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1.
Medicine (Baltimore) ; 98(31): e16674, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374046

RESUMO

BACKGROUND AND OBJECTIVE: A recent striking advance in the treatment of depression has been the finding of rapid antidepressant effects in over 70% of patients with treatment-resistant depression (TRD) using ketamine. However, the potential risk of addiction may limit its clinical use. Recent research revealed that blockade of N-methyl-D-aspartate receptor (NMDAR) dependent bursting activity in the lateral habenula (LHb) could mediate the fast antidepressant effects of ketamine. Further, LHb bursting plays an important role in the pathophysiology of depression that requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Ethosuximide, which is used to treat absence seizures, is a T-VSCCs inhibitor, may be a novel drug candidate for depression. The objective of this clinical trial is to investigate the efficacy and safety of ethosuximide in patients with TRD. DESIGN: The study is a single center, randomized, double-blind, placebo-controlled, parallel-group, two-stage clinical trial. Forty patients with TRD will be randomly assigned to Group A (treatment group) or Group B (control group). In the first stage ethosuximide or placebo will be given for 2 weeks. In the second stage, escitalopram (or another antidepressant if escitalopram has been used before) will be given for the next 4 weeks for all trial patients to ensure effective treatment. The primary outcome measure is the Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Secondary outcome measures include the Quick Inventory of Depressive Symptomatology-Self Report score, Hamilton Anxiety Rating Scale scores, individual scores of MADRS, and Young Mania Rating Scale scores. All these scales are measured at baseline and at each treatment visit. Two-way repeated measures analysis of variance is used to analyze the study outcomes. DISCUSSION: A statistical analysis plan is employed to enhance the transparency of the clinical trial and reduce the risks of outcome reporting bias and data-driven results.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Etossuximida/uso terapêutico , Método Duplo-Cego , Etossuximida/farmacologia , Humanos , Escalas de Graduação Psiquiátrica , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
2.
Expert Opin Pharmacother ; 20(17): 2115-2120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446808

RESUMO

Introduction: Atypical absences are generalized epileptic seizures typically affecting children with severe epilepsies and learning difficulties along with other seizure types. Video-EEG is essential for their diagnosis. Recently, atypical absence seizures have been reported as a hallmark of some developmental and epileptic encephalopathies.Areas covered: This is a narrative review of the literature which describes the electroclinical features of atypical seizures, the characteristics of developmental epileptic encephalopathies in which this seizure type can occur, and the evidence supporting the use of individual antiseizure drugs for the treatment of atypical absences.Expert opinion: Treatment of absence seizures typically relies on ethosuximide (ineffective against tonic-clonic seizures), valproate (associated with larger proportion of adverse events), or lamotrigine (less effective than the other two). However, unlike typical absences, atypical absences are usually intractable, persist lifetime, and their prognosis depends on the underlying etiology or associated epilepsy syndrome. Besides efficacy, other relevant factors, such as drug formulation, ease of titration and dosing, and drug interactions, should be considered. Drugs that may worsen epilepsy, cognition and behavior should be avoided. In the vast majority of patients, a polytherapy is required, although usually with limited efficacy. Finally, epilepsy syndromes featuring atypical absences require a multidisciplinary approach.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Generalizada/tratamento farmacológico , Etossuximida/uso terapêutico , Humanos , Lamotrigina/uso terapêutico , Síndrome de Lennox Gastaut/tratamento farmacológico , Síndrome de Lennox Gastaut/patologia , Ácido Valproico/uso terapêutico , Proteínas Ativadoras de ras GTPase/genética , Proteínas Ativadoras de ras GTPase/metabolismo
3.
Pediatr Dermatol ; 36(4): e99-e101, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31132165

RESUMO

Lymphadenopathy is a common sign for drug reaction and eosinophilia with systemic symptoms (DRESS) syndrome, but hilar and mediastinal lymphadenopathy may be underreported. We describe a 7-year-old boy who started taking ethosuximide for absence seizures and presented with diffuse rash, fever, elevated transaminases, facial swelling, and hilar and mediastinal lymphadenopathy. His mediastinal lymphadenopathy was concerning for lymphoma, which led to more invasive testing to rule out malignancy. This report highlights an unusual and likely underreported presenting sign of DRESS syndrome in children.


Assuntos
Corticosteroides/uso terapêutico , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/efeitos adversos , Linfadenopatia/induzido quimicamente , Biópsia por Agulha , Criança , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Síndrome de Hipersensibilidade a Medicamentos/patologia , Eosinofilia/induzido quimicamente , Eosinofilia/fisiopatologia , Epilepsia Tipo Ausência/diagnóstico , Etossuximida/uso terapêutico , Seguimentos , Humanos , Imuno-Histoquímica , Linfadenopatia/patologia , Linfadenopatia/fisiopatologia , Masculino , Mediastino/patologia , Recidiva , Medição de Risco
4.
Neurología (Barc., Ed. impr.) ; 34(4): 224-228, mayo 2019. tab
Artigo em Espanhol | IBECS | ID: ibc-180811

RESUMO

Introducción: La epilepsia ausencia infantil (EAI) se considera una forma de epilepsia de fácil control farmacológico solo si se emplean criterios estrictos para la clasificación de los pacientes. Supone el 10% de las epilepsias infantiles de inicio antes de los 15 años y es más frecuente en niñas escolares. El objetivo es conocer la evolución a largo plazo de los pacientes atendidos en la etapa infantil con EAI empleando los criterios de Loiseau y Panayiotopoulos Métodos: Estudio retrospectivo de 69 pacientes con EAI con edad actual mayor de 11 años, realizado mediante revisión de historias clínicas, EEG y cuestionario telefónico. Resultados: Cumplieron los criterios de Loiseau y Panayiotopoulos 52 pacientes, edad actual media 17,61 años. Relación mujeres/hombres: 1,65/1; edad de inicio media: 6 años y 2 meses; duración total de tratamiento media: 3 años y 9 meses; antecedentes familiares de epilepsia: 30,8%; antecedentes personales de crisis febriles: 7,7%; tipo de ausencias: simples 73,5%, complejas: 26,5%; respuesta al primer tratamiento: ácido valproico 46,3% o ácido valproico con etosuximida simultáneos 90,9%; respuesta al segundo tratamiento (etosuximida o lamotrigina) 84,2%; crisis tras supresión de tratamiento: 4%; pacientes en remisión terminal: 78,8%; necesidad de apoyo psicopedagógico: 25%. Conclusiones: Nuestros datos muestran la utilidad de clasificar a los pacientes utilizando criterios estrictos ya que el pronóstico de las crisis del síndrome de EAI puro es excelente. Encontramos que la tasa de recaídas ha sido muy baja. A pesar del favorable pronóstico en cuanto al control de crisis necesitan apoyos psicopedagógicos en un alto porcentaje


Introduction: Childhood absence epilepsy (CAE) is considered easily manageable with medication provided that a strict patient classification system is employed. It accounts for 10% of all childhood epilepsy cases starting before the age of 15 and it is most frequent in school-aged girls. The aim of this study is to analyse long-term outcomes of patients diagnosed with CAE according to the Loiseau and Panayiotopoulos criteria and treated during childhood. Methods: We conducted a retrospective study including 69 patients with CAE who are currently older than 11; data were gathered from medical histories, EEG records, and telephone questionnaires. Results: 52 patients met the Loiseau and Panayiotopoulos criteria. Mean age is now 17.16 years. Female-to-male ratio was 1.65:1; mean age at onset was 6 years and 2 months; mean duration of treatment was 3 years and 9 months. A family history of epilepsy was present in 30.8% of the patients and 7.7% had a personal history of febrile convulsions. Absence seizures were simple in 73.5% of the patients and complex in 26.5%. Response rates to first-line treatment were as follows: valproic acid, 46.3%; and valproic acid plus ethosuximide, 90.9%. The rate of response to second-line therapy (ethosuximide or lamotrigine) was 84.2%; 4% of the patients experienced further seizures after treatment discontinuation, 78.8% achieved seizure remission, and 25% needed psychological and academic support. Conclusions: Our data show that epileptic patients should be classified according to strict diagnostic criteria since patients with true CAE have an excellent prognosis. The relapse rate was very low in our sample. Despite the favourable prognosis, psychological and academic support is usually necessary


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Epilepsia Tipo Ausência/epidemiologia , Ácido Valproico/uso terapêutico , Anticonvulsivantes/uso terapêutico , Etossuximida/uso terapêutico , Epilepsia Tipo Ausência/tratamento farmacológico , Estudos Retrospectivos , Assistência de Longa Duração/estatística & dados numéricos , Epilepsia Generalizada/epidemiologia
5.
Epilepsy Res ; 152: 7-10, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30856420

RESUMO

We retrospectively analyzed published studies to investigate historical trends in outcome of childhood absence epilepsy (CAE). We included patients based on onset of absence seizures in childhood, 3 Hz bilateral spike-wave discharges on EEG, and availability of seizure-free outcome data. The primary endpoint was seizure-freedom off medications by study publication year. We also analyzed relationships between seizure-freedom and 1. treatment medication, and 2. CAE diagnostic criteria. We included 29 studies published 1945-2013, encompassing 2416 patients. Seizure-freedom off medications was higher for studies after 1985 versus before 1975 (82% versus 35%; p < 0.001). Ethosuximide and valproate were used more commonly after 1985, and patients previously treated with ethosuximide or valproate had higher seizure-freedom off medications than those treated only with other medications (64% versus 32%; χ2>10; p < 0.001). Although differences in diagnostic criteria for early vs. later studies did not reach statistical significance, later studies tended to use normal EEG background (p = 0.09) and absence of comorbid disorders (p = 0.09) as criteria more commonly. These findings demonstrate that seizure-freedom off medications has improved in published CAE studies after 1985. Our results are limited due to retrospective analysis. Further work is needed with prospective, controlled trials to establish factors leading to improved long-term prognosis in CAE.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Resultado do Tratamento , Ácido Valproico/uso terapêutico , Anticonvulsivantes/história , Criança , Pré-Escolar , Etossuximida/história , Feminino , História do Século XXI , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Ácido Valproico/história
6.
Paediatr Drugs ; 21(1): 15-24, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30734897

RESUMO

Childhood absence epilepsy (CAE) is a common pediatric epilepsy syndrome with distinct seizure semiology, electroencephalography (EEG) features, and treatment. A diagnosis of CAE can be obtained during an office visit with a careful history, physical exam including prolonged hyperventilation, and a routine EEG. The treatment of choice for CAE with absence seizures only is ethosuximide. Valproic acid and lamotrigine are also effective treatments for many patients, but when compared to ethosuximide, valproic acid has more adverse effects and lamotrigine is less effective. Attention to predictors of response to treatment, including clinical, electrographic, and genetic factors, is increasing. Refractory CAE occurs in fewer than half of patients, and treatment strategies are available, though efficacy data are lacking. Careful assessment and treatment of psychosocial comorbidities is essential in caring for patients with CAE.


Assuntos
Epilepsia Tipo Ausência/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Eletroencefalografia , Epilepsia Tipo Ausência/diagnóstico , Etossuximida/uso terapêutico , Feminino , Humanos , Lamotrigina/uso terapêutico , Masculino , Guias de Prática Clínica como Assunto , Convulsões/tratamento farmacológico , Resultado do Tratamento , Ácido Valproico/uso terapêutico
7.
Cochrane Database Syst Rev ; 2: CD003032, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30734919

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2017.Absence seizures (AS) are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with AS. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures (AS), when compared with placebo or each other. SEARCH METHODS: For the latest update we searched the Cochrane Register of Studies (CRS Web, 29 May 2018), which includes the Cochrane Epilepsy Group's Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to 29 May 2018), ClinicalTrials.gov (29 May 2018) and the WHO International Clinical Trials Registry Platform (ICTRP, 29 May 2018). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014), but this is no longer necessary because randomised controlled trials (RCTs) and quasi-RCTs in Embase and SCOPUS are now included in CENTRAL. No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with AS: ethosuximide, sodium valproate, lamotrigine, or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). We used GRADE quality assessment criteria to evaluate the certainty of evidence derived from all included studies. MAIN RESULTS: On the basis of our selection criteria, we included no new studies in the present review. Eight small trials (total number of participants: 691) were included from the earlier review. Six of them were of poor methodological quality (unclear or high risk of bias) and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from RCTs to support a specific effect on AS for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in 453 children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the valproic acid group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and valproic acid compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. The risk of bias for this study was low. We rated the overall certainty of the evidence available from the included studies to be moderate or high. AUTHORS' CONCLUSIONS: Since the last version of this review was published, we have found no new studies. Hence, the conclusions remain the same as the previous update. With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with AS. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Lamotrigina/uso terapêutico , Ácido Valproico/uso terapêutico , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Etossuximida/efeitos adversos , Humanos , Lamotrigina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Valproico/efeitos adversos
8.
Neurologia ; 34(4): 224-228, 2019 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28325560

RESUMO

INTRODUCTION: Childhood absence epilepsy (CAE) is considered easily manageable with medication provided that a strict patient classification system is employed. It accounts for 10% of all childhood epilepsy cases starting before the age of 15 and it is most frequent in school-aged girls. The aim of this study is to analyse long-term outcomes of patients diagnosed with CAE according to the Loiseau and Panayiotopoulos criteria and treated during childhood. METHODS: We conducted a retrospective study including 69 patients with CAE who are currently older than 11; data were gathered from medical histories, EEG records, and telephone questionnaires. RESULTS: 52 patients met the Loiseau and Panayiotopoulos criteria. Mean age is now 17.16 years. Female-to-male ratio was 1.65:1; mean age at onset was 6 years and 2 months; mean duration of treatment was 3 years and 9 months. A family history of epilepsy was present in 30.8% of the patients and 7.7% had a personal history of febrile convulsions. Absence seizures were simple in 73.5% of the patients and complex in 26.5%. Response rates to first-line treatment were as follows: valproic acid, 46.3%; and valproic acid plus ethosuximide, 90.9%. The rate of response to second-line therapy (ethosuximide or lamotrigine) was 84.2%; 4% of the patients experienced further seizures after treatment discontinuation, 78.8% achieved seizure remission, and 25% needed psychological and academic support. CONCLUSIONS: Our data show that epileptic patients should be classified according to strict diagnostic criteria since patients with true CAE have an excellent prognosis. The relapse rate was very low in our sample. Despite the favourable prognosis, psychological and academic support is usually necessary.


Assuntos
Epilepsia Tipo Ausência/diagnóstico , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Progressão da Doença , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Ácido Valproico/uso terapêutico
9.
J Pharmacol Sci ; 137(2): 162-169, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29945769

RESUMO

We previously showed that nicotine evoked kinetic tremor by activating the inferior olive, which is implicated in the pathogenesis of essential tremor, via α7 nicotinic acetylcholine receptors. Here, we evaluated the effects of various anti-tremor and anti-epileptic agents on nicotine-induced tremor in mice to clarify the pharmacological characteristics of nicotine tremor. Drugs effective for essential tremor, propranolol, diazepam and phenobarbital, all significantly inhibited kinetic tremor induced by an intraperitoneal (i.p.) injection of nicotine (1 mg/kg). In contrast, none of the medications for Parkinson's disease, l-DOPA, bromocriptine or trihexyphenidyl, affected the nicotine tremor. Among the anti-epileptic agents examined, valproate, carbamazepine and ethosuximide, significantly inhibited nicotine-induced tremor. In addition, a selective T-type Ca2+ channel blocker, TTA-A2, also suppressed the nicotine tremor. However, neither gabapentin, topiramate, zonisamide nor levetiracetam significantly affected nicotine-induced tremor. The present results show that nicotine-induced tremor resembles essential tremor not only on the neural basis, but also in terms of the pharmacological responses to anti-tremor agents, implying that nicotine-induced tremor can serve as a model for essential tremor. In addition, it is suggested that anti-epileptic agents, which have stimulant actions on the GABAergic system or blocking actions on voltage-gated Na+ channels and T-type Ca2+ channels, can alleviate essential tremor.


Assuntos
Anticonvulsivantes/uso terapêutico , Benzenoacetamidas/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Carbamazepina/uso terapêutico , Diazepam/uso terapêutico , Modelos Animais de Doenças , Tremor Essencial/induzido quimicamente , Tremor Essencial/tratamento farmacológico , Etossuximida/uso terapêutico , Nicotina/efeitos adversos , Fenobarbital/uso terapêutico , Propranolol/uso terapêutico , Piridinas/uso terapêutico , Ácido Valproico/uso terapêutico , Animais , Antiparkinsonianos/uso terapêutico , Masculino , Camundongos Endogâmicos
10.
Epilepsia ; 59(5): 971-981, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29633248

RESUMO

OBJECTIVE: The understanding of childhood absence epilepsy (CAE) has been revolutionized over the past decade, but the biological mechanisms responsible for variable treatment outcomes are unknown. Our purpose in this prospective observational study was to determine how pretreatment ictal network pathways, defined using a combined electroencephalography (EEG)-functional magnetic resonance imaging (EEG-fMRI) and magnetoencephalography (MEG) effective connectivity analysis, were related to treatment response. METHODS: Sixteen children with newly diagnosed and drug-naive CAE had 31 typical absence seizures during EEG-fMRI and 74 during MEG. The spatial extent of the pretreatment ictal network was defined using fMRI hemodynamic response with an event-related independent component analysis (eICA). This spatially defined pretreatment ictal network supplied prior information for MEG-effective connectivity analysis calculated using phase slope index (PSI). Treatment outcome was assessed 2 years following diagnosis and dichotomized to ethosuximide (ETX)-treatment responders (N = 11) or nonresponders (N = 5). Effective connectivity of the pretreatment ictal network was compared to the treatment response. RESULTS: Patterns of pretreatment connectivity demonstrated strongest connections in the thalamus and posterior brain regions (parietal, posterior cingulate, angular gyrus, precuneus, and occipital) at delta frequencies and the frontal cortices at gamma frequencies (P < .05). ETX treatment nonresponders had pretreatment connectivity, which was decreased in the precuneus region and increased in the frontal cortex compared to ETX responders (P < .05). SIGNIFICANCE: Pretreatment ictal connectivity differences in children with CAE were associated with response to antiepileptic treatment. This is a possible mechanism for the variable treatment response seen in patients sharing the same epilepsy syndrome.


Assuntos
Encéfalo/fisiopatologia , Resistência a Medicamentos/fisiologia , Epilepsia Tipo Ausência/fisiopatologia , Vias Neurais/fisiopatologia , Anticonvulsivantes/uso terapêutico , Criança , Eletroencefalografia , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Feminino , Humanos , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Resultado do Tratamento
11.
Eur J Pain ; 22(7): 1321-1330, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29577519

RESUMO

BACKGROUND: T-type calcium channels have been shown to play an important role in the initiation and maintenance of neuropathic pain and represent a promising therapeutic target for new analgesic treatments. Ethosuximide (ETX), an anticonvulsant and a T-type channel blocker has shown analgesic effect in several chronic pain models but has not yet been evaluated in patients with neuropathic pain. METHODS: This proof-of-concept, multicentre, double-blind, controlled and randomized trial compared the efficacy and safety of ETX (given as add-on therapy) to an inactive control (IC) in 114 patients with non-diabetic peripheral neuropathic pain. After a 7-day run-in period, eligible patients aged over 18 years were randomly assigned (1:1) to ETX or IC for 6 weeks. The primary outcome was the difference between groups in the pain intensity (% of change from the baseline to end of treatment) assessed in the intention-to-treat population. This study is registered with EudraCT (2013-004801-26) and ClinicalTrials.gov (NCT02100046). RESULTS: The study was stopped during the interim analysis due to the high number of adverse events in the active treatment group. ETX failed to reduce total pain and showed a poor tolerance in comparison to IC. In the per-protocol analysis, ETX significantly reduced pain intensity by 15.6% (95% CI -25.8; -5.4) from baseline compared to IC (-7.8%, 95% CI -14.3; -1.3; p = 0.033), but this result must be interpreted with caution because of a small subgroup of patients. CONCLUSION: Ethosuximide did not reduce the severity of neuropathic pain and induces, at the doses used, many adverse events. SIGNIFICANCE: This article shows that ETX is not effective to treat neuropathic pain. Nevertheless, per-protocol analysis suggests a possible analgesic effect of ETX. Thus, our work adds significant knowledge to preclinical and clinical data on the benefits of T-type calcium channel inhibition for the treatment of neuropathic pain.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Dor Crônica/tratamento farmacológico , Etossuximida/uso terapêutico , Neuralgia/tratamento farmacológico , Adulto , Idoso , Analgésicos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito
12.
Epilepsia ; 59(2): 297-314, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29270989

RESUMO

OBJECTIVE: To estimate the comparative efficacy among antiepileptic drugs in the pediatric population (0-18 years). METHODS: Using the Embase and MEDLINE databases, we updated to February 2017 the search strategy of the National Institute for Health and Care Excellence guidelines for epilepsy. We only included randomized clinical trials conducted in children and mixed-age populations. According to the PRISMA network meta-analysis guideline, the study-level quality assessment was made with the Cochrane risk-of-bias tool. Three investigators independently selected articles. The efficacy outcome was considered to be seizure freedom or ≥50% seizure reduction. RESULTS: We selected 46 randomized clinical trials. A total of 5652 individuals were randomized to 22 antiepileptic drugs and placebo. The point estimates of carbamazepine and lamotrigine efficacy showed their superiority with respect to all comparator antiepileptic drugs for the treatment of newly diagnosed focal epilepsy. In refractory focal epilepsy, levetiracetam (odds ratio [OR] = 3.3, 95% credible interval [CrI] = 1.3-7.6) and perampanel (OR = 2.5, 95% CrI = 1.1-5.8) were more effective compared to placebo. Ethosuximide and valproic acid were both superior to lamotrigine against absence seizures. The OR point estimate showed the superiority of adrenocorticotropic hormone over all comparators in infantile spasms. A wide heterogeneity in the length of follow-up was observed among the studies. SIGNIFICANCE: This network meta-analysis suggests that the quality of studies should be improved through the use of comparative designs, relevant outcomes, appropriate follow-up length, and more reliable inclusion criteria.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Adolescente , Corticosteroides/uso terapêutico , Hormônio Adrenocorticotrópico/uso terapêutico , Carbamazepina/uso terapêutico , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsias Parciais/tratamento farmacológico , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Hormônios/uso terapêutico , Humanos , Lactente , Lamotrigina , Levetiracetam , Metanálise em Rede , Razão de Chances , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Piridonas/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico
13.
BMJ Case Rep ; 20172017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29222216

RESUMO

A 50-year-old man with known multidrug resistant coexistent focal and generalised epilepsy was commenced on ethosuximide, with normalisation of his electroencephalogram and cessation of absence seizures. Within 3 weeks, he developed a rapidly worsening paranoid psychosis with visual and olfactory hallucinations. A month after the cessation of ethosuximide and concurrent treatment with olanzapine, his psychosis resolved and permitted reinitiation of ethosuximide at a lower dose without recurrence of psychotic symptoms.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Etossuximida/uso terapêutico , Alucinações/diagnóstico , Transtornos Psicóticos/diagnóstico , Anticonvulsivantes/efeitos adversos , Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Diagnóstico Diferencial , Eletroencefalografia , Epilepsia/fisiopatologia , Etossuximida/efeitos adversos , Alucinações/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Transtornos Psicóticos/etiologia
14.
J Physiol ; 595(23): 7249-7260, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28901011

RESUMO

KEY POINTS: In two monogenic models of absence epilepsy, interictal beta/gamma power is augmented in homozygous stargazer (stg/stg) but not homozygous tottering (tg/tg) mice. There are distinct gene-linked patterns of aberrant phase-amplitude coupling in the interictal EEG of both stg/stg and tg/tg mice, compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both genotypes, but the abnormal phase-amplitude coupling remains. Seizure-free stg/+ mice have normal power and phase-amplitude coupling, but beta/gamma power is significantly reduced with NMDA receptor blockade, revealing a latent cortical network phenotype that is separable from, and therefore not a result of, seizures. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers free from epileptiform activity, and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment. ABSTRACT: In childhood absence epilepsy, cortical seizures are brief and intermittent; however there are extended periods without behavioural or electrographic ictal events. This genetic disorder is associated with variable degrees of cognitive dysfunction, but no consistent functional biomarkers that might provide insight into interictal cortical function have been described. Previous work in monogenic mouse models of absence epilepsy have shown that the interictal EEG displays augmented beta/gamma power in homozygous stargazer (stg/stg) mice bearing a presynaptic AMPA receptor defect, but not homozygous tottering (tg/tg) mice with a P/Q type calcium channel mutation. To further evaluate the interictal EEG, we quantified phase-amplitude coupling (PAC) in stg/stg, stg/+, tg/tg and wild-type (+/+) mice. We found distinct gene-linked patterns of aberrant PAC in stg/stg and tg/tg mice compared to +/+ and stg/+ mice. Treatment with ethosuximide significantly blocks seizures in both stg/stg and tg/tg, but the abnormal PAC remains. Stg/+ mice are seizure free with normal baseline beta/gamma power and normal theta-gamma PAC, but like stg/stg mice, beta/gamma power is significantly reduced by NMDA receptor blockade, a treatment that paradoxically enhances seizures in stg/stg mice. Stg/+ mice, therefore, have a latent cortical network phenotype that is veiled by NMDA-mediated neurotransmission. Altogether, these findings reveal gene-linked quantitative electrographic biomarkers in the absence of epileptiform activity and provide a potential network correlate for persistent cognitive deficits in absence epilepsy despite effective treatment.


Assuntos
Anticonvulsivantes/farmacologia , Ondas Encefálicas , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/farmacologia , Genótipo , Animais , Anticonvulsivantes/uso terapêutico , Canais de Cálcio/genética , Canais de Cálcio Tipo N/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/genética , Etossuximida/uso terapêutico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Neurology ; 89(16): 1698-1706, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-28916534

RESUMO

OBJECTIVE: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE). METHODS: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure. RESULTS: A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]). CONCLUSIONS: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE. CLINICALTRIALSGOV IDENTIFIER: NCT00088452. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.


Assuntos
Anticonvulsivantes/uso terapêutico , Transtornos do Comportamento Infantil/etiologia , Epilepsia Tipo Ausência/complicações , Epilepsia Tipo Ausência/tratamento farmacológico , Adolescente , Lista de Checagem , Criança , Transtornos do Comportamento Infantil/diagnóstico , Transtornos do Comportamento Infantil/tratamento farmacológico , Pré-Escolar , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia , Etossuximida/uso terapêutico , Feminino , Seguimentos , Humanos , Lamotrigina , Masculino , Testes Neuropsicológicos , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico
16.
BMJ Open ; 7(7): e015380, 2017 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720615

RESUMO

INTRODUCTION: Irritable bowel syndrome (IBS) is characterised by the association of abdominal chronic pain with bowel habit disorders in the absence of identifiable organic disease. This is the first reason for consultation in gastroenterology, with an estimated prevalence of 10%-15% in industrialised countries. Although this is a benign gastrointestinal disease, its chronicity profoundly impacts the patient's quality of life and causes considerable health spending. Actual medical treatments are poorly efficient on IBS-related abdominal pain, making it a major public health concern. The mechanisms causing IBS symptoms are unknown. Recent studies have shown the involvement of T-type channel in abdominal pain. We aim to evaluate the therapeutic potential of ethosuximide, a T-type channel blocker, on the abdominal pain of patients presenting an IBS. METHODS AND ANALYSIS: The IBSET trial is a randomised, controlled, parallel, double-blind and multicentre study. It is the first clinical trial evaluating the efficacy and safety of ethosuximide on abdominal pain related to IBS. Adults with IBS that report significant abdominal pain (≥4/10) at least for 3 months will be included. 290 patients will be randomly assigned to receive either ethosuximide or placebo over 12 weeks after 1 week of run-in period. The primary endpoint is the rate of responders (pain reduction ≥30% and Subject Global Assessment of Relief score ≥4). The intensity of abdominal pain will be assessed by an 11-point Numerical Rating Scale before and after 12 weeks of treatment and the score of the Subject Global Assessment of Relief scale at the end of treatment. The secondary endpoints are the safety of ethosuximide, the intensity and features of IBS and quality of life. ETHICS AND DISSEMINATION: The study was approved by an independent medical ethics committee (CPP Sud-Est VI, Clermont-Ferrand, France). The results will be published in a peer-review journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT02973542; Pre-results.


Assuntos
Dor Abdominal/tratamento farmacológico , Dor Crônica/tratamento farmacológico , Etossuximida/uso terapêutico , Síndrome do Intestino Irritável/fisiopatologia , Dor Abdominal/etiologia , Dor Crônica/etiologia , Método Duplo-Cego , França , Humanos , Medição da Dor , Qualidade de Vida , Análise de Regressão , Projetos de Pesquisa , Resultado do Tratamento
18.
Ugeskr Laeger ; 179(13)2017 Mar 27.
Artigo em Dinamarquês | MEDLINE | ID: mdl-28397652

RESUMO

Until now, ethosuximide (ESM), sodium valproate (VPA) and lamotrigine have been considered the drugs of choice in the management of childhood absence epilepsy, and there has been no high-validated evidence to distinguish their effects. New research shows, however, that while VPA and ESM are equally effective, ESM is the best tolerated of the two drugs, when considering cognitive adverse effects. This is of major importance, as cognitive comorbidities can be dire in childhood absence epilepsy, possibly affecting the psychosocial prognosis of the patients. More research is needed in this area.


Assuntos
Epilepsia Tipo Ausência , Anticonvulsivantes/uso terapêutico , Criança , Transtornos Cognitivos/epidemiologia , Comorbidade , Eletroencefalografia , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/epidemiologia , Epilepsia Tipo Ausência/fisiopatologia , Etossuximida/uso terapêutico , Medicina Baseada em Evidências , Humanos , Prognóstico , Ácido Valproico/uso terapêutico
19.
J AAPOS ; 21(3): 257-258, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28359767

RESUMO

A healthy 7-year-old boy presented with bilateral symmetrical lacrimal gland enlargement; a week later salivary gland enlargement was also noted. Clinical investigations suggested no diagnosis, and surgical biopsy was considered. Valproic acid (sodium valproate), which he was taking for absence seizures, has been reported to cause salivary gland swelling in adults. Suspecting that a similar mechanism could be causal, the drug was discontinued. Complete resolution of the lacrimal and salivary gland enlargement rapidly ensued. This is the first report of lacrimal gland enlargement caused by valproic acid.


Assuntos
Anticonvulsivantes/efeitos adversos , Dacriocistite/induzido quimicamente , Doenças do Aparelho Lacrimal/induzido quimicamente , Ácido Valproico/efeitos adversos , Doença Aguda , Criança , Dacriocistite/diagnóstico , Diagnóstico Diferencial , Substituição de Medicamentos , Etossuximida/uso terapêutico , Humanos , Doenças do Aparelho Lacrimal/diagnóstico , Masculino , Doenças da Glândula Submandibular/induzido quimicamente , Doenças da Glândula Submandibular/diagnóstico
20.
Cochrane Database Syst Rev ; 2: CD003032, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28195639

RESUMO

BACKGROUND: This is an updated version of the original Cochrane review originally published in 2003, Issue 3, and updated in 2005, Issue 4.Absence seizures are brief epileptic seizures which present in childhood and adolescence. Depending on clinical features and electroencephalogram (EEG) findings they are divided into typical, atypical absences, and absences with special features. Typical absences are characterised by sudden loss of awareness and an EEG typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of antiepileptic drug for children and adolescents with typical absence seizures. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialized Register (1 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 1 September 2016), MEDLINE (Ovid, 1946 to 1 September 2016), ClinicalTrials.gov (1 September 2016) and the WHO International Clinical Trials Registry Platform ICTRP (1 September 2016). Previously we searched Embase (1988 to March 2005) and SCOPUS (1823 to 31 March 2014). No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine; or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (1) proportion of individuals seizure free at one, three, six, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test; and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as risk ratios (RR) with 95% confidence intervals (95% CIs). MAIN RESULTS: Eight small trials were found (three of them not included in the previous version of the review). Six of them were of poor methodological quality and seven recruited less than 50 participants. There are no placebo-controlled trials for ethosuximide or valproate, and hence, no evidence from randomised controlled trials to support a specific effect on absence seizures for either of these two drugs. Due to the differing methodologies used in the trials comparing ethosuximide, lamotrigine and valproate, we thought it inappropriate to undertake a meta-analysis. One large randomised, parallel double-blind controlled trial comparing ethosuximide, lamotrigine and sodium valproate in children with newly diagnosed childhood absence epilepsy found that at 12 months, the freedom-from-failure rates for ethosuximide and valproic acid (VPA) were similar and were higher than the rate for lamotrigine. The frequency of treatment failures due to lack of seizure control (P < 0.001) and intolerable adverse events (P < 0.037) was significantly different among the treatment groups, with the largest proportion of lack of seizure control in the lamotrigine cohort, and the largest proportion of adverse events in the VPA group. Overall, this large study demonstrates the superior effectiveness of ethosuximide and VPA compared to lamotrigine as initial monotherapy aimed to control seizures without intolerable adverse effects in children with childhood absence epilepsy. AUTHORS' CONCLUSIONS: With regards to both efficacy and tolerability, ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizures. However, if absence and generalised tonic-clonic seizures coexist, valproate should be preferred, as ethosuximide is probably inefficacious on tonic-clonic seizures.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Tipo Ausência/tratamento farmacológico , Etossuximida/uso terapêutico , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico , Adolescente , Anticonvulsivantes/efeitos adversos , Criança , Etossuximida/efeitos adversos , Humanos , Lamotrigina , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazinas/efeitos adversos , Ácido Valproico/efeitos adversos
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