Made available in DSpace on 2015-07-22T20:50:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-03-25 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Objetivos: avaliar a evolução clínica e eletrencefalográfica em 28 pacientes que tiveram diagnóstico de Síndrome de West (SW). Métodos: estudo retrospectivo no qual foram incluídos pacientes que tiveram diagnóstico clínico e eletrográfico de SW e admitidos para seguimento no Hospital São Paulo da Universidade Federal de São Paulo / Escola Paulista de Medicina, entre março de 2006 e dezembro de 2007. Todos foram submetidos a avaliações periódicas durante o tratamento da SW, incluindo VEEG e, no mínimo, um exame de VEEG, com duração de 6 a 12 horas, após o controle da SW por pelo menos um ano. Foram analisados dados demográficos, freqüência e semiologia das crises. Os EEGs e os VEEGs foram revisados para a quantificação e classificação das alterações eletrencefalográficas e das crises epilépticas. Resultados: a amostra foi composta por 28 pacientes com tempo médio de seguimento de 46,5 ± 13 meses, sendo 19 do sexo masculino (68%) e 9 (32%) do sexo feminino. A média de idade na admissão foi 10,5 ± 6,3 meses. Todos os pacientes apresentaram algum grau de atraso no DNPM. Os pacientes foram subdivididos em 2 grupos, criptogênicos (5 casos) e sintomáticos (23 casos). Dos 28 pacientes 16 (57%) evoluíram com crises epilépticas ao final do estudo e 12 (43%) evoluíram sem crises. Do total, 13 (46%) tiveram recidiva da SW. Dentre os 5 criptogênicos 4 (80%) evoluíram com controle de crises e dentre os 23 sintomáticos, apenas 8 (34,7%) evoluíram com controle das crises. Apenas 10,7% dos pacientes evoluíram para SLG (todos do grupo sintomático), permanecendo com crises de difícil controle até o final do seguimento. Dos que permaneceram com crises, 35,7% evoluíram para epilepsia focal, 14,2% com epilepsia generalizada e 7,1% tiveram ambos tipos de crises, focal e generalizada, sendo classificados como epilepsia indeterminada. Conclusões: A maioria dos casos de SW evoluiu para epilepsia focal, portanto, a SLG não foi a síndrome mais freqüente em nosso estudo. O grupo de pacientes sintomáticos apresentou pior evolução quanto ao controle das crises quando comparado com o grupo criptogênico. O tempo de duração da SW também influenciou na evolução. Recidiva da SW tem alta correlação com pior prognóstico. / Objectives: The goal of this study was to evaluate the clinical and electroencephalographic evolution of 28 patients that had WS. Patients and Methods: Retrospective study in which we included patients who had clinical diagnosis and electrographic of WS and admitted in the Hospital São Paulo, Federal University of São Paulo / Escola Paulista de Medicina, between March 2006 and December 2007, who had been submitted to periodic evaluations during treatment of SW, including video-EEG (VEEG) and, after controlling the same, at least, an examination of VEEG, lasting from 6 to 12 hours after the SW under control for at least 1 year. They were revised the handbooks of these patients for analysis of demographic data, frequency and semiology of seizures. The EEGs along the follow-up and the VEEGs were also reviewed for the quantification and classification of electroencephalographic changes and of epileptic seizures. Results: The sample consisted of 28 patients with mean follow-up of 46,5 ± 13 months, with 19 males (68%) and 9 (32%) female. The mean age at admission was 10,5 ± 6,3 months. All patients had some degree of delay in DNPM. The patients were divided into 2 groups, cryptogenics (5 cases) and symptomatics (23 cases). Of the 28 patients 16 (57%) evolved with seizures the end of the study and 12 (43%) evolved without crises. Of the total of patients, 13 (46%) had recurrence of the SW. Of the 5 cryptogenics 4 (80%) evolved with control of seizures and of the 23 symptomatic patients, only 8 (34,7%) evolved with control of the seizures. Only 10,7% of patients evolved to SLG (all of the symptomatic group) and remained with these crises difficult to control until the end of follow up. Of those who remain with crises, 35,7% evolved to focal epilepsy, 14,2% with generalized epilepsy and 7,1% had both types of crises, focal and generalized, being classified as undetermined epilepsy. Conclusions: The SLG wasn’t the evolution most frequent of the SW in our study. The most of these cases evolved with focal epilepsy. The group of symptomatic patients presented worse evolution in the control of seizures when compared with the group criptogenic. The time in which the patient remained in SW seems also influence the evolution. Recurrence of the SW has high correlation with poor prognosis. / TEDE / BV UNIFESP: Teses e dissertações

Le syndrome de West (SW), communément appelé spasmes infantiles (SI), est un trouble épileptique généralement caractérisé par la triade de spasmes infantiles, un modèle d'électroencéphalogramme (EEG) pathognomonique appelé hypsarythmie, et la régression du développement. Alors que des études précédentes ont été en mesure d'obtenir une réponse relativement adéquate par rapport au contrôle des spasmes et la résolution d’hypsarythmie, elles n’ont pas réussi à fournir des options thérapeutiques décisives à l’égard des séquelles neurodéveloppementales souvent associées aux SI. Notre étude, sur laquelle est basée cette thèse, est la première à utiliser un traitement complémentaire aux médicaments antiépileptiques conventionnels, avec l'intention d'améliorer les résultats neurodéveloppementaux de cette population. Les patients recrutés dans notre essai clinique randomisé (ECR) original ont suivi un protocole de traitement standardisé composé de vigabatrin (VGB) comme traitement de première intention pendant deux semaines, suivi de l'hormone corticotrope (ACTH) chez les non-répondeurs pour une période de deux autres semaines, et le topiramate dans les cas réfractaires. En plus, les patients ont été randomisés pour recevoir soit le traitement expérimental, flunarizine, soit un placebo, pendant six mois. Notre ECR multicentrique consistait à recruter et évaluer 68 patients, la plupart suivis à 8 différentes visites sur une période de cinq ans afin de précisément évaluer leurs progrès neurodéveloppementaux. Notre essai clinique a généré trois études principales qui forment le coeur de cette thèse. Dans une première étude, les données cliniques et cognitives des deux premières années d’évaluation ont été analysées. Les résultats cliniques à court terme indiquent un taux élevé de cessation de spasmes et de l’hypsarythmie. De plus, cette étude rapporte les premiers résultats cognitifs mesurés par le Bayley Scales of Infant Development (BSID) et le Vineland Adaptive Behavior Scale (VABS). Notre deuxième étude a essentiellement fourni des données cognitives à plus long terme, 5 ans après le début de son initiation. Les réponses cognitives ont été mesurées par le BSID, le VABS, et aussi par le Stanford-Binet Intelligence Scale (SB5) chez les patients ayant un fonctionnement cognitif plus élevé. Une amélioration significative et progressive des fonctions cognitives a été observée, indépendamment de la thérapie adjuvante. Des facteurs de risque cognitifs à long terme ont également été révélés dans cette étude. Notre dernière étude a essayé d’élucider la relation entre les SI et les troubles du spectre autistique (TSA). Un test de dépistage avec le Checklist for Autism in Toddlers (CHAT) a été effectué à 24 mois, et un diagnostic a été obtenu par moyen du Autism Diagnostic Observation Schedule (ADOS) à 30 et 60 mois. L’ADOS a évalué 44 patients, dont 10 ont été diagnostiqués avec TSA. Une description des facteurs de risque associés aux TSA ont été présentés dans cet article. Enfin, basé sur nos résultats et les informations à ce sujet dans la littérature, nous avons tenté d'élucider les caractéristiques physiopathologiques de la maladie. Une description des mécanismes biologiques sous-jacents impliqués dans le syndrome de West et des traitements cibles associés ont été présentés. Bien que le traitement complémentaire, le flunarizine ne se soit pas avéré être avantageux pour notre cohorte, notre protocole de traitement a tout de même été en mesure de démontrer des résultats cliniques et cognitifs supérieurs dans le sous-groupe de patients avec SI dont l’étiologie est inconnue. Ces résultats, ainsi que l’identification de nouveaux facteurs de risque neurodéveloppementaux potentiels, pourraient être utilisés cliniquement afin d’améliorer le diagnostic et le suivi médical des patients atteints du syndrome de West. / West syndrome (WS), commonly referred to as infantile spasms (IS), is an epileptic disorder usually characterized by the triad of infantile spasms, a pathognomonic electroencephalogram (EEG) pattern called hypsarrhythmia, and developmental regression. While previous treatment studies were able to achieve relatively adequate spasm control and hypsarrhythmia resolution in this population of patients, they have failed to provide conclusive and definite therapeutic options aimed at improving the poor cognitive outcome often associated to IS. Our study, on which this thesis is based, was the first to use an add-on treatment to conventional antiepileptic drugs, with the intent to improve long-term cognitive outcome in this population. Patients recruited in our original randomized clinical trial (RCT) followed a standardized treatment protocol consisting of vigabatrin (VGB) as first-line treatment for two weeks, followed by adrenocorticotropic hormone (ACTH) in non-responders for another two-week period, and topiramate in refractory cases. In addition, patients were randomized to either receive placebo or flunarizine adjunct therapy for six months. Our multi-centric RCT recruited and evaluated 68 patients, most of which were followed at 8 different time points over a five-year period, to precisely evaluate their neurodevelopmental progress. Our clinical trial generated three main studies which comprise the core of this thesis. In a first study, clinical and cognitive data from the first two years were analyzed. Spasm arrest and hypsarrhythmia resolution were the short-term clinical endpoint measures, while the Vineland Adaptive Behavior Scale (VABS) and Bayley Scales of Infant Development (BSID) were used as cognitive outcome measures at 2 years. This first study most importantly reports on the superior short-term clinical response rate achieved in our study population. Preliminary cognitive results were also presented in this work. Our second study essentially presented long-term cognitive data 5 years after the start of the study. Cognitive outcome measures were similar to those used at two years with the addition of the Stanford-Binet Intelligence Scale, Fifth Edition (SB5) for higher functioning patients. Most IS patients, particularly those with no known etiology, displayed a significant and progressive improvement of cognitive functions, irrespective of adjunctive therapy. Risk factors of long term poor cognitive outcome were also revealed in this study. Our last study tried to understand the relationship between IS and autism spectrum disorders (ASD). Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-up visits using the Autism Diagnostic Observation Schedule (ADOS). ADOS was performed in 44 patients, 10 of which were diagnosed with ASD. A description of risk factors associated with an ASD outcome in the IS population were presented in this article. Finally, based on our study results and in conjunction with literature information on the topic, we attempted to elucidate the pathophysiological characteristics of the disorder. A conceivable description of the underlying biological mechanisms implicated in West syndrome and associated target treatments were presented. Although our complementary treatment, flunarizine, did not prove to be beneficial in our cohort, our treatment protocol was nonetheless able to demonstrate superior clinical and cognitive outcomes in patients with unknown etiologies. These findings, as well as the identification of new potential neurodevelopmental risk factors, could be used clinically to improve the diagnosis and medical follow-up of patients with West syndrome.