Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. METHODS: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 µg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). FINDINGS: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 µg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 µg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 µg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 µg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. INTERPRETATION: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease. FUNDING: Orphalan.

Comparison of screening tests in the evaluation of cognitive status of patients with epilepsy.

Epilepsy, a chronic neurological condition which is associated with neurobiological and psychosocial changes, affects 0.5 to 1% of the world's population, presenting in most cases a deficit in reasoning, memory and attention. OBJECTIVE: To contribute to the implementation of screening strategies for cognitive decline and memory deficits in patients with epilepsy. METHODS: Two questionnaires, MMSE and MoCA, were used in this cross-sectional and observational study. Fifty-four patients diagnosed with different types of epilepsy (55% refractory) were assessed; they were all over 18 years old, of both genders, with autonomy to answer the questionnaire. They were followed exclusively at an outpatient clinic of the Neurology Service Department, specialized in epilepsy, which is part of the tertiary healthcare level of the Brazilian Unified Health System (SUS). RESULTS: The final sample consisted of 54 patients. There was a significant correlation (p<0.001) between the scores of both tests, indicating that low values in the MMSE score also corresponded to low values in the MoCA score. Sensitivity was 90% (ROC curve adjusted) and 87.5% of the patients with a normal score in the MMSE test obtained alterations in the MoCA scores. None of them showed a low MMSE score with a normal MOCA score. The Spearman correlation coefficient was 0.80. Also, there was a significant relationship between both immediate memory and delayed recall memory and the type of seizure (p<0.03) and level of schooling (p<0.001), respectively. CONCLUSION: The MoCA is a well-suited test to be performed in epilepsy patients to evaluate their cognition as it seems more extensive and complete compared to MMSE.

A epilepsia, condição neurológica crônica associada a alterações neurobiológicas e psicossociais, afeta de 0,5 a 1% da população mundial. Na maior parte dos casos, há redução de raciocínio, memória e atenção. OBJETIVOS: Contribuir para a implementação de estratégias de rastreio de declínio cognitivo e distúrbios na memória nos pacientes com epilepsia. MÉTODOS: Estudo transversal observacional de 54 pacientes diagnosticados com epilepsia de diversos tipos (55% refratários) e com idade superior a 18 anos, de ambos os sexos, com autonomia para responder o questionário e em acompanhamento exclusivamente pelo Sistema Único de Saúde (SUS) em um ambulatório especializado em epilepsia, do serviço de neurologia, que faz parte do nível terciário de atenção à saúde. Foram aplicados dois questionários: o MEEM e o MoCA. RESULTADOS: Amostra final de 54 pacientes. Encontrou-se uma correlação significativa (p<0,001) entre os escores dos dois testes, o que significa que valores baixos do escore MEEM correspondem a valores baixos do escore MoCA. Sensibilidade de 90% (curva ROC ajustada). Verificou-se que dentre os pacientes considerados normais no MEEM, 87,5% deles obtiveram escore com alterações por meio do teste de rastreio MoCA. Não se obteve nenhum caso de escore no MEEM baixo com pontuação no MoCA normal. O coeficiente de correlação Spearman foi 0,80. Há relação significativa da memória imediata e evocação tardia com o tipo de crise (p<0,03) e escolaridade (p<0,001), respectivamente. CONCLUSÃO: Torna-se pertinente a adição do teste MoCA para rastreio cognitivo em pacientes com epilepsia por ser um instrumento mais extenso e preciso, minimizando as chances de "falsos-negativos" quando comparado ao MEEM.

Comparison of screening tests in the evaluation of cognitive status of patients with epilepsy / Comparação de testes rastreio na avaliação do estado cognitivo em pacientes com epilepsia

ABSTRACT. Epilepsy, a chronic neurological condition which is associated with neurobiological and psychosocial changes, affects 0.5 to 1% of the world's population, presenting in most cases a deficit in reasoning, memory and attention. Objective: To contribute to the implementation of screening strategies for cognitive decline and memory deficits in patients with epilepsy. Methods: Two questionnaires, MMSE and MoCA, were used in this cross-sectional and observational study. Fifty-four patients diagnosed with different types of epilepsy (55% refractory) were assessed; they were all over 18 years old, of both genders, with autonomy to answer the questionnaire. They were followed exclusively at an outpatient clinic of the Neurology Service Department, specialized in epilepsy, which is part of the tertiary healthcare level of the Brazilian Unified Health System (SUS). Results: The final sample consisted of 54 patients. There was a significant correlation (p<0.001) between the scores of both tests, indicating that low values in the MMSE score also corresponded to low values in the MoCA score. Sensitivity was 90% (ROC curve adjusted) and 87.5% of the patients with a normal score in the MMSE test obtained alterations in the MoCA scores. None of them showed a low MMSE score with a normal MOCA score. The Spearman correlation coefficient was 0.80. Also, there was a significant relationship between both immediate memory and delayed recall memory and the type of seizure (p<0.03) and level of schooling (p<0.001), respectively. Conclusion: The MoCA is a well-suited test to be performed in epilepsy patients to evaluate their cognition as it seems more extensive and complete compared to MMSE.

RESUMO. A epilepsia, condição neurológica crônica associada a alterações neurobiológicas e psicossociais, afeta de 0,5 a 1% da população mundial. Na maior parte dos casos, há redução de raciocínio, memória e atenção. Objetivos: Contribuir para a implementação de estratégias de rastreio de declínio cognitivo e distúrbios na memória nos pacientes com epilepsia. Métodos: Estudo transversal observacional de 54 pacientes diagnosticados com epilepsia de diversos tipos (55% refratários) e com idade superior a 18 anos, de ambos os sexos, com autonomia para responder o questionário e em acompanhamento exclusivamente pelo Sistema Único de Saúde (SUS) em um ambulatório especializado em epilepsia, do serviço de neurologia, que faz parte do nível terciário de atenção à saúde. Foram aplicados dois questionários: o MEEM e o MoCA. Resultados: Amostra final de 54 pacientes. Encontrou-se uma correlação significativa (p<0,001) entre os escores dos dois testes, o que significa que valores baixos do escore MEEM correspondem a valores baixos do escore MoCA. Sensibilidade de 90% (curva ROC ajustada). Verificou-se que dentre os pacientes considerados normais no MEEM, 87,5% deles obtiveram escore com alterações por meio do teste de rastreio MoCA. Não se obteve nenhum caso de escore no MEEM baixo com pontuação no MoCA normal. O coeficiente de correlação Spearman foi 0,80. Há relação significativa da memória imediata e evocação tardia com o tipo de crise (p<0,03) e escolaridade (p<0,001), respectivamente. Conclusão: Torna-se pertinente a adição do teste MoCA para rastreio cognitivo em pacientes com epilepsia por ser um instrumento mais extenso e preciso, minimizando as chances de "falsos-negativos" quando comparado ao MEEM.

Presence of generalized periodic discharges and hospital mortality / Presença de descargas periódicas generalizadas e mortalidade hospitalar

ABSTRACT Background: Generalized periodic discharges (GPDs) are rare patterns that can be found in long-term electroencephalographic monitoring in critical patients. These patterns have been correlated with non-seizure crisis and non-convulsive status epilepticus, associated with poor prognosis. Objective: To compare the outcome between patients who developed GPDs and patients with other abnormalities in long-term electroencephalographic monitoring. Methods: A retrospective study was performed by analyzing the medical records of 112 patients over 18 years who developed GPDs during long-term electroencephalographic monitoring (12‒16 hours of monitoring) in the intensive care unit of a general hospital, compared with a group that had only nonspecific abnormalities in the monitoring. Results: Age and cardiorespiratory arrest (CA) were risk factors for death - OR 1.04 (95% CI 1,02 - 1,07) and p<0.001; OR 3.00 (95% CI 1,01 - 8,92) and p=0.046, respectively. It was not possible to evaluate if GPDs alone were associated with an unfavorable outcome or would be a bias for the development of CA in these patients. However, of the six isolated GPDs cases, 2/3 evolved to death, showing a tendency to worse prognosis. A significant difference (p=0.031) was observed for a worse outcome when comparing the group of 28 patients who presented GPD or CA with the other group which did not present any of these variables; of these 28 patients, 20 (71.4%) died. Conclusions: The presence of post-CA GPDs was associated with worse prognosis, but it was not clear whether these patterns are independent factors of an unfavorable evolution.

RESUMO Introdução: As descargas periódicas generalizadas (DPG) são padrões raros que podem ser encontrados durante monitorização eletroencefalográfica prolongada (MEP) em pacientes críticos. Esses padrões têm sido correlacionados com crises não convulsivas e estado de mal epiléptico não convulsivo, associados a um pior prognóstico. Objetivo: Comparar o desfecho entre pacientes que desenvolveram DPG e pacientes com anormalidades inespecíficas na MEP. Métodos: Foi realizado um estudo retrospectivo através da análise dos prontuários de 112 pacientes acima de 18 anos que desenvolveram DPG durante MEP (de 12‒16 horas de monitorização) na unidade de terapia intensiva de um hospital geral, comparando com um grupo que apresentou apenas anormalidades inespecíficas na MEP. Resultados: As variáveis idade e parada cardiorrespiratória (PCR) se mostraram como fatores de risco estatisticamente significativos para óbito - OR 1,04 (IC 95% 1,02 - 1,07) e p<0,001; OR 3,00 (IC 95% 1,01 - 8,92) e p=0,046, respectivamente. Não foi possível avaliar se DPG isoladamente se associaram a um desfecho desfavorável ou seriam um viés para o desenvolvimento de PCR nesses pacientes. Porém, dos seis casos de DPG isoladas, 2/3 evoluíram para óbito, o que revela uma tendência a pior prognóstico. Foi observada diferença significativa (p=0,031) para pior desfecho ao comparar o grupo de 28 pacientes que apresentou DPG ou PCR com o outro grupo que não apresentou nenhuma dessas variáveis, sendo que desses 28 pacientes, 20 (71,4%) foram a óbito. Conclusões: A presença de DPG pós-PCR está associada a pior prognóstico, porém não ficou claro se esses padrões são fatores independentes de evolução desfavorável.

Presence of generalized periodic discharges and hospital mortality.

BACKGROUND: Generalized periodic discharges (GPDs) are rare patterns that can be found in long-term electroencephalographic monitoring in critical patients. These patterns have been correlated with non-seizure crisis and non-convulsive status epilepticus, associated with poor prognosis. OBJECTIVE: To compare the outcome between patients who developed GPDs and patients with other abnormalities in long-term electroencephalographic monitoring. METHODS: A retrospective study was performed by analyzing the medical records of 112 patients over 18 years who developed GPDs during long-term electroencephalographic monitoring (12‒16 hours of monitoring) in the intensive care unit of a general hospital, compared with a group that had only nonspecific abnormalities in the monitoring. RESULTS: Age and cardiorespiratory arrest (CA) were risk factors for death - OR 1.04 (95% CI 1,02 - 1,07) and p<0.001; OR 3.00 (95% CI 1,01 - 8,92) and p=0.046, respectively. It was not possible to evaluate if GPDs alone were associated with an unfavorable outcome or would be a bias for the development of CA in these patients. However, of the six isolated GPDs cases, 2/3 evolved to death, showing a tendency to worse prognosis. A significant difference (p=0.031) was observed for a worse outcome when comparing the group of 28 patients who presented GPD or CA with the other group which did not present any of these variables; of these 28 patients, 20 (71.4%) died. CONCLUSIONS: The presence of post-CA GPDs was associated with worse prognosis, but it was not clear whether these patterns are independent factors of an unfavorable evolution.

CYP2C9 polymorphisms in epilepsy: influence on phenytoin treatment.

Phenytoin (PHT) is an antiepileptic drug widely used in the treatment of focal epilepsy and status epilepticus, and effective in controlling focal seizures with and without tonic-clonic generalization and status epilepticus. The metabolization of PHT is carried out by two oxidative cytochrome P450 enzymes CYP2C9 and CYP2C19; 90% of this metabolization is done by CYP2C9 and the remaining 10% by CYP2C19. Genetic polymorphism of CYP2C9 may reduce the metabolism of PHT by 25-50% in patients with variants *2 and *3 compared to those with wild-type variant *1. The frequency distribution of CYP2C9 polymorphism alleles in patients with epilepsy around the world ranges from 4.5 to 13.6%, being less frequent in African-Americans and Asians. PHT has a narrow therapeutic range and a nonlinear pharmacokinetic profile; hence, its poor metabolization has significant clinical implications as it causes more frequent and more serious adverse effects requiring discontinuation of treatment, even if it had been effective. There is evidence that polymorphisms of CYP2C9 and the use of PHT are associated with an increase in the frequency of some side effects, such as cerebellar atrophy, gingival hypertrophy or acute cutaneous reactions. The presence of HLA-B*15:02 and CYP2C9 *2 or *3 in the same patient increases the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis; hence, PHT should not be prescribed in these patients. In patients with CYP2C9 *1/*2 or *1/*3 alleles (intermediate metabolizers), the usual PHT maintenance dose (5-10 mg/kg/day) must be reduced by 25%, and in those with CYP2C9 *2/*2, *2/*3 or *3/*3 alleles (poor metabolizers), the dose must be reduced by 50%. It is controversial whether CYP2C9 genotyping should be done before starting PHT treatment. In this paper, we aim to review the influence of CYP2C9 polymorphism on the metabolization of PHT and the clinical implications of poor metabolization in the treatment of epilepsies.

The role of CYP2C9 polymorphisms in phenytoin-related cerebellar atrophy.

PURPOSE: Phenytoin is known to be able to induce cerebellar atrophy in patients with epilepsy. It is also known that a CYP2C9 mutation (*2 or *3) reduces phenytoin metabolism by 25-50% and can increase the risk of phenytoin-related side effects. We examined the influence of CYP2C9 polymorphisms on total cerebellar volume and cerebellar gray and white matter volumes in patients with epilepsy taking phenytoin. METHODS: For the genotyping, 100 adult patients with documented epilepsy who had been taking phenytoin for >1 year were selected. From this group, we randomly selected 19 mutant individuals (MT group; CYP2C9*2 and *3) for a whole-brain volume measurement using MRI and 19 wild-type individuals (group WT; CYP2C9*1) with similar clinical and demographic characteristics to those in the MT group for comparison. Total intracranial volume measurements were used to normalize the acquired volumes, which were separated into gray matter volume, white matter volume, and total volume. RESULTS: The MT group exhibited a significant reduction in cerebellar white matter volume (p=0.002) but not in total cerebellar volume. CONCLUSION: Our study is the first to report evidence linking CYP2C9 polymorphism and a reduction in cerebellar volume in epileptic users of phenytoin.

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes and phenytoin adverse reactions correlation.

OBJECTIVE: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. METHOD: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. RESULTS: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84%), CYP2C9*2 (9%) and CYP2C9*3 (7%) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15% patients, without correlation with the CYP2C9 polymorphism (p=0.34). CONCLUSION: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results.

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation / Polimorfismo do CYP2C9 em pacientes com epilepsia: estudo da frequência genotípica e correlação com os efeitos colaterais da fenitoína

OBJECTIVE: CYP2C9 is a major enzyme in human drug metabolism and the polymorphism observed in the corresponding gene may affect therapeutic outcome during treatment. The distribution of variant CYP2C9 alleles and prevalence of phenytoin adverse reactions were hereby investigated in a population of patients diagnosed with epilepsy. METHOD: Allele-specific PCR analysis was carried out in order to determine frequencies of the two most common variant alleles, CYP2C9*2 and CYP2C9*3 in genomic DNA isolated from 100 epileptic patients. We also analyzed the frequency of phenytoin adverse reactions among those different genotypes groups. The data was presented as mean±standard deviation. RESULTS: The mean age at enrollment was 39.6±10.3 years (range, 17-72 years) and duration of epilepsy was 26.5±11.9 years (range 3-48 years). The mean age at epilepsy onset was 13.1±12.4 years (range, 1 month-62 years). Frequencies of CYP2C9*1 (84 percent), CYP2C9*2 (9 percent) and CYP2C9*3 (7 percent) were similar to other published reports. Phenytoin adverse reactions were usually mild and occurred in 15 percent patients, without correlation with the CYP2C9 polymorphism (p=0.34). CONCLUSION: Our findings indicate an overall similar distribution of the CYP2C9 alleles in a population of patients diagnosed with epilepsy in the South of Brazil, compared to other samples. This sample of phenytoin users showed no drug related adverse reactions and CYP2C9 allele type correlation. The role of CYP2C9 polymorphism influence on phenytoin adverse reaction remains to be determined since some literature evidence and our data found negative results.

OBJETIVO: A CYP2C9 é uma das principais enzimas do metabolismo de drogas humano e o polimorfismo observado no respectivo gene pode afetar o resultado terapêutico durante o tratamento. Neste trabalho investigamos em uma população de pacientes portadores de epilepsia a distribuição dos alelos variantes do CYP2C9 e a frequência de efeitos adversos da fenitoína tentando estabelecer uma correlação. MÉTODO: Realizamos uma análise através de uma PCR alelo específica para determinar a frequência dos alelos variantes mais comuns, CYP2C9*2 e CYP2C9*3, isolados da amostra de 100 pacientes com epilepsia. Também levantamos a frequência de reações adversas da fenitoína nestes diferentes grupos genotípicos. Os dados são apresentados na forma de média e desvio-padrão. RESULTADOS: A idade média na inclusão foi 39,6±10,3 anos (variando de 17-72 anos) e a duração da epilepsia era 26,5±11,9 anos (variando de 3-48 anos). A idade média dos pacientes no início da epilepsia era 13,1±12,4 anos (variando de 1 mês-62 anos). As frequências do CYP2C9*1 (84 por cento), CYP2C9*2 (9 por cento) e CYP2C9*3 (7 por cento) foram similares a outros estudos publicados. As reações adversas da fenitoína foram frequentemente leves e ocorreram em 15 por cento dos pacientes, sem correlação com o polimorfismo do CYP2C9 (p=0.34). CONCLUSÃO: Nossos achados indicam uma distribuição similar dos alelos variantes *2 e *3 nesta população de pacientes com epilepsia comparado a outros estudos. Esta amostra de usuários de fenitoína mostrou não haver correlação entre efeitos colaterais relacionados à droga e o tipo de alelo variante. O papel da influência do polimorfismo do CYP2C9 nos efeitos colaterais da fenitoína precisam ser melhor determinados, já que algumas evidencias da literatura e este trabalho mostraram resultados negativos.

Analysis of 621 death certificates issued from 1998 to 2007 in Curitiba, Brazil, mentioning epilepsy, epileptic seizures and/or status epilepticus.

PURPOSE: This study aims to study death records mentioning epilepsy, epileptic seizures and/or status epilepticus, in order to survey the population demographics and associated medical conditions, making it possible to outline the patient's profile. METHODS: A qualitative analysis was performed on the data gathered from death certificates from the Curitiba county records ranging from 1998 to 2007 bracket, in which epilepsy, seizure and/or status epilepticus were mentioned as the basic, intermediate, immediate or associated cause of death. RESULTS: Epilepsy was mentioned on 621 death cases in this 10-year-period. The deaths were mainly of male individuals (57.3%), Caucasian (71.6%), single (48.6%) and aged between 20 and 60 years (51.8%). Most of those who died were hospitalized patients (62.5%) and in 64.3% of the reported deaths, the patient received medical care during the event that led to his/her death. Epilepsy itself was considered to be the cause of death in 44%, followed by status epilepticus (9.7%). The most common intermediary and immediate causes were pulmonary infections (11.1%) and cardiac arrest (19.2%), respectively DISCUSSION: Hospitalized younger Caucasian males with epilepsy were the most common cases in this 10-year-period survey. Pulmonary infections were a common finding, but other aspects such as previous trauma, cerebrovascular disease or neoplasm were eventual associated factors. Public health and medical preventative measures can be planned based on the results of this study.

General practice physician knowledge about headache: evaluation of the municipal continual medical education program.

OBJECTIVE: Headache is a common condition not always managed satisfactorily by primary care providers (PCPs). In an effort to improve headache care, the Curitiba City Hall in consortia with Hospital de Clínicas da Universidade Federal do Paraná - Brazil developed an educational program directed to the PCPs. The goal of the project was to evaluate, to update and to train the PCP on headache knowledge and care. METHOD: The program was designed to have a theoretical phase and a practical phase. Knowledge on headache and medical care of headache were surveyed before and after the theoretical phase thorough a specific questionnaire. RESULTS: Significant improvement in post-CME scores on headache prevalence (p<0.001), migraine diagnosis (p<0.001) and management (p=0.01), secondary headache diagnosis (p=0.005) and management (p=0.005) was reached by the respondents. CONCLUSION: Improvement in post-CME scores confirms that the program had a significant immediate impact on the PCPs knowledge directly affecting the patient's health.

General practice physician knowledge about headache: evaluation of the municipal continual medical education program / Conhecimento dos médicos generalistas sobre cefaléias: avaliação de um programa municipal de educação médica continuada

OBJECTIVE: Headache is a common condition not always managed satisfactorily by primary care providers (PCPs). In an effort to improve headache care, the Curitiba City Hall in consortia with Hospital de Clínicas da Universidade Federal do Paraná - Brazil developed an educational program directed to the PCPs. The goal of the project was to evaluate, to update and to train the PCP on headache knowledge and care. METHOD: The program was designed to have a theoretical phase and a practical phase. Knowledge on headache and medical care of headache were surveyed before and after the theoretical phase thorough a specific questionnaire. RESULTS: Significant improvement in post-CME scores on headache prevalence (p<0.001), migraine diagnosis (p<0.001) and management (p=0.01), secondary headache diagnosis (p=0.005) and management (p=0.005) was reached by the respondents. CONCLUSION: Improvement in post-CME scores confirms that the program had a significant immediate impact on the PCPs knowledge directly affecting the patient's health.

OBJETIVO: Cefaléia é uma condição comum nem sempre tratada de forma adequada pelos médicos generalistas (MG). Com o objetivo de melhorar essa situação, a Prefeitura de Curitiba em parceria com o Hospital de Clínicas da Universidade Federal do Paraná - Brasil desenvolveu um programa para os MG. O objetivo principal desse projeto foi avaliar, atualizar e capacitar médicos a respeito do conhecimento e manejo das cefaléias. MÉTODO: O programa consistiu de uma fase teórica e uma fase prática. O conhecimento sobre cefaléia e seu manejo foi avaliado através de um questionário específico antes e depois da fase teórica. RESULTADOS: Significativa melhora no pós-teste nos itens de prevalência de cefaléias (p<0,001), diagnóstico de migrânea (p<0,001) e seu manejo (p=0,01), diagnóstico de cefaléia secundária (p=0,005) e seu manejo (p=0,005) foram alcançados pelos participantes. CONCLUSÃO: Melhorias na pontuação dos pós-testes confirmam que o programa teve um impacto imediato e significante no conhecimento dos MG afetando diretamente a saúde dos pacientes.

Right and left mesial temporal lobe seizures in one patient: bona fide semiological, interictal, ictal, and MRI evidence.

We present the case of a 36-year-old patient with bilateral independent manual automatisms associated with seizures coming independently from the left and right temporal lobes, as documented by surface EEG ictal recordings. An MRI showed evidence of bilateral mesial temporal sclerosis, more prominent on the right side. We speculate whether clinical semiology (along with the ictal EEG and imaging findings) discourages the pursuit of invasive monitoring, leading to more aggressive medical management in this particular case.

Trigeminal sensory neuropathy and facial contact dermatitis due to Anthurium sp.

BACKGROUND: Trigeminal sensory neuropathy (TSN) describes a heterogeneous group of disorders manifesting as facial numbness. OBJECTIVE: We report the case of a patient who had TSN associated with contact dermatitis due to Anthurium sp. METHOD/RESULTS: A 21-year-old female patient developed left hemifacial contact dermatitis after exposure to the anthurium plant. The patient had paresthesias and pain in the V2 and V3 divisions of the left trigeminal nerve. Eight days after its onset the dermatitis resolved, but numbness developed in the V2 and V3 divisions of the left trigeminal nerve. Cranial CT scan and MRI, as well as CSF and extensive work-up exams, were normal. After one month the symptoms disappeared completely. CONCLUSION: Anthurium sp, an indoor ornamental plant that contains calcium oxalate crystals, and can causes contact dermatitis. To our knowledge, this is the first report associating TSN with contact dermatitis due to Anthurium sp.

Pontine and extrapontine osmotic myelinolysis after the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report.

Osmotic demyelination syndrome (ODS) may be precipitated by aggressive correction of a hypo or hyper-osmolar states. We describe the case of a 53-year-old woman that was started on fluoxetine 20 mg/day for depression and nine days later was found to have fluoxetine-induced syndrome of inappropriate secretion of antidiuretic hormone. After hyponatremia correction the mental status of the patient gradually improved, but subsequently she had intermittent difficulty in speaking, naming objects, memory deficits and psychomotor slowness. Magnetic resonance revealed bilateral symmetric hyperintense lesions in the basal ganglia, temporal lobe and hippocampal formation compatible with ODS. These symptoms gradually resolved and she was discharged home without any deficits. Two months later, a new image showed lesion in pons and the other lesions had disappeared. Fluoxetine therapy had never been related with a complication like that.