Submitted by MARCIA ROVADOSCHI (marciar@unifra.br) on 2018-08-16T19:38:00Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_CatianeBisogninAlves.pdf: 1685484 bytes, checksum: f55dbdb3d23dcf00e605bf4bcddc7bb7 (MD5) / Made available in DSpace on 2018-08-16T19:38:00Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Dissertacao_CatianeBisogninAlves.pdf: 1685484 bytes, checksum: f55dbdb3d23dcf00e605bf4bcddc7bb7 (MD5) Previous issue date: 2015-03-06 / Statins are cholesterol-lowering agents due to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies have shown pleiotropic effects for statins, such as anti-epileptic effect in rodents. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. The nanoparticles have become an important focus of therapeutic research on brain because they are an especially effective form of drug delivery. Therefore, considering the therapeutic potentials of nanocapsules, in the present study the protective effect of simvastatin in nanoencapsulated (SN) or free form (SF) is evaluated in QA-induced seizures in rats. Male adult Wistar rats (250-300 g) were pretreated orally during 21 days with control formulation (drug-unloaded NCs, CF), SN or SF at 1 mg/kg/day. After pretreatment, rats were infused with 4 μL of 239.2 nmol QA at right lateral brain ventricle and observed for behavioral changes during 10 min. Twenty four hours after seizures, rats were evaluated for locomotion, balance, gait and memory. CF had pH 6.75 ± 0.19, particle diameter of 213.91 ± 19.96 nm, polydispersity index of 0.167 ± 0.05 and zeta-potential values were -16,28 ± 7,90. SN had pH 6.68 ± 0.25, particle diameter of 215.25 ± 30.58 nm, polydispersity index of 0.151 ± 0.07 and zeta potential values were -16.13 ± 8.19 mV. The body weight of rats did not change during the treatment period. The pretreatment com SN or SF did not change the seizures or number of death following QA infusion. In the group CF + QA the number of rats with fall in the Beam Balance task was higher than Naive group, effect prevented by SN and SF. The groups CF + Sal and SF + QA showed a reduced number of rearings in the Open Field test, besides the increased stride length in the Footprint test. Rats infused with SF + QA had impairment of memory in the Avoidance Inhibitory Memory task and SN or SF did not change this damage effect. Altogether, the present results exhibit that simvastatin in nanoencapsulated or free form at the dose 1 mg/kg/day administered for 21 days was not able to protect rats against the behavioral damages induced by QA in rats (with exception on balance parameter). Another strategies need to investigate to better evaluate the effect of nanocapsules against cerebral damage induced by QA. / As estatinas são agentes de redução de colesterol devido à inibição da 3-hidroxi-3-metilglutaril coenzima A (HMG-CoA) redutase. Estudos recentes demonstram que as estatinas possuem efeitos pleiotrópicos, como efeito anti-epilético em roedores. Contudo, pequenas quantidades de sinvastatina atravessam a barreira hematoencefálica, sendo necessárias elevadas quantidades do fármaco, gerando os efeitos colaterais indesejáveis, o que poderia ser um problema na sua utilização para o tratamento de doenças que afetam o sistema nervoso central. O ácido quinolínico (AQ) é um análogo endógeno do neurotransmissor glutamato, que está envolvido na etiologia da epilepsia devido a perturbações na liberação e captação de glutamato. As nanopartículas tornaram-se um importante foco de pesquisas terapêuticas para o cérebro, pois é uma forma especialmente eficaz de entrega de fármacos em locais onde há baixa permeabilidade. Portanto, considerando as potencialidades terapêuticas de nanocápsulas, no presente estudo é avaliado o efeito protetor da sinvastatina na forma nanoencapsulada (NS) e livre (SL) no modelo de convulsão induzida por AQ em ratos. Os ratos Wistar adultos machos (250-300 g) foram pré-tratados via oral por 21 dias com nanocápsulas brancas (sem fármaco, NB), NS ou SL, na dose de 1 mg/kg/dia. Após o pré-tratamento, os ratos receberam uma infusão de 4 μL de 239,2 nmol de AQ no ventrículo cerebral lateral direito. Os animais foram observados por 10 minutos para a ocorrência de alterações comportamentais. Vinte e quatro horas após as convulsões, os ratos foram testados quanto locomoção, equilíbrio, marcha e memória. As NB apresentaram um pH 6,75 ± 0,19, diâmetro de partícula de 213,91 ± 19,96 nm, índice de polidispersão de 0,167 ± 0,05 e potencial zeta -16,28 ± 7,90 mV. As NS apresentaram um pH de 6,68 ± 0,25, diâmetro de partícula de 215,25 ± 30,58 nm, índice de polidispersão de 0,151 ± 0,07 e potencial zeta -6,13 ± 8,19mV. Não houve redução do peso corporal dos animais ao longo do tratamento. O pré-tratamento com NS ou SL não causou alteração nas convulsões ou número de mortes ocasionadas pela infusão de AQ. O grupo NB + AQ possui maior número de animais com quedas na tarefa de Equilíbrio na Passarela Elevada, efeito prevenido pelo pré-tratamento com NS ou SL. Os grupos NS + Sal e SL + AQ tiveram uma redução no número de explorações verticais no Campo Aberto, além de apresentarem um aumento no padrão do comprimento da passada no teste de Impressão das Patas. Os ratos tratados com NB + AQ tiveram prejuízo de memória avaliado na tarefa da Esquiva Inibitória, e o pré-tratamento com NS ou SL não preveniu esse efeito. No geral, os resultados demonstram que a sinvastatina nanoencapsulada ou na forma livre na dose de 1 mg/kg/dia administrada por 21 dias não induziu efeitos protetores contra os danos observados após a infusão de AQ (com exceção do equilíbrio). Outras estratégias devem ser exploradas para avaliar o efeito dessas formulações no dano cerebral induzido pelo AQ.

A crise não-epilética psicogênica é definida como uma manifestação corporal semelhante àquela das crises epiléticas, porém sem um correlato neurológico que justifique a sua ocorrência. Sua etiologia é atribuída a fatores psicológicos, entretanto as questões subjetivas que estão na origem dos sintomas são pouco estudadas. Esta pesquisa tem por objetivo investigar os traços histéricos da personalidade em dois pacientes encaminhados para psicoterapia de orientação psicanalítica após receberem esse diagnóstico médico, além de analisar os conteúdos afetivos latentes que se relacionam às manifestações sintomáticas nos casos estudados. O material coletado durante o atendimento prestado a esses pacientes se constituiu como registro e fonte de informação, por meio do qual os elementos relativos à personalidade histérica e mecanismos inconscientes que engendram os sintomas são descritos e estudados. Este trabalho tem por referencial a psicanálise e o estudo dos casos foi realizado considerando seus pressupostos conceituais sobre sintoma, conflito, conversão e histeria. O material obtido durante o curso das sessões evidenciou elementos como erotização do espaço analítico, constante reivindicação para ocupar o lugar de objeto de desejo alheio, além da recusa em abandonar a posição de insatisfação e buscar um estado de contentamento. Também foi observado um investimento em fantasias infantis, nas quais há o desejo inconsciente de união exclusiva com as figuras parentais. / A psychogenic nonepileptic seizure is defined as a physical manifestation similar to that of epileptic seizures, but lacking a neurological correlation to justify its occurrence. Its etiology is attributed to psychological factors although subjective questions concerning the origin of symptoms are barely studied. This research aims to investigate hysterical personality traits in two patients forwarded for psychoanalytic psychotherapy after receiving this medical diagnosis, as well as analyze latent affective contents associated with the symptomatic manifestations in these case studies. The material collected during the patient consultation served as a file and source of information through which elements relative to hysterical personality and unconscious mechanisms linked to the symptoms are described and studied. This work has psychoanalysis as a reference and the case studies were carried out considering its conceptual assumptions of symptoms, conflict, conversion and hysteria. The material obtained during the sessions evidenced elements, such as erotization of the analytic space, continuous demands to occupy the place of an object of beauty, as well as refusal to abandon discontentment and search for a contented state. Investment in infantile fantasies with an unconscious desire of exclusive union with parental figures was also observed.

As crises não-epilépticas são definidas como crises, ataques ou acessos recorrentes que podem ser confundidos com epilepsia, devido à semelhança das manifestações comportamentais existentes entre ambas, mas difere da crise epiléptica por não ser conseqüente de descargas elétricas cerebrais anormais. Podem ter origem fisiogênica ou psicogênica. Os diagnósticos psiquiátricos que mais freqüentemente apresentam-se sob a forma de crises não-epilépticas psicogênicas são o transtorno conversivo e o transtorno de somatização. Na prática clínica, a diferenciação entre crises epilépticas e crises não-epilépticas desafia e confunde os clínicos, os neurologistas e os psiquiatras desde tempos remotos. A introdução da monitorização pelo vídeo-eletroencefalograma vídeo-EEG, considerado o padrão ouro para o diagnóstico diferencial, levou a um aumento significativo no número de diagnósticos de crises não-epilépticas psicogênicas. Apesar de se tratar de uma situação clínica de difícil manejo, com conseqüências médicas e sociais significativas, fica evidente que o conhecimento técnico e instrumental sobre as crises não-epilépticas psicogênicas são insuficientes para abordar este problema. O objetivo geral deste estudo é de o de enriquecer a compreensão das crises não-epilépticas psicogênicas, nos últimos quarenta anos. As condições de emergência histórica e as implicações práticas do conceito de crise não-epiléptica psicogênica foram investigadas. Para tanto, foram selecionados artigos que abordam o conceito de crises não-epilépticas psicogênicas em três periódicos de neurologia e em três de psiquiatria. Esta pesquisa partiu de projetos epistemológicos que possibilitam um pensamento reflexivo sobre a produção de conhecimentos científicos, no que diz respeito à formação, às mudanças e à formalização dos conceitos, teorias e práticas. Houve uma aproximação da metodologia histórico-epistemológica de Canguilhem e Bachelard, passando pela análise crítica de Foucault e alcançando o pensamento hermenêutico de Habermas e Gadamer. Foi verificado que os conceitos de histeria e epilepsia vêm sendo reformulados, ao longo do tempo. As crises não-epilépticas psicogênicas foram demarcadas em períodos. Na década de 1970, predominam os artigos que discutem a redução da prevalência da histeria e da personalidade histérica nas mulheres. Na década de 1980, existe uma preocupação com a formulação de diagnósticos através de instrumentos e entrevistas padronizadas e um aumento explosivo do número de artigos, dos periódicos de neurologia, que discutem o uso do vídeo-EEG. Na década de 1990, surgem os artigos que abordam os múltiplos diagnósticos psiquiátricos e as pesquisas sobre o abuso e a dissociação associados à crise não-epiléptica psicogênica. Conclui-se que as crises não-epilépticas psicogênicas, tal qual o conhecimento científico, tem uma história, que interage com outros tipos de conhecimento e que são influenciadas por variáveis sociais. Nesta direção, sugere-se que a possibilidade de abertura e diálogo entre as dimensões técno-científica e prática possam criar condições para um modelo de cuidado mais adequado e integrado junto aos pacientes com crises não-epilépticas psicogênicas / Psychogenic non-epileptic seizures are recurrent crisis, or attacks, or paroxysmal behavioral changes that can be misunderstood as epileptic seizure due to the behavioral similarity between both, however, these manifestations are not associated with abnormal electrical brain discharges that cause epileptic seizures. Non-epileptic seizures are classified into physiologic and psychogenic origin. The most common psychiatric diagnoses associated with psychogenic non-epileptic seizures are conversion disorder and somatization disorder. In clinical practice, the distinction between non-epileptic seizure and epilepsy challenges and confuses the clinicians, the neurologists and the psychiatrists, since ancient times. The long-term video-electroencephalographic monitoring video-EEG, considered as the gold standard for the differential diagnosis, has led to a significant increase in the number of cases of psychogenic non-epileptic seizures. Although being a clinical situation difficult to manage, with medical and social poor prognosis, it is evident that the instrumental and technological knowledge about non-epileptic seizures are insufficient to deal with this problem. The aim of this study is to enrich the comprehension of the psychogenic non-epileptic seizures in the last fifty years. The historical emergence conditions of the psychogenic non-epileptic seizure and its clinical practical implications were investigated. For this purpose, it was examined papers that discuss the concept of psychogenic non-epileptic seizure in three neurological journals and in three psychiatric journals. This research was guided by epistemological projects focused upon conditions of possibility for reflexive thinking about conceptualization, changing and formalization of the concepts, theories and practices. The methodological approach was influenced by Canguilhems and Bachelards historical epistemology, pursued by Foucault´s critical analysis and culminating in Habermas e Gadamers hermeneutics thought. The research pointed out that hysteria and epilepsy concepts have been reformulated over time, and uncovered fundamental concepts that organized psychogenic non-epileptic seizures in different historical periods. In the 1970s, there was a predominance of papers that discuss the reduction of hysteria and the hysterical personality in women. In the 1980s, there was a concern with the development of diagnostic instruments and structured interviews, and an explosive increase in the number of papers in the neurological journals discussing the use of video-EEG. In the 1990s and on, papers have been focused on the multiple psychiatric diagnoses and research on dissociation and abuse associated to psychogenic non-epileptic seizure. The conclusion is that psychogenic non-epileptic seizures, as scientific knowledge, have a history, which interact with various kinds of knowledge and it is influenced by social variables. In this sense, the possibility of openness and dialogue between technological and practical dimensions could provide underlying conditions to a better and more integral care model among patients with psychogenic non-epileptic seizures

INTRODUÇÃO: A classificação recente das Crises Hipercinéticas (CH) proposta por Rheims et al. (2008) sugere dois padrões de CH, baseado na semiologia ictal (Tipos I e II): no Tipo I, a zona epileptogênica foi identificada na região ventral pré-frontal, enquanto que no Tipo II, na região mesial pré-motora. Estudos com SPECT ictal em pacientes com CH evidenciaram hiperperfusão nas regiões frontais e extrafrontais, incluindo ínsula e lobo temporal, além de áreas subcorticais, tais como cerebelo, tálamo, gânglios da base e tronco encefálico. OBJETIVO: Avaliar a rede neural ativada nas CH através do SPECT ictal, correlacionando-a aos dois subtipos de CH (Tipos I e II). MATERIAL E MÉTODOS: Uma amostra de 25 pacientes com idade entre 0 e 60 anos com CH que realizaram SPECT ictal foi submetida a análise do VEEG e das imagens do SPECT ictal a fim de determinar o tipo de CH e as áreas de hiperpefusão ativadas, bem como sua correlação. RESULTADOS: Nove pacientes (36%) tiveram CH do Tipo I, dez (40%), do Tipo II e seis (24%), do Tipo Misto. Não houve diferenças significativas entre os tipos de CH e a presença de semiologia ictal não hipercinética durante as crises, bem como o tempo de doença, frequência das crises, história familiar positiva e exame de neuroimagem anormal. A duração média do tempo de injeção do RF foi de 32,2 segundos. O SPECT demonstrou ativação difusa, com predomínio nas regiões subcorticais, temporal lateral, occipital mesial e frontal dorsolateral. Não houve correlação entre os diferentes tipos de CH e as áreas hiperperfundidas, exceto pela região occipital mesial, que foi significativamente maior no Tipo II. CONCLUSÃO: A classificação proposta por Rheims et al. (2008) é útil porém simplista, já que as CH abrangem uma fenomenologia complexa, não sendo possível classificar todos os pacientes em somente dois tipos (I e II). O SPECT ictal nesta amostra demonstrou a presença de hiperperfusão em diferentes áreas cerebrais, reforçando a hipótese de que uma rede neural ampla, que engloba as regiões frontais e possivelmente extrafrontais, incluindo áreas subcorticais, está envolvida na gênese destas crises. / BACKGROUND: The recent classification of hyperkinetic seizures (HS) proposed by Reims et al (2008) suggests two patterns of HS based on ictal symptomatology (Type I and II), whereas in Type I epileptogenic zone was identified in the ventromesial frontal córtex while in Type II, in the mesial premotor córtex. Ictal SPECT studies in patients with HS showed hyperperfusion in frontal and extrafrontal regions, including insula and temporal lobe, and subcortical areas, such as cerebellum, thalamus, basal ganglia and brain stem. OBJECTIVE: To evaluate the neural network activated in HS through the ictal SPECT and to correlate it to the two subtypes of HS (Type I and II). METHODS: We retrospective analyzed ictal signs and ictal SPECT data in 25 patients with HS aged between 0 and 60 years in order to determine the type of HS and the hyperperfused areas, as well as their correlation. RESULTS: Nine patients (36%) were classified as Type I, ten (40%) as Type II and 6 (24%) as a mixed type. There were no significant differences between the types of HS and the presence of non-hyperkinetic ictal semiology, as well as epilepsy duration, frequency of seizures, positive family history and abnormal neuroimage. The average injection duration time was 32.2 seconds. The ictal SPECT showed diffuse activation, predominantly in subcortical regions and the following areas: lateral temporal, mesial occipital and dorsolateral frontal cortex. There was no correlation between the different types of HS and the hyperperfused areas but the mesial occipital region that was significantly higher in Type II. CONCLUSION: The classification proposed by Rheims et al (2008) is useful but simplistic. Since the HS consists of a complex phenomenology, it is not possible to classify all patients in only two types (I and II). The ictal SPECT in this sample showed the presence of hyperperfusion in different brain areas, reinforcing the hypothesis that a broad neural network, which includes the frontal and possibly extrafrontal regions, including subcortical areas, are involved in the genesis of these seizures.

Introdução: a epilepsia reflexa é uma condição na qual todas as crises são desencadeadas por um estímulo específico e, na grande maioria dos casos, apresenta-se com crises refratárias ao tratamento. São vários os fatores desencadeantes, entre os quais se destaca pela raridade a evacuação. Objetivos: realizar revisão de literatura sobre epilepsia reflexa, identificar a evacuação como possível fator desencadeador de crise epiléptica e relatar o caso de um paciente com crise reflexa evacuatória documentada à monitorização por vídeo-eletroencefalograma Métodos: revisão de literatura acerca de epilepsias reflexas e revisão de prontuário de um paciente com suspeita clínica de epilepsia reflexa evacuatória. Resultados: o paciente deste estudo, um menino de 10 anos de idade, com dominância manual esquerda, iniciou, aos 4 anos, crises associadas à evacuação. Na monitorização por vídeo-eletroencefalograma, durante episódio de evacuação, apresentou parada comportamental, desvio cefálico para a direita, automatismos em membro superior esquerdo e arresponsividade, coçando o nariz tardiamente com a mão esquerda. O EEG ictal demonstrou atividade rítmica teta em região temporal esquerda com posterior envolvimento frontal esquerdo e de áreas homólogas contralaterais. As ressonâncias magnéticas de encéfalo não evidenciaram alterações e o SPECT interictal identificou hipoperfusão discreta na porção anterior do lobo temporal esquerdo. Com uso de ácido valpróico e carbamazepina o paciente segue livre de crises. Avaliações neuropsicológicas e de qualidade de vida sugerem comprometimento global, tanto antes como após o controle da epilepsia. Conclusão: este é apenas o terceiro caso de epilepsia reflexa evacuatória descrito na literatura, e o segundo com crises dessa ordem documentadas por vídeo-eletroencefalograma. Ambos sugeriram lateralização e localização em região temporal esquerda, elegendo esta região como potencial zona epileptogênica. O tratamento com ácido valpróico e carbamazepina mostrou-se eficaz para controle de crises neste paciente, podendo ser uma opção de tratamento em outros pacientes com este tipo de epilepsia. / Background: Reflex epilepsy is a condition in which all seizures are triggered by a specific stimulus. There are many known stimulus, including defecation which has rarely been reported. In the majority of cases, it presents with refractory seizures. Objective: review the literature on reflex epilepsy, as well as identify defecation as a possible trigger and report a case of a patient with reflex seizures triggered by defecation documented by video-electroencephalogram monitoring. Methods: literature review on reflex epilepsies and review of medical records of a patient with reflex epilepsy triggered by defecation. Results: we present a 10-year-old-boy patient, left-handed, whose epilepsy onset was at the age of four. Its seizures were characterized by episodes of loss of consciousness and atonia during defecation. Video-electroencephalogram monitoring had shown a seizure triggered by defecation, characterized by right head deviation, left upper limb automatisms, associated with consciousness impairment and afterwards nose wiping with the left hand. The ictal EEG demonstrated theta rhythmic activity in the left temporal lobe. The brain magnetic resonance was normal. The interictal SPECT identified left anterior temporal lobe mild hypoperfusion. The patient became seizure free after the treatment with valproic acid and carbamazepine. Neuropsychological and quality of life assessments suggested global impairment, before and after seizure control. Conclusion: this is the third case of epilepsy induced by defecation, and the second with seizures documented by videoelectroencephalogram. Similar to this case, both had suggested lateralization and localization over the left temporal region, suggesting this region as a potential epileptogenic zone in patients with this type of reflex epilepsy. In our patient, the treatment with valproic acid and carbamazepine was effective for the seizure control and may be an option to other patients with this condition.

This thesis explores the perspectives of people on psychogenic non-epileptic seizures (PNES). It is presented in three separate papers: a systematic literature review; an empirical research paper and a critical reflection of the research process as a whole. The systematic literature review aimed to provide a detailed understanding of stakeholder perspectives on PNES. A systematic search identified relevant studies that were subsequently synthesised using thematic analysis and the broader principles of narrative synthesis. Three broad themes relating to stakeholder perspectives were identified: the nature of PNES as a condition; diagnosis; and management and treatment issues. It was found that both patients and professionals experienced uncertainties in relation to understanding and managing the condition. This highlighted the need for further information and awareness of PNES and the development of clear treatment guidelines. Important differences in opinion were also identified between patients and professionals and consideration was given to how these may disrupt the development of effective partnerships in care. The research into patients' and families' perspectives was found to be lacking and further research was identified as being needed in this area. The empirical paper reports an exploratory qualitative study that aimed to provide an in-depth understanding of the perceived treatment needs of patients with PNES. Semi-structured interviews were conducted and findings were analysed inductively using the principles of thematic analysis. Four key themes were identified: return to normality; post-diagnostic limbo; uncertainty and apprehension about therapy; and need for validation. Patients with PNES described clear goals for their recovery and clear ideas about their treatment needs. However, following their diagnosis, many felt caught in 'limbo' due to uncertainties about their diagnosis and as a result of a lack of post-diagnostic support. Being in 'limbo' also linked to patients' uncertainties about psychology meeting their needs and for some there was apprehension about the potential negative consequences of therapy. The clinical implications of the research are discussed and recommendations for future research are made. The third paper is a critical reflection of the research process as a whole. It provides an overview and evaluation of the first two papers and personal reflections of the lead researcher are offered throughout. Implications for further research and clinical practice are offered and a summary of the research as a whole is offered.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Methylmalonic acidemias comprehend a group of innate error of the metabolism (EIM)characterized clinically and biochemically for the tissue accumulation of acid methylmalonic (MMA)and neurological dysfunction, including seizures. The clinical experience suggests that infections precipitate metabolic crises in methylmalonic acidemic patients. Since it has been demonstrated that MMA cause seizures, and that inflammation facilitates the occurrence of seizures in some animal models, is possible that inflammatory mediators, such as the prostaglandins, also facilitate MMAinduced seizures. Ciclooxigenase (COX) is the rate-limiting enzyme in the metabolic route by which the arachidonic acid is converted to prostaglandins. COX-2 is an isoform of cicloooxigenase that is induced at sites of injury / inflammation, and that is also constitutively expressed in some tissues, such as the central nervous system (CNS). It has been suggested that prostaglandin E2 (PGE2), the main product of COX-2 in the CNS, plays an important role in some neurodegenerative diseases, including epilepsy. However, no study has evaluated whether inflammatory mediators, such as the PGE2, facilitates MMA-induced seizures, to date. Thus, in this study we investigated the role of COX-2 and of PGE2 in seizures induced by MMA (2,5 µmol/2,5 µL, i.c.v.). While PGE2 (100 ng/2 μL, i.c.v.) facilitated, the selective COX-2 inhibitor celecoxib, attenuated MMA-induced seizures, assessed by electroencephalographic recordings in the hippocampus and cerebral cortex of rats. The ´protective effect of celecoxib against MMA-induced seizures was prevented by the PGE2. The results of this study support a facilitatory role for COX-2/PGE2 pathway in the MMA-induced seizures. / A acidemia metilmalônica é um erro inato do metabolismo (EIM) caracterizado bioquimicamente e clinicamente pelo acúmulo tecidual de ácido metilmalônico (MMA) e disfunção neurológica, que inclui convulsões. A experiência clínica sugere que infecções precipitam crises metabólicas em pacientes metilmalonicacidêmicos. À medida em que foi demonstrado que o MMA causa convulsões, e que a inflamação pode contribuir para a ocorrência de convulsões em vários modelos animais, é possível que mediadores inflamatórios, como as prostaglandinas, facilitem as convulsões induzidas por MMA. A ciclooxigenase (COX) é a enzima marca-passo na rota metabólica pela qual o ácido araquidônico é convertido em prostaglandinas, e a COX-2 uma isoforma da cicloooxigenase, é induzida em sítios de lesão/inflamação, e também se expressa constituivamente em alguns tecidos, como o sistema nervoso central (SNC). Tem sido sugerido que a prostaglandina E2 (PGE2), principal produto da via COX-2 no SNC, tenha um papel importante em várias doenças neurodegenerativas, incluindo epilepsia. Contudo, até a presente data nenhum estudo avaliou se mediadores inflamatórios, como a PGE2, facilitam as convulsões induzidas por MMA. Assim, neste estudo investigamos o papel da COX-2 e da PGE2 nas convulsões induzidas por MMA (2,5 µmol/2,5 µL, i.c.v.). Verificamos que a PGE2 (100 ng/2 μL, i.c.v.) facilita as convulsões induzidas por este ácido orgânico. Além disso, verificamos que o celecoxibe, um inibidor seletivo da COX-2, na dose de 2 mg/kg (v.o.), atenuou as convulsões comportamentais e eletrográficas induzidas por MMA no hipocampo e córtex cerebral de ratos. O efeito protetor do celecoxibe contra as convulsões induzidas por MMA foi revertido pela administração i.c.v. de prostaglandina E2. O conjunto de dados deste estudo suporta um papel facilitatório para a via COX-2/PGE2 nas convulsões induzidas por MMA.

In the last decades, although the scientific community has attempted to explain a series of complex phenomena, ranging from natural hazards to physical conditions and economic crises, aspects of their generation process still escape our full understanding. The present thesis intends to promote our understanding of the spatiotemporal behavior and the generation mechanisms that govern large and strong earthquakes, employing a broad multidisciplinary perspective for the interpretation of catastrophic events. Two main questions are debated. The first question concentrates on “whether the generation process of an extreme event has more than one facets prior to its final appearance”. In the scientific study of earthquakes, attention is drawn to the predictive capability and monitoring of different precursory observations. Among them preseismic electromagnetic emissions have been also observed indicating that the science of earthquake prediction should be from the start multidisciplinary. Drawing on recently introduced models for earthquake dynamics, that address issues such as long-range correlations, self-affinity, complexity-organization and fractal structures, the present work endeavors to further penetrate on the analysis of preseismic electromagnetic emissions and elucidate their link with the generation process of large and strong earthquakes. A second question deals with “whether there is a unified approach for the study of catastrophic events”. This question implies the possibility for common statistical behavior of diverse extreme events and the potential for transferability of methods from the study of earthquake dynamics across other fields. On these grounds, the present work extends the focus of inquiry to the analysis of electroencephalogram recordings related to epileptic seizures, in the prospect to identify common mechanisms that may explain the nature and the generation process of both phenomena, and to open up different directions for future research. Finally, with a view to consider alternative ways of studying key theoretical principles associated with the generation process of catastrophic phenomena, a relevant framework based on proposed algorithms is presented, focusing on parameters such as: the energy of earthquakes, the mean and maximum magnitude of the sample, the probability that two samples may come from the same population. Such an attempt aims to contribute to the knowledge of natural phenomena, by extending the existing theory and models and providing a few more ways for their interpretation.

Bakgrund: Akuta krampanfall drabbar många människor, både nationellt och internationellt. Detta behandlas i första hand med Bensodiazepiner, såsom Diazepam och Midazolam. Sveriges prehospitala behandlingsriktlinjer skiljer sig åt vid behandling av akuta krampanfall. Region Halland förnyade behandlingsriktlinjerna år 2011 och införde intranasal administrering av Midazolam Syfte: Att sammanställa behandlingsriktlinjerna angående medicinsk behandling vid kramper prehospitalt i Sverige samt kartlägga användandet av bensodiazepiner vid kramper prehospitalt i Region Halland. Metod: En kvantitativ registerstudie med en retrospektiv design användes. En sammanställning av Sveriges prehospitala behandlingsriktlinjer för medicinsk behandling av kramper utfördes. Chi-Två samt Fishers exakta test användes vid analysen av den insamlade datan från 127 ambulansjournaler i Region Halland. Resultat: Sammanställningen av Sveriges prehospitala behandlingsriktlinjer vid kramper visade att behandlingsriktlinjerna skiljer sig åt nationellt. Resultatet från kartläggningen av användandet med bensodiazepiner vid kramper prehospitalt i Region Halland visade att Diazepam var det vanligast använda läkemedlet samt att det fanns en signifikant skillnad i behandlingen med Diazepam rektalt relaterat till patientens ålder. Flertalet patienter som hade behandlats med Midazolam intranasalt behövde kompletterande behandling med Diazepam intravenöst. Slutsats: Behandlingsriktlinjerna för kramper prehospitalt skiljer sig åt nationellt. Diazepam var det vanligast använda läkemedlet samt en bristfällig följsamhet till behandlingsriktlinjerna framkom i Region Halland. Mer forskning behövs avseende ambulanssjuksköterskors erfarenheter av att behandla pågående kramper prehospitalt för ge patienterna möjlighet till en god omvårdnad på ett säkert sätt. / Background: Acute seizures affects a large number of people both nationally and internationally. Seizures are primarily treated with benzodiazepines, such as Diazepam and Midazolam. Sweden's prehospital treatment guidelines differ in the treatment of acute seizures. Region Halland renewed the treatment guidelines in 2011 and introduced intranasal administration of Midazolam. Objective: To compile the treatment guidelines for medical treatment in prehospital seizures in Sweden and to survey the use of benzodiazepines in prehospital seizures in Region Halland. Method: A quantitative register study with a retrospective design was used. A compilation of Sweden's prehospital treatment guidelines was performed. Chi-Two and Fishers exact test are used in the analysis of the collected data from 127 ambulance journals in Region Halland.  Results: The compilation of Swedish prehospital treatment guidelines for seizures showed that the treatment guidelines differ nationally. The survey of the use of benzodiazepines in prehospital seizures in Region Halland showed that Diazepam was the most commonly used drug, and that there was a significant difference in treatment with Diazepam rectally related to the age of the patient. Most patients treated with Midazolam intranasally needed additional therapy with Diazepam intravenously. Conclusion: The prehospital treatment guidelines for seizures differs nationally. Diazepam was the most commonly used drug and the compliance with the treatment guidelines is inadequate in Region Halland. More research is needed regarding from the ambulance nurse's experiences of treating ongoing prehospital seizures in order to provide patients with proper care in a safe way.

Epileptic seizures are characterised by an onset of abnormal brain activity that evolves in space and time, which ultimately returns to normal background activity. For different types of seizures, the abnormal activity can be vastly different both in duration, electrographic morphology and spatial extent. Mechanistic understanding of the different seizure dynamics (spatially, as well as temporally) is crucial for the advancement and improvement of clinical treatment. To gain a deeper mechanistic insight into different seizure dynamics, mathematical models of brain processes were developed in this thesis. These models are used to explain electrographic seizure dynamics in their temporal, as well as their spatio-temporal evolution. Our studies show that the temporal evolution of seizure dynamics can be understood in terms of prototypic waveforms, which in turn can be represented in terms of three neural population processes. Such a minimal framework lends itself to a detailed phase space analysis, which elucidates seizure waveforms and seizure transitions as topological properties of the phase space. Based on the phase space considerations we show how during spike-wave seizures, single-pulse stimuli can have more complex effects than previously thought. In terms of the spatio-temporal dynamics of seizures, mechanisms for focal seizure onset and propagation are investigated in a model cortical sheet of coupled, discretised columns. The coupling followed nearest-neighbour, as well as realistic mesoscopic cortical connectivities. Different possible causes (e.g. spatial heterogeneities) of seizure generation, as well as different seizure spreading patterns (via different networks) have been investigated. We conclude that focal seizure onset can be due to global (e.g. whole-brain level) causes, global conditions & local triggers, and local (e.g. cortical column level) causes. Clinically relevant predictions from this work include the suggestion of a specific stimulation protocol in spike-wave seizures that incorporates phase space information; and the suggestion of using microscopic cortical incisions to disrupt the integrity of abnormal cortical tissue in order to prevent focal seizure onset. In conclusion, multi-scale computational modelling of seizure dynamics is proposed as an important tool to link theoretical understanding, experimental results, and patient-specific clinical data.