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- Long‐term efficacy and safety of eslicarbazepine acetate monotherapy for adults with newly diagnosed focal epilepsy: An open‐label extension studyPublication . Trinka, Eugen; Rocamora, Rodrigo; Chaves, João; Moreira, Joana; Ikedo, Fábio; Soares‐da‐Silva, Patrício; Estol, Conrado; Newton, Mark; Carne, Ross; Kowacs, Pedro; Petrova, Dorina; Syankov, Dimitar; Maslarov, Dimitar; Stanev, Slavi; Lasso, Jorge; Bašić, Silvio; Bar, Michal; Vyskočilová, Dana; Pazdera, Ladislav; Haldre, Sulev; Kaarina Kälviäinen, Reetta; Peltola, Jukka; Georges Maillard, Louis; Deckert‐Schmitz, Maria; Springub, Joachim; Barcs, Gábor; Ménes, Andrea; Tóth, Marianna; Giallonardo, Anna Teresa; Paganini, Marco; Asmane, Santa; Logina, Lnara; Meilute Lescinskiene, Loreta; Cruz, Ana; Umeres, Hugo; Czapiński, Piotr; Trzebińska‐Frydrychowska, Ewa; Sales, Francisco; Falup‐Pecurariu, Cristian Gavril; Silviu Manescu, Emilian; Roceanu, Adina‐Maria; Odinak, Miroslav; Tretyakova, Evgeniya; Volkova, Larisa; Lebedeva, Anna; Lipatova, Liudmila; Bogdanov, Enver; Vladimirovna Polezhaeva, Tatiana; Gebauer‐Bukurov, Ksenija; Jovanovic‐Mihajlovic, Natalija; Milovanovic, Maja; Spasic, Mirjana; Lipovský, L'Ubomír; Perichtová, Magdaléna; Chamilová, Jana; Balaguer, Ernest; Ugarte, Antonio; Dubenko, Andriy; Kharchuk, Sergii; Moroz, Svitlana; Shkrobot, Svitlana; Mar'yenko, Lidiya; Litovchenko, Tetyana; Cock, HannahObjective: To assess the efficacy, safety, and tolerability of eslicarbazepine acetate (ESL) monotherapy during long-term treatment. Methods: An open-label extension (OLE) study was conducted in adults completing a phase 3, randomized, double-blind, noninferiority trial, during which they had received monotherapy with either once-daily ESL or twice-daily controlled-release carbamazepine (CBZ-CR) for newly diagnosed focal epilepsy. In the OLE study, all patients received ESL (800-1600 mg/d) for 2 years. Primary efficacy outcome was retention time (from baseline of the OLE study). Secondary efficacy assessments included seizure freedom rate (no seizures during the OLE study) and responder rate (≥50% seizure frequency reduction from baseline of double-blind trial). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs). Results: Of 206 randomized patients, 96 who received ESL in the double-blind trial (ESL/ESL) and 88 who received CBZ-CR in the double-blind trial (CBZ-CR/ESL) were treated with ESL monotherapy (89.3% overall). Treatment retention time was similar between groups, with low probability of ESL withdrawal overall (<0.07 at any time). After 24 months, the probability of ESL withdrawal was 0.0638 (95% confidence interval [CI] = 0.0292-0.1366) in the ESL/ESL group and 0.0472 (95% CI = 0.0180-0.1210) in the CBZ-CR/ESL group. Seizure freedom rates were 90.6% (ESL/ESL) and 80.7% (CBZ-CR/ESL; P = .0531). Responder rates remained >80% in both groups throughout the study. Incidence of serious TEAEs was similar between groups (7.3% vs 5.7%; 0% vs 1.1% possibly related), as were the incidences of TEAEs considered at least possibly related to treatment (17.7% vs 18.2%) and TEAEs leading to discontinuation (3.1% vs 4.5%). The types of TEAEs were generally consistent with the known safety profile of ESL. Significance: ESL monotherapy was efficacious and generally well tolerated over the long term, including in patients who transitioned from CBZ-CR monotherapy. No new safety concerns emerged.
- Female preponderance in genetic generalized epilepsiesPublication . Videira, Gonçalo; Gabriel, Denis; Freitas, Joel; Samões, Raquel; Chorão, Rui; Lopes, João; Ramalheira, João; Ramalheira, João E.P.; Lemos, Carolina; Leal, Bárbara; da Silva, António Martins; Chaves, JIntroduction: Epilepsy is more prevalent in men but Genetic Generalized Epilepsies (GGE) seem to be more common in women. A predominant maternal inheritance has been previously described in GGE. Our objective was to determine sex and inheritance patterns in a GGE population compared to mesial temporal lobe epilepsy with hippocampal sclerosis (MTLEHS). Methods: We performed a prospective observational study including adult GGE and MTLEHS patients followed up at a tertiary epilepsy center from January 2016 to December 2019. Patients' familial history was obtained by a detailed questionnaire. Clinical and demographic data was retrieved from clinical notes. Results: A cohort of 641 patients, 403 with GGE and 238 with MTLEHS, was analyzed. GGE was more common in women than MTLEHS (58.8% vs 44.5%, OR=1.63, p = 0.004). Compared to MTLEHS patients, more GGE patients had familial history of epilepsy (45.4% vs 25.2%; p<0.001). The GGE group had a higher percentage of female relatives with epilepsy (55% vs 37%; p = 0.006). The prevalence of maternal inheritance was not different between GGE and MTLEHS groups (62.9% vs 57.7%; p = 0.596). Photosensitivity was more common in females than in males (44.7% vs 34.3%, p = 0.036). Conclusion: There is a female preponderance in GGE when compared to MTLEHS, as both GGE patients and their affected relatives are more frequently women. The prevalence of maternal inheritance was not higher in GGE than in MTLEHS.
- Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense TherapyPublication . Matos, L.; Duarte, A.; Ribeiro, D.; Chaves, J.; Amaral, O.; Alves, S.Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5'ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases.