Bakgrund: I Sverige förekommer epilepsi hos 1-2 % av alla hundar. De första anfallen visar sig oftast när hunden är mellan ett och sex år gammal. Det nuvarande förstahands­preparatet är fenobarbital, en substans som ökar tröskeln för elektrisk stimulering av motorcortex samt minskar monosynaptisk transmission som leder till minskad neuronal retbarhet. I februari 2013 registrerades ett nytt antiepileptikum med det verksamma äm­net imepitoin. Imepitoin är en partiell agonist som binder till bensodiazepinsätet på GABAA-receptorn. Det förstärker de GABAA-receptormedierade effekterna på neuro­nen samt har en svag kalciumblockerande verkan. Syfte: Arbetets syfte var att undersöka om imepitoin har förutsättningar att bli det nya förstahandspreparatet vid behandling av idiopatisk epilepsi. Vidare var syftet att under­söka i vilken utsträckning imepitoin fungerar som antiepileptikum samt vilken biverk­ningsprofil det har. Resultat: Behandling med imepitoin gav en sänkning av antalet epileptiska anfall per månad (MSF), liknande den som erhölls vid fenobarbitalbehandling. Imepitoin sänkte MSF både som monoterapi och i kombination med fenobarbital eller kaliumbromid. Biverkningsprofilen var överlag skonsammare för imepitoin jämfört med fenobarbital. Fenobarbital visade en leverpåverkan medan imepitoin påverkade kolesterolvärdet. Slutsats: Imepitoin har en antiepileptisk effekt, liknande den som fås vid behandling med fenobarbital. Behandling med imepitoin kan ske både som mono- samt kombina­tionsterapi. Den mildare biverkningsprofilen talar för användning av imepitoin. Samti­digt har fenobarbital använts under en längre tid så biverkningar vid långtids­användning är mer välkända än de vid imepitoinanvändning. / Background: In Sweden, approximately 1-2 % of all dogs suffer from epilepsy. The first seizures often occur when the dog is between one and six years old. In Sweden the first-line drug is phenobarbital, a substance which increases the threshold of electrical stimulation in the motor cortex. It also decreases synaptic transmission which leads to decreased neuronal excitability. In February 2013 a new antiepileptic drug was regis­tered with imepitoin as active substance. Imepitoin is a partial agonist which binds to the benzodiazepine binding site at the GABAA receptor and amplifies the effects medi­ated by GABAA receptors at the neurons. Additionally, imepitoin has a weak calcium channel blocking effect. Objective: The main aim of the study was to examine if imepitoin should be the first-line drug instead of phenobarbital when treating dogs diagnosed with idiopathic epi­lepsy. A further aim was to look into which effect imepitoin had in controlling the epilepsy and which adverse effects were experienced when dogs are treated with imepitoin. Results: Treatment with imepitoin resulted in a decrease in monthly seizure frequency (MSF), similar to the decrease seen upon treatment with phenobarbital. Imepitoin was decreasing MSF both when used as monotherapy and in combination with phenobarbital or potassium bromide. The adverse effects were in general less severe with imepitoin than with phenobarbital. Treatment with phenobarbital affected the liver while treatment with imepitoin affected the cholesterol levels. Conclusion: Imepitoin has a good antiepileptic effect, similar to that of phenobarbital. Treatment with imepitoin can be used both as monotherapy and in combination with other antiepileptic drugs. Less severe adverse effects makes imepitoin a possible choice for treating idiopathic epilepsy in dogs. On the other hand, phenobarbital has been used during a long period of time and adverse effects of long term use are therefore better known than for imepitoin.

The aim of this thesis was to describe the medical, cognitive and psychosocial consequences of epilepsy in young adulthood. Four studies were carried out with this patient group. The first two papers were based on a follow-up study regarding young adults with epilepsy that investigated medical and psychosocial aspects and compared the present results with those five years earlier. We then conducted focus group interviews with young adults with epilepsy and subjective cognitive decline to assess the deeper meaning of living with epilepsy accompanied by cognitive difficulties. In the fourth study we studied cognitive dysfunction further, choosing the language function in young adults with epilepsy. We firstly examined whether language impairments were associated to functional brain alterations and secondly related the language performance to demographics, clinical data, Quality of Life (QoL) and self-esteem. The five-year follow up of 97 young adults with uncomplicated epilepsy revealed no improvement regarding seizure frequency or side effects from anti-epileptic drugs (AEDs) over time, even though many new-generation AEDs had been established during this period. During the study period 21% had recovered from epilepsy, Seizure frequency among those who still had epilepsy had not improved, and 42% had experienced seizures during the past year. New-generation anti-epileptic drugs (AEDs) had been introduced to PWE, especially to women. There is still need for new and more effective treatment options for this group in the future. It is essential to find alternative approaches to develop better treatment options for this group in the future. However QoL was normal compared to the general population, indicating that new options regarding treatment can have made an impact. Lower QoL was correlated to high seizure frequency and to cognitive side effects. Self-esteem and Sence of Coherence were impaired compared to the situation at adolescence. Self-esteem was correlated to seizure frequency and to side-effects of antiepileptic drugs. Sence of Coherence was not correlated to epilepsy-related factors in the same way as QoL, but mirrored the phenomenon of epilepsy. The qualitative study showed that the consequences of epilepsy are not only restricted to the consequences of seizures, but also concerns many other aspects of life. The interviews revealed four themes: “affecting the whole person“, “influencing daily life”, ”affecting relations” and ”meeting ignorance in society”. Another important factor was language function; when one loses some language ability, this gives a feeling of losing one’s capability. The fourth study examined language by neuropsychological methods and correlated this function to brain activation measured by fMRI. Language functions measured in verbal fluency and abstract language comprehension were impaired in participants with both generalized epilepsy and epilepsy of focal onset. Age at onset of epilepsy and education are the most important factors correlating to language function. An additional factor that impacts abstract language comprehension is the frequency of convulsive seizures, while use of topiramate /zonisamide affect verbal fluency negatively. QoL was not correlated to language impairments, but for patients with focal onset seizures there was a correlation between self-esteem and abstract language comprehension. The fMRI investigation revealed altered activity during language tasks in participants with epilepsy compared to controls. In epilepsy with focal seizures originating in the left hemisphere, we found increased bilateral activation of supporting areas, in the anterior mid-cingulate cortex and the anterior ventral insulae, indicating a compensational functional reorganization. In generalized epilepsy, the functional language network showed an imbalance, as this group expressed an inadequate suppression of activation in the anterior temporal lobe during semantic processing. Subtle language impairment can, even if it does not occur in everyday dialogue, be of importance and have consequences for the person affected. The negative consequences of language decline must be addressed in people with epilepsy of different etiology. Young adults with epilepsy are still substantially affected by the condition. The consequences are not only restricted to the seizures, but concern many aspects of life and there is a great need for new treatment options for this group in the future.

Abstract Febrile seizures (FS) occur in 2-5% of children. Their pathogenesis is unknown. Elevated levels of prostaglandins (PG) have been found in cerebrospinal fluid after such seizures, and a third of all patients have recurrences. No safe ways of reducing the risk of recurrences have been found. The outcome has been shown in prospective studies to be good, by they have been linked to mesial temporal sclerosis (MTS) in patients with severe temporal lobe epilepsy (TLE). The aim was to analyze the records on the role of PGs in the pathogenesis of FS, to find risk factors for recurrences that are amenable to intervention and to evaluate the prevention of recurrences and the connection of FSs with MTS. We performed a systematic review of the effect of PGs and their synthetase inhibitors on seizures and a meta-analysis of the prevention of recurrences. The prophylactic effect of diazepam and acetaminophen on recurrences was evaluated in a placebo-controlled trial with 180 FS patients, and risk factors for recurrences were analysed from these data. To find MTS, MRI volumetry was performed after 12 years of follow-up on 64 cases chosen out of 329 unselected FS patients: twenty-four with a prolonged initial seizure, eight with a later unprovoked seizure and 32 age, sex and handedness-matched controls. PGD2, PGE1 and PGE2 had mainly anticonvulsive effects and PGF2alfa proconvulsive ones. NSAIDs had seizure-modulating effects in adult animals ranging from attenuation to provocation. Each degree of increase in fever doubled the recurrence risk, and each febrile episode increased it by 18%. The meta-analysis showed phenobarbital and valproate to prevent recurrences, but they cannot be recommended for FS as they have severe side-effects. The meta-analysis nullified the alleged effect of diazepam, and neither this nor acetaminophen prevented recurrences in a clinical trial. No MTS was found in any patient group. PGs may be involved in the pathogenesis of FS. No safe prophylaxis for recurrences is available, although the effect of antipyretics needs further evaluation. Measures to reduce feverish infections in order to prevent FS recurrences seem logical. MTS is uncommon even after prolonged FS.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24881号 / 医博第5015号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 阪上 優 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introdução: A vigabatrina (VGB - Gama-Vinil-GABA) é um fármaco que eleva os níveis de GABA no organismo, por inibição irreversível da GABA transaminase, cuja eficácia foi bem demonstrada no controle dos espasmos epilépticos em lactentes, especialmente na síndrome de West secundária à esclerose tuberosa. Há escassez de estudos clínicos evidenciando um possível papel deste fármaco no controle de crises epilépticas neonatais e pouco se sabe sobre o potencial impacto do seu uso nessa faixa etária, seus possíveis efeitos adversos, ou se sua introdução teria associações positivas com controle mais adequado das crises na evolução e melhor desenvolvimento neuropsicomotor da criança. A VGB foi introduzida em nosso serviço como terapia de adição para o controle de crises neonatais refratárias, há vários anos, instigando nossa impressão sobre a eficácia deste medicamento no período neonatal. Objetivos: Avaliar a efetividade do uso da VGB como adjuvante no controle das crises eletrográficas e eletroclínicas do período neonatal e seus efeitos sobre o padrão do eletroencefalograma (EEG); Avaliar a evolução clínica e eletrográfica das crianças durante seguimento ambulatorial; Pesquisar associação entre \"controle de crises neonatais com introdução de VGB\" e diversas características demográficas, clínicas e evolutivas destes recém nascidos; Quantificar e caracterizar a ocorrência de efeitos adversos precoces e durante o seguimento. Pacientes e métodos: Estudo transversal retrospectivo, envolvendo o levantamento dos prontuários de uma amostra de recém-nascidos que receberam VGB como tratamento para crises neonatais refratárias aos fármacos convencionais e status epilepticus, no período de janeiro de 2007 a março de 2014, no Serviço de Neonatologia e Terapia Intensiva Neonatal do HCFMRP-USP, mantendo seguimento ambulatorial por pelo menos 1 ano. Foram avaliados os dados demográficos, etiologia e semiologia clínico-eletroencefalográfica das crises, esquema terapêutico prescrito, indicação da introdução da VGB, tempo de internação e tempo para atingir o controle das crises, evolução clínica e eletrencefalográfica durante a internação e no seguimento ambulatorial, época da suspensão da VGB, além de seus efeitos adversos. Resultados: De 48 recém-nascidos avaliados, 34 (79,2 %) obtiveram controle de crises eletrográficas e/ou clínicas durante o período neonatal, havendo melhora no padrão eletrográfico após a introdução da VGB em 79%. Quanto aos critérios para sua indicação, 33,3% (16 indivíduos) iniciaram VGB devido a falha terapêutica no controle das crises com fenobarbital e/ou fenitoína; 27,1% (13 recém nascidos), pela presença de estado de mal epilético e, em 12 crianças (25%), por falha terapêutica do midazolam. Ao final do primeiro ano de vida, a atividade de base do EEG mostrou-se desorganizada em 58,1% (18 de 29 pacientes que o realizaram aos 12 meses de vida). No seguimento ambulatorial de 38 pacientes, algum grau de atraso do desenvolvimento neuropsicomotor foi detectado em 20 crianças (52,6%); 19 lactentes (39,5%) mantiveram o uso da VGB em politerapia, tendo 22 crianças (57,9%) evoluído com persistência das crises epilépticas. Já 37,8% (14 pacientes) enquadraram-se em um padrão de encefalopatia epiléptica, que correspondeu à síndrome de West em 13,9% (5 de 36 crianças). Quanto ao EEG realizado em 34 crianças nessa fase, 17,6% (6 casos) demonstraram a presença de hipsarritmia, enquanto anormalidades focais ou multifocais foram detectadas em 50% (17 lactentes). A taxa de óbito ao final do primeiro ano foi de 23,3% (10 de 43 crianças analisadas quanto a este dado). Não foi possível comprovar déficit visual relacionado diretamente ao uso da VGB. A variável \"controle de crises no período neonatal com o uso da VGB\" foi associada aos seguintes desfechos clínicos favoráveis: melhora no padrão eletrográfico (92,1%), proporção menor de crianças evoluindo para síndrome de West e outras encefalopatias epilépticas (71,9% não tiveram tal desfecho); menor frequência de hipsarritmia no EEG (92,9% sem hipsarritmia), maior alcance de desenvolvimento neuropsicomotor normal (56,2% com bom desenvolvimento neurológico), menor índice de óbito neonatal (97,4% vivos nesta fase) e durante os primeiros doze meses de vida (87,9%). Conclusão: Acreditamos que a VGB seja uma opção terapêutica efetiva e com adequada relação custo-benefício, a ser implementada no controle de crises epilépticas neonatais refratárias como fármaco adjuvante aos convencionais. Entretanto, estudos randomizados e controlados são necessários para confirmar sua eficácia quando comparada a outros medicamentos disponíveis para uso nesta população, bem como para avaliar seus possíveis efeitos adversos a longo prazo. / Introduction: Vigabatrin (VGB - Gama-Vinil-GABA) is an antiepileptic drug which increases systemic GABA levels by irreversibly inhibiting GABA transaminase, with well demonstrated efficacy in the control of infantile epileptic spasms, specially related to West syndrome due to tuberous sclerosis. Clinical studies demonstrating a possible role of VGB in the control of neonatal seizures are still very scarce and very little is known on the impact of its use at this early age, as well as on its possible side effects or eventual positive associations from its use with more adequate seizure control or better neuropsychomotor development in the outcome. VGB has been used in our service as an add-on therapy for refractory neonatal seizures arising the impression that this could be an effective antiepileptic medication in the neonatal period. Objectives: To evaluate the use of VGB as an add-on medication regarding its effectiveness for the control of neonatal electrographic and electroclinical seizures, as well as its effects over the EEG pattern; To evaluate clinical and electrographic evolution of the children in follow-up; To estimate VGB efficacy on the control of neonatal seizures in relation to the demographical and clinical characteristics of those newborns; To quantify and characterize the occurrence of early and late side effects of this medication along follow-up. Patients and methods: This is a transverse retrospective study carried out through charts analysis from a sample of newborns who received VGB as add-on medication for seizures and/or status epilepticus refractory to conventional drugs, from January 2007 through March 2014, at the Neonatal Intensive Care Service of HCFMRP-USP, keeping follow-up in our institution for at least 1 year. Demographical and etiological data were analyzed, as well as clinical-electrographical semiology, VGB prescription indication, therapeutic schedule, time to reach seizure control, clinical and electrographical evolution while in hospital and at the follow-up, age at VGB withdrawal, besides adverse effects. Results: Among 48 newborns evaluated, 34 (79.2%) reached control of electrographic and/or clinical seizures during neonatal period, with improvement of the EEG pattern after VGB introduction in 79%. As for drug introduction criteria, 33.3% (16 children) were started on VGB due to therapeutic failure of phenobarbital and/or phenytoin; 27.1% (13 newborns), due to status epilepticus and, in 12 babies (25%), due to therapeutic failure of midazolam. By the end of the first year of life, EEG background activity was disorganized in 58.1% (18 out of 29 children who had EEG registered at 12 month of life). Along the one year follow-up of 38 patients, 20 infants (52.6%) showed some degree of neurodevelopmental delay; 19 children (39.5%) remained on VGB in polytherapy, with seizure persistence in 22 (57.9%). Evolution to an epileptic encephalopathy was found in 14 kids (37.8%), with West Syndrome being characterized in 13.9% (5 out of 36 kids). As for the EEG carried out in 34 children at the follow-up, 17.6% (6 cases) showed hypsarrhythmia while focal or multifocal abnormalities were seen in 50% (17 infants). Up to 12 month of life, the death rate was 23.3% (10 out of 43 children evaluated for such endpoint). Visual deficit directly related to VGB use could not be determined. The variable \"seizure control during the neonatal period after VGB use\" was associated to the following endpoints: improvement of the EEG pattern (92,1% of children with seizure control after VGB), lower proportion of children evolving into West syndrome and other epileptic encephalopathies (71.9% did not show such endpoint), lower frequency of hypsarrhythmia in the EEG (92.9% without hypsarrhythmia), better milestones reached regarding neuropsychomotor development (56.2% with good neurological outcome), lower rate of neonatal death (97.4% alive by the end of neonatal period) and along the first year of life (87.9%). Conclusion: VGB is an effective therapeutic option with adequate cost-benefit relationship which should be implemented for the control of refractory neonatal seizures as add-on therapy to conventional drugs. However, controlled randomized studies are necessary to confirm such efficacy as compared to other drugs available for use in the neonatal period, as well as to evaluate its possible long term side effects.

Submitted by Fernanda Furlanetto Bellentani null (fernandafbelle@gmail.com) on 2017-03-07T01:02:32Z No. of bitstreams: 1 Tese Bellentani FF.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-03-10T16:53:16Z (GMT) No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) / Made available in DSpace on 2017-03-10T16:53:16Z (GMT). No. of bitstreams: 1 bellentani_ff_dr_bot.pdf: 1557146 bytes, checksum: 788737393ee9b836ba8bd34728ed2c3d (MD5) Previous issue date: 2017-02-17 / A conectividade funcional é anormal na epilepsia do lobo temporal mesial (ELTm). O objetivo deste estudo foi investigar os efeitos de fármacos antiepilépticos (FAES) na conectividade funcional de pacientes com ELTm. Para isso, 31 pacientes com ELTm (16 à direita e 15 à esquerda) e 36 controles foram investigados. Sequências 3D volumétricas T1 e imagens funcionais a partir de sinal BOLD foram adquiridas em um equipamento 3T. Os dados da ressonância magnética funcional (RMf) em repouso foram processados e analisados utilizando o programa CONN. Para cada sujeito, duas formas de análise foram realizadas: uma de correlação entre as várias regiões de interesse e outra de região interesse para todos os voxels. A análise de grupos foi feita utilizando um modelo linear geral com nível de significância de p < 0,05 corrigido para múltiplas comparações. Foram realizadas comparações entre pacientes com ELTm (direita ou esquerda) e controles, seguidas de comparações de acordo com a carga de FAEs. A partir dessas análises, foi constatado uma redução de conectividade com volume total de 9092 mm3 (p<0,0001), em pacientes com ELTm esquerda e 5234 mm3 (p<0,0001), em pacientes com ELTm direita . Quando considerada a carga de medicação, pacientes com ELTm esquerda, recebendo doses altas, apresentaram redução de conectividade nas regiões temporais. Nos pacientes que recebiam doses baixas, essa redução atingiu uma área total mais extensa, no córtex frontal medial, na região posterior do cíngulo e pré-cúneo. Para o lado direito, em pacientes recebendo doses altas, a redução de conectividade foi observada apenas na área do cótex frontal medial. Nos que receberam doses baixas, 2 áreas com redução foram observadas (córtex frontal medial e região posterior do cíngulo) e com uma extensão maior. A análise de correlação envolvendo regiões de interesse mostrou, para ambos os lados, que o circuito amígdalo-hipocampal e a rede de modo padrão apresentaram maior conectividade quando utilizadas maiores doses de FAEs. Com base nesses resultados, foram confirmadas áreas de conectividade funcional anormal em pacientes com ELTm e que se apresentam mais difusas em pacientes com ELTm esquerda. Conclui-se também que as doses de medicamentos podem influenciar nestas observações, uma vez que o aumento de dose tende a normalizar a conectividade funcional cerebral. / The functional connectivity is abnormal in mesial temporal lobe epilepsy (MTLE). The objective of this study was to investigate the effects of antiepileptic drugs (AED) laterality and medication effect in the functional connectivity of MTLE. For this, 31 patients with MTLE (16 right and 15 left) and 36 controls were investigated. 3D volumetric sequences T1 and functional images from BOLD signal were acquired in a 3T equipment. Functional magnetic resonance imaging (fMRI) data were processed and analyzed using the CONN program. Two forms of analysis were performed for each patient: one of correlation between the various regions of interest and other of region of interest for all the voxels. The group analyzes was done following a general linear model with a level of significance of p < 0,05 corrected for the multiple comparisons. Comparisons were made between patients with MTLE (right or left) and controls, following of comparisons according to the AED. From these analysis, it was observed that in patients with left MTLE, there was a reduction in connectivity with total volume of 9092 mm³ (p<0,0001) and in patients with right MTLE, the areas of decreased connectivity totaled 5234 mm³ (p<0,0001). When considering the medication load, patients with left MTLE receiving high doses presented reduced connectivity in the temporal regions and in patients receiving low doses, this reduction reached a more extensive total area, in the medial frontal cortex, in the posterior region of the cingulate and pre-cuneous. To the right side, in patients receiving high doses, a reduced connectivity was observed only in the area of the medial frontal cortex, whereas in those receiving low doses, 2 areas with reduction were observed (medial frontal cortex and posterior cingulate region). The analysis of correlation involving regions of interest showed, to both sides that the amygdalo-hippocampal circuit and the network pattern mode presented greater connectivity when higher doses of AED. Based on these results were confirmed areas of abnormal functional connectivity in patients with MTLE and are more difuse in patients with left MTLE. It was also concluded that drug doses can influence these observations, once the doses increase tends to normalize functional brain connectivity.

No description available.

Introdução: A vigabatrina (VGB - Gama-Vinil-GABA) é um fármaco que eleva os níveis de GABA no organismo, por inibição irreversível da GABA transaminase, cuja eficácia foi bem demonstrada no controle dos espasmos epilépticos em lactentes, especialmente na síndrome de West secundária à esclerose tuberosa. Há escassez de estudos clínicos evidenciando um possível papel deste fármaco no controle de crises epilépticas neonatais e pouco se sabe sobre o potencial impacto do seu uso nessa faixa etária, seus possíveis efeitos adversos, ou se sua introdução teria associações positivas com controle mais adequado das crises na evolução e melhor desenvolvimento neuropsicomotor da criança. A VGB foi introduzida em nosso serviço como terapia de adição para o controle de crises neonatais refratárias, há vários anos, instigando nossa impressão sobre a eficácia deste medicamento no período neonatal. Objetivos: Avaliar a efetividade do uso da VGB como adjuvante no controle das crises eletrográficas e eletroclínicas do período neonatal e seus efeitos sobre o padrão do eletroencefalograma (EEG); Avaliar a evolução clínica e eletrográfica das crianças durante seguimento ambulatorial; Pesquisar associação entre \"controle de crises neonatais com introdução de VGB\" e diversas características demográficas, clínicas e evolutivas destes recém nascidos; Quantificar e caracterizar a ocorrência de efeitos adversos precoces e durante o seguimento. Pacientes e métodos: Estudo transversal retrospectivo, envolvendo o levantamento dos prontuários de uma amostra de recém-nascidos que receberam VGB como tratamento para crises neonatais refratárias aos fármacos convencionais e status epilepticus, no período de janeiro de 2007 a março de 2014, no Serviço de Neonatologia e Terapia Intensiva Neonatal do HCFMRP-USP, mantendo seguimento ambulatorial por pelo menos 1 ano. Foram avaliados os dados demográficos, etiologia e semiologia clínico-eletroencefalográfica das crises, esquema terapêutico prescrito, indicação da introdução da VGB, tempo de internação e tempo para atingir o controle das crises, evolução clínica e eletrencefalográfica durante a internação e no seguimento ambulatorial, época da suspensão da VGB, além de seus efeitos adversos. Resultados: De 48 recém-nascidos avaliados, 34 (79,2 %) obtiveram controle de crises eletrográficas e/ou clínicas durante o período neonatal, havendo melhora no padrão eletrográfico após a introdução da VGB em 79%. Quanto aos critérios para sua indicação, 33,3% (16 indivíduos) iniciaram VGB devido a falha terapêutica no controle das crises com fenobarbital e/ou fenitoína; 27,1% (13 recém nascidos), pela presença de estado de mal epilético e, em 12 crianças (25%), por falha terapêutica do midazolam. Ao final do primeiro ano de vida, a atividade de base do EEG mostrou-se desorganizada em 58,1% (18 de 29 pacientes que o realizaram aos 12 meses de vida). No seguimento ambulatorial de 38 pacientes, algum grau de atraso do desenvolvimento neuropsicomotor foi detectado em 20 crianças (52,6%); 19 lactentes (39,5%) mantiveram o uso da VGB em politerapia, tendo 22 crianças (57,9%) evoluído com persistência das crises epilépticas. Já 37,8% (14 pacientes) enquadraram-se em um padrão de encefalopatia epiléptica, que correspondeu à síndrome de West em 13,9% (5 de 36 crianças). Quanto ao EEG realizado em 34 crianças nessa fase, 17,6% (6 casos) demonstraram a presença de hipsarritmia, enquanto anormalidades focais ou multifocais foram detectadas em 50% (17 lactentes). A taxa de óbito ao final do primeiro ano foi de 23,3% (10 de 43 crianças analisadas quanto a este dado). Não foi possível comprovar déficit visual relacionado diretamente ao uso da VGB. A variável \"controle de crises no período neonatal com o uso da VGB\" foi associada aos seguintes desfechos clínicos favoráveis: melhora no padrão eletrográfico (92,1%), proporção menor de crianças evoluindo para síndrome de West e outras encefalopatias epilépticas (71,9% não tiveram tal desfecho); menor frequência de hipsarritmia no EEG (92,9% sem hipsarritmia), maior alcance de desenvolvimento neuropsicomotor normal (56,2% com bom desenvolvimento neurológico), menor índice de óbito neonatal (97,4% vivos nesta fase) e durante os primeiros doze meses de vida (87,9%). Conclusão: Acreditamos que a VGB seja uma opção terapêutica efetiva e com adequada relação custo-benefício, a ser implementada no controle de crises epilépticas neonatais refratárias como fármaco adjuvante aos convencionais. Entretanto, estudos randomizados e controlados são necessários para confirmar sua eficácia quando comparada a outros medicamentos disponíveis para uso nesta população, bem como para avaliar seus possíveis efeitos adversos a longo prazo. / Introduction: Vigabatrin (VGB - Gama-Vinil-GABA) is an antiepileptic drug which increases systemic GABA levels by irreversibly inhibiting GABA transaminase, with well demonstrated efficacy in the control of infantile epileptic spasms, specially related to West syndrome due to tuberous sclerosis. Clinical studies demonstrating a possible role of VGB in the control of neonatal seizures are still very scarce and very little is known on the impact of its use at this early age, as well as on its possible side effects or eventual positive associations from its use with more adequate seizure control or better neuropsychomotor development in the outcome. VGB has been used in our service as an add-on therapy for refractory neonatal seizures arising the impression that this could be an effective antiepileptic medication in the neonatal period. Objectives: To evaluate the use of VGB as an add-on medication regarding its effectiveness for the control of neonatal electrographic and electroclinical seizures, as well as its effects over the EEG pattern; To evaluate clinical and electrographic evolution of the children in follow-up; To estimate VGB efficacy on the control of neonatal seizures in relation to the demographical and clinical characteristics of those newborns; To quantify and characterize the occurrence of early and late side effects of this medication along follow-up. Patients and methods: This is a transverse retrospective study carried out through charts analysis from a sample of newborns who received VGB as add-on medication for seizures and/or status epilepticus refractory to conventional drugs, from January 2007 through March 2014, at the Neonatal Intensive Care Service of HCFMRP-USP, keeping follow-up in our institution for at least 1 year. Demographical and etiological data were analyzed, as well as clinical-electrographical semiology, VGB prescription indication, therapeutic schedule, time to reach seizure control, clinical and electrographical evolution while in hospital and at the follow-up, age at VGB withdrawal, besides adverse effects. Results: Among 48 newborns evaluated, 34 (79.2%) reached control of electrographic and/or clinical seizures during neonatal period, with improvement of the EEG pattern after VGB introduction in 79%. As for drug introduction criteria, 33.3% (16 children) were started on VGB due to therapeutic failure of phenobarbital and/or phenytoin; 27.1% (13 newborns), due to status epilepticus and, in 12 babies (25%), due to therapeutic failure of midazolam. By the end of the first year of life, EEG background activity was disorganized in 58.1% (18 out of 29 children who had EEG registered at 12 month of life). Along the one year follow-up of 38 patients, 20 infants (52.6%) showed some degree of neurodevelopmental delay; 19 children (39.5%) remained on VGB in polytherapy, with seizure persistence in 22 (57.9%). Evolution to an epileptic encephalopathy was found in 14 kids (37.8%), with West Syndrome being characterized in 13.9% (5 out of 36 kids). As for the EEG carried out in 34 children at the follow-up, 17.6% (6 cases) showed hypsarrhythmia while focal or multifocal abnormalities were seen in 50% (17 infants). Up to 12 month of life, the death rate was 23.3% (10 out of 43 children evaluated for such endpoint). Visual deficit directly related to VGB use could not be determined. The variable \"seizure control during the neonatal period after VGB use\" was associated to the following endpoints: improvement of the EEG pattern (92,1% of children with seizure control after VGB), lower proportion of children evolving into West syndrome and other epileptic encephalopathies (71.9% did not show such endpoint), lower frequency of hypsarrhythmia in the EEG (92.9% without hypsarrhythmia), better milestones reached regarding neuropsychomotor development (56.2% with good neurological outcome), lower rate of neonatal death (97.4% alive by the end of neonatal period) and along the first year of life (87.9%). Conclusion: VGB is an effective therapeutic option with adequate cost-benefit relationship which should be implemented for the control of refractory neonatal seizures as add-on therapy to conventional drugs. However, controlled randomized studies are necessary to confirm such efficacy as compared to other drugs available for use in the neonatal period, as well as to evaluate its possible long term side effects.

La résistance aux médicaments antiépileptiques (MAEs) est un des problèmes majeurs des épilepsies infantiles, comme par exemple le syndrome de Dravet. La pharmacoresistance de l’épilepsie pourrait s’expliquer par une diminution du passage des MAEs dans le cerveau, à travers la Barrière Hémato-Encéphalique (BHE). La BHE comporte des transporteurs des familles « ATP-binding cassette » (ABC) et « SoLute Carrier » (SLC) localisés au niveau de la membrane des cellules endothéliales qui contrôlent leur passage entre le sang et le cerveau. La pharmacoresistance des épilepsies a été associée à ces transporteurs car des MAEs ont été identifiés comme substrats de transporteurs comme la glycoprotéine-P (P-gP) et la « Breast Cancer Resistance Protein » (BCRP). L’hypothèse de cette relation est confortée par l’observation de l’augmentation de l’expression de ces transporteurs d’efflux dans le foyer épileptogène et par l’identification des polymorphismes dans les gènes des transporteurs chez des patients pharmacorésistants. L’interaction au cours du développement cérébral entre les cellules endothéliales et les neurones et astrocytes pourrait modifier le profil des transporteurs de la BHE. Les MAEs sont aussi connus pour être soit des inducteurs, soit des inhibiteurs des enzymes du métabolisme des médicaments et des transporteurs membranaires. Ces données nous permettent de faire les hypothèses suivantes: 1) La BHE en développement présente un profil de transporteurs différent de la BHE mature qui pourrait modifier le passage des MAEs vers le cerveau ; et 2) le traitement chronique administré au cours du syndrome de Dravet pourrait changer le phénotype des transporteurs de la BHE en développement. Nous résultats ont montré que la P-gP et la BCRP augment leur expression au cours du développement. La maturation de la BHE a aussi un impact sur le passage des MAEs étudiés. Nous avons constaté une augmentation de l’expression des différents transporteurs ABC et SLC étudiés pendant le développement de la BHE, suite au traitement chronique avec la thérapie du Syndrome de Dravet. L’acide valproïque, un des MAEs utilisé dans ce traitement, diminue l’activité d’efflux de la P-gP chez les rats en développement et adultes, ce qui a été confirmé dans un modèle in-vitro de BHE immature. Ces résultats mettent en évidence l’interaction entre la BHE en développement et le traitement chronique par les MAEs peut modifier leur distribution au niveau du cerveau et la réponse aux MAEs. / Resistance to Antiepileptic Drugs (AEDs) has been a major concern in infantile epilepsies such as for example the Dravet Syndrome. One hypothesis concerning the pharmacoresistance in epilepsy is that a decreased delivery of these drugs to the brain may occur in relation to changes in the Blood-Brain Barrier (BBB) function. BBB exhibits ATP-binding cassette (ABC) and SoLute Carrier (SLC) transporters at the surface of endothelial cells that control the blood-brain transport. Pharmacoresistance in epilepsy may be linked to changes in the functions of these transporters since some AEDs are substrates of the P-glycoprotein (P-gP) and Breast Cancer Resistance Protein (BCRP) transporters. The increased expression of efflux transporters in epileptogenic tissue and the identification of polymorphisms in the efflux transporters genes of resistant patients further support this potential relationship. The interaction of endothelial cells with astrocytes and neurons during brain development could change the pattern of transporters in the BBB. AEDs are also known as either inducers or inhibitors of drug metabolic enzymes and membrane transporters. Taken together, these facts led us to test the following hypothesis: 1) the developing BBB in immature animals presents a different pattern of transporters that could change AEDs disposition in the brain of immature subjects; and 2) the chronic pharmacotherapy used in infantile epilepsies such as the Dravet Syndrome may change the transporters phenotype of the BBB. Our work showed that the expression of P-gP and BCRP increases during development as a function of age. We also showed the maturation of the BBB has an impact on brain disposition of the studied AEDs. We finally observed an increase in the expression of various ABC and SLC transporters induced by the pharmacotherapy of the Dravet Syndrome in immature animals. One of the drugs used, valproic acid, appeared nonetheless to reduce the efflux activity of P-gP in developing and adult animals, which was confirmed in an in-vitro model of the immature BBB. Taken together, these results demonstrated that the interaction between the developing BBB and the AEDs chronic treatment may lead to differences in brain disposition of the AEDs that may impact on the response to AEDs.

O fígado desempenha um papel central na disposição metabólica de vários agentes químicos endógenos e exógenos, incluindo quase todos os fármacos. Neste processo de biotransformação pode ocorrer a formação de metabólitos intermediários altamente reativos que se não forem convenientemente eliminados podem interagir com macromoléculas celulares lesando o órgão. A hepatotoxicidade idiossincrática associada ao uso de antiepilépticos aromáticos (AEA) é bem conhecida e tem sido atribuída ao acúmulo de intermediários tóxicos (areno-óxidos) formados durante a bioativação hepática. Embora a participação de processos imunológicos no mecanismo de ação tóxica dos AEA tenha sido demonstrada, existe a possibilidade de mecanismos adjuvantes envolvendo a toxicidade mitocondrial, evento ainda não explorado na literatura científica. Neste estudo avaliou-se, in vitro, o efeito dos AEA: carbamazepina, fenitoína e fenobarbital, bem como dos seus respectivos metabólitos na função mitocondrial e na indução do estresse oxidativo em mitocôndrias de fígado de rato, como possível mecanismo de ação hepatotóxica desses fármacos. Sistema microssomal hepático de rato foi utilizado para bioativação dos fármacos e produção dos respectivos metabólitos in vitro. Sem a bioativação, somente o fenobarbital (em concentrações elevadas) apresentou efeitos inibidores sobre o estado 3 da respiração, síntese de ATP e potencial de membrana, sem, contudo induzir o estresse oxidativo. Quando bioativados, todos os fármacos apresentaram efeitos sobre a função mitocondrial através de processo mediado por estresse oxidativo. Todos os fármacos bioativados afetaram a respiração mitocondrial, causando diminuição do consumo de oxigênio no estado 3, diminuição do RCR e aumento do consumo de oxigênio no estado 4. Foram também evidenciadas alterações na captação/liberação de cálcio, inibição da síntese de ATP, diminuição do potencial de membrana e inibição do intumescimento mitocondrial induzido pelo cálcio. A oxidação de proteínas e lipídeos mitocondriais foi demonstrada pela formação de proteínas carboniladas, diminuição de proteínas com grupamentos sulfidrila, aumento de malondialdeído (MDA) e pela oxidação da cardiolipina. O sistema de defesa antioxidante mitocondrial também foi afetado, como evidenciado pela diminuição da relação GSH/GSSG (glutationa reduzida/glutationa oxidada). Os resultados sugerem fortemente a participação do dano mitocondrial, mediado pelo estresse oxidativo causado pelos metabólitos dos AEA, no desenvolvimento da hepatotoxicidade idiossincrática induzida por esses fármacos. / The liver plays a central role in the metabolic disposition of various endogenous and exogenous chemicals, including almost all drugs. During the biotransformation process, highly reactive metabolites can be produced, and if they are not detoxified, they can interact with cellular macromolecules and cause organ injury. Idiosyncratic hepatotoxicity is a well-known complication associated with aromatic antiepileptic drugs (AAED), and it has been suggested to occur due to the accumulation of toxic arene oxide metabolites. Although the participation of an immune process in the toxic action mechanism of AAED has been demonstrated, adjuvant mechanisms involving mitochondrial toxicity is also possible and such event has not been studied yet. Therefore, we investigated, in vitro, the effects of carbamazepine (CB), phenytoin (PT), phenobarbital (PB) and their respective metabolites on the hepatic mitochondrial function as well as their ability to induce oxidative stress in rat liver mitochondria, as a possible hepatotoxic action mechanism. The murine hepatic microsomal system was used to bioactivate the drugs and to produce the anticonvulsant metabolites in vitro. As an unaltered drug, only phenobarbital (in high concentrations) presented inhibitory effects on state 3 respiration, ATP synthesis, and membrane potential; however, it did not induce oxidative stress. All the bioactivated drugs affected mitochondrial function through an oxidative stress-mediated process. All the bioactivated drugs affected mitochondrial function causing decrease in state 3 respiration, decrease in RCR and increase in state 4 respiration. They also caused impairment of Ca+2 uptake /release, decrease in ATP synthesis, decrease in membrane potential and inhibition of calcium-induced swelling. Oxidation of proteins and lipids was evidenced by carbonil proteins formation, decrease in thiol proteins, increase in malonaldehyde (MDA) and cardiolipin oxidation. The mitochondrial antioxidant defense system was also affected, as evidenced by the decreased GSH/GSSG ratio (reduced glutathione/oxidized glutathione). Results strongly suggest the involvement of mitochondrial damage, which is mediated by the oxidative stress caused by the AAED metabolites, in the development of AAED-induced idiosyncratic hepatotoxicity.