Analysis of the Generators of Epileptic Activity in Early-Onset Childhood Benign Occipital Lobe Epilepsy

Objective: The Panayiotopoulos type of idiopathic occipital epilepsy has peculiar and easily recognizable ictal symptoms, which are associated with complex and variable spike activity over the posterior scalp areas. These characteristics of spikes have prevented localization of the particular brain regions originating clinical manifestations. We studied spike activity in this epilepsy to determine their brain generators. Methods: The EEG of 5 patients (ages 7–9) was recorded, spikes were submitted to blind decomposition in independent components (ICs) and those to source analysis (sLORETA), revealing the spike generators. Coherence analysis evaluated the dynamics of the components. Results: Several ICs were recovered for posterior spikes in contrast to central spikes which originated a single one. Coherence analysis supports a model with epileptic activity originating near lateral occipital area and spreading to cortical temporal or parietal areas. Conclusions: Posterior spikes demonstrate rapid spread of epileptic activity to nearby lobes, starting in the lateral occipital area. In contrast, central spikes remain localized in the rolandic fissure. Significance: Rapid spread of posterior epileptic activity in the Panayitopoulos type of occipital lobe epilepsy is responsible for the variable and poorly localized spike EEG. The lateral occipital cortex is the primary generator of the epileptic activity.

Origin of Frontal Lobe Spikes in the Early Onset Benign Occipital Lobe Epilepsy (Panayiotopoulos Syndrome)

Objective: Early onset benign occipital lobe epilepsy (Panayiotopoulos syndrome [PS]) is a common and easily recognizable epilepsy. Interictal EEG spike activity is often multifocal but most frequently localized in the occipital lobes. The origin and clinical significance of the extra-occipital spikes remain poorly understood. Methods: Three patients with the PS and interictal EEG spikes with frontal lobe topography were studied using high-resolution EEG. Independent component analysis (ICA) was used to decompose the spikes in components with distinct temporal dynamics. The components were mapped in the scalp with a spline-laplacian algorithm. Results: The change in scalp potential topography from spike onset to peak, suggests the contribution of several intracranial generators, with different kinetics of activation and significant overlap. ICA was able to separate the major contributors to frontal spikes and consistently revealed an early activating group of components over the occipital areas in all the patients. The local origin of these early potentials was established by the spline-laplacian montage. Conclusions: Frontal spikes in PS are consistently associated with early and unilateral occipital lobe activation, suggesting a posteroanterior spike propagation. Significance: Frontal spikes in the PS represent a secondary activation triggered by occipital interictal discharges and do not represent an independent focus.

Analysis of the Dynamics and Origin of Epileptic Activity in Patients with Tuberous Sclerosis Evaluated for Surgery of Epilepsy

Objective: The epilepsies associated with the tuberous sclerosis complex (TSC) are very often refractory to medical therapy. Surgery for epilepsy is an effective alternative when the critical link between the localization of seizure onset in the scalp and a particular cortical tuber can be established. In this study we perform analysis of ictal and interictal EEG to improve such link. Methods: The ictal and interictal recordings of four patients with TSC undergoing surgery for epilepsy were submitted to independent component analysis (ICA), followed by source analysis, using the sLORETA algorithm. The localizations obtained for the ictal EEG and for the average interictal spikes were compared. Results: The ICA of ictal EEG produced consistent results in different events, and there was good agreement with the tubers that were successfully removed in three of the four patients (one patient refused surgery). In some patients there was a large discrepancy between the localization of ictal and interictal sources. The interictal activity produced more widespread source localizations. Conclusions: The use of ICA of ictal EEG followed by the use of source analysis methods in four cases of epilepsy and TSC was able to localize the epileptic generators very near the lesions successfully removed in surgery for epilepsy. Significance: The ICA of ictal EEG events may be a useful add-on to the tools used to establish the connection between epileptic scalp activity and the cortical tubers originating it, in patients with TSC considered for surgery of epilepsy.

Análise espectral com wavelets do ECoG em crises epilépticas

Dissertação para obtenção do Grau de Mestre em Engenharia Biomédica

Neuropsychological Abnormalities in Children with the Panayiotopoulos Syndrome Point to Parietal Lobe Dysfunction

Panayiotopoulos syndrome (PS) is a common epilepsy syndrome associated with rare clinical seizures and unknown localization of the epileptogenic area. Despite findings of normal development in patientswith PS, recent neuropsychological studies point to subtle and diverse cognitive impairments. No well-outlined hypothesis about the localization of the brain dysfunction responsible for these impairments has been proposed.We further explored the cognitive dysfunctions in PS andmade inferences on the most likely anatomical localization of brain impairment. A group of 19 patients (aged 6–12) with PS was rated according to spike activity and lateralization. The patients were submitted to a neuropsychological evaluation to assess general intelligence, memory, language, visual–perceptual abilities, attention, and executive functions. Using 35-channel scalp EEG recordings, the N170 face-evoked event-related potential (ERP)was obtained to assess the functional integrity of the ventral pathway. All patientswith PS showed normal IQ but subtle and consistent neurocognitive impairments. Namely, we found abnormalities in the copy task of the Rey–Osterrieth Complex Figure and in theNarrative Memory Test. There was no correlation between neuropsychological impairments with spike activity and hemispheric spike lateralization. The N170 ERP was normal in all patients except for one. Our neuropsychological findings demonstrate impairments in visual–perceptual abilities and in semantic processing. These findings, paired with the absence of occipital lobe dysfunction in all neuropsychological studies of PS performed to this date, support the existence of parietal lobe dysfunction.

The BOLD Effect of Interictal Spike Activity in Childhood Occipital Lobe Epilepsy

Occipital lobe epilepsy (OLE) presents in childhood with different manifestations, age of onset and EEG features that form distinct syndromes. The ictal clinical symptoms are difficult to correlate with onset in particular areas in the occipital lobes, and the EEG recordings have not been able to overcome this limitation. The mapping of epileptogenic cortical regions in OLE remains therefore an important goal in our understanding of these syndromes.

Different Electroclinical Manifestations of the Epilepsy Associated with Hamartomas Connecting to the Middle or Posterior Hypothalamus

PURPOSE: The epilepsy associated with hypothalamic hamartomas (HHs) has typical clinical, electrophysiologic, and behavioral manifestations refractory to drug therapy and with unfavorable evolution. It is well known that only sessile lesions produce epilepsy, but no correlation has been established between the different types of sessile hamartomas and the diverse manifestations of the epilepsy. We correlate anatomic details of the hamartoma and the clinical and neurophysiologic manifestations of the associated epilepsy. METHODS: HHs of seven patients with epilepsy (ages 2- 25 years) were classified as to lateralization and connection to the anteroposterior axis of the hypothalamus by using high-resolution brain magnetic resonance imaging. We correlated the anatomic classification with the clinical and neurophysiologic manifestations of the epilepsy as evaluated in long-term (24 h) video-EEG recordings. RESULTS: HHs ranged in size from 0.4 to 2.6 cc, with complete lateralization in six of seven patients. Ictal manifestations showed good correlation with the lobar involvement of ictal/interictal EEGs. These manifestations suggest the existence of two types of cortical involvement, one associated with the temporal lobe, produced by hamartomas connected to the posterior hypothalamus (mamillary bodies), and the other associated with the frontal lobe, seen in lesions connecting to the middle hypothalamus. CONCLUSIONS: A consistent clinical and neurophysiologic pattern of either temporal or frontal lobe cortical secondary involvement was found in the patients of our series. It depends on whether the hamartoma connects to the mamillary bodies (temporal lobe cases) or whether it connects to the medial hypothalamus (frontal lobe cases).

Dynamics of Epileptic Activity in a Peculiar Case of Childhood Absence Epilepsy and Correlation with Thalamic Levels of GABA

Childhood absence epilepsy (CAE) is a syndrome with well-defined electroclinical features but unknown pathological basis. An increased thalamic tonic GABA inhibition has recently been discovered on animal models (Cope et al., 2009), but its relevance for human CAE is unproven. METHODS: We studied an 11-year-old boy, presenting the typical clinical features of CAE, but spike-wave discharges (SWD) restricted to one hemisphere. RESULTS: High-resolution EEG failed to demonstrate independent contralateral hemisphere epileptic activity. Consistently, simultaneous EEG-fMRI revealed the typical thalamic BOLD activation, associated with caudate and default mode network deactivation, but restricted to the hemisphere with SWD. Cortical BOLD activations were localized on the ipsilateral pars transverse. Magnetic resonance spectroscopy, using MEGA-PRESS, showed that the GABA/creatine ratio was 2.6 times higher in the hemisphere with SWD than in the unaffected one, reflecting a higher GABA concentration. Similar comparisons for the patient's occipital cortex and thalamus of a healthy volunteer yielded asymmetries below 25%. SIGNIFICANCE: In a clinical case of CAE with EEG and fMRI-BOLD manifestations restricted to one hemisphere, we found an associated increase in thalamic GABA concentration consistent with a role for this abnormality in human CAE.

A influência da posição postural no ciclo percepção - acção durante estimulação visual dinâmica

A influência da posição postural no ciclo percepção – acção foi investigada com base no potencial evocado visual relacionado com o movimento (M-VEP). Para tal, sinais EEG multicanal de 25 indivíduos saudáveis foram adquiridos durante as posições posturais ortostática (O) e sentada (S), sob estimulação visual dinâmica (ED) de afastamento (AF) e aproximação (AP) de um cenário virtual. Para gerar ED, os móveis e utensílios do cenário virtual foram expandidos (ou reduzidos) enquanto o piso, as paredes e o teto deslocam-se linearmente no sentido anterior (ou posterior) com uma velocidade de 1,2 m/s durante 1 s. O M-VEP foi estimado para cada posição e estimulação pelo cálculo da média coerente dos sinais EEG sincronizados com o início do movimento da ED, a qual evidenciou as componentes P1, N2 e P3 (dominânica N2 em relação a P1). Embora o M-VEP não dependa do sentido da estimulação (Wilcoxon, p > 0,20), o running t-test indicou que no intervalo 470 a 900 ms, após o início da ED, o grand-averaged do M-VEP para posição O difere (p < 0,10) daquele da posição S nas derivações parietais, frontais e centrais. Além disso, a distribuição da latência da componente P3 para O também difere daquela de S (Wilcoxon: p < 0,06), para as mesmas derivações, independentemente do sentido da ED. A correlação cruzada indicou atraso da componente P3 de S em relação à de O, em particular (p < 0,10) nas derivações frontais e centrais durante AP (50 ms) e somente centrais durante AF (30 ms). Estes resultados reflectem a antecipação do processamento cortical hierárquico relacionado com a cognição, o planeamento e a acção motora, associados às maiores exigências da posição ortostática para manter o equilíbrio evidenciando, portanto, a potencialidade deste protocolo para investigar o ciclo percepção – acção durante posições posturais distintas.

Conectividade efectiva em epilepsia

A epilepsia é uma das mais comuns patologias que afectam o cérebro humano e caracteriza-se por uma actividade cerebral oscilatória desordenada e excessiva que prejudica gravemente a qualidade de vida do doente. Com o objectivo de detectar o percurso da actividade cerebral anormal a ressonância magnética, em conjunto com a técnica de electroencefalografia (EEG) têm evoluído no sentido de tornar a identificação do foco epiléptico e respectivas vias de propagação mais clara e fácil para o neurocirurgião. Esta detecção pode recorrer ao efeito BOLD (do inglês “Blood Oxygenation Level Dependent”) para, de forma indirecta, obter um mapa de activação neuronal da zona em estudo contribuindo para uma possível intervenção cirúrgica à área epiléptica. No entanto, para chegar a uma conclusão definitiva sobre este mapa neuronal é necessário ter em conta que diferentes regiões podem apresentar HRFs (do inglês “Hemodynamic Response Functions”) diferentes, influenciando o resultado de qualquer análise se este facto não for tido em conta. Na presente dissertação foi aplicado um método de cálculo de influência causal entre regiões do cérebro humano a dados de epilepsia obtidos através da técnica EEG+fMRI. Foram utilizadas técnicas de conectividade efectiva (causalidade de Granger) usando um pacote de software (PyHRF) para estimar com precisão a HRF da região em estudo e permitir a desconvolução do sinal antes do cálculo de conectividade. Foi demonstrada a utilidade desta contribuição metodológica para a caracterização topográfica e dinâmica de uma crise epiléptica.

Avaliação do efeito da prótese auditiva usando a análise eletroencefalográfica

Dados atuais da Organização Mundial da Saúde (OMS) sobre a prevalência global da perda auditiva, indicam que mais de 360 milhões de pessoas no mundo sofrem de perda auditiva incapacitante. Sendo esta uma deficiência sensorial que afeta a comunicação e o inter-relacionamento das pessoas é particularmente limitante na população idosa e nos primeiros anos de vida. Atualmente a ciência e a tecnologia permitem a reabilitação auditiva de forma muito aceitável. No entanto, quando se trata de crianças com surdez congénita, a re(h)abilitação tem que ser eficaz, sendo importante avaliar a perceção auditiva (se ouve, o que ouve, como ouve). Considerando que a re(h)abilitação deve iniciar-se o mais cedo possível, é importante ter instrumentos que permitam perceber realmente não só se ouve, o que se ouve, mas também como se ouve, ajustando os equipamentos a cada caso. A presente tese apresenta um estudo onde se utilizou o Eletroencefalograma (EEG) como instrumento de avaliação do efeito das próteses auditivas, em crianças com surdez congénita adaptadas proteticamente, numa perspetiva de Avaliação de Tecnologia. A utilização nos casos do estudo pretendeu comparar a variação dos sinais cerebrais obtidos no EEG efetuado quando a criança com e sem as próteses auditivas foi submetida a um estímulo sonoro, dando ideia sobre a funcionalidade das mesmas. A validação do EEG neste contexto, teria o potencial de ser associado à re(h)abilitação auditiva como rotina, contribuindo para a otimização da funcionalidade das próteses auditivas desde o primeiro momento da adaptação. Esta utilização seria útil não só nas crianças mas também noutras situações, nomeadamente em indivíduos impedidos de verbalizar as suas queixas (que sofreram AVC, com atraso cognitivo, demência, entre outros). A análise e interpretação dos sinais de EEG mostrou-se inesperadamente complexa, possivelmente devido a interferências de estímulos visuais e outras fontes de distração presentes no momento em que o EEG foi realizado, levando apenas a uma análise qualitativa do resultado: Verificou-se que o EEG pode ser utilizado mesmo nas pessoas que têm próteses auditivas; o sinal de EEG apresenta variação quando a criança tem ou não as próteses auditivas colocadas; mas não foi possível correlacionar a variação do sinal de EEG com o som produzido ou a capacidade de escutar através de um algoritmo de MATLAB (ou EEGLAB), simples e reprodutível. A perspetiva da Avaliação de Tecnologia acompanhou este estudo desde o início, orientando a identificação do problema e a pesquisa bibliográfica inicial, e prosseguindo ao longo de toda a tese, levando ao aprofundamento de cada tema e subtema pensado ou relacionado com o assunto em estudo. Mais do que avaliar, esta metodologia de Avaliação de Tecnologia permitiu construir um enquadramento científico, político e de saúde sobre a surdez congénita, quando estudada nos mais novos adaptados proteticamente, resultando numa sequência de secções e subsecções teóricas que constituem o state of the art atual e completo. Foi também a Avaliação de Tecnologia que evidenciou a importância que a avaliação do efeito das próteses auditivas possa ter na re(h)abilitação auditiva, apresentando pistas que poderão ser úteis na tomada de decisão sobre o tipo de próteses, sobre a forma mais eficaz de as adequar às necessidades do défice da criança com surdez congénita, realçando a atualidade e interesse crescente que a metodologia aqui apresentada vem suscitando entre investigadores, engenheiros, profissionais de saúde e cuidadores, em todo o mundo.

Equity offerings, stock price crash risk, and the impact of securities regulation: international evidence

We examine whether earnings manipulation around seasoned equity offerings (SEOs) is associated with an increase in the likelihood of a stock price crash post-issue and test whether the enactment of securities regulations attenuate the relation between SEOs and crash risk. Empirical evidence documents that managerial tendency to conceal bad news increases the likelihood of a stock price crash (Jin and Myers, 2006; Hutton, Marcus, and Tehranian, 2009). We test this hypothesis using a sample of firms from 29 EU countries that enacted the Market Abuse Directive (MAD). Consistent with our hypothesis, we find that equity issuers that engage in earnings management experience a significant increase in crash risk post-SEO relative to control groups of non-issuers; this effect is stronger for equity issuers with poor information environments. In addition, our findings show a significant decline in crash risk post-issue after the enactment of MAD that is stronger for firms that actively manage earnings. This decline in post-issue crash risk is more effective in countries with high ex-ante institutional quality and enforcement. These results suggest that the implementation of MAD helps to mitigate managers’ ability to manipulate earnings around SEOs.

Cross-delisting, financial constraints and investment sensitivities

We investigate the impact of cross-delisting on firms’ financial constraints and investment sensitivities. We find that firms that cross-delisted from a U.S. stock exchange face stronger post-delisting financial constraints than their cross-listed counterparts, as measured by investment-to-cash flow sensitivity. Following a delisting, the sensitivity of investment-to-cash flow increases significantly and firms also tend to save more cash out of cash flows. Moreover, this increase appears to be primarily driven by informational frictions that constrain access to external financing. We document that information asymmetry problems are stronger for firms from countries with weaker shareholders protection and for firms from less developed capital markets.