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The purpose of this study was to identify clinical and demographic predictors of seizure recurrence in medically-treated patients with epilepsy. Innovus Invision™ Data Mart insurance claims from January 1, 2007 to September 30, 2010 were retrospectively analyzed. Patients aged 18-64 years with a primary or secondary diagnosis of epilepsy and >1 prescription claim for an antiepileptic drug (AED) pre-index were included. The primary outcome was incidence of seizures defined as an occurrence of an emergency room visit, ambulance service use or hospitalization with a primary or secondary diagnosis of epilepsy during the 1-year follow-up period. Predictor variables included antiepileptic drug (AED) adherence (Proportion of Days Covered ≥ 80 %), general comorbidity (Charlson’s Comorbidity Index ≥ 1), any mental health comorbidity, evidence of a prior seizure, type of epilepsy diagnosis (intractable versus non-intractable), presence of AED-interacting medications and any bioequivalent AED switch. The covariates included age, gender and geographic region of residence. The overall incidence of post-index seizures in the 1-year follow-up period for all four monotherapy cohorts combined was 5.3 % (n=166/3140), but was higher for the Keppra®/levetiracetam cohort (7.9%; n=88/1114) compared to the other cohorts [Lamictal®/lamotrigine (3.9%; n=45/1143), Trileptal®/oxcarbazepine (4.0%; n=18/456) and Topamax®/topiramate (3.5%; n=15/427)]. The combined cohort analysis demonstrated that pre-index seizures (odds ratio [OR] = 4.28; 95% CI, 2.81-6.53), any mental health comorbidity ([OR] = 3.41; 95% CI, 2.10-5.54), Charlson comorbidity Index ≥1 ([OR] = 2.88; 95% CI, 1.96-4.24) and monotherapy with Keppra®/levetiracetam ([OR] = 1.54; 95% CI, 1.03-2.31) were significant predictors of seizure recurrence. Among covariates, only geographic region was a significant predictor, with patients residing in the Northeast U.S. having higher odds of post-index seizure ([OR] = 1.92; 95% CI, 1.19-3.10), while controlling for clinical, medication and demographic characteristics. A bioequivalent AED switch, type of epilepsy diagnosis, AED adherence and the presence of interacting medications were not significant predictors of seizure recurrence in the combined cohort (p>0.05). Results indicate that epilepsy patients with comorbid conditions (both mental and somatic diseases), as well as patients who may have initially been unstable (with previous seizure occurrences) were more likely to experience seizures during the follow-up period. / text

archives@tulane.edu / The thalamocortical network generates rhythmic oscillations of various frequencies that underlie different brain states. Importantly, the transition from a faster frequency of firing, spindle, to slower oscillations, spike and wave discharges, is indicative of the pathological epileptic seizure development. Previous investigations have shown that the complex interactions between neurons in the thalamocortical network based on intrinsic and synaptic properties give rise to the observed frequency changes. However, the exact mechanism of how perturbations in this circuit disrupt the oscillations is not known. In this project, we used a well-established thalamocortical network computational model to perform receptor conductance changes to see how the oscillatory activity in the thalamocortical network changes. Computational methods can be used to provide some mathematical explanations regarding the mechanism of oscillations. Therefore, we generated several phase resetting curves by perturbing neurons during its oscillating period. Our results showed that the frequency reduction under the pathological state in the thalamocortical network might be caused by hyper-synchronization of neuronal activities in this circuit mediated by glutamatergic AMPA receptors. Notably, thalamic reticular neurons are capable of firing at a faster or slower frequency depending on the timing of the input that they receive from other neurons. Overall, our results provided evidence to support the hypothesis that thalamic reticular neurons might be the ultimate pacemakers in the thalamocortical network. / 1 / Hanyun Wang

Eclampsia is defined as de novo seizure in a woman with the hypertensive complication of pregnancy known as preeclampsia (PE), and is a leading cause of maternal and fetal morbidity and mortality worldwide. The pathogenesis of eclamptic seizure remains unknown, but is considered a form of hypertensive encephalopathy where an acute rise in blood pressure causes loss of cerebral blood flow (CBF) autoregulation and hyperperfusion of the brain that results in vasogenic edema formation and subsequent seizure. However, eclamptic seizure can occur during seemingly uncomplicated pregnancies, in the absence of hypertension and PE, suggesting that normal pregnancy may predispose the brain to hypertensive encephalopathy or seizure, independently of PE. The overall goal of this dissertation was to investigate the effect of pregnancy and PE on the cerebrovasculature and neurophysiological properties that may promote brain injury and eclamptic seizure. For this dissertation project, a rat model of PE was established that combined placental ischemia, induced by restricting blood flow to the uteroplacental unit, and maternal endothelial dysfunction that was induced by a prolonged high cholesterol diet. Rats with PE developed several PE-like symptoms, including elevated blood pressure, fetal growth restriction, placental dysfunction, and were in a state of oxidative stress and endothelial dysfunction. We found that pregnancy had an overall protective effect on the maintenance of CBF that was potentially due to a nitric-oxide dependent enhancement of the vasodilation of cerebral arteries to decreased intravascular pressure. Further, maintenance of CBF during acute hypertension was similar in pregnancy and PE. Thus, it does not appear that pregnancy and PE are states during which CBF autoregulation is compromised in a manner that would promote the development of hypertensive encephalopathy. However, the brain was found to be in a hyperexcitable state during normal pregnancy that was augmented in PE, and could contribute to onset of eclamptic seizure. Under chloral hydrate anesthesia, generalized seizure was induced by timed infusion of the convulsant pentylenetetrazole (PTZ), with simultaneous electroencephalography that was stopped at the first onset of spikewave discharge indicative of electrical seizure. Seizure threshold was determined as the amount of PTZ required to elicit seizure. Compared to the nonpregnant state, seizure threshold was ~44% lower in pregnant rats and ~80% lower in rats with PE. Further, pregnant rats were more susceptible to seizure-induced vasogenic edema formation than the nonpregnant state. Mechanisms by which pregnancy and PE lowered seizure threshold appeared to be through pregnancy-associated decreases in cortical gamma-aminobutyric acid type A receptor (GABAAR) subunits and PE-induced disruption of the blood-brain barrier (BBB) and microglial activation, indicative of neuroinflammation. Magnesium sulfate (MgSO4), the leading treatment for seizure prophylaxis in women with PE, restored seizure threshold to control levels by reversing neuroinflammation in PE rats, without affecting BBB permeability. Overall, this dissertation provides evidence that pregnancy increases susceptibility of the brain to seizure and vasogenic edema formation that likely contribute to the onset of eclampsia during seemingly uncomplicated pregnancies. Further, the pathogenesis of eclampsia during PE likely involves breakdown of the BBB and subsequent neuroinflammation, resulting in a state of greater seizure susceptibility that is ameliorated by MgSO4 treatment.

"A combined hardware and software platform for ambulatory seizure onset detection is presented. The hardware is developed around commercial off-the-shelf components, featuring ADS1299 analog front ends for electroencephalography from Texas Instruments and a Broadcom ARM11 microcontroller for algorithm execution. The onset detection algorithm is a patient-specific support vector machine algorithm. It outperforms a state-of-the-art detector on a reference data set, with 100% sensitivity, 3.4 second average onset detection latency, and on average 1 false positive per 24 hours. The more comprehensive European Epilepsy Database is then evaluated, which highlights several real-world challenges for seizure onset detection, resulting in reduced average sensitivity of 93.5%, 5 second average onset detection latency, and 85.5% specificity. Algorithm enhancements to improve this reduced performance are proposed."

Epilepsy -- the condition of recurrent, unprovoked seizures -- manifests in brain voltage activity with characteristic spatio-temporal patterns. One of the patterns typically observed during a seizure is a traveling wave. To characterize these waves, we analyze high-density local field potential (LFP) data recorded in vivo from human cortex during a seizure from three patients. We show that traveling wave patterns emerge in the LFP with consistent quantitative features. Using a mean-field approach we model the neuronal population activity observed in the LFP and obtain explicit traveling wave solutions for this model. We then employ the LFP data to constrain the model and obtain parameter configurations that support traveling wave solutions with features consistent with the observed LFP waves. In particular, our model formulation is able to capture the "reverberation" of the activity following the traveling wave that was found in the clinical data. We obtain biologically reasonable parameter estimates for two important features: the timescales of the model and the extent of the connectivity. In this way, we link the observed LFP waves during seizure to proposed biological mechanisms. We also study the linear stability of the traveling wave solutions by constructing an Evans function. We find for some parameters the existence of two waves: one wave is slow and narrow whereas the other wave is fast and wide. Moreover, the fast and wide wave has speed and width consistent with the observed LFP waves. We numerically analyze the Evans function to determine stability (instability) of the fast (slow) wave.

O floroglucinol é um composto fenólico precursor de diversas moléculas com atividades biológicas já descritas na literatura, com destaque para a antidepressiva. O modelo experimental com zebrafish tem sido bastante utilizado em várias linhas de pesquisa biológica, como, por exemplo, para avaliação da atividade anticonvulsivante. A partir de estudos que mostram uma correlação entre compostos antidepressivos e anticonvulsivantes, nosso grupo administrou floroglucinol e dois derivados sintéticos (composto 7 e composto 8) em zebrafish para observação da atividade locomotora e exploratória no open tank e, posteriormente, à avaliação através do modelo convulsivo induzido por pentilenotetrazol (PTZ). Além disso, os níveis de captação de glutamato e a toxicidade dos compostos foram avaliados em cérebro total de zebrafish. O comportamento dos animais não sofreu alteração em relação ao controle para nenhum dos compostos testados. O composto 7 aumentou significativamente o tempo para os animais atingirem a primeira convulsão além de reduzir a intenidade da crise convulsiva. Também se observou aumento na captação de glutamato para esse composo, sem sinais de toxicidade envolvidos. Desta forma, nossos resultados contribuem para a busca de compostos potencialmente ativos frente a crises convulsivas induzidas por PTZ. / Phloroglucinol, a phenolic compound, which is precursor of several molecules with biological activities are described in the literature, mainly for antidepressant activity. The zebrafish experimental model has been widely used in many kinds of biological research, for example, to evaluate the anticonvulsant activity. From studies that shows correlation between antidepressants and anticonvulsant compounds, our group managed phloroglucinol and two synthetic derivatives (compound 7 and compound 8) in zebrafish in order to observe the locomotor and exploratory activity on open tank and subsequently, conduct the evaluation through the seizure model induced by pentylenetetrazol (PTZ). Furthermore, glutamate uptake and toxicity levels of the compounds were evaluated in zebrafish’s whole brain. The animals' behavior did not change compared to control for any of the tested compounds. The compound 7 increased significantly the time for the animals reach the first seizure and reduce the seizure intensity. It was also observed an increase in glutamate uptake for this compound without signs of toxicity involved. Thus, our results contribute to the search for potentially active compounds against seizures induced by PTZ.

Elevations in extracellular potassium (K+e) accompany seizure-like events (SLEs), but elevated K+ may also participate in seizure cessation. The objective of this thesis was to investigate the possibility that K+ may undergo a pro- to anti-convulsant switch in the epileptic juvenile (postnatal day 17-21) rat hippocampus. Field recordings were performed in the CA1 pyramidal layer. SLEs and primary afterdischarges (PADs) were induced with 0.25 mM Mg/5 mM K+ perfusion or tetanic stimulation of the Schaffer collaterals respectively. In these seizure models, elevating [K+]e beyond 7.5 mM showed anticonvulsant properties. The addition of ZD7288, a blocker of the hyperpolarization activated nonspecific cationic current (Ih) and allowed SLEs to continue even in elevated [K+]e. This suggests that [K+]e switches from being pro- to anti-convulsant, in part due to an elevated [K+]e-induced potentiation of Ih. Ih likely contributes to this anticonvulsant behavior by decreasing membrane resistance and subsequently attenuating summation of incoming EPSPs.

Epilepsy, which manifests itself as spontaneous bouts of abnormal low complexity brain activity, is the second most common neurological disorder after stroke. This thesis explores the effect of variable frequency stimulation on seizure control. A responsive variable frequency electrical stimulation system is proposed and validated using a computational model capable of generating spontaneous seizure like events. The proposed stimulation system is demonstrated to outperform open-loop fixed frequency stimulation and responsive fixed frequency stimulation using seizure time based measures and a control energy measure.

Epilepsy, which manifests itself as spontaneous bouts of abnormal low complexity brain activity, is the second most common neurological disorder after stroke. This thesis explores the effect of variable frequency stimulation on seizure control. A responsive variable frequency electrical stimulation system is proposed and validated using a computational model capable of generating spontaneous seizure like events. The proposed stimulation system is demonstrated to outperform open-loop fixed frequency stimulation and responsive fixed frequency stimulation using seizure time based measures and a control energy measure.