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1.
Open Vet J ; 12(4): 445-450, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118733

RESUMO

Background: Idiopathic or genetic epilepsy commonly affects dogs; affected dogs are often refractory to anti-seizure drug therapy. Felbamate is an anti-seizure drug with established pharmacokinetic and safety data for dogs, but little published evidence of efficacy for managing generalized seizures in this species. Aim: The purpose of this retrospective case series was to evaluate the clinical efficacy and tolerability of oral felbamate in six presumptive epileptic dogs experiencing generalized seizures. Methods: Medical records from six dogs with presumptive idiopathic/genetic epilepsy manifesting as generalized seizure activity, for which oral felbamate was used as an add-on treatment, were reviewed. The number of seizures recorded for the 3-month period immediately before instituting felbamate was recorded for each dog. Short-term (3 months) and long-term (6 months or greater) seizure frequency post-felbamate therapy was recorded for each dog and compared with baseline. Results: Overall, dogs experienced a reduction (82%) in seizures after adding felbamate in the short term, with 5/6 dogs (83%) classified as responders (50% or greater reduction in seizures) and 3/6 dogs (50%) attaining seizure-free status. Mean and median long-term follow-up times were 13 and 11 months, respectively (range: 6 to 23 months). Four of the 6 dogs (67%) remained drug responders at final follow-up, with an average seizure reduction of 98%, 2 of which remained seizure-free at 8 and 21 months. Two dogs (33%) experienced increased seizure activity during long-term follow-up (12 and 23 months) and were considered non-responders. The non-responder dogs had an average long-term seizure reduction of 33%. No dog experienced any obvious adverse effects associated with felbamate administration. However, one dog not included in the analysis because of insufficient (<3 month) post-felbamate follow-up, was weaned off felbamate because of suspected hepatotoxicity. Conclusion: Our small case series suggests that oral felbamate might show promise as an add-on drug for epileptic dogs experiencing generalized seizures resistant to drug therapy. These results warrant a more controlled, prospective investigation into felbamate as a therapeutic agent for canine epilepsy.


Assuntos
Doenças do Cão , Epilepsia , Animais , Anticonvulsivantes/uso terapêutico , Doenças do Cão/etiologia , Cães , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Epilepsia/veterinária , Felbamato/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/veterinária
2.
Cochrane Database Syst Rev ; 8: CD008295, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35914010

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review first published in 2011, and most recently updated in 2019. Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. SEARCH METHODS: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 13 July 2021) on 15 July 2021. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, a third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data. Only one study reported the outcome of 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate whilst another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants. We assessed the evidence for all outcomes using GRADE and rated the evidence as very low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.


Assuntos
Epilepsia Resistente a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Epilepsias Parciais , Anticonvulsivantes/efeitos adversos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Quimioterapia Combinada , Epilepsias Parciais/tratamento farmacológico , Felbamato/uso terapêutico , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológico , Método Simples-Cego
3.
J Toxicol Sci ; 47(7): 277-288, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35786679

RESUMO

Felbamate (FBM) is an antiepileptic drug that has minimal toxicity in preclinical toxicological species but has a serious idiosyncratic drug toxicity (IDT) in humans. The formation of reactive metabolites is common among most drugs associated with IDT, and 2-phenylpropenal (2-PP) is believed to be the cause of IDT by FBM. It is important to consider the species difference in susceptibility to IDT between experimental animals and humans. In the present study, we used an in vitro and in vivo model system to reveal species difference in IDT of FBM. Human cytochrome P450 (CYP) and carboxylesterase (CES) expressing microsomes were used to clarify the isozymes involved in the metabolism of FBM. The remaining amount of FBM was significantly reduced in incubation with microsomes expressing human CYP2C8, 2C9, 2E1, and CES1c isozymes. Chimeric mice with humanized liver are expected to predict IDT in humans. Therefore, metabolite profiles in chimeric mice with humanized liver were investigated after administration of FBM. Metabolites after glutathione (GSH) conjugation of 2-phenylpropenal (2-PP), which is the reactive metabolite responsible for FBM-induced IDT, were detected in chimeric mice plasma and liver homogenate. Mass spectrometry imaging (MSI) visualizes distribution of FBM and endogenous GSH, and GSH levels in human hepatocyte were decreased after administration of FBM. In this study, we identified CYP and CES isozymes involved in the metabolism of FBM and confirmed reactive metabolite formation and subsequent decrease in GSH using humanized animal model. These results would provide useful information for the susceptibility to IDT between experimental animals and humans.


Assuntos
Isoenzimas , Fígado , Ativação Metabólica , Animais , Modelos Animais de Doenças , Felbamato , Glutationa , Humanos , Camundongos
4.
Mitochondrion ; 66: 27-37, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35842181

RESUMO

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aß), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.


Assuntos
Demência , Epilepsia , Doença de Parkinson , Anticonvulsivantes/uso terapêutico , Carbamazepina/efeitos adversos , Demência/induzido quimicamente , Demência/complicações , Demência/tratamento farmacológico , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Felbamato/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Inflamassomos , Lamotrigina/uso terapêutico , Mitofagia , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Oxcarbazepina/uso terapêutico , Fenitoína/uso terapêutico , Convulsões , Topiramato/uso terapêutico , Triazinas/efeitos adversos , Ubiquitina-Proteína Ligases , Ácido Valproico/uso terapêutico
5.
Toxicol Appl Pharmacol ; 427: 115655, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34329640

RESUMO

Several studies with larvae and adult zebrafish have shown that old and new antiseizure drugs (ASDs) produce discrepant results in seizure tests, locomotor activity or anxiety models. In this study, the pentylenetetrazole seizure test (PTZ) was performed to assess the effectiveness of four new ASDs: lamotrigine (LTG), topiramate (TPM), felbamate (FBM), and levetiracetam (LEV) in the subsequent stages of seizures in adult fish. All ASDs were administered intraperitoneally (i.p.). The time of maximal anticonvulsant effect and the dose-response relationship of the drugs were assessed. The effects of studied ASDs on the locomotor activity and the anxiety-like behavior in the color preference test were also investigated. Furthermore, drug concentrations in zebrafish homogenates were determined. LTG, TPM, and LEV significantly increased the seizure latency at three subsequent stages of seizures (SI-SIII), while FBM was effective only at SI. Locomotor activity decreased after TPM treatment. TPM and FBM exhibited a strong anxiolytic-like effect in the color preference test. LEV at the highest dose tested had a weak anxiolytic-like effect. The HPLC analysis showed average concentrations of the studied ASDs in the fish body during their maximum anticonvulsant activity. The present study shows that FBM cannot inhibit all subsequent PTZ seizure stages in the adult fish. Except for LTG, the studied drugs affected the anxiety-like behavior of treated animals. Furthermore, only TPM significantly changed locomotion parameters. Our findings support the need to accurately characterize the efficacy of new ASDs at different stages of the PTZ-induced seizures in adult zebrafish.


Assuntos
Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Ansiedade/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fatores Etários , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Ansiedade/psicologia , Relação Dose-Resposta a Droga , Felbamato/farmacologia , Felbamato/uso terapêutico , Feminino , Lamotrigina/farmacologia , Lamotrigina/uso terapêutico , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Pentilenotetrazol/toxicidade , Convulsões/psicologia , Topiramato/farmacologia , Topiramato/uso terapêutico , Peixe-Zebra
6.
Cochrane Database Syst Rev ; 4: CD003277, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33825230

RESUMO

BACKGROUND: Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013. OBJECTIVES: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes. MAIN RESULTS: We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.


Assuntos
Síndrome de Lennox-Gastaut/tratamento farmacológico , Adolescente , Adulto , Idade de Início , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Criança , Pré-Escolar , Cinamatos/administração & dosagem , Cinamatos/efeitos adversos , Clobazam/administração & dosagem , Eletroencefalografia , Felbamato/administração & dosagem , Humanos , Lamotrigina/administração & dosagem , Pessoa de Meia-Idade , Placebos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Topiramato/administração & dosagem , Triazóis/administração & dosagem , Vigília/fisiologia , Adulto Jovem
7.
Eur Rev Med Pharmacol Sci ; 24(12): 7083-7091, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32633403

RESUMO

OBJECTIVE: We aimed to compare immunological, histological and oxidative effects of antiepileptic agents; felbamate and levetiracetam on head trauma in rats. MATERIALS AND METHODS: In this study, 32 Sprague-Dawley genus male rats were used. A closed head trauma mechanism was constituted in order to perform head trauma in rats. Rats were divided into 4 groups, and each group had 8 rats. Following head trauma, Group 1 (Control); normal saline was administered, Group 2; levetiracetam 50 mg/kg was administered, Group 3; felbamate 100 mg/kg was administered, and Group 4; levetiracetam 50 mg/kg and felbamate 100 mg/kg were administered with a combination. Injections were administered intraperitoneally once a day for 20 days. The rats were decapitated at the end of the 20th day. Blood and tissue samples were collected and analyzed for biochemical, immunohistochemical and histological parameters. RESULTS: Serum cytokine levels in Group 2, 3 and 4 were lower when compared to the control group. In Group 4, in which combined therapy was performed, cytokine levels were found to be the lowest. In Groups 2 and 3, a significant decrease in vascular congestion, mononuclear cell infiltration, hemorrhage, and neural degeneration was noticed in the pia mater. In Group 2, a decrease in vascular congestion and Purkinje cell degeneration was obtained in the cerebellum. However, the best outcomes were determined in Group 4. CONCLUSIONS: We determined that levetiracetam and felbamate alone are useful with respect to immunological, oxidative and histological alterations. However, their utility is better when used in a combination.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/imunologia , Felbamato/farmacologia , Felbamato/uso terapêutico , Levetiracetam/farmacologia , Levetiracetam/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Lesões Encefálicas Traumáticas/patologia , Citocinas/sangue , Citocinas/imunologia , Relação Dose-Resposta a Droga , Felbamato/administração & dosagem , Injeções Intraperitoneais , Levetiracetam/administração & dosagem , Masculino , Estresse Oxidativo/imunologia , Ratos , Ratos Sprague-Dawley
8.
Epilepsy Res ; 161: 106284, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32058261

RESUMO

Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weighted-average weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Felbamato/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Vigabatrina/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento
10.
Dev Med Child Neurol ; 62(5): 581-586, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31850517

RESUMO

AIM: To analyse the effects of felbamate in refractory infantile spasms/West syndrome. METHOD: We conducted a 10-year retrospective study of infants (including all infants younger than 18mo) treated with felbamate for electroencephalography-recorded epileptic spasms persisting after first-line treatment. RESULTS: In total, 29 infants (17 males, 12 females) were included in the study. Felbamate was initiated at a mean age of 13.8 months (range 4.5-66mo) after sequential administration or combination of vigabatrin and oral steroids; a ketogenic diet was implemented in 23 infants. Eight infants became spasm-free at a mean dose of 34.6mg/kg/day felbamate (range 26-45mg/kg/day). Mean duration of felbamate use was 19 months (range 1-67mo) for the 19 infants whose treatment was terminated. No severe side effects were observed. Reversible neutropenia led to withdrawal of felbamate in six patients. One spasm-free patient demonstrated recurrence when felbamate was withdrawn. INTERPRETATION: N-methyl-d-aspartate receptors with felbamate controlled epileptic spasms in eight infants resistant to first-line treatment should be targeted.


Assuntos
Anticonvulsivantes/uso terapêutico , Felbamato/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Resistência a Medicamentos , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Espasmos Infantis/fisiopatologia , Resultado do Tratamento
11.
Cochrane Database Syst Rev ; 8: CD008295, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425617

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2017.Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Felbamato/uso terapêutico , Humanos , Fenilcarbamatos/efeitos adversos , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/efeitos adversos , Propilenoglicóis/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Fundam Clin Pharmacol ; 33(6): 621-633, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30951217

RESUMO

Felbamate is an anticonvulsant used in the treatment of epilepsy. In this study, we investigated the antidepressant-like actions of felbamate in mice. The effects of felbamate were first assessed using the forced swimming test (FST) and tail suspension test (TST), and then investigated in the chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models of depression. The changes in the hippocampal brain-derived neurotrophic factor (BDNF) signaling cascade after chronic stress and felbamate treatment were also examined. It was found that felbamate exhibited antidepressant-like activities in the FST and TST without affecting the locomotor activity of mice. Felbamate was also effective in both the CUMS and CSDS models of depression. Moreover, felbamate administration fully restored the decreased hippocampal BDNF signaling pathway in both the CUMS-stressed and CSDS-stressed mice. Collectively, felbamate has antidepressant-like actions in mice involving the hippocampal BDNF system.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Felbamato/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Modelos Animais de Doenças , Elevação dos Membros Posteriores , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico
13.
Epilepsy Behav ; 78: 14-19, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29161629

RESUMO

Antiepileptic medications are the frontline treatment for seizure conditions but are not without cognitive side effects. Previously, our laboratory reported learning deficits in phenytoin-, carbamazepine-, and valproate-treated rats. In the present experiment, the effects of felbamate (FBM) have been compared to water-treated controls (controls) using the same instrumental training tasks employed here. Rats treated with FBM displayed a deficit in acquiring a tone-signaled avoidance response, relative to controls, but this was true only if they had no prior appetitive experience. Terminal avoidance behavior was equivalent to healthy controls. In contrast, the FBM-treated rats showed enhanced acquisition of the avoidance response relative to controls when given the benefit of prior experience in the appetitive condition. Relative to animals treated with phenytoin, carbamazepine, or valproate, FBM-treated rats showed the lowest overall pattern of deficits using these instrumental learning tasks. While FBM treatment has been severely restricted because of rather low risks of serious medical side effects, we suggest that the risks are not substantially higher than those shown to exist for phenytoin, carbamazepine, or valproate. As psychologists, we further suggest that negative cognitive deficits associated with these various drugs, along with their quality-of-life costs, are of relevance in the design of treatment strategies for individuals with seizure disorders.


Assuntos
Anticonvulsivantes/farmacologia , Comportamento Apetitivo/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Cognição/efeitos dos fármacos , Condicionamento Operante , Fenilcarbamatos/farmacologia , Propilenoglicóis/farmacologia , Animais , Carbamazepina/farmacologia , Felbamato , Feminino , Fenitoína/farmacologia , Ratos , Ratos Sprague-Dawley , Ácido Valproico/farmacologia
14.
Cochrane Database Syst Rev ; 7: CD008295, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28718506

RESUMO

BACKGROUND: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2014) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and we have assessed its effects as an add-on therapy to standard drugs in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: For the latest update we searched the Cochrane Epilepsy Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform, up to 20 October 2016. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomised placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: We included four randomised controlled trials with a total of 236 participants. Two trials were parallel design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. Two studies were at an unclear risk of bias for random sequence generation and allocation concealment. These two studies did not include any description of their methods for outcome assessment and performance blinding (i.e. participants or doctors). Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. Only one study reported 50% or greater reduction in seizure frequency. One study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. One study reported percentage reduction in seizure frequency compared to placebo, but there were no P values. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/uso terapêutico , Anticonvulsivantes/efeitos adversos , Resistência a Medicamentos , Felbamato , Humanos , Fenilcarbamatos/efeitos adversos , Propilenoglicóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
J Crit Care ; 36: 116-124, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27546759

RESUMO

OBJECTIVES: The aim of this review was to evaluate current literature for dosing recommendations for the use of antiepileptic medications in patients receiving renal replacement therapy (RRT). DATA SOURCES: With the assistance of an experienced medical librarian specialized in pharmacy and toxicology, we searched MEDLINE, EMBASE, CINAHL, Web of Science, WorldCat, and Scopus through May 2016. STUDY SELECTION AND DATA EXTRACTION: Four hundred three articles were screened for inclusion, of which 130 were identified as potentially relevant. Micromedex® DRUGDEX as well as package inserts were used to obtain known pharmacokinetic properties and dosage adjustment recommendations in RRT if known. DATA SYNTHESIS: Data regarding antiepileptic drug use in RRT are limited and mostly consist of case reports limiting our proposed dosing recommendations. Known pharmacokinetic parameters should guide dosing, and recommendations are provided where possible. CONCLUSION: Additional studies are necessary before specific dosing recommendations can be made for most antiepileptic drugs in critically ill patients receiving RRT, specifically with newer agents.


Assuntos
Injúria Renal Aguda/terapia , Anticonvulsivantes/administração & dosagem , Diálise Renal , Convulsões/tratamento farmacológico , Acetamidas/administração & dosagem , Injúria Renal Aguda/complicações , Aminas/administração & dosagem , Anticonvulsivantes/efeitos adversos , Carbamatos/administração & dosagem , Estado Terminal , Ácidos Cicloexanocarboxílicos/administração & dosagem , Dibenzazepinas/administração & dosagem , Relação Dose-Resposta a Droga , Etossuximida/administração & dosagem , Felbamato , Frutose/administração & dosagem , Frutose/análogos & derivados , Gabapentina , Humanos , Isoxazóis/administração & dosagem , Lacosamida , Lamotrigina , Levetiracetam , Fenobarbital/administração & dosagem , Fenilcarbamatos/administração & dosagem , Fenilenodiaminas/administração & dosagem , Fenitoína/administração & dosagem , Piracetam/administração & dosagem , Piracetam/análogos & derivados , Propilenoglicóis/administração & dosagem , Terapia de Substituição Renal , Convulsões/complicações , Topiramato , Triazinas/administração & dosagem , Ácido Valproico/administração & dosagem , Zonisamida , Ácido gama-Aminobutírico/administração & dosagem
16.
Epilepsy Behav ; 56: 50-3, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26828692

RESUMO

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500 mg (mean: 1800 ± 900 mg). The duration of therapy ranged from 1 month to 20 years (mean duration: 35 ± 45 months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved ≥ 50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.


Assuntos
Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Fenilcarbamatos/efeitos adversos , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/efeitos adversos , Propilenoglicóis/uso terapêutico , Convulsões/tratamento farmacológico , Adolescente , Adulto , Idade de Início , Anemia Aplástica/induzido quimicamente , Criança , Estudos de Coortes , Rotulagem de Medicamentos , Felbamato , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
17.
Expert Rev Neurother ; 15(12): 1373-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26566191

RESUMO

Felbamate has been approved for refractory partial seizures since the early nineties. Due to safety concerns regarding its use, namely, in aplastic anemia and hepatic failure, felbamate's use has been restricted and a 'Black Box' warning has been inserted. Nonetheless, it is a useful drug in refractory cases of partial epilepsy. There are certain precautions which can prevent and minimize the serious idiosyncratic reactions associated with felbamate, thereby providing an option in refractory cases where no other drug works.


Assuntos
Anemia Aplástica/etiologia , Epilepsias Parciais/tratamento farmacológico , Falência Hepática/etiologia , Fenilcarbamatos/efeitos adversos , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/efeitos adversos , Propilenoglicóis/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Felbamato , Humanos
18.
Pediatr Neurol ; 53(6): 527-31, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26421989

RESUMO

BACKGROUND: Mutations of SLC9A6 may cause an X-linked clinical syndrome first described by Christianson in 1999 in which affected males exhibited profound intellectual disability, autism, drug-resistant epilepsy, ophthalmoplegia, mild craniofacial dysmorphism, microcephaly, and ataxia. METHODS: We describe a child with an SLC9A6 mutation and an electroencephalographic pattern consistent with electrographic status epilepticus of sleep. RESULTS: Our patient's electrographic status epilepticus of sleep resolved after treatment with felbamate. Following treatment, he remained seizure-free but did not make significant or lasting gains in language. CONCLUSION: Our report extends the clinical epilepsy phenotype in children with SLC9A6 mutations to include electrographic status epilepticus of sleep. In addition, felbamate was an effective treatment for electrographic status epilepticus of sleep in our patient.


Assuntos
Anticonvulsivantes/farmacologia , Ataxia/complicações , Epilepsia/complicações , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Deficiência Intelectual/complicações , Microcefalia/complicações , Transtornos da Motilidade Ocular/complicações , Fenilcarbamatos/farmacologia , Propilenoglicóis/farmacologia , Transtornos do Sono-Vigília/tratamento farmacológico , Trocadores de Sódio-Hidrogênio/genética , Estado Epiléptico/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Ataxia/genética , Criança , Epilepsia/genética , Felbamato , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Transtornos da Motilidade Ocular/genética , Fenilcarbamatos/administração & dosagem , Propilenoglicóis/administração & dosagem , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/genética , Estado Epiléptico/etiologia , Estado Epiléptico/genética , Resultado do Tratamento
19.
Cochrane Database Syst Rev ; (7): CD008295, 2014 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-25036694

RESUMO

BACKGROUND: This review is an update of a previously published review in The Cochrane Database of Systematic Reviews (Issue 1, 2011) on 'Felbamate as an add-on therapy for refractory epilepsy'. Epilepsy is a chronic and disabling neurologic disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second-generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (24 July 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), and PubMed (24 July 2013). This search was run for the original review on 20 May 2010. There were no language and time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. We resolved disagreements by discussion. If disagreements persisted, the third review author arbitrated. We assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: Three randomised controlled trials with a total of 153 participants were included. The first was a parallel design, the second had a two-period crossover design, and the third had a three-period crossover design. One study was at unclear risk of bias for random sequence generation and allocation concealment. And in the same study, there was no description of how to blind outcome assessment, performance blinding was for participants, might not be for doctors. Two studies were at high risk of bias for incomplete outcome data. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.Since the last version of this review no new studies have been found.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/uso terapêutico , Anticonvulsivantes/efeitos adversos , Felbamato , Humanos , Fenilcarbamatos/efeitos adversos , Propilenoglicóis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Eur J Paediatr Neurol ; 18(6): 658-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24906615

RESUMO

BACKGROUND: Despite the introduction of multiple new antiepileptic drugs in the past two decades, many patients with epilepsy continue to experience uncontrolled seizures or significant side effects. AIM: To present our experience with felbamate therapy in children with drug-resistant epilepsy. METHODS: We retrospectively reviewed the medical charts and video-EEG recordings of all patients receiving felbamate until May 2012. Efficacy was determined according to seizure frequency during the week prior to treatment initiation and the week after the maximal dosage of felbamate was reached. RESULTS: Fifty patients (34 boys) aged 4 months to 17 years (mean--5.5 years) were identified. Nearly third of the patients had Lennox-Gastaut syndrome. Mean epilepsy duration was 3.4 years (range--1 month to 13 years). The mean number of previous antiepileptic drugs was 7.5. The mean duration of follow-up was 1.1 years. Seizure frequency decreased by at least 50% in 29 (58%) patients. Side effects were reported in 22 (44%) patients, none of them included aplastic anemia or liver failure. In the responder group, the maximal dose of felbamate was lower and the patients were older compared to non-responders. CONCLUSIONS: Despite current recommendations, felbamate is initiated following multiple AEDs. Based on its efficacy and safety data, earlier initiation of felbamate is recommended in children with refractory epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Fenilcarbamatos/uso terapêutico , Propilenoglicóis/uso terapêutico , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/fisiopatologia , Felbamato , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Gravação em Vídeo
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