Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy.

BACKGROUND: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. OBJECTIVE: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. METHODS: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. RESULTS: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. CONCLUSION: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

Efficacy and safety of levetiracetam as adjunctive therapy for refractory focal epilepsy / Eficácia e segurança do levetiracetam como terapia adjunta na epilepsia focal refratária

ABSTRACT Background: Epilepsy affects about 50 million people worldwide and around 30% of these patients have refractory epilepsy, with potential consequences regarding quality of life, morbidity and premature mortality. Objective: The aim of treatment with antiseizure medications (ASMs) is to allow patients to remain without seizures, with good tolerability. Levetiracetam is a broad-spectrum ASM with a unique mechanism of action that differs it from other ASMs. It has been shown to be effective and safe for treating adults and children with epilepsy. Methods: This was a phase III, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of levetiracetam in children and adults (4-65 years) as an adjuvant treatment for focal-onset seizures. It was conducted among 114 patients undergoing treatment with up to three ASMs. The primary efficacy analysis was based on the proportion of patients who achieved a reduction of ≥ 50% in the mean number of focal seizures per week, over a 16-week treatment period. The patients were randomized to receive placebo or levetiracetam, titrated every two weeks from 20 mg/kg/day or 1,000 mg/day up to 60 mg/kg/day or 3,000 mg/day. Results: Levetiracetam was significantly superior to placebo (p = 0.0031); 38.7% of the participants in the levetiracetam group and 14.3% in the control group shows reductions in focal seizures. Levetiracetam was seen to have a favorable safety profile and an adverse event rate similar to that of placebo. Conclusion: Corroborating the results in the literature, levetiracetam was shown to be effective and safe for children and adults with refractory focal-onset epilepsy.

RESUMO Introdução: A epilepsia afeta cerca de 50 milhões de pessoas em todo o mundo e aproximadamente 30% desses pacientes apresentam epilepsia refratária, com possíveis consequências na qualidade de vida, morbidade e mortalidade prematura. Objetivo: O objetivo do tratamento com fármacos antiepilépticos (FAEs) é permitir que os pacientes permaneçam sem crises epilépticas com boa tolerabilidade. O levetiracetam (LEV) é um FAE de amplo espectro, com mecanismo de ação único, diferente dos demais e que demonstra ser eficaz e seguro no tratamento de adultos e crianças. Métodos: Estudo de fase III, multicêntrico, randomizado, duplo-cego e controlado por placebo avalia a eficácia e a segurança do LEV em crianças e adultos (4-65 anos) como tratamento adjuvante para crises de início focal em 114 pacientes já tratados com até três FAEs. A análise de eficácia primária foi baseada na proporção de pacientes que apresentaram redução ≥50% no número médio de crises epilépticas focais semanais, durante 16 semanas. Os pacientes foram randomizados para receber placebo ou LEV, titulado a cada duas semanas de 20 mg/kg/dia ou 1.000 mg/dia até 60 mg/kg/dia ou 3.000 mg/dia. Resultados: LEV foi significativamente superior ao placebo (p=0,0031), com 38,7% dos participantes no grupo LEV e 14,3% no grupo controle que apresentaram redução das crises focais. LEV apresenta bom perfil de segurança com eventos adversos semelhantes ao placebo. Conclusão: Corroborando com os resultados da literatura, o levetiracetam mostra-se eficaz e seguro para crianças e adultos com epilepsia focal refratária.

Analysis of genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in Induced Pluripotent Stem Cells (iPSCs) from patients with Focal Cortical Dysplasia.

Focal cortical dysplasia (FCD) is a malformation of cortical development which is strongly associated with drug-refractory epilepsy. Certain studies have demonstrated an increase in mTOR signaling in patients with FCD on the basis of observation of phosphorylated molecules. The aim of the present study was to verify the differences in genes involved in cell proliferation, adhesion, and control of apoptosis during embryonic neurogenesis in iPSCs derived from the Focal Cortical Dysplasia. Fibroblasts were obtained from the skin biopsies of patients with FCD (n = 2) and controls (n = 2). iPSCs were generated by exposing the fibroblasts to viral vectors that contained the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC genes) responsible for promoving cell reprogramation. The fibroblasts and iPSCs were tested during different phases of neurodifferentiation for migration capacity and expression of the genes involved in the PI3K pathway. Fibroblasts of patients with FCD migrated with greater intensity during the first two time points of analyses. iPSCs did not exhibit any difference in cell migration between the groups. Fibroblasts, brain tissue, and iPSCs of the patients with FCD exhibited a significant reduction in the relative expression values of 4EBP-1. During neurodevelopment, the iPSCs from patients with FCD exhibited a reduction in the expression of cIAP-1, cIAP-2, PI3K, ß-Catenin and 4EBP-1 gene. We suggest that the differences observed in the migration potential of adult cells and in the gene expression related to the fundamental processes involved in normal brain development during the neurodifferentiation process might be associated with cortical alteration in the patients with FCD.

Migration and Synaptic Aspects of Neurons Derived from Human Induced Pluripotent Stem Cells from Patients with Focal Cortical Dysplasia II.

Malformations of cortical development (MCDs) include many different Central Nervous System (CNS) disorders related to a complex process of cortex formation. In children with refractory epilepsy to drug treatment undergoing surgery, focal cortical dysplasia (FCD), one of the MCDs, is considered the most common structural brain lesion found. This study aimed to study the possible alterations in neural differentiation process of human induced pluripotent stem cells (hiPSCs) related to migration and synaptic aspects from fibroblasts of two individuals affected by FCD type IIb (45-year-old male and 12-year-old female) and normal individuals. At the days 14th, 22nd and 35th, hiPSCs were neural differentiated and analyzed. Using qRT-PCR approach, the expression of 9 genes associated with synaptic and neural migration were quantified. Diagnostic of both patients was consistent with FCD type IIb. Our results showed that in all processes and groups, individuals with dysplasia presented alterations in most part of the genes in relation to control individuals. According to our results, it is suggested that the different expressions are mainly involved in alterations of the expression of receptors and capture sites, timing, coupling of synaptic vesicles with the presynaptic membrane, regulation of ion channel and synaptic exocytosis, imbalance of the apoptosis process and abnormal microtubules that may also contribute to delays in synaptogenesis. Thus, brain formation with dysplasia is probably influenced by these genes studied.

Suicide risk, temperament traits, and sleep quality in patients with refractory epilepsy.

OBJECTIVES: The objective of the study was to access the suicide risk (SR) in patients with refractory epilepsy and its association with temperament and sleep quality. METHODS: A total of 50 consecutive patients referred for epilepsy surgery evaluation in the Porto Alegre Epilepsy Surgery Program were included. All patients had a detailed neurologic and psychiatric evaluation, including video-electroencephalogram (VEEG), high-resolution magnetic ressonance imaging (MRI), and neuropsychologic assessment. In addition, structured questionnaires were applied: module C of the MINI-plus (International Neuropsychiatric Interview-Brazilian version 5.0.0), Affective and Emotional Composite Temperament Scale (AFECTS), and Pittsburgh Sleep Quality Index (PSQI). RESULTS: Ten patients (20.0%) showed an increased SR. The most frequent location of the epileptic focus was in the temporal lobe (50%; n=25). Final diagnosis on VEEG comprised epilepsy in 74.0% (n=37), psychogenic nonepileptic seizures (PNES) in 8.0% (n=4), and both in 12%. Thirty patients (60.0%) received surgery indication. Mood disorders were the main psychiatric diagnosis, found in 19 subjects (70.4%), with major depressive disorder (MDD) encountered in 15 patients (55.6%). In the group, SR was more frequent in patients with sleep disorders (p=0.001) and elevated scores of high emotional sensitivity (p=0.003). CONCLUSION: In this cohort of patients with highly refractory epilepsy, there was a significant association between SR, sleep disorders, and high emotional sensitivity. Careful evaluation of these factors should be performed in these patients to fully access SR.

Diagnóstico e manejo da diplopia aguda no adulto / Overview of acute diplopia in adults

Diplopia aguda é um sintoma incomum, mas presente na cena de urgência e nos consultórios clínicos. A avaliação da diplopia é desafiadora para o médico generalista, pois envolve conhecimentos de múltiplas áreas. A correta avaliação inicial e identificação dos sinais de gravidade são fundamentais para manejo de condições potencialmente ameaçadoras à vida do paciente.

Acute diplopia is an uncommon but present symptom in emergence scene and generalists practice. The evaluation of diplopia is challenging for the general practitioner because it demands multiple medical areas knowledge. The proper initial evaluation of this symptom and identification of gravity signals is crucial to life threatening conditions.

Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study).

UNLABELLED: The effects of galantamine (GAL) on quality of life (QoL) and cognitive speed, as well its effects combined with nimodipine (NIM) in Alzheimer disease (AD) with cerebrovascular disease (mixed dementia), have not been explored. METHOD: Double-blind, placebo-controlled, multicenter Brazilian trial, studying the effects of GAL/NIM vs. GAL/placebo (PLA) in mild to moderate mixed dementia. Patients were randomized to receive GAL/NIM or GAL/PLA for 24 weeks. Primary efficacy measures were changes on a computerized neuropsychological battery (CNTB) and QoL Scale in Alzheimer's Disease (QoL-AD) from baseline to week 24. RESULTS: Twenty-one patients received at least one drug dose (9 GAL/NIM and 12 GAL/PLA). Groups were matched for age, sex, education, cognitive and QoL scores at baseline. No significant differences were observed between groups on primary or secondary measures. QoL and cognitive performance showed significant improvement (p<0.05) from baseline when all GAL-treated patients were analyzed. Adverse events were predominantly mild to moderate. CONCLUSION: GAL treatment improved QoL in mixed dementia, in addition to its previously known cognitive benefits. The combination GAL/NIM was not advantageous. However, the small sample size precludes any definitive conclusions. Trial registered at ClinicalTrials.gov: NCT00814658.

Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study) / Efeitos da galantamina e da galantamina combinada à nimodipina sobre a velocidade de processamento cognitivo e qualidade de vida na demência mista: ensaio clínico exploratório, randomizado e controlado com placebo (estudo REMIX)

The effects of galantamine (GAL) on quality of life (QoL) and cognitive speed, as well its effects combined with nimodipine (NIM) in Alzheimer disease (AD) with cerebrovascular disease (mixed dementia), have not been explored. Method : Double-blind, placebo-controlled, multicenter Brazilian trial, studying the effects of GAL/NIM vs. GAL/placebo (PLA) in mild to moderate mixed dementia. Patients were randomized to receive GAL/NIM or GAL/PLA for 24 weeks. Primary efficacy measures were changes on a computerized neuropsychological battery (CNTB) and QoL Scale in Alzheimer's Disease (QoL-AD) from baseline to week 24. Results : Twenty-one patients received at least one drug dose (9 GAL/NIM and 12 GAL/PLA). Groups were matched for age, sex, education, cognitive and QoL scores at baseline. No significant differences were observed between groups on primary or secondary measures. QoL and cognitive performance showed significant improvement (p<0.05) from baseline when all GAL-treated patients were analyzed. Adverse events were predominantly mild to moderate. Conclusion : GAL treatment improved QoL in mixed dementia, in addition to its previously known cognitive benefits. The combination GAL/NIM was not advantageous. However, the small sample size precludes any definitive conclusions. Trial registered at ClinicalTrials.gov: NCT00814658 .

Os efeitos da galantamina (GAL) sobre qualidade de vida (QdV) e velocidade de processamento cognitivo, bem como da combinação com nimodipina (NIM) no tratamento da doença de Alzheimer (DA) com doença cerebrovascular (demência mista) ainda não foram investigados. Método : Estudo multicêntrico brasileiro, duplo-cego, controlado com placebo, avaliando os efeitos de GAL/NIM x GAL/placebo (PLA) na demência mista leve a moderada. Pacientes receberam tratamento com GAL/NIM ou GAL/PLA por 24 semanas. Medidas de eficácia primária foram as variações no desempenho em bateria de testes neuropsicológicos computadorizados e na escala QdV-DA ao final do estudo. Resultados : Vinte um pacientes receberam pelo menos uma dose da droga (9 GAL/NIM e 12 GAL/PLA). Os grupos foram emparelhados por idade, sexo, escolaridade, escores cognitivos e de QdV na linha de base. Não foram observadas diferenças significativas entre os dois grupos nas medidas de eficácia primária e secundária. Na avaliação de todos os pacientes que receberam GAL, houve melhora significativa (p<0,05) em QdV-DA e desempenho cognitivo. Os eventos adversos foram predominantemente leves a moderados. Conclusão : O tratamento com GAL proporcionou melhora da QdV na demência mista, além dos benefícios cognitivos previamente conhecidos. A combinação GAL/NIM não foi vantajosa. O reduzido tamanho amostral impede conclusões definitivas. .

A multicenter, open-label trial to evaluate the quality of life in adults with ADHD treated with long-acting methylphenidate (OROS MPH): Concerta Quality of Life (CONQoL) study.

UNLABELLED: The available literature provides few studies on the effectiveness of methylphenidate in improving quality of life in individuals with ADHD. OBJECTIVE: To assess the effectiveness of methylphenidate OROS formulation (OROS MPH) through QoL in adults with ADHD. METHOD: A 12-week, multicenter, open-label trial involving 60 patients was used. The measures used were Adult Self-Rating Scale, Adult ADHD Quality of Life Scale (AAQoL), State and Trait Anxiety Inventory (STAI), Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression (CGI), and safety measures. A significance statistic level of 5% was adopted. RESULTS: Analyses included 60 patients (66.7% male; M age = 31.1 years) for safety and 58 patients for effectiveness. All AAQoL subscales improved from baseline to Week 12 (p < .0001), as well as the Total AAQoL (p < .0001). A significant reduction on Clinical Global Impression-Improvement (CGI-I), HAM-D, STAI, and ASRS scores was observed (p < .0001). No serious adverse event was reported. CONCLUSION: Treatment of adult ADHD patients with OROS MPH improves QoL.

Incidence of SUDEP in a cohort of patients with refractory epilepsy: the role of surgery and lesion localization / Incidência de SUDEP numa coorte de pacientes com epilepsia refratária: papel da cirurgia e da localização da lesão

OBJECTIVE: The aim of this study was to verify incidence and characteristics of sudden unexpected death in patients (SUDEP) with refractory epilepsy and its relation to previous surgery and lesion localization. METHOD: A cross sectional study was carried out in a cohort of 550 patients with refractory epilepsy followed up by the Epilepsy Surgery Program of the University Hospital of PUCRS, Porto Alegre, Brazil, between January, 1992 and July, 2002. Patients were allocated in two groups (operated and non operated). Seizure type, distribution of interictal spikes and MRI findings were correlated with the SUDEP outcome. RESULTS: The estimated incidence of probable SUDEP amounted to 29:1000 individuals. Probable SUDEP occurred in 1.2 percent of the 166 patients of the non operated group and in 3.7 percent of the 384 patients who were operated (OR=3.02, 95 percent CI 0.69-13.16) (p=0.11). Comparing patients who died to patients alive in the operated group a significant difference was observed concerning the following variables: SUDEP patients had a predominance of generalized seizures (p=0.002), extratemporal lesion on MRI (p<0.001) and epileptiform activity over extratemporal regions (p=0.001). CONCLUSION: In surgically treated patients with refractory epilepsy, an extratemporal location of the lesion and of the epileptiform discharges significantly correlated to SUDEP. Thus it is possible that in those patients; the underlying disease may play a role in the pathogenesis of SUDEP.

OBJETIVO: O objetivo deste estudo é avaliar a incidência e características de morte súbita em pacientes com epilepsia refratária (SUDEP) e sua relação com cirurgia prévia e localização da lesão. MÉTODO: Estudo de Coorte realizado com 550 pacientes com epilepsia refratária seguidos no Programa de Epilepsia do Hospital Universitário da PUCRS, Porto Alegre, Brasil, entre Janeiro, 1992 e Julho, 2002. Os pacientes foram distribuídos em dois grupos (operados e não operados). Tipo de epilepsia, distribuição das descargas interictais e achados em RNM foram correlacionados com SUDEP. RESULTADOS: A incidência estimada de SUDEP foi 29:1000 indivíduos. A incidência de provável SUDEP nos 166 pacientes do grupo de não operados foi 1,2 por cento e nos 384 pacientes no grupo operado 3,7 por cento (OR=3,02, 95 por cento IC 0,69-13,16) (p=0,11). Comparando os pacientes que morreram com os sobreviventes do grupo operado houve diferença significativa nas seguintes variáveis: pacientes com SUDEP apresentam uma predominância de crises epilépticas generalizadas (p=0,002), lesões extratemporais na RNM (p<0,001) e atividade epileptiforme na região extratemporal (p=0,001). CONCLUSÃO: A localização da lesão e as descargas extratemporais em pacientes tratados cirurgicamente com epilepsia refratária correlacionaram-se significativamente com SUDEP. Então, é possível que nestes pacientes uma doença sobrejacente possa estar envolvida na patogênese da SUDEP.

Incidence of SUDEP in a cohort of patients with refractory epilepsy: the role of surgery and lesion localization.

OBJECTIVE: The aim of this study was to verify incidence and characteristics of sudden unexpected death in patients (SUDEP) with refractory epilepsy and its relation to previous surgery and lesion localization. METHOD: A cross sectional study was carried out in a cohort of 550 patients with refractory epilepsy followed up by the Epilepsy Surgery Program of the University Hospital of PUCRS, Porto Alegre, Brazil, between January, 1992 and July, 2002. Patients were allocated in two groups (operated and non operated). Seizure type, distribution of interictal spikes and MRI findings were correlated with the SUDEP outcome. RESULTS: The estimated incidence of probable SUDEP amounted to 29:1000 individuals. Probable SUDEP occurred in 1.2% of the 166 patients of the non operated group and in 3.7% of the 384 patients who were operated (OR=3.02, 95% CI 0.69-13.16) (p=0.11). Comparing patients who died to patients alive in the operated group a significant difference was observed concerning the following variables: SUDEP patients had a predominance of generalized seizures (p=0.002), extratemporal lesion on MRI (p<0.001) and epileptiform activity over extratemporal regions (p=0.001). CONCLUSION: In surgically treated patients with refractory epilepsy, an extratemporal location of the lesion and of the epileptiform discharges significantly correlated to SUDEP. Thus it is possible that in those patients; the underlying disease may play a role in the pathogenesis of SUDEP.

Displasias corticais associadas à epilepsia: Delineamento de uma nova síndrome, revisão de conceitos localizacionais e proposta de uma nova classificação / Cortical displasias associated with epilepsy: outlining of a new syndrome, review of localized concepts and proposal of a new classification

O advento de modernas técnicas de neuroimagem, particularmente da ressonância magnética (RM), tem permitido a identificação "in vivo" de lesões displásicas em pacientes previamente diagnosticados como portadores de epilepsias criptogênicas. Estas lesões são heterogêneas do ponto de vista clínico, anatômico, histopatológico e fisiopatogênico, embora tal heterogeneidade não seja sistematicamente reconhecida, dificultando uma compreensão mais aprofundada do quadro clínico e da história natural dos diversos tipos de displasias corticais. Para determinar a relevância dos aspectos anatômicos e histopatológicos na apresentação clínico-eletrográfica das displasias corticais, identificar síndromes epilépticas específicas e reavaliar conceitos localizacionais, estudamos 99 pacientes com formas variadas porém bem caracterizadas de displasia cortical e 39 pacientes com crises refratárias associadas a lesões epileptogênicas extra-hipocampais não displásicas. Uma revisão de conceitos localizacionais é sugerida para as formas difusas de displasia cortical como a SCD, uma vez que, a despeito da heterotopia ser usualmente bilateral e difusa, a maioria dos pacientes apresenta de acentuação focal do quadro epileptogênico.

Indicaçäo de medicamentos por balconistas de farmácia em Porto Alegre, RS / Indication of drugs by pharmacy attendants in Porto Alegre, RS

Com o objetivo de avaliar alguns aspectos da indicaçäo de medicamentos por balconistas de farmácia, foram escolhidas cinco queixas prevalentes na prática médica ambulatorial. Estas foram simuladas em 215 entrevistas, das quais, em 92%, pelo menos um medicamento foi indicado para "tratar" a queixa apresentada. Os balconistas emitiram uma opiniäo diagnóstica em 62% e 84% dos casos respectivamente. Näo houve qualquer preocupaçäo com recomendaçöes higiênico-dietéticas ou quanto a efeitos adversos dos medicamentos indicados. Säo analisados aspectos ético-legais, médicos e sócio-econômicos da venda de medicamentos em farmácias, sendo propostas alternativas para disciplinar essa atividade, que ainda permanece como problema prioritário em saúde pública no Brasil