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1.
Doc Ophthalmol ; 138(3): 195-203, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30826910

RESUMO

PURPOSE: The anti-epileptic drug vigabatrin is associated with reduction in light-adapted 30-Hz flicker electroretinogram (ERG) amplitude. Ophthalmological assessments, including ERGs, monitor retinal health during vigabatrin treatment. RETeval™ is a hand-held ERG device adapted for dilation-free ERG assessment. To evaluate the usefulness of RETeval™ for vigabatrin ERG assessment, we evaluated intra-visit reliability and clinical feasibility of RETeval™ ERG assessment in children under 3 years of age undergoing vigabatrin treatment. METHODS: In this prospective study, children underwent 30-Hz flicker ERG assessment with RETeval™ before routine vigabatrin monitoring including sedated-ERG using the Espion E2 Colour Dome. Intraclass correlation coefficient (ICC) statistics identified the degree of intra-visit reliability from two repeated measurements of the same participant within one testing session. The omega squared (ω2) statistic identified the level of association between RETeval™ and Espion light-adapted 30-Hz flicker responses. RESULTS: Nine children completed RETeval™ ERG testing. The intra-visit ICCs for the RETeval™ 30-Hz flicker amplitude (µV) were high: 0.81 (right eye) and 0.86 (left eye), while the implicit times (ms) were 0.79 (right eye) and 0.42 (left eye). The RETeval™ 30-Hz flicker amplitude was positively associated with the Espion 30-Hz flicker response (ω2 = 0.71). The Bland-Altman plot showed no bias in the mean difference of amplitudes between the two systems. CONCLUSION: This is the first study to assess the utility of RETeval™ device in children under 3 years of age undergoing vigabatrin treatment. RETeval™ demonstrated high intra-visit reliability with responses consistent with the standard Espion ERG. RETeval™ may be beneficial for assessment of retinal toxicity in young children treated with vigabatrin.


Assuntos
Anticonvulsivantes/uso terapêutico , Eletrorretinografia/efeitos dos fármacos , Eletrorretinografia/instrumentação , Retina/fisiologia , Vigabatrina/uso terapêutico , Pré-Escolar , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Estimulação Luminosa , Estudos Prospectivos , Reprodutibilidade dos Testes , Retina/efeitos dos fármacos , Transtornos da Visão/induzido quimicamente , Transtornos da Visão/fisiopatologia
2.
Epilepsy Res ; 150: 38-45, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30639958

RESUMO

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100 mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients. This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2-3 g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data. For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5-77.9 mg.h/L). From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50 mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Convulsões/tratamento farmacológico , Vigabatrina/farmacocinética , Vigabatrina/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Método de Monte Carlo
3.
Pediatrics ; 142(5)2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30381472

RESUMO

Catatonia is a rare, underdiagnosed syndrome in children. We report the case of a 4-year-old child admitted for recent social withdrawal alternating with psychomotor excitement, verbigeration, and a loss of toilet readiness. He had a history of neonatal seizures, had been stabilized with vigabatrin, and was seizure free without treatment for several months. The pediatric and psychiatric examination revealed motor stereotypes, mannerism, bilateral mydriasis, and visual hallucinations. Laboratory and brain imaging explorations were initially negative. Catatonic symptoms, as measured with the Pediatric Catatonia Rating Scale, significantly decreased after introducing lorazepam, the first-line recommended treatment of this condition. On the basis of the neonatal seizure history, complementary genetic investigations were performed and revealed a mutation in the SCN2A gene, which encodes the voltage-gated sodium channel Nav1.2. Catatonic symptoms progressively disappeared after reintroducing vigabatrin. At the syndromic level, catatonia in young children appears responsive to high-dose lorazepam and is well monitored by using the Pediatric Catatonia Rating Scale. This case reveals the need for wide-ranging explorations in early-onset catatonia because specific targeted treatments might be available.


Assuntos
Anticonvulsivantes/uso terapêutico , Catatonia/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Vigabatrina/uso terapêutico , Catatonia/tratamento farmacológico , Pré-Escolar , Humanos , Lorazepam/uso terapêutico , Mutação , Convulsões/tratamento farmacológico , Convulsões/etiologia
4.
Epilepsy Res ; 148: 1-7, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30296632

RESUMO

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses. We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P = 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 - 0.90, P = 0.026). This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.


Assuntos
Anticonvulsivantes/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Vigabatrina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Recidiva , Risco , Espasmos Infantis/complicações , Espasmos Infantis/epidemiologia , Esclerose Tuberosa/epidemiologia
5.
Medicina (B Aires) ; 78 Suppl 2: 2-5, 2018.
Artigo em Espanhol | MEDLINE | ID: mdl-30199357

RESUMO

West syndrome or infantile spasms is an epileptic encephalopathy, classified as generalized epilepsies and syndromes. There are multiple reports of the evolution from West to Lennox-Gastaut syndrome of 25 up to 60%, without a specific cause is determined. It has been reported that they may be only an epileptic entity age dependent that it would be in relation to the degree of brain immaturity. In this retrospective review of 130 cases of West syndrome, only 14 (10.7%) evolved to Lennox-Gastaut. Having received in all cases vigabatrin as a treatment, makes us suppose that the low incidence could be related to the use of this drug. Given that vigabatrin has a gabaergic action and increased levels of ACTH, may explain this relationship but this must be confirmed with the best knowledge of the intimate mechanisms of these serious epileptic encephalopathies.


Assuntos
Síndrome de Lennox Gastaut/etiologia , Espasmos Infantis/complicações , Anticonvulsivantes/uso terapêutico , Progressão da Doença , Eletroencefalografia , Feminino , Humanos , Lactente , Síndrome de Lennox Gastaut/diagnóstico , Síndrome de Lennox Gastaut/tratamento farmacológico , Imagem por Ressonância Magnética , Metilprednisolona/uso terapêutico , Estudos Retrospectivos , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Síndrome , Vigabatrina/uso terapêutico
6.
Lancet Child Adolesc Health ; 2(10): 715-725, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30236380

RESUMO

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age. METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27. FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], p<0·001) and with higher likelihood of absence of seizures at 18 months (in 39 [17·0%] of 229 infants who achieved spasm cessation vs 67 [51·9%] of 129 who did not; difference 34·9% [24·8 to 45·0], p<0·001). Increasing lead-time to treatment was associated with lower VABS scores (analysis of variance: F[4,354]=6·38, p<0·001) and worse epilepsy outcomes (p=0·023). INTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes. FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.


Assuntos
Cosintropina/uso terapêutico , Prednisolona/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Vigabatrina/uso terapêutico , Cosintropina/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Prednisolona/administração & dosagem , Espasmos Infantis/prevenção & controle , Vigabatrina/administração & dosagem
7.
Clin Neurophysiol ; 129(10): 2137-2148, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30114662

RESUMO

OBJECTIVE: Epileptic spasms (ES) are associated with pathological neuronal networks, which may underlie characteristic EEG patterns such as hypsarrhythmia. Here we evaluate EEG functional connectivity as a quantitative marker of treatment response, in comparison to classic visual EEG features. METHODS: We retrospectively identified 21 ES patients and 21 healthy controls. EEG data recorded before treatment and after ≥10 days of treatment underwent blinded visual assessment, and functional connectivity was measured using cross-correlation techniques. Short-term treatment response and long-term outcome data were collected. RESULTS: Subjects with ES had stronger, more stable functional networks than controls. After treatment initiation, all responders (defined by cessation of spasms) exhibited decreases in functional connectivity strength, while an increase in connectivity strength occurred only in non-responders. There were six subjects with unusually strong pre-treatment functional connectivity, and all were responders. Visually assessed EEG features were not predictive of treatment response. CONCLUSIONS: Changes in network connectivity and stability correlate to treatment response for ES, and high pre-treatment connectivity may predict favorable short-term treatment response. Quantitative measures outperform visual analysis of the EEG. SIGNIFICANCE: Functional networks may have value as objective markers of treatment response in ES, with potential to facilitate rapid identification of personalized, effective treatments.


Assuntos
Anticonvulsivantes/uso terapêutico , Ondas Encefálicas , Sincronização Cortical , Espasmos Infantis/fisiopatologia , Hormônio Adrenocorticotrópico/uso terapêutico , Feminino , Humanos , Lactente , Masculino , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento , Vigabatrina/uso terapêutico
8.
Epilepsy Res ; 145: 127-133, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29966811

RESUMO

OBJECTIVE: Hormonal therapy and vigabatrin are now accepted as the first-line or standard therapies for West syndrome (WS). However, the superiority of these drugs in terms of monotherapy or combination therapy is still in question. In this study, we designed a treatment protocol for WS and prospectively assessed the efficacy of these therapies in controlling spasms, stabilizing electroencephalography (EEG), and allowing for developmental catch-up. METHODS: In patients diagnosed with WS, vigabatrin was first administered alone for 2 weeks, and then prednisolone was administered in combination with vigabatrin if patients did not respond to vigabatrin. The detailed drug administration protocol was as follows: vigabatrin 50 mg/kg/day for 1 day, followed by vigabatrin 100 mg/kg/day for 3 days, vigabatrin 150 mg/kg/day if spasms were still present or the burden of amplitudes and epileptiform discharges (BASED) score on EEG was ≥3 on day 5; 40 mg/day of prednisolone was added if spasms were still present or the BASED score was ≥3 on day 14. The prednisolone dose was increased to 60 mg/day if spasms were still present or the BASED score was ≥3 on day 21. RESULTS: Sixty-six patients newly diagnosed with WS (median seizure onset age: 5.7 [IQR, 4.1-7.1] months, median age at diagnosis: 6.6 [IQR, 5.4-8.1] months, n = 40 [60.6%] boys) were subjected to the vigabatrin and prednisolone therapy protocol. Of the 66 patients, 22 (33.3%) patients showed resolution of spasms and a BASED score of ≤2 after vigabatrin alone, and 26 (39.4%) patients showed resolution of spasms and a BASED score of ≤2 after a combination of vigabatrin and prednisolone, for a total of 48 (72.7%) patients who were responsive to the protocol without relapse for at least 7 months after WS diagnosis. The mental and psychomotor age quotients were higher at the time of diagnosis and remained significantly higher 6 months after the diagnosis in responsive patients (p <  0.001). No serious adverse reactions leading to discontinuation or reduction of drug doses were observed. CONCLUSION: Using a treatment protocol involving vigabatrin and prednisolone for WS, 72.7% of patients showed resolution of spasms and a BASED score of ≤2. This study also found that this drug administration protocol was safe. However, further studies are warranted as this study describes results from observational study with limited sample size.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticonvulsivantes/uso terapêutico , Prednisolona/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Vigabatrina/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Lactente , Masculino , Espasmos Infantis/fisiopatologia , Resultado do Tratamento
9.
Rev. cuba. pediatr ; 90(2): 321-329, abr.-jun. 2018. ilus
Artigo em Espanhol | CUMED | ID: cum-72247

RESUMO

Introducción: la incontinencia pigmenti es una genodermatosis rara ligada al cromosoma X, afecta al sexo femenino y tiene diferentes expresiones clínicas en una misma familia. Presentación del caso: preescolar de 20 meses de edad, con antecedente familiar de incontinencia pigmenti, que presentó lesiones típicas en la piel desde la primera semana de vida, de aspectos lineales, vesículo-costro-ampollosas, verrucosas, y luego hiperpigmentadas, en diferentes fases y múltiples brotes. Comienza desde el primer mes de vida con crisis epilépticas que evoluciona a una encefalopatía de West, con buena respuesta a la vigabatrina y control de los espasmos infantiles. Conclusiones: la incontinencia pigmenti se caracteriza por afectar, de forma variable, a los tejidos derivados del neuroectodermo, la piel y otras faneras, ojos y el sistema nervioso central, provoca daño multisistémico. Las lesiones de la piel son las más significativas desde el nacimiento, y la biopsia de piel confirma el diagnóstico(AU)


Introduction: incontinentia pigmenti is a rare genodermatosis linked to the X chromosome. It affects the female sex and has different clinical manifestations in the same family. Case presentation: a 20-month-old infant with a family history of incontinentia pigmenti, who from the first week of life presented typical lesions on the skin of linear, vesicular-crust-bullous, warty, and then hyperpigmented aspects, in different phases and multiple outbreaks. From the first month of life, the patient presented epileptic seizures that evolved to West encephalopathy, with good response to vigabatrin and control of infantile spasms. Conclusions: incontinentia pigmenti is characterized by affecting, in a variable way, the tissues derived from the neuroectoderm, the skin and other skin´s structures, the eyes and the central nervous system causing multisystem damage. Skin lesions are the most significant since birth, and skin biopsy confirms the diagnosis(AU)


Assuntos
Humanos , Feminino , Lactente , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos da Pigmentação/complicações , Espasmos Infantis/complicações , Vigabatrina/uso terapêutico
10.
J Child Neurol ; 33(8): 519-524, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29687739

RESUMO

Vigabatrin is recommended as first-line treatment for infantile spasms in tuberous sclerosis complex (TSC), but other indications in children with tuberous sclerosis complex are less known. We retrospectively reviewed 201 children with tuberous sclerosis complex, and identified 21 children older than 1 year started on vigabatrin for any indication and with sufficient follow-up data. The indication for vigabatrin was epileptic spasms (n = 13), tonic seizures (n = 5), both (n = 2), and status epilepticus (n = 1). Mean age of treatment onset was 4.0 years (range 1.1-18.3). All but 1 patient had a reduction in seizures. Ten patients became seizure free and 4 had an improvement of >90%. In 9 patients, vigabatrin was tapered successfully after 8 to 33 months. Side effects reported included rash (n = 1) and behavioral decline (n = 1). No retinal toxicity was detected in 14 of 21 patients with adequate ophthalmologic surveillance data. In conclusion, vigabatrin may be an effective treatment for epileptic spasms and tonic seizures beyond the infantile age.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Esclerose Tuberosa/tratamento farmacológico , Vigabatrina/uso terapêutico , Adolescente , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Epilepsia/etiologia , Epilepsia/fisiopatologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Resultado do Tratamento , Esclerose Tuberosa/complicações , Esclerose Tuberosa/fisiopatologia
11.
Brasília; CONITEC; abr. 2018. graf, ilus, tab.
Não convencional em Português | LILACS, BRISA/RedTESA | ID: biblio-905573

RESUMO

CONTEXTO: A epilepsia é uma doença cerebral crônica caracterizada pela recorrência de crises epilépticas não provocadas. De acordo com o Protocolo Clínico e Diretrizes Terapêuticas (PCDT) do Ministério da Saúde (MS) aproximadamente 30% dos pacientes, tratados adequadamente, continuam a ter crises, sem remissão. O tratamento disponível no SUS inclui os agentes antiepilépticos fenobarbital, fenitoína, primidona, topiramato, lamotrigina, carbamazepina e valproato de sódio. Recentemente foi avaliado e incorporado o levetiracetam. TECNOLOGIA: Lacosamida (Vimpat®). INDICAÇÃO: Terapia aditiva para o tratamento da epilepsia focal em pacientes refratários aos tratamentos prévios já disponíveis pelo Sistema Único de Saúde (SUS). PERGUNTAS: 1) A lacosamida oral como terapia adjuvante é tão segura e eficaz quanto a lamotrigina, topiramato, vigabatrina e gabapentina no tratamento da epilepsia focal em pacientes já submetidos a duas linhas de monoterapia? 2) Qual a efetividade da lacosamida como tratamento adjuvante na epilepsia focal não controlada, em pacientes adultos, em comparação ao uso de esquemas terapêuticos convencionais, quanto à redução da frequência de crises epilépticas, eventos adversos e custos? EVIDÊNCIAS CIENTÍFICAS: Não existem estudos de comparação direta entre a lacosamida e outro antiepiléptico. As evidências apresentaram comparações indiretas que apontam similaridade de eficácia e segurança entre a lacosamida e os medicamentos antiepilépticos disponíveis no SUS para o tratamento aditivo de pacientes com epilepsia focal, refratários a monoterapia. AVALIAÇÃO ECONÔMICA: Foi apresentada análise de custo-minimização para o tratamento aditivo da epilepsia focal refratária com lacosamida, porém o custo do tratamento com lacosamida, por paciente, só foi inferior ao custo do tratamento utilizando a vigabatrina. Os demais medicamentos já disponíveis para esta condição apresentam menor custo ao sistema. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A incorporação da lacosamida proporcionaria economia ao sistema de saúde apenas se comparado ao tratamento com vigabatrina. EXPERIÊNCIA INTERNACIONAL: Em outros países a lacosamida é fornecida para o tratamento da epilepsia focal refratária, em similaridade de condições à carbamazepina, clobazam, gabapentina, lamotrigina, levetiracetam, oxcarbazepina, valproato de sódio ou topiramato, se ocorrer refratariedade ou intolerância ao tratamento em primeira linha. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Há medicamentos em fase de desenvolvimento clínico para o tratamento da epilepsia focal, com diferentes mecanismos de ação, em estágios avançados de pesquisa clínica. RECOMENDAÇÃO PRELIMINAR: De acordo com o exposto, a CONITEC em sua 62ª reunião, no dia 7 de dezembro de 2017, recomendou a não incorporação da lacosamida no SUS como terapia aditiva em pacientes com epilepsia focal, refratários aos tratamentos prévios com os fármacos antiepilépticos disponíveis. A matéria será disponibilizada em consulta pública. CONSULTA PÚBLICA: Foram recebidas 13 contribuições técnico-científicas e 23 contribuições de experiência ou opinião, sendo quase a totalidade discordante da recomendação preliminar da CONITEC. As contribuições técnico-científicas embasaram-se no fato das comparações indiretas se tratarem da melhor qualidade de evidência disponível, sobre a efetividade da lacosamida em resposta à pergunta de pesquisa realizada. As contribuições de experiência e opinião expressaram o desejo dos participantes em agregar mais um medicamento ao tratamento disponibilizado pelo SUS como uma alternativa a mais para os pacientes refratários. A CONITEC entendeu que não houve evidência adicional e/ou argumentação suficientes para alterar sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 07/03/2018 deliberaram por não recomendar a lacosamida como terapia aditiva em pacientes com epilepsia focal, refratários aos tratamentos prévios com os fármacos antiepilépticos disponíveis no SUS. Foi assinado o Registro de Deliberação nº 335/2018. DECISÃO FINAL: O Secretário de Ciência, Tecnologia e Insumos Estratégicos do Ministério da Saúde, por meio da Portaria SCTIE/MS nº 20, de 27 de abril de 2018, publicada no DOU nº 82 de 30 de abril de 2018, Seção I, tornou pública a decisão de não incorporar a lacosamida como terapia aditiva em pacientes com epilepsia focal refratários aos tratamentos prévios com os fármacos antiepilépticos disponíveis no SUS no âmbito do Sistema Único de Saúde - SUS.(AU)


Assuntos
Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Vigabatrina/uso terapêutico , Brasil , Resistência a Medicamentos , Avaliação em Saúde , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde
12.
Epilepsia ; 59(4): e40-e44, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29473152

RESUMO

The histopathology, "white matter spongiosis," defined by electron microscopy (EM) as "intramyelinic edema," has been associated with vigabatrin therapy in various animal models, but its role or significance in clinical studies is unknown. We conducted a neuropathological examination on a 27-month-old boy with bilateral polymicrogyria and epilepsy after sudden unexpected death in epilepsy (SUDEP). The patient was initiated on vigabatrin at 4 months of age, which controlled infantile spasms, and was continued as maintenance therapy. Autopsy showed a combination of developmental and acquired lesions: (1) bilateral gyral malformations of the frontal, parietal, temporal, and insular cortex; (2) agenesis of the olfactory tracts and bulbs; (3) hippocampal abnormalities: dentate gyrus bilamination and granule cell dispersion; and (4) areas of microscopic bilateral, symmetric white matter spongiosis in the brainstem central tegmental tract, amiculum and hilum of the inferior olive, medial longitudinal fasciculus, paragigantocellularis lateralis, optic nerves and chiasm, and hypothalamus. The white matter spongiosis was identical to the histopathologic lesions (which by EM exhibited intramyelinic edema) that were demonstrated in animal models on vigabatrin therapy, indicating that vigabatrin toxicity is not restricted to animal models.


Assuntos
Anticonvulsivantes/uso terapêutico , Edema Encefálico/induzido quimicamente , Edema Encefálico/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem , Vigabatrina/uso terapêutico , Substância Branca/diagnóstico por imagem , Anticonvulsivantes/efeitos adversos , Edema Encefálico/tratamento farmacológico , Pré-Escolar , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Espasmos Infantis/tratamento farmacológico , Vigabatrina/efeitos adversos , Substância Branca/efeitos dos fármacos
13.
Epilepsy Behav ; 78: 134-141, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29190579

RESUMO

Vigabatrin was approved for the treatment of infantile spasms by the US Food and Drug Administration, but not in Japan at the time of initiating this clinical study because of concerns about irreversible peripheral visual field defects (VFDs). This study evaluated the efficacy and safety of vigabatrin for Japanese patients with infantile spasms. Of 15 patients (aged ≥4weeks and <2years) enrolled, with the exception of two patients who did not receive vigabatrin, 13 were treated with a titrated dosage of vigabatrin (50-150mg/kg/day; limited to 3000mg/day). Twelve out of 13 patients receiving vigabatrin had spasms that were treatment refractory; these patients were concurrently treated with at least one other antiepileptic drug. One patient received vigabatrin monotherapy. Eight of the 13 patients (61.5% [95% CI: 31.6-86.1%]) had a ≥50% reduction during the dose-adjustment phase compared with baseline in the frequency of spasms, with efficacy maintained through a 2-week maintenance phase. Spasms disappeared in six out of nine patients (66.7% [95% CI: 29.9-92.5%]) who transitioned to the maintenance phase and hypsarrhythmia on electroencephalography also resolved in four patients. Hypsarrhythmia was improved in another two patients. Six out of seven patients who continued treatment through Week 32 of an extension study reported ongoing efficacy for vigabatrin. The most common adverse events (AEs) were psychiatric disorders and nervous system disorders (n=8; 61.5%) that were generally mild in severity. No treatment-related peripheral VFDs were observed. No severe AEs or AEs resulting in discontinuation of vigabatrin therapy were reported. An abnormality in magnetic resonance images was observed in one patient during the extension period. Vigabatrin was deemed to be clinically effective and well tolerated in Japanese patients with infantile spasms.


Assuntos
Anticonvulsivantes/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Vigabatrina/uso terapêutico , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/efeitos adversos , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Japão , Masculino , Espasmos Infantis/etnologia , Resultado do Tratamento , Vigabatrina/efeitos adversos
14.
Clin Drug Investig ; 38(2): 113-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29086890

RESUMO

West syndrome (WS), also known as infantile spasms, occurs in infancy with a peak between 4 and 7 months. Spasms, neurodevelopmental regression and hypsarrhythmia on electroencephalogram (EEG) basically define WS. The International League Against Epilepsy commission classifies the aetiologies of WS into genetic, structural, metabolic and unknown. Early diagnosis and a shorter lag time to treatment are essential for the overall outcome of WS patients. These goals are feasible with the addition of brain magnetic resonance imaging (MRI) and genetic and metabolic testing. The present work analysed the medical literature on WS and reports the principal therapeutic protocols of its management. Adrenocorticotropic hormone (ACTH), vigabatrin (VGB) and corticosteroids are the first-line treatments for WS. There is no unique therapeutic protocol for ACTH, but most of the evidence suggests that low doses are as effective as high doses for short-term treatment, which is generally 2 weeks followed by dose tapering. VGB is generally administered at doses from 50 to 150 mg/kg/day, but its related retinal toxicity, which occurs in 21-34% of infants, is most frequently observed when treatment periods last longer than 6 months. Among corticosteroids, a treatment of 14 days of oral prednisolone (40-60 mg/day) has been considered effective and well tolerated. Considering that an early diagnosis and a shorter lag time to treatment are essential for successful outcomes in these patients, further studies on efficacy of the different therapeutic approaches with evaluation of final outcome after cessation of therapy are needed.


Assuntos
Pediatras/normas , Guias de Prática Clínica como Assunto/normas , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/tratamento farmacológico , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Hormônio Adrenocorticotrópico/farmacologia , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Espasmos Infantis/fisiopatologia , Resultado do Tratamento , Vigabatrina/farmacologia , Vigabatrina/uso terapêutico
15.
Epilepsia ; 58(12): 2098-2103, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29105055

RESUMO

OBJECTIVE: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. METHODS: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. RESULTS: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . SIGNIFICANCE: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.


Assuntos
Espasmos Infantis/terapia , Hormônio Adrenocorticotrópico/uso terapêutico , Idade de Início , Anticonvulsivantes/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Prednisolona/uso terapêutico , Cobertura de Condição Pré-Existente , Estudos Prospectivos , Fatores Sexuais , Espasmos Infantis/fisiopatologia , Resultado do Tratamento , Vigabatrina/uso terapêutico
16.
J Pediatr ; 190: 215-221.e1, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29144248

RESUMO

OBJECTIVES: To characterize and quantify diagnostic and treatment delay among children with infantile spasms, and to estimate the developmental impact of this delay. STUDY DESIGN: In this cohort study, we surveyed the parents of 100 patients with infantile spasms about their experiences with diagnosis and treatment, and ascertained medical and sociodemographic factors potentially related to care of these infants. We specifically determined the latency to first visit an "effective provider," defined as a provider who identified infantile spasms, and prescribed an appropriate first-line treatment, namely adrenocorticotropic hormone, corticosteroids, or vigabatrin. Time to the first visit to an effective provider was evaluated using Cox proportional hazards regression. RESULTS: The median time from the onset of infantile spasms to first visit with an effective provider was 24.5 days. Only 29% of patients were evaluated by an effective provider within 1 week of infantile spasms onset. The time to first effective provider visit was associated with parental language preference, but with no other sociodemographic characteristics. Parents' suspicions that "something is wrong" were often discounted by healthcare providers, and survey respondents frequently reported that pediatricians and neurologists were unfamiliar with infantile spasms. CONCLUSION: This study demonstrates that substantial delay (ie, >1 week) in appropriate care is common, and suggests that the poor awareness of infantile spasms among healthcare providers is at least partly responsible for preventable and potentially significant delays in treatment.


Assuntos
Diagnóstico Tardio/estatística & dados numéricos , Espasmos Infantis/diagnóstico , Corticosteroides/uso terapêutico , Hormônio Adrenocorticotrópico/uso terapêutico , Anticonvulsivantes/uso terapêutico , Competência Clínica , Eletroencefalografia , Feminino , Seguimentos , Humanos , Lactente , Los Angeles , Masculino , Neurologia , Pais , Pediatria , Relações Profissional-Família , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espasmos Infantis/tratamento farmacológico , Centros de Atenção Terciária , Vigabatrina/uso terapêutico
17.
Epilepsia ; 58(10): 1734-1741, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28857179

RESUMO

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. METHODS: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. RESULTS: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. SIGNIFICANCE: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo/patologia , Adolescente , Adulto , Idoso , Aminas/uso terapêutico , Ataxia/induzido quimicamente , Benzodiazepinas/uso terapêutico , Carbamazepina/análogos & derivados , Carbamazepina/uso terapêutico , Clobazam , Ácidos Cicloexanocarboxílicos/uso terapêutico , Bases de Dados Factuais , Diplopia/induzido quimicamente , Tontura/induzido quimicamente , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Frutose/análogos & derivados , Frutose/uso terapêutico , Gabapentina , Humanos , Lamotrigina , Letargia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Oxcarbazepina , Pregabalina/uso terapêutico , Estudos Retrospectivos , Esclerose , Topiramato , Resultado do Tratamento , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico , Vertigem/induzido quimicamente , Vigabatrina/uso terapêutico , Transtornos da Visão/induzido quimicamente , Adulto Jovem , Ácido gama-Aminobutírico/uso terapêutico
18.
Epilepsia ; 58(9): 1575-1585, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28691157

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. METHODS: We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. RESULTS: One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8 months (interquartile range [IQR] 5-15). Median starting dose was 48.1 mg/kg per day (IQR 29.8-52.3) with a median target of 100 mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1 months (n = 89, IQR 5.0-22.9) overall, and 13.3 months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p = 0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. SIGNIFICANCE: Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1 months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Vigabatrina/uso terapêutico , Anticonvulsivantes/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Vigabatrina/efeitos adversos
19.
Pediatr Neurol ; 72: 76-80, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28506505

RESUMO

BACKGROUND: Seizures are a common early presentation in infants with tuberous sclerosis complex (TSC) and can be preceded by electrographic changes on electroencephalography (EEG) before clinical seizure onset. A limited number of studies have addressed the initial EEG findings in TSC and the outcome of early treatment with antiepileptic medication prior to clinical seizure onset. METHODS: We describe two infants with tuberous sclerosis complex whose surveillance EEG showed focal seizures that were not previously recognized by caregivers. We review previously reported patients with TSC with early EEG findings. Our patients were started on vigabatrin after the onset of focal seizures with the aim of preventing seizure recurrence, halting the possible progression to infantile spasms or focal seizures, and preventing neurodevelopmental decline. RESULTS: Both patients remain seizure free and have reached appropriate developmental milestones. CONCLUSIONS: We recommend early serial EEG monitoring once a diagnosis of TSC is suspected or confirmed in infants. Additional prospective studies are needed to assess the long-term outcome of early antiepileptic drug initiation as soon as electrographic seizure activity is detected.


Assuntos
Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Convulsões/tratamento farmacológico , Esclerose Tuberosa/tratamento farmacológico , Vigabatrina/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Lactente , Estudos Prospectivos , Resultado do Tratamento , Esclerose Tuberosa/fisiopatologia
20.
Epilepsia ; 58(5): 872-881, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28401986

RESUMO

OBJECTIVES: To investigate acoustic auditory processing in patients with recent infantile spasms (IS). METHODS: Patients (n = 22; 12 female; median age 8 months; range 5-11 months) had normal preceding development, brain magnetic resonance imaging (MRI), and neurometabolic testing (West syndrome of unknown cause, uWS). Controls were healthy babies (n = 22; 11 female; median age 6 months; range 3-12 months). Event-related potentials (ERPs) and psychometry (Bayley Scales of Infant Development, Second Edition, BSID-II) took place at a month following IS remission. RESULTS: Following a repeated pure tone, uWS patients showed less suppression of the N100 at the mid-temporal electrodes (p = 0.006), and a prolonged response latency (p = 0.019). Their novelty P300 amplitude over the mid-temporal electrodes was halved (p = 0.001). The peak of the novelty P300 to environmental broadband sounds emerged later over the left temporal lobe in patients (p = 0.015), the lag correlating with duration of spasms (r = 0.547, p = 0.015). BSID-II scores were lower in patients (p < 0.001), with no correlation to ERP. SIGNIFICANCE: Complex acoustic information is processed poorly following IS. This would impair language. Treatment did not reverse this phenomenon, but may have limited its severity. The data are most consistent with altered connectivity of the cortical acoustic processing areas induced by IS.


Assuntos
Percepção Auditiva/fisiologia , Potenciais Evocados Auditivos/fisiologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/fisiopatologia , Estimulação Acústica , Vias Auditivas/efeitos dos fármacos , Vias Auditivas/fisiopatologia , Percepção Auditiva/efeitos dos fármacos , Estudos de Casos e Controles , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Estudos Transversais , Eletroencefalografia , Potencial Evocado P300/efeitos dos fármacos , Potencial Evocado P300/fisiologia , Potenciais Evocados Auditivos/efeitos dos fármacos , Feminino , Humanos , Lactente , Masculino , Prednisolona/uso terapêutico , Prognóstico , Estudos Prospectivos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Processamento de Sinais Assistido por Computador , Espasmos Infantis/tratamento farmacológico , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/fisiologia , Gravação em Vídeo , Vigabatrina/uso terapêutico
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