HLA alleles and antiseizure medication-induced cutaneous reactions in Brazil: A case-control study.

In this observational case-control study, 107 cutaneous adverse reaction (CAR) cases (CAR+) manifesting up to 12 weeks after the start of treatment with antiseizure medication (ASM) were identified. Control groups consisted of 98 epilepsy patients without a history of CAR (CAR-) and 3965 healthy individuals in the Brazilian National Registry of Bone Marrow Donors. All participants were HLA typed by high-resolution Next Generation Sequencing for HLA-A, B, C, DQB1 and DRB1; HLA-DPA1, DPB1, DQA1, DRB3, DRB4 and DRB5 were also sequenced in samples from CAR+ and CAR- individuals. The relationship between the carrier frequency of each allele, CAR type and ASM for all participants was investigated. The ASMs most frequently associated with CAR were carbamazepine (48% of CAR+ subjects), lamotrigine (23%), phenytoin (18%), phenobarbital (13%) and oxcarbazepine (5%). The main alleles associated with a risk of CAR were HLA-A*02:05 (OR = 6.28; p = 0.019, carbamazepine or oxcarbazepine); HLA-DPA1*02:02 (OR = 4.16, p = 0.003, carbamazepine); HLA-B*53:01 (OR = 47.9, p = 0.014, oxcarbazepine), HLA-DPA1*03:01/DPB1*105:01 (OR = 25.7, p = 0.005, phenobarbital); HLA-C*02:10 (OR = 25.7, p = 0.005, phenobarbital) and HLA-DRB1*04:02 (OR = 17.22, p = 0.007, phenytoin). HLA-A*03:01 increased the risk for phenytoin-induced maculopapular exanthema 4.71-fold (p = 0.009), and HLA-B*35:02 was associated with a 25.6-fold increase in the risk of carbamazepine-induced Stevens-Johnson syndrome (p = 0.005). None of the 4170 subjects carried the HLA-B*15:02 allele, and HLA-A*31:01 was not associated with CAR. Hence, HLA-A*31:01 and HLA-B*15:02 were not associated with CAR in this population. Although other HLA class I and II alleles tested were associated with a risk of CAR, none of these associations were strong enough to warrant HLA testing before prescribing ASM.

Relationship between hippocampal subfields and Verbal and Visual memory function in Mesial Temporal Lobe Epilepsy patients.

OBJECTIVE: High-resolution protocols used in magnetic resonance imaging (MRI) currently enable the detailed analysis of the hippocampus along with its subfield segmentation. The relationship between episodic memory and the hippocampus is well established, and there is growing evidence that some specific memory processing steps are associated with individual hippocampal segments, but there are inconsistencies in the literature. We focused our analysis on hippocampal subfield volumetry and neuropsychological visual and verbal memory tests in patients with temporal lobe epilepsy (TLE) presenting with unilateral hippocampal atrophy. METHODS: The study involved a cohort of 62 patients with unilateral TLE, including unilateral hippocampal atrophy (29 on the left side) based on MRI and unequivocal ipsilateral ictal onsets based on surface video electroencephalography recordings. The hippocampal subfield volumes were evaluated using FreeSurfer version 7.1. We used the Rey-Auditory Verbal Learning Test to evaluate short-term (A1), learning (ΣA1-A5), immediate (A6), and delayed (A7) recall of episodic verbal memory. We used the Rey-Osterrieth Complex Figure Test to evaluate the immediate and delayed recall of visual memory. We analyzed the correlations between the asymmetry index scores for the hippocampal subfield volumes of thecornu ammonis (CA)1, CA2/3, and CA4 and memory test performance. RESULTS: Moderate associations were established between the CA2/3 asymmetry index scores and visual memory in TLE (both right and left hippocampal atrophy), as well as visual memory and CA4 in the right atrophy cases. The CA1 asymmetry index scores did not correlate with any of the memory test results. We did not find any significant correlation between verbal memory tests and specific hippocampal subfields. CONCLUSIONS: The use of high-resolution MRI protocols andin vivo automated segmentation processing revealed moderate associations between hippocampal subfields and memory parameters. Further investigations are needed to establish the utility of these results for clinical decisions.

The First Unprovoked Seizure in Typically Developing Children: A Real-Life Setting in Southern Brazil.

AIM: To describe the first unprovoked seizure in typically developing children, its clinical characteristics, recurrence rate, and possible risk factors in a real-life setting in Southern Brazil. METHOD: In this retrospective cohort study, medical records of typically developing children aged 28 days to 14 years who had a first unprovoked seizure in a single tertiary care center were reviewed, in a 10-year period (2006-2016). RESULTS: Seventy-four children were included, 41 males and 33 females. The most frequent age group of the first seizure was 5 to 10 years and seizure main type was focal (50%). Most seizures occurred while children were awake (70%). All patients underwent an electroencephalogram (EEG), which was normal in 44.6%. Neuroimaging was performed in 81%, in 2 cases the etiology was considered structural, the remaining was classified as unknown. Median follow-up period was 32.5 months. Seizure recurrence rate was 56.7% and age younger than 5 years was a possible risk factor. INTERPRETATION: In the subpopulation of Brazilian typically developing children with a first unprovoked epileptic seizure there is a high recurrence rate. An abnormal EEG was a common finding, although it was not associated with a higher risk of seizure recurrence. A possible risk factor was age younger than 5 years, which may suggest a more rigorous follow-up of these patients.

Mesial temporal lobe epilepsy: Revisiting the relation of hippocampal volumetry with memory deficits.

OBJECTIVE: Neuropsychological tests can infer the lateralization of the epileptogenic focus, associating verbal memory to mesial structures in the left temporal lobe and visual or nonverbal memory to the right side. High-field magnetic resonance imaging (MRI) with high-resolution protocols allows acquisitions suitable for advanced postprocessing with precise volumetry of brain structures, and functional MRI demonstrates evidence that epilepsy should be seen as a network pathology, involving several structures in the brain. Since the literature showing associations between the volumetry of brain structures in left and right mesial temporal lobe epilepsy (MTLE) and verbal and visual memory performance on neuropsychological tests is conflicting, we revisited these relationships, considering the hippocampal volumetry of patients with unilateral MTLE. METHODS: Automatized hippocampal volumes were obtained using FreeSurfer software from MRI exams of 35 patients with unilateral MTLE and hippocampal atrophy and homolateral ictal onset zone defined by video electroencephalography concordant to the side of hippocampal volume reduction (15 on the left side). Verbal memory was assessed using the Rey Auditory-Verbal Learning Test (RAVLT), and visual memory tests employed the Rey-Osterrieth Complex Figure Test (ROCFT). The statistical analysis explored relationships between hippocampal volumetry, lateralization, and performance on memory tests. RESULTS: In general, we observed deficits in both verbal and visual memory for patients with left and right hippocampal volume reduction. Patients with left hippocampal volume reduction had poorer performance on verbal memory tests compared with those with right hippocampal atrophy (t = -3.813, p < 0.001). Visual memory deficits were seen on both left and right MTLE without a statistically significant difference (t = 0.074, p = 0.942). The correlation between the Hippocampal Asymmetry Index (HAI) and visual and verbal Z-scores was significant only for visual Z-score in right MTLE (R = -0.45, p = 0.048). CONCLUSIONS: Verbal memory deficit seems to be more consistent in patients with left hippocampal volume reduction. Although it had only a moderate correlation to HAI, visual memory deficit is suggested as a poorer indicator for right MTLE. Considering that verbal and visual memory deficits are seen on both right and left MTLE, MTLE should not be regarded as a unilateral, focal, or local insult but as a multifactorial and network pathology, possibly involving several brain structures.

Guidelines for the assessment and acceptance of potential brain-dead organ donors. / Diretrizes para avaliação e validação do potencial doador de órgãos em morte encefálica.

Organ transplantation is the only alternative for many patients with terminal diseases. The increasing disproportion between the high demand for organ transplants and the low rate of transplants actually performed is worrisome. Some of the causes of this disproportion are errors in the identification of potential organ donors and in the determination of contraindications by the attending staff. Therefore, the aim of the present document is to provide guidelines for intensive care multi-professional staffs for the recognition, assessment and acceptance of potential organ donors.

Diretrizes para avaliação e validação do potencial doador de órgãos em morte encefálica / Guidelines for the assessment and acceptance of potential brain-dead organ donors

RESUMO O transplante de órgãos é a única alternativa para muitos pacientes portadores de algumas doenças terminais. Ao mesmo tempo, é preocupante a crescente desproporção entre a alta demanda por transplantes de órgãos e o baixo índice de transplantes efetivados. Dentre as diferentes causas que alimentam essa desproporção, estão os equívocos na identificação do potencial doador de órgãos e as contraindicações mal atribuídas pela equipe assistente. Assim, o presente documento pretende fornecer subsídios à equipe multiprofissional da terapia intensiva para o reconhecimento, a avaliação e a validação do potencial doador de órgãos.

ABSTRACT Organ transplantation is the only alternative for many patients with terminal diseases. The increasing disproportion between the high demand for organ transplants and the low rate of transplants actually performed is worrisome. Some of the causes of this disproportion are errors in the identification of potential organ donors and in the determination of contraindications by the attending staff. Therefore, the aim of the present document is to provide guidelines for intensive care multi-professional staffs for the recognition, assessment and acceptance of potential organ donors.

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis? / Quando o diagnóstico deveria ser MELAS (Miopatia mitocondrial, encefalopatia, acidose lática, e episódios semelhantes a acidente vascular cerebral)?

ABSTRACTMitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

RESUMOMiopatia mitocondrial, encefalopatia, acidose lática, e episódios semelhantes a acidente vascular cerebral (MELAS) é uma rara doença mitocondrial. Os critérios diagnósticos para MELAS incluem as manifestações típicas da doença: episódios semelhantes a acidente vascular cerebral, encefalopatia, evidência de disfunção mitocondrial (laboratorial ou histológica) e mutação conhecida em genes do DNA mitocondrial. Na fase inicial da doença, as manifestações clínicas podem não ser uniformes, e sua correlação com a fisiopatologia não está completamente elucidada. Estima-se que as mutações de ponto no gene tRNALeu(UUR) do DNAmt, principalmente a A3243G, sejam responsáveis por cerca de 80% dos casos de MELAS. As alterações morfológicas na biópsia muscular incluem uma grande proporção de fibras vermelhas rasgadas (RRF) e presença de vasos com forte reação para succinato desidrogenase. Nesta revisão, são discutidos os principais critérios diagnósticos, manifestações clínicas e laboratoriais, imagens cerebrais, padrões eletrofisiológicos, histológicos e alterações moleculares, bem como alguns dos diagnósticos diferenciais e tratamentos atuais.

When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments.

The Wada Test: contributions to standardization of the stimulus for language and memory assessment

O Teste de Wada (TW) é parte integrante da avaliação pré-cirúrgica para epilepsias de difícil controle. O TW não é padronizado e os protocolos diferem em vários aspectos, incluindo tipos de estímulos para avaliação de memória, tempo de apresentação e metodologia de avaliação. O objetivo deste estudo foi contribuir no estabelecimento de parâmetros para utilização TW para a população brasileira, investigando o desempenho de 100 controles normais, sem medicação. Dois modelos (Modelos A e B) foram utilizados, baseados no Procedimento de Montreal e adaptadas do protocolo de Gail Risse (MEG-MN,EUA). Foram observadas as proporções de acerto dos sujeitos normais para os modelos de TW, em seguida, os dois modelos foram comparados entre si. Os resultados demonstraram que os dois modelos são similares mas, observaram-se significativas diferenças entre os tipos de estímulos. Os resultados sugerem que tipos de estímulos podem influenciar os resultados do TW e esses dados devem ser considerados na construção de modelos e comparações entre diferentes protocolos.

The Wada Test: contributions to standardization of the stimulus for language and memory assessment.

The Wada Test (WT) is part of the presurgical evaluation for refractory epilepsy. The WT is not standardized and the protocols differ in important ways, including stimulus type of material presented for memory testing, timing of presentations and methods of assessment. The aim of this study was to contribute to establish parameters for a WT to Brazilian population investigating the performance of 100 normal subjects, without medication. Two parallel models were used based on Montreal Procedure adapted from Gail Risse's (MEG-MN,EUA) protocol. The proportions of correct responses of normal subjects submitted to two parallel WT models were investigated and the two models were compared. The results showed that the two models are similar but significant differences among the stimulus type were observed. The results suggest that the stimulus type may influence the results of the WT and should be considered when constructing models and comparing different protocols.

Recomendaçöes técnicas para o registro do eletrencefalograma (EEG) na suspeita da morte encefálica / Technical recomendations for the electroencephalogram (EEG) recording in suspected brain death

Neste trabalho, desenvolvido por uma comissao nomeada pela Sociedade Brasileira de Neurofisiologia Clínica, sao apresentadas as recomendaçoes referentes ao registro do eletrencefalograma (EEG) nos casos de suspeita de morte encefálica, enfatizando que, apesar do necessário respeito aos parâmetros técnicos, o método nao visa substituir o exame neurológico, mas complementá-lo.

Protocolo de estudos em epilepsia: um modelo simples e eficiente / Protocol for studies in epilepsy: a simple and efficient model

O protocolo de estudos em epilepsia utilizado em dois hospitais gerais em Curitiba é apresentado. O valor do protocolo foi provado através do seu uso durante 5 anos por residentes em medicina interna e neurologia tanto quanto por epileptólogos. Cerca de 800 pacientes foram incluídos em vários estudos que produziram um número de publicaçöes sobre a freqüência de tipos de crise e anormalidades do EEG em uma populaçäo brasileira sem o uso de monitorizaçäo de concentraçöes séricas e com monitorizaçäo em populaçöes européias. Outros estudos mostraram que epilepsia refratária a barbitúricos pode ser significantemente melhorada por substituiçäo terapêutica com carbamazepina, fenitoina ou valproato de sódio. Além disso, o protocolo proporcionou as bases para escolher os pacientes que participaram de estudos controlados e duplo-cegos com novas drogas sendo avaliadas em epilepsia. O protocolo é conciso e objetivo, ocupando os dois lados de uma folha de papel de tamanho normal