Cannabinoids and epilepsy

Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and high-light scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

A low mortality, high morbidity reduced intensity status epilepticus (RISE) model of epilepsy and epileptogenesis in the rat

Animal models of acquired epilepsies aim to provide researchers with tools for use in understanding the processes underlying the acquisition, development and establishment of the disorder. Typically, following a systemic or local insult, vulnerable brain regions undergo a process leading to the development, over time, of spontaneous recurrent seizures. Many such models make use of a period of intense seizure activity or status epilepticus, and this may be associated with high mortality and/or global damage to large areas of the brain. These undesirable elements have driven improvements in the design of chronic epilepsy models, for example the lithium-pilocarpine epileptogenesis model. Here, we present an optimised model of chronic epilepsy that reduces mortality to 1% whilst retaining features of high epileptogenicity and development of spontaneous seizures. Using local field potential recordings from hippocampus in vitro as a probe, we show that the model does not result in significant loss of neuronal network function in area CA3 and, instead, subtle alterations in network dynamics appear during a process of epileptogenesis, which eventually leads to a chronic seizure state. The model’s features of very low mortality and high morbidity in the absence of global neuronal damage offer the chance to explore the processes underlying epileptogenesis in detail, in a population of animals not defined by their resistance to seizures, whilst acknowledging and being driven by the 3Rs (Replacement, Refinement and Reduction of animal use in scientific procedures) principles.

Experience With Lacosamide in a Series of Children With Drug-Resistant Focal Epilepsy

We report our pediatric experience with lacosarnide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n = 3), vagus nerve stimulation (n = 9), and ketogenic diet (n = 3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n = 10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P < 0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (>= 50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with >= 50% seizure reduction) without severe adverse events. (C) 2011 Elsevier Inc. All rights reserved.

The non-coding RNA BC1 is down-regulated in the hippocampus of Wistar Audiogenic Rat (WAR) strain after audiogenic kindling

The aim of this study was to identify molecular pathways involved in audiogenic seizures in the epilepsy-prone Wistar Audiogenic Rat (WAR). For this, we used a suppression-subtractive hybridization (SSH) library from the hippocampus of WARs coupled to microarray comparative gene expression analysis, followed by Northern blot validation of individual genes. We discovered that the levels of the non-protein coding (npc) RNA BC1 were significantly reduced in the hippocampus of WARs submitted to repeated audiogenic seizures (audiogenic kindling) when compared to Wistar resistant rats and to both naive WARs and Wistars. By quantitative in situ hybridization, we verified lower levels of BC1 RNA in the GD-hilus and significant signal ratio reduction in the stratum radiatum and stratum pyramidale of hippocampal CA3 subfield of audiogenic kindled animals. Functional results recently obtained in a BC1-/- mouse model and our current data are supportive of a potential disruption in signaling pathways, upstream of BC1, associated with the seizure susceptibility of WARs. (C) 2010 Elsevier B.V. All rights reserved.

Short- and long-term anxiogenic effects induced by a single injection of subconvulsant doses of pilocarpine in rats: investigation of the putative role of hippocampal pathways

Behavioral consequences of convulsive episodes are well documented, but less attention was paid to changes that occur in response to subconvulsant doses of drugs. We investigated short- and long-term effects of a single systemic injection of a subconvulsant dose of pilocarpine on the behavior of rats as evaluated in the elevated plus maze. Pilocarpine induced an anxiogenic-like profile 24 h later, and this effect persisted for up to 3 months (% of time spent on open arms at 24 h, control = 35.47 +/- 3.23; pilocarpine 150 = 8.2 +/- 2.6; 3 months, control = 31.9 +/- 5.5; pilocarpine 150 = 9.3 +/- 4.9). Temporary inactivation of fimbria-fornix with lidocaine 4% promoted an anxiolytic-like effect per se, suggesting a tonic control of this pathway on the modulation of anxiety-related behaviors. Lidocaine also reduced the anxiogenic-like profile of animals tested 1 month after pilocarpine treatment (% of time spent on open arms, saline + phosphate-buffered saline (PBS) = 31.7 + 3.7; saline + lidocaine = 54.4 + 4.7; pilocarpine + PBS = 10.3 + 4.1; pilocarpine + lidocaine = 40.1 + 9.1). To determine whether the anxiogenic-like effect was mediated by septal region or by direct hippocampal projections to the diencephalon, the neural transmission of post-commissural fornix was blocked, and a similar reduction in the anxiogenic-like effect of pilocarpine was observed. Our findings suggest that a single systemic injection of pilocarpine may induce long-lasting anxiogenic-like behavior in rats, an effect that appears to be mediated, in part, through a direct path from hippocampus to medial hypothalamic sites involved in fear responses.

Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy

Reactive oxygen species (ROS) appear to be involved in several neurodegenerative disorders. We tested the hypothesis that oxidative stress could have a role in the hippocampal neurodegeneration observed in temporal lobe epilepsy induced by pilocarpine. We first determined the spatio-temporal pattern of ROS generation, by means of detection with dihydroethidium oxidation, in the CA1 and CA3 areas and the dentate gyrus of the dorsal hippocampus during status epilepticus induced by pilocarpine. Fluoro-Jade B assays were also performed to detect degenerating neurons. ROS generation was increased in CA1, CA3 and the dentate gyrus after pilocarpine-induced seizures, which was accompanied by marked cell death. Treatment of rats with a NADPH oxidase inhibitor (apocynin) for 7 days prior to induction of status epilepticus was effective in decreasing both ROS production (by an average of 20%) and neurodegeneration (by an average of 61%). These results suggest an involvement of ROS generated by NADPH oxidase in neuronal death in the pilocarpine model of epilepsy. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Effects of voluntary running on spatial memory and mature brain-derived neurotrophic factor expression in mice hippocampus after status epilepticus

Voluntary physical activity improves memory and learning ability in rodents, whereas status epilepticus has been associated with memory impairment. Physical activity and seizures have been associated with enhanced hippocampal expression of BDNF, indicating that this protein may have a dual role in epilepsy. The influence of voluntary physical activity on memory and BDNF expression has been poorly studied in experimental models of epilepsy. In this paper, we have investigated the effect of voluntary physical activity on memory and BDNF expression in mice with pilocarpine-incluced epilepsy. Male Swiss mice were assigned to four experimental groups: pilocarpine sedentary (PS), pilocarpine runners (PRs), saline sedentary (SS) and saline runners (SRs). Two days after pilocarpine-induced status epilepticus, the affected mice (PR) and their running controls (SR) were housed with access to a running wheel for 28 days. After that, the spatial memory and the expression of the precursor and mature forms of hippocampal BDNF were assessed. PR mice performed better than PS mice in the water maze test. In addition, PR mice had a higher amount of mature BDNF (14 kDa) relative to the total BDNF (14 kDa + 28 kDa + 32 kDa forms) content when compared with PS mice. These results show that voluntary physical activity improved the spatial memory and increased the hippocampal content of mature BDNF of mice with pilocarpine-induced status epilepticus. (C) 2009 Elsevier B.V. All rights reserved.

Alteration of purinergic P2X(4) and P2X(7) receptor expression in rats with temporal-lobe epilepsy induced by pilocarpine

Although ATP and P2X receptor activity have been lately associated with epilepsy, little is known regarding their exact roles in epileptogenesis. Temporal-lobe epilepsy (TLE) in rat was induced by pilocarpine in order to study changes of hippocampal P2X(2), P2X(4) and P2X(7) receptor expression during acute, latent or chronic phases of epilepsy. During acute and chronic phases increased P2X(7) receptor expression was principally observed in glial cells and glutamatergic nerve terminals, suggesting participation of this receptor in the activation of inflammatory and excitotoxic processes during epileptogenesis. No significant alterations of hippocampal P2X(2) and P2X(4) receptor expression was noted during the acute or latent phase when compared to the control group, indicating that these receptors are not directly involved with the initiation of epilepsy. However, the reduction of hippocampal P2X(4) receptor immunostaining in the chronic phase could reflect neuronal toss or decreased GABAergic signaling. (C) 2008 Elsevier B.V. All rights reserved.

Desenvolvimento neurológico e resposta apendicular ao movimento do tronco de crianças prematuras, durante o primeiro ano de vida

A ausência de estudos de acompanhamento do desenvolvimento neurológico de crianças nascidas prematuras, em nosso meio, motivou a realização desta pesquisa. Com o intuito de estabelecer marcos desse desenvolvimento e de verificar as respostas apendiculares ao movimento do tronco e a uniformidade entre as funções motoras, perceptivas e de linguagem, foram avaliados prematuros aos 3, 6, 9 e 12 meses de idade corrigida, em um estudo de coorte não controlado, com enfoque prognóstico. As respostas apendiculares ao movimento do tronco foram estudadas por meio das reações de paraquedismo e de apoio lateral. A amostra foi constituída de 40 recém-nascidos (RN) prematuros, nascidos no Hospital de Clínicas de Porto Alegre, que foram acompanhados no ambulatório do hospital aos 3, 6, 9 e 12 meses de idade corrigida. Foram incluídos no estudo RN com idade gestacional até 36 semanas e 6 dias, com 2.000g ou menos de peso no nascimento. Foram excluídos os RN com índices de Apgar <7 no 5o minuto, hemorragia cerebral, crises convulsivas, alterações no estado de consciência, infecção do sistema nervoso central (SNC), infecções congênitas, síndromes genéticas e intoxicações pré-natais. Também foram excluídos os RN que apresentaram intercorrências capazes de interferir no desenvolvimento neurológico e os que apresentaram exame neurológico alterado. As reações de paraquedismo e de apoio lateral estavam ambas presentes em 8,1% das crianças aos 6 meses de idade corrigida. Aos 9 meses de idade corrigida, a reação de paraquedismo estava presente em 87% das crianças e a reação de apoio lateral, em 90%. Aos 12 meses de idade corrigida, 100% dos casos apresentaram as reações posturais. Estes resultados não foram semelhantes aos encontrados em RN de termo de 6 e 9 meses de idade. O desenvolvimento do RN prematuro foi uniforme em relação às funções perceptivas e de linguagem para as idades corrigidas de 3, 6, 9 e 12 meses de idade corrigida. O desenvolvimento do equilíbrio estático foi o aspecto motor em desacordo com o esperado para cada idade corrigida. A evolução dos reflexos primitivos coincidiu com o esperado para cada idade corrigida; e o reflexo cutâneo-plantar se tornou flexor simultaneamente ao desaparecimento da preensão plantar.

Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model

TORRES, F ; FILHO, M.S. ; ANTUNES, C. ; KALININE, E. ; ANTONIOLLI, E. ; PORTELA, Luis Valmor ; SOUZA, Diogo Onofre ; TORT, A. B. L. . Electrophysiological effects of guanosine and MK-801 in a quinolinic acid-induced seizure model. Experimental Neurology , v. 221, p. 296-306, 2010

ANÁLISE COMPARATIVA DO CONHECIMENTO, ATITUDES E PRECONCEITOS DE UNIVERSITÁRIOS DOS CURSOS DE PEDAGOGIA, EDUCAÇÃO FÍSICA E MEDICINA EM RELAÇÃO À EPILEPSIA

Epilepsy is a chronic disorder of the central nervous system, most frequently characterized by abnormal electrical impulses in the brain. It is the oldest recorded neurological disease and has been surrounded by myths, mistaken beliefs and preconceptions. Three professionals work with epileptic patients on a daily basis: teachers, physical educators and physicians . This study aimed to analyze and compare the level of knowledge, preconceptions and attitudes of undergraduate students in the courses of Pedagogy, Physical Education and Medicine, future professionals who will deal with epileptic patients. This descriptive observational study was conducted with 286 university undergraduates of both sexes (women 99/34.6% and men 187/65.4%) from the first to fourth year of Pedagogy, Physical Education and Medicine courses at the Universidade Estadual Rio Grande do Norte (UERN), with mean age of 23 years. A validated and adapted 17-question questionnaire, divided into nine knowledge-based questions, five related to preconceptions and three on attitudes, was applied. Results allowed elaboration of a manuscript entitled Comparative Analysis of Knowledge, Attitude and Preconceptions in University Undergraduates of Pedagogy, Physical Education and Medicine Courses in Relation to Epilepsy. The findings of this article show that knowledge of epilepsy in the three groups is very satisfactory. The low level of preconception indicates that educational or clarifying information is being transmitted, albeit by television, a layman s information vehicle, which has undoubtedly contributed to reducing the stigma of epilepsy through educational information. Results also suggest a lack of knowledge on how to act during a seizure, especially in education professionals. Although there are limitations in our sample, the relevance and contribution of this study is to call attention to the importance and need for these future professionals to be informed and learn correct attitudes with respect to epilepsy during their academic formation. This is essential at a time when the disease is being brought out of the shadows. This research was supported by the Office of the Dean of Teaching, and Deans of Pedagogy, Physical Education and Medicine at UERN. The research was made possible by the multidisciplinary interaction among a physical educator, child neurologist and statistician, all contributing to achieving the aims set out here

Anestesia na Pré-Eclâmpsia

JUSTIFICATIVA E OBJETIVOS: Embora a pré-eclâmpsia acometa pequena porcentagem da população obstétrica, ela é responsável por considerável morbidade e mortalidade maternas. Assim sendo, o controle anestésico adequado deste grupo de pacientes ainda hoje é um desafio para os anestesiologistas. Este artigo tem a finalidade de apresentar a fisiopatologia, o tratamento farmacológico e as opções anestésicas para o parto normal ou cirúrgico, em pacientes com pré-eclâmpsia. CONTEÚDO: Estão descritos a classificação e terminologia da hipertensão arterial induzida pela gestação, a fisiopatologia, as alterações nos diversos órgãos e sistemas, os princípios gerais no controle das pacientes e as opções anestésicas para o parto normal e cirúrgico. CONCLUSÕES: O conhecimento, pelo anestesiologista, da fisiopatologia, das formas de tratamento e das características farmacológicas das drogas utilizadas para o controle da hipertensão arterial e a profilaxia das convulsões, assim como sua interação com as drogas e técnicas anestésicas, possibilita a redução das complicações peri-operatórias e da mortalidade materna e fetal.

Mola hidatiforme completa e eclâmpsia: relato de caso

O desenvolvimento de pré-eclâmpsia ou eclâmpsia antes da 20ª semana deve levar à suspeita de mola hidatiforme. Descrevemos um caso de mola hidatiforme completa (MHC) e eclâmpsia concomitante em paciente com 20 anos que apresentava sangramento genital, anemia, tamanho uterino excessivo e cistos de ovário, associados a hipertensão arterial e proteinúria. Os níveis de b-hCG estavam elevados e a função tiroidiana, alterada. A ultra-sonografia mostrou-se compatível com MHC. Após o esvaziamento uterino apresentou cefaléia e alterações visuais, seguidas por convulsões tônico-clônicas que cessaram com sulfato de magnésio hepta-hidratado a 50%. No seguimento pós-molar foi diagnosticado tumor trofoblástico gestacional (TTG) prontamente tratado com quimioterapia. A associação de MHC e eclâmpsia determina esvaziamento uterino imediato e seguimento pós-molar rigoroso, pelo risco aumentado de desenvolvimento de TTG.

Síndromes hipertensivas da gestação: identificação de casos graves

A hipertensão arterial está entre as causas mais freqüentes de morte materna. Entre os tipos presentes na gravidez destacam-se as manifestações específicas, isto é, a pré-eclâmpsia e a hipertensão gestacional, definidas clinicamente por aumento dos níveis da pressão arterial após a 20ª semana de gestação, associado (pré-eclâmpsia) ou não (hipertensão gestacional) à proteinúria. Na fase inicial a doença é assintomática, porém, quando não tratada ou não se interrompe a gestação, sua evolução natural é desenvolver as formas graves, como a eclâmpsia e a síndrome HELLP. Eclâmpsia é definida pela manifestação de uma ou mais crises convulsivas tônico-clônicas generalizadas e/ou coma, em gestante com hipertensão gestacional ou pré-eclâmpsia, na ausência de doenças neurológicas. Pode ocorrer durante a gestação, durante o trabalho de parto e no puerpério imediato. É comumente precedida pelos sinais e sintomas de eclâmpsia iminente (distúrbios do sistema nervoso central, visuais e gástricos). A associação de hemólise, plaquetopenia e disfunção hepática já era relatada na literatura na década de cinqüenta. em 1982, Weinstein reuniu estas alterações sob o acrônimo de HELLP, significando hemólise (H), aumento de enzimas hepáticas (EL) e plaquetopenia (LP), e denominou-as de síndrome HELLP. A literatura diverge em relação aos valores dos parâmetros que definem a síndrome. Sibai et al. (1986) propuseram sistematização dos padrões laboratoriais e bioquímicos para o diagnóstico da mesma, que foi adotada pelo Ministério da Saúde do Brasil. As manifestações clínicas podem ser imprecisas, sendo comuns queixas como dor epigástrica, mal-estar geral, inapetência, náuseas e vômitos. O diagnóstico precoce é, eminentemente, laboratorial e deve ser pesquisado de maneira sistemática nas mulheres com pré-eclâmpsia grave/eclâmpsia e/ou dor no quadrante superior direito do abdome. Diferenciar a síndrome HELLP de outras ocorrências, com manifestações clínicas e/ou laboratoriais semelhantes, não é tarefa fácil. O diagnóstico diferencial é particularmente difícil para doenças como púrpura trombocitopênica trombótica, síndrome hemolítico-urêmica e fígado gorduroso agudo da gravidez, devido à insuficiente história clínica e à semelhança dos aspectos fisiopatológicos. O conhecimento da fisiopatologia da pré-eclâmpsia, o diagnóstico precoce e a atuação precisa no momento adequado nas situações complicadas pela eclâmpsia e/ou síndrome HELLP permitem melhorar o prognóstico materno e perinatal.

Edema cerebral crônico na neurocisticercose

Neste estudo retrospectivo, relatam-se as características clínicas do edema cerebral crônico (ECCr) em 34 pacientes com neurocisticercose (NCC), que apresentavam edema cerebral difuso, à tomografia computadorizada (TC), como característica comum. Todos foram tratados com dextroclorofeniramina e, 32 deles, com albendazol. O ECCr predominou no sexo feminino (73,5%) na faixa etária dos 11 - 40 anos (92,3%). A cefaléia ocorreu em 94,1% dos pacientes, náuseas/vômitos em 47,1%, crises epilépticas em 41,1% e distúrbios psíquicos em 38,2%. A hiperreflexia ocorreu em 82,3% e o papiledema em 58,8% e o exame neurológico normal em 11,8%. Na TC, o edema esteve associado a calcificações em 61,8% dos casos. As pressões liquóricas foram mais elevadas (p< 0,05) antes do tratamento. Atualmente, estão assintomáticos, ou com melhora clínica, 79,4% dos pacientes (57,1% deles sem medicação). Discute-se a possibilidade do ECCr, na NCC, ser uma manifestação antigênica, sem a presença concomitante de cistos parasitários, e poder representar mais uma condição clínica associada à hipertensão intracraniana benigna.