajda F, and Gaily E

Subjects
Humans, Female, Child, Pregnancy, Male, Neuropsychological Tests, Triazines adverse effects, Cohort Studies, Piracetam analogs & derivatives, Piracetam adverse effects, Adult, Cognition drug effects, Prospective Studies, Intelligence drug effects, Prenatal Exposure Delayed Effects chemically induced, Anticonvulsants adverse effects, Levetiracetam adverse effects, Valproic Acid adverse effects, Lamotrigine adverse effects, Lamotrigine therapeutic use, Carbamazepine adverse effects, Epilepsy drug therapy
Abstract

Purpose: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy., Methods: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex., Results: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001)., Conclusions: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
Full Text
View/download PDF

41. Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). I. Drugs in preclinical and early clinical development.

Author

Bialer M, Johannessen SI, Koepp MJ, Perucca E, Perucca P, Tomson T, and White HS

Subjects
Animals, Humans, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Congresses as Topic, Drug Development methods, Drug Evaluation, Preclinical, Anticonvulsants pharmacology, Anticonvulsants therapeutic use, Epilepsy drug therapy, Epilepsy genetics, Seizures drug therapy, Seizures genetics
Abstract

For >30 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided a forum for the discussion of advances in the development of new therapies for seizures and epilepsy. The EILAT XVII conference took place in Madrid, Spain, on May 5-8, 2024. Participants included basic scientists and clinical investigators from industry and academia, other health care professionals, and representatives from lay organizations. We summarize in this article information on treatments in preclinical and in early clinical development discussed at the conference. These include AMT-260, a gene therapy designed to downregulate the expression of Glu2K subunits of kainate receptors, in development for the treatment of drug-resistant seizures associated with mesial temporal sclerosis; BHV-7000, a selective activator of heteromeric Kv7.2/7.3 potassium channels, in development for the treatment of focal epilepsy; ETX101, a recombinant adeno-associated virus serotype 9 designed to increase Na V 1.1 channel density in inhibitory γ-aminobutyric acidergic (GABAergic) neurons, in development for the treatment of SCN1A-positive Dravet syndrome; GAO-3-02, a compound structurally related to synaptamide, which exerts antiseizure activity at least in part through an action on cannabinoid type 2 receptors; LRP-661, a structural analogue of cannabidiol, in development for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex; OV329, a selective inactivator of GABA aminotransferase, in development for the treatment of drug-resistant seizures; PRAX-628, a functionally selective potent sodium channel modulator with preference for the hyperexcitable state of sodium channels, in development for the treatment of focal seizures; RAP-219, a selective negative allosteric modulator of transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor regulatory protein γ-8, in development for the treatment of focal seizures; and rozanolixizumab, a humanized anti-neonatal Fc receptor monoclonal antibody, in development for the treatment of LGI1 autoimmune encephalitis. Treatments in more advanced development are summarized in Part II of this report., (© 2024 International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

42. Progress report on new medications for seizures and epilepsy: A summary of the 17th Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVII). II. Drugs in more advanced clinical development.

Author

Bialer M, Johannessen SI, Koepp MJ, Perucca E, Perucca P, Tomson T, and White HS

Subjects
Humans, Drug Development, Drugs, Investigational therapeutic use, Animals, Anticonvulsants therapeutic use, Epilepsy drug therapy, Epilepsy genetics, Seizures drug therapy
Abstract

The 17th Eilat Conference on New Antiepileptic Drugs and Devices took place in Madrid, Spain on May 5-8, 2024. As usual, the core part of the conference consisted of presentations on investigational drugs at various stages of development for epilepsy-related indications. Summaries of information on compounds in preclinical or early clinical development are included in an accompanying publication (Part I). In this article, we provide summaries for five compounds in more advanced clinical development, i.e. compounds for which some information on antiseizure activity in individuals with epilepsy is available. These investigational treatments include azetukalner (XEN1101), a potent, K V 7.2/7.3-specific potassium channel opener in development for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder; bexicaserin (LP352), a selective 5-HT 2C receptor superagonist in development for the treatment of seizures associated with developmental and epileptic encephalopathies; radiprodil, a selective negative allosteric modulator of NR2B subunit-containing N-methyl-D-aspartate glutamate receptors, in development for the treatment of seizures and behavior manifestations associated with disorders caused by gain-of-function mutations in the GRIN1, -2A, -2B, or -2D genes; soticlestat (TAK-935), a selective inhibitor of cholesterol 24-hydroxylase in development for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome; and STK-001, an antisense oligonucleotide designed to upregulate Na v 1.1 protein expression and improve outcomes in individuals with Dravet syndrome. The diversity in mechanisms of action of these agents illustrates different approaches being pursued in the discovery of novel treatments for seizures and epilepsy. For two of the compounds discussed in this report (azetukalner and soticlestat), clinical evidence of efficacy has already been obtained in a randomized placebo-controlled adjunctive-therapy trial. For the other compounds, adequately powered placebo-controlled efficacy trials have not been completed to date., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

43. Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Infants, Children, and Adolescents with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

Author

Mitchell JW, Sossi F, Miller I, Jaber PB, Das-Gupta Z, Fialho LS, Amos A, Austin JK, Badzik S, Baker G, Ben Zeev B, Bolton J, Chaplin JE, Cross JH, Chan D, Gericke CA, Husain AM, Lally L, Mbugua S, Megan C, Mesa T, Nuñez L, von Oertzen TJ, Perucca E, Pullen A, Ronen GM, Sajatovic M, Singh MB, Wilmshurst JM, Wollscheid L, and Berg AT

Subjects
Humans, Child, Adolescent, Infant, Delphi Technique, Child, Preschool, Epilepsy diagnosis, Outcome Assessment, Health Care standards, Outcome Assessment, Health Care methods, Consensus
Abstract

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient-centered outcomes in daily practice., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

44. Development of an International Standard Set of Outcomes and Measurement Methods for Routine Practice for Adults with Epilepsy: The International Consortium for Health Outcomes Measurement Consensus Recommendations.

Author

Mitchell JW, Sossi F, Miller I, Jaber PB, Das-Gupta Z, Fialho LS, Amos A, Austin JK, Badzik S, Baker G, Zeev BB, Bolton J, Chaplin JE, Cross JH, Chan D, Gericke CA, Husain AM, Lally L, Mbugua S, Megan C, Mesa T, Nuñez L, von Oertzen TJ, Perucca E, Pullen A, Ronen GM, Sajatovic M, Singh MB, Wilmshurst JM, Wollscheid L, and Berg AT

Subjects
Humans, Adult, Epilepsy diagnosis, Epilepsy therapy, Outcome Assessment, Health Care standards, Outcome Assessment, Health Care methods, Consensus
Abstract

At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement (ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient-clinician decision-making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross-cultural applicability. The essential outcomes included many non-seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient-centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

45. Safe delivery, perinatal outcomes and breastfeeding in women with epilepsy.

Author

Mesraoua B, Brigo F, Lattanzi S, Perucca E, Ali M, and Asadi-Pooya AA

Subjects
Humans, Female, Pregnancy, Anticonvulsants adverse effects, Anticonvulsants therapeutic use, Delivery, Obstetric, Pregnancy Outcome epidemiology, Breast Feeding, Epilepsy, Pregnancy Complications
Abstract

Safe delivery and optimal peripartum and postpartum care in women with epilepsy (WWE) is a major concern which has received limited attention in recent years. A diagnosis of epilepsy per se is not an indication for a planned cesarean section or induction of labor, even though epidemiological studies indicate that cesarean delivery is more common among WWE compared to the general population. Pregnancy in WWE is associated with an increased risk of obstetrical complications and increased perinatal morbidity and mortality, and these risks may be greater among WWE taking ASMs. Wherever feasible, pregnant WWE should be directed to specialist care. Risk minimization includes, when appropriate, dose adjustment to compensate for pregnancy-related changes in the pharmacokinetics of some ASMs. With respect to postpartum management, WWE should be advised that the benefits of breastfeeding outweigh the small risk of adverse drug reactions in the infant., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This review was presented at the 6th Qatar International Epilepsy Course in April 26th ,2024 by the authors. We thank Hamad Medical Corporation, Neurosciences and Medical Education Departments for supporting this event., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
Full Text
View/download PDF

46. Restricting valproate prescribing in men: wisdom or folly?

Author

Berkovic SF and Perucca E

Subjects
Humans, Male, Epilepsy drug therapy, Drug Prescriptions standards, Valproic Acid therapeutic use, Anticonvulsants therapeutic use
Abstract

Competing Interests: Competing interests: SFB receives research funding from NHMRC and has received unrestricted educational grants from UCB Pharma, Eisai, SEER, Chiesi and Liva Nova. He has received consultancy fees for Praxis Precision Medicines and receives remuneration as chief medical officer for the Epilepsy Foundation of Victoria. EP received speaker’s or consultancy fees from Angelini, Eisai, Janssen, PMI Life Sciences, Sanofi group of companies, UCB Pharma, Shackelford Pharma, Sintetica, SKL Life Science, Takeda, UCB Pharma and Xenon Pharma, and royalties from Wiley, Elsevier and Wolters Kluwers. He is also on the board of EURAP-International Registry of Antiepileptic Drugs and Pregnancy, a non-profit organisation which received financial support from Accord, Angelini, Bial, EcuPharma, Eisai, Glenmark, GW Pharma, GlaxoSmithKline, Sanofi, SF Group, Teva, UCB and Zentiva.

Published
2024
Full Text
View/download PDF

47. Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy.

Author

Battino D, Tomson T, Bonizzoni E, Craig J, Perucca E, Sabers A, Thomas S, Alvestad S, Perucca P, and Vajda F

Subjects
Humans, Female, Adult, Pregnancy, Young Adult, Adolescent, Middle Aged, Longitudinal Studies, Prospective Studies, Valproic Acid adverse effects, Valproic Acid therapeutic use, Prenatal Exposure Delayed Effects epidemiology, Prenatal Exposure Delayed Effects chemically induced, Phenytoin adverse effects, Phenytoin therapeutic use, Lamotrigine adverse effects, Lamotrigine therapeutic use, Carbamazepine adverse effects, Phenobarbital adverse effects, Phenobarbital therapeutic use, Cohort Studies, Oxcarbazepine adverse effects, Oxcarbazepine therapeutic use, Prevalence, Anticonvulsants adverse effects, Anticonvulsants therapeutic use, Epilepsy drug therapy, Epilepsy epidemiology, Abnormalities, Drug-Induced epidemiology, Abnormalities, Drug-Induced etiology, Pregnancy Complications drug therapy, Pregnancy Complications epidemiology
Abstract

Importance: Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring., Objective: To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time., Design, Setting, and Participants: This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023., Exposure: Maternal use of ASMs at conception., Main Outcomes and Measures: MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors., Results: A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern., Conclusions and Relevance: Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.

Published
2024
Full Text
View/download PDF

48. Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

Author

Perucca E, French JA, Aljandeel G, Balestrini S, Braga P, Burneo JG, Felli AC, Cross JH, Galanopoulou AS, Jain S, Jiang Y, Kälviäinen R, Lim SH, Meador KJ, Mogal Z, Nabbout R, Sofia F, Somerville E, Sperling MR, Triki C, Trinka E, Walker MC, Wiebe S, Wilmshurst JM, Wirrell E, Yacubian EM, and Kapur J

Subjects
Humans, Anticonvulsants therapeutic use, Behavior Therapy, Consensus, Caregivers, Epilepsy drug therapy, Epilepsy etiology
Abstract

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

49. Stereoselective Analysis of the Antiseizure Activity of Fenfluramine and Norfenfluramine in Mice: Is l -Norfenfluramine a Better Follow-Up Compound to Racemic-Fenfluramine?

Author

Erenburg N, Perucca E, Bechard J, Dube C, Weishaupt N, Sherrington R, and Bialer M

Subjects
Mice, Animals, Norfenfluramine metabolism, Anticonvulsants, Follow-Up Studies, Mice, Inbred DBA, Seizures, Fenfluramine, Epilepsy, Reflex
Abstract

The aim of this study was to investigate the comparative antiseizure activity of the l -enantiomers of d , l -fenfluramine and d , l -norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d , l -Fenfluramine, d , l -norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d , l -Fenfluramine, d , l -norfenfluramine and their individual l -enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED 50 values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l -norfenfluramine was 9 times more potent than d , l -fenfluramine and 15 times more potent than l -fenfluramine based on ED 50 (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC 50 values, l -norfenfluramine was 7 times more potent than d , l -fenfluramine and 13 times more potent than l -fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC 50 values for metabolically formed d , l -norfenfluramine and l -norfenfluramine were similar to brain EC 50 values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d -norfenfluramine to d , l -fenfluramine to cardiovascular and metabolic adverse effects, their l -enantiomers could potentially be safer follow-up compounds to d , l -fenfluramine. We found that, in the models tested, the activity of l -fenfluramine and l -norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l -norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.

Published
2024
Full Text
View/download PDF

50. Call for the use of the ILAE terminology for seizures and epilepsies by health care professionals and regulatory agencies to benefit patients and caregivers.

Author

Auvin S, Arzimanoglou A, Brambilla I, French J, Knupp KG, Lagae L, Perucca E, Trinka E, and Dlugos D

Subjects
Humans, Caregivers, Seizures diagnosis, Forecasting, Epilepsy diagnosis, Epileptic Syndromes
Abstract

The International League Against Epilepsy (ILAE) introduced a classification for seizure types in 2017 and updated the classification for epilepsy syndromes in 2022. These classifications aim to improve communication among healthcare professionals and help patients better describe their condition. So far, regulatory agencies have used different terminology. This paper stresses the crucial need for consistently adopting ILAE terminology in both regulatory processes and clinical practice. It highlights how language plays a significant role in healthcare communication and how standardized terminology can enhance patient comprehension. The ongoing review of guidelines by regulatory bodies offers a timely opportunity. Aligning regulatory terminologies holds the potential to facilitate discussions on future drug development and harmonize practices across diverse regions, ultimately fostering improved care and research outcomes in epilepsy treatment., (© 2023 International League Against Epilepsy.)

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results