Orientador: Fernando Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T02:54:43Z (GMT). No. of bitstreams: 1 Goncalves_EleonoraBorges_D.pdf: 2276279 bytes, checksum: d153e20d01fc2adb69c63827fff175d1 (MD5) Previous issue date: 2013 / Resumo: Objetivos: Avaliar os transtornos depressivos em comorbidade com a epilepsia do lobo temporal (ELT), em pacientes com crises refratárias às drogas antiepilépticas (DAEs). Pacientes e métodos: Realizamos um estudo transversal, entrevistando e coletando informações dos prontuários de pacientes que procuraram atendimento no Ambulatório de epilepsia de difícil controle do HC-UNICAMP. A população foi de adultos, com idade igual ou maior de 24 anos, em acompanhamento no HC-UNICAMP, com diagnóstico de ELT refratária, em uso adequado da medicação instituída e ausência de rebaixamento intelectual, demência ou problemas de linguagem. Os pacientes foram submetidos a uma entrevista psiquiátrica semiestruturada, o que conferiu diagnóstico segundo a Classificação Internacional de Doenças (CID-10)-OMS. Aplicamos os seguintes instrumentos: (1) Mini Entrevista Neuropsiquiátrica Internacional (MINI) e (2) Inventário de Depressão de Beck (IDB). Resultados: Foram incluídos 40 pacientes com idade de 24-60 anos, trinta e um dos 40 pacientes (77,5%) apresentaram transtornos depressivos: 14 (45,2 %) com distimia, 11 (35,5%) com transtorno depressivo recorrente e 6 (19,3%) com transtorno bipolar, na ocasião depressivo. Dois (5%) apresentaram transtorno misto de ansiedade e depressão. Os outros 7 pacientes (15%) apresentaram eventuais manifestações de depressão e ansiedade, sem constituírem um diagnóstico de depressão, sendo um deles com transtorno orgânico de ansiedade. Apenas 8 dos 31 pacientes (25,8%) receberam tratamento antidepressivo satisfatório prévio. A duração da epilepsia apresentou uma tendência a ser maior nos pacientes com transtorno depressivo (p=0.10); não houve associação entre depressão e frequência de crises. Conclusões: Este trabalho confirma que o transtorno depressivo é frequente e subdiagnosticado em pacientes com ELTM refratária às DAEs. A duração da epilepsia apresenta uma tendência a ser maior nos pacientes deprimidos. Não houve associação entre depressão e frequência de crises / Abstract: Objectives: To assess depressive disorders in patients with temporal lobe epilepsy (TLE), refractory to antiepileptic drugs (AEDs). Patients and methods: We performed a cross-sectional study, interviewing and collecting information from records of patients who sought treatment at the Epilepsy Clinic of the HC-UNICAMP. The population consisted of adults aged greater than 24 years followed at UNICAMP, diagnosed with refractory TLE, in appropriate use of AEDs and lack of established mental retardation, dementia or language problems. Patients underwent a semi-structured psychiatric interview, which gave diagnosis according to the International Classification of Diseases (CID-10) - WHO. We applied the following instruments: (1) Mini International Neuropsychiatric Interview (MINI) and (2) the Beck Depression Inventory (BDI). Results: There were 40 patients aged 24-60 years. Thirty-one of these (77.5%) had depressive disorders: 14 (45.2%) with dysthymia, 11 (35.5%) with recurrent depressive disorder and 6 (19.3%) with bipolar disorder who had depression at the time of evaluation. Two (5%) had mixed anxiety disorder and depression. The other 7 patients (15%) showed signs of depression and anxiety, without imposing a diagnosis of depression, one of them with organic anxiety disorder. Only 8 of the 31 patients (25.8%) had received prior satisfactory antidepressant treatment. The duration of epilepsy tended to be higher in patients with depressive disorder (p = 0.10). There was no association between depression and seizure frequency. Conclusions: This study confirms that depressive disorder is common and underdiagnosed in patients with TLE refractory to AEDs. The duration of epilepsy had a tendency to be higher in depressed patients. There was no association between depression and seizure frequency / Doutorado / Neurologia / Doutora em Ciências Médicas

Transient epileptic amnesia (TEA) is a form of epilepsy of which the principle manifestation is recurrent, transient episodes of isolated memory loss. Although the phenomenon has been recognised for over a century, it is scantily documented in the medical literature and is often misdiagnosed by clinicians. Recent work has highlighted a number of apparently consistent clinical features among the published cases. However, to date there has been no large, systematic study of the condition. The aim of the work reported in this thesis was to investigate a substantial number of prospectively recruited patients with TEA, and thus be able to provide a detailed and authoritative description of its clinical, neuropsychological and radiological characteristics. Fifty patients with TEA were recruited from around the United Kingdom using established diagnostic criteria, together with a group of matched healthy control subjects. Participants underwent a clinical interview, comprehensive neuropsychological testing and structural magnetic resonance imaging of the brain. The study demonstrated the following features. TEA typically begins in later life. The amnesic episodes are frequent, brief and often occur upon waking. They are characterised by a mixed anterograde and retrograde amnesia, the anterograde component of which is often incomplete. Attacks are commonly associated with olfactory hallucinations. They respond well to anticonvulsant medication. Nevertheless, many patients complain of persistent difficulties with memory. Despite generally performing well on standard tests of anterograde memory, many patients show i) accelerated forgetting of new information over a three-week delay and ii) temporally extensive deficits in autobiographical memory. TEA is associated with subtle medial temporal lobe atrophy on magnetic resonance imaging. This atrophy correlates with performance on standard memory tests, but not with long-term forgetting rates or autobiographical memory deficits. It is proposed that TEA is a distinctive syndrome of epilepsy, typically misdiagnosed at presentation, caused by medial temporal seizure activity and associated with accelerated long-term forgetting and autobiographical memory loss. These unusual forms of memory impairment have been documented in other forms of epilepsy. They pose challenges to current models of memory. The syndrome of TEA is therefore both clinically and theoretically important.

Acousto-electric (AE) effect comes from an interaction between electrical current and acoustic pressure generated when acoustic waves travel through a conducting material. It currently has two main application areas, ultrasound current source density imaging (UCSDI) and AE hydrophone. UCSDI can detect the current direction by modulating the dipole field with ultrasound pulse, and it is now used to form 3D imaging of dipole changing in one period of treatment, such as arrhythmia in the heart and epilepsy in the brain. As ultrasound pulse passes through electrical field, it convolutes or correlates with the inner product of the electric fields formed by the dipole and detector. The polarity of UCSDI is not determined by Doppler effect that exists in pulse echo (PE) signal, but the gradient of lead field potentials created by dipole and recording electrode, making the base-banded AE voltage positive at the anode and negative at cathode. As convolution shifts spectrum lower, the base band frequency for polarity is different from the center frequency of AE signal. The simulation uses the principles of UCSDI, and helps to understand the phenomena in the experiment. 3-D Fast Fourier Transform accelerates the computing velocity to resolve the correlation in the simulation of AE signal. Most single element hydrophones depend on a piezoelectric material that converts pressure changes to electricity. These devices, however, can be expensive, susceptible to damage at high pressure, and/or have limited bandwidth and sensitivity. An AE hydrophone requires only a conductive material and can be constructed out of common laboratory supplies to generate images of an ultrasound beam pattern consistent with more expensive hydrophones. Its sensitivity is controlled by the injected bias current, hydrophone shape, thickness and width of sensitivity zone. The design of this device needs to be the tradeoff of these parameters. Simulations were made to optimize the design with experimental validation using specifically fabricated devices composed of a resistive element of indium tin oxide (ITO).

No description available.

The present research examined the hypothesis that omega-3 polyunsaturated fatty acids would increase seizure threshold in rats in vivo, and reduce neuronal excitability in mouse hippocampal slices. Seizure thresholds were measured in rats using the maximal pentylenetetrazol and electrical stimulation seizure tests following α-linolenic acid (ALA) or docosahexaenoic acid administration. ALA raised seizure threshold in the maximal PTZ seizure test, but this effect probably occurred because ALA displaced DHA from liver to the brain. DHA itself was therefore tested in the PTZ and electrical stimulation seizure tests. Direct administration of DHA by subcutaneous injection raised seizure thresholds in the PTZ seizure test, which models tonic-clonic attacks in humans. Dietary enrichment with DHA raised afterdischarge seizure thresholds in the cortex and amygdala, which model simplex and complex partial seizures in humans, although this effect took some time to occur. In vitro, the application of DHA also reduced the incidence of excitatory sharp waves in mouse hippocampal slices. This effect did not appear to be due to either an increase in GABAergic inhibitory tone, nor to a decrease in glutamatergic drive. The fatty acid composition of phospholipids and unesterified fatty acids were measured in the brain following microwave fixation in order to determine whether the effects of DHA on seizure thresholds were due to its de-esterification from the phospholipid membrane. The assay surprisingly revealed that subcutaneous administration of DHA at a dose that raised seizure threshold, increased unesterified arachidonic acid, but not unesterified DHA concentrations during seizures. The results of these studies support the hypothesis that DHA raises seizure threshold in rats, and reduces neuronal excitability in vitro. The effects of DHA on seizure threshold are possibly mediated by the de-esterification of arachidonic acid, which is known to have effects on the voltage-dependent sodium channel.

It is well established that patients with temporal lobe epilepsy (TLE) commonly report memory difficulties. The aim of this thesis was to use a novel approach adopting Nelson & Narens' (1990) theoretical framework to investigate whether metacognitive knowledge and memory performance were differentially disrupted in patients with TLE. More specifically, investigating to what extent poor memory in TLE could result from inadequate metamemory monitoring, inadequate metamemory control or both. Experiment I employed a combined Judgement-of-Learning and Feeling-of-Knowing task to investigate whether participants could monitor their memory successfully at both the item-by-item and global levels. The results revealed a dissociation between memory and metamemory in TLE patients. TLE patients presented with a clear episodic memory deficit compared with controls yet preserved metamemory abilities. Experiments 2 and 3 explored the sensitivity approach to examine metacognitive processes that operate during encoding in TLE patients and controls. Both these experiments demonstrated that TLE patients were sensitive to monitoring and control processes at encoding. The final experiment further investigated memory performance by examining the role of lateralisation of the seizure focus using material specific information and the 'Remember-Know' paradigm. The findings from the verbal task provided partial support to the material-specific hypothesis. The results from these experiments are discussed in terms of their association with executive functioning and memory deficits in TLE, and have important implications for future research examining memory and metamemory in TLE patients and other clinical populations.

People with learning disabilities constitute about 2% of the general population. Epilepsy is more prevalent among people with learning disabilities compared with the general population. Effective communication is central to the management of people with learning disabilities and epilepsy. It has both therapeutic and health promotion functions including psycho-social benefits to the individual and their carers. Carers play vital roles in supporting individuals who live in the community to manage their conditions and the need for effective communication between service users and health care professionals is crucially important. Effective communication may not only lead to improved quality of life but may reduce mortality through the promotion of better understanding of seizures and encouraging efficient use of medication. Despite this communication regarding community-based adults with mild learning disabilities has not been fully studied, in particular the service users‘ views and experiences regarding communication has been a neglected area. Yet, the service users‘ views may be the best source for the definition of effective communication. This study was triggered by the paucity of research that investigated service users‘ views and experiences regarding communication. Furthermore, numerous health policies have been formulated that emphasise the involvement of patients as consumers in the provision and delivery of health services. This study is purported to bridge this communication gap by offering service users a rare opportunity for them to express their views and experiences regarding communication to inform health policies and clinical practice. This study adopts a naturalistic qualitative approach and employs in-depth semi-structured interviews to solicit service users‘ and their carers‘ views and experiences regarding communication. The interviews also investigated service users‘ and carers‘ perspectives in regard to communication with health care professionals‘. Carer communication diaries were used to supplement the carers‘ interview data and also to endorse the credibility of the study findings. Six main findings emerged from this study that described service users‘ and carers‘ views and experiences regarding communication: communication needs and expectations; ‗engagement‘ as a predictor of effective communication; strategies of communication; facilitating factors of communication; methods of communication; barriers to communication. This study suggests that effective communication with people with learning disabilities and epilepsy requires a reflective model that incorporates self-assessment and awareness of the individual‘s communication needs and expectations. The model and recommendations that emerged from this study may be a useful resource for health and social care professionals.

<p>Multiple lines of evidence reveal that activation of the tropomyosin related kinase B (TrkB) receptor is a critical molecular mechanism underlying status epilepticus (SE) induced epilepsy development. However, the cellular consequences of such signaling remain unknown. To this point, localization of SE-induced TrkB activation to CA1 apical dendritic spines provides an anatomic clue pointing to Schaffer collateral-CA1 synaptic plasticity as one potential cellular consequence of TrkB activation. Here, we combine two-photon glutamate uncaging with two photon fluorescence lifetime imaging microscopy (2pFLIM) of fluorescence resonance energy transfer (FRET)-based sensors to specifically investigate the roles of TrkB and its canonical ligand brain derived neurotrophic factor (BDNF) in dendritic spine structural plasticity (sLTP) of CA1 pyramidal neurons in cultured hippocampal slices of rodents. To begin, we demonstrate a critical role for post-synaptic TrkB and post-synaptic BDNF in sLTP. Building on these findings, we develop a novel FRET-based sensor for TrkB activation that can report both BDNF and non-BDNF activation in a specific and reversible manner. Using this sensor, we monitor the spatiotemporal dynamics of TrkB activity during single-spine sLTP. In response to glutamate uncaging, we report a rapid (onset less than 1 minute) and sustained (lasting at least 20 minutes) activation of TrkB in the stimulated spine that depends on N-methyl-D-aspartate receptor (NMDAR)-Ca2+/Calmodulin dependent kinase II (CaMKII) signaling as well as post-synaptically synthesized BDNF. Consistent with these findings, we also demonstrate rapid, glutamate uncaging-evoked, time-locked release of BDNF from single dendritic spines using BDNF fused to superecliptic pHluorin (SEP). Finally, to elucidate the molecular mechanisms by which TrkB activation leads to sLTP, we examined the dependence of Rho GTPase activity - known mediators of sLTP - on BDNF-TrkB signaling. Through the use of previously described FRET-based sensors, we find that the activities of ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) require BDNF-TrkB signaling. Taken together, these findings reveal a spine-autonomous, autocrine signaling mechanism involving NMDAR-CaMKII dependent BDNF release from stimulated dendritic spines leading to TrkB activation and subsequent activation of the downstream molecules Rac1 and Cdc42 in these same spines that proves critical for sLTP. In conclusion, these results highlight structural plasticity as one cellular consequence of CA1 dendritic spine TrkB activation that may potentially contribute to larger, circuit-level changes underlying SE-induced epilepsy.</p> / Dissertation

<p>Temporal lobe epilepsy is a common and devastating disorder that features recurrent seizures and is often associated with pathologic anxiety and hippocampal sclerosis. An episode of prolonged seizures (status epilepticus) is thought to promote development of human temporal lobe epilepsy years later. A chemical-genetic approach established proof of concept that transiently inhibiting the receptor tyrosine kinase, TrkB, following status epilepticus prevented epilepsy, anxiety-like behavior and hippocampal damage in a mouse model, providing rationale for developing a therapeutic targeting TrkB signaling. To circumvent the undesirable consequence that global inhibition of TrkB exacerbates neuronal degeneration following status epilepticus, we sought to identify both the TrkB-activated signaling pathway mediating these pathologies and a compound that uncouples TrkB from the responsible signaling effector. To accomplish these goals, we used genetically modified mice and a model of seizures and epilepsy induced by a chemoconvulsant. Genetic inhibition of TrkB-mediated phospholipase C gamma 1 (PLC gamma 1) signaling suppressed seizures induced by a chemoconvulsant, leading to design of a peptide (pY816) that inhibited the interaction of TrkB with PLC gamma 1. We demonstrate that pY816 selectively inhibits TrkB-mediated activation of PLC gamma 1 both in vitro and in vivo. Treatment with pY816 prior to administration of a chemoconvulsant suppressed seizures in a dose- and time-dependent manner. Treatment with pY816 initiated after chemoconvulsant-evoked status epilepticus and continued for just three days suppressed seizure-induction of epilepsy, anxiety-like behavior and hippocampal damage assessed months later. This study elucidates the signaling pathway by which TrkB activation produces diverse neuronal activity-driven pathologies and demonstrates therapeutic benefits of an inhibitor of this pathway in an animal model in vivo. A strategy of uncoupling a receptor tyrosine kinase from a signaling effector may prove useful in diverse diseases in which excessive receptor tyrosine kinase signaling contributes.</p> / Dissertation

This thesis describes the preparation of 5-substituted-amino derivatives of 5-phenylhydantoin. The hydantoin derivatives are to be tested for anticonvulsant activity by the Pharmacology Department of the Eli Lilly Company of Indianapolis, Indiana.