Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

Risk factors of postictal generalized EEG suppression in generalized convulsive seizures.

OBJECTIVE: To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS). METHODS: We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures. RESULTS: A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9). CONCLUSION: The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen.

Weakened functional connectivity in patients with psychogenic non-epileptic seizures (PNES) converges on basal ganglia.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) are involuntary paroxysmal events that are unaccompanied by epileptiform EEG discharges. We hypothesised that PNES are a disorder of distributed brain networks resulting from their functional disconnection.The disconnection may underlie a dissociation mechanism that weakens the influence of unconsciously presented traumatising information but exerts maladaptive effects leading to episodic failures of behavioural control manifested by psychogenic 'seizures'. METHODS: To test this hypothesis, we compared functional connectivity (FC) derived from resting state high-density EEGs of 18 patients with PNES and 18 age-matched and gender-matched controls. To this end, the EEGs were transformed into source space using the local autoregressive average inverse solution. FC was estimated with a multivariate measure of lagged synchronisation in the θ, α and β frequency bands for 66 brain sites clustered into 18 regions. A multiple comparison permutation test was applied to deduce significant between-group differences in inter-regional and intraregional FC. RESULTS: The significant effect of PNES-a decrease in lagged FC between the basal ganglia and limbic, prefrontal, temporal, parietal and occipital regions-was found in the α band. CONCLUSION: We believe that this finding reveals a possible neurobiological substrate of PNES, which explains both attenuation of the effect of potentially disturbing mental representations and the occurrence of PNES episodes. By improving understanding of the aetiology of this condition, our results suggest a potential refinement of diagnostic criteria and management principles.

Levetiracetam versus Phenobarbital. Effects in the neurodevelopment in newborns treated for neonatal seizures: a clinical trial

Purpose: To analyze if the use of Phenobarbital compared with Levetiracetam, it’s associated with more neurodevelopmental problems in newborns treated for neonatal seizures. As a secondary objective identify which are the most affected areas of the neurodevelopment: cognition, socio-­‐emotional, motor or language skills.Design: A 5 years long clinical trial administering, with double-­‐blind and a randomized distribution of the sample, Phenobarbital or Levetiracetam for the management of neonatal seizures

Kainic acid-induced seizures: inflammation and excitotoxic neuronal damage in the developing rat hippocampus

Epileptic seizures are harmful to the developing brain. During epileptic seizures, overactivation of glutamate receptors (GluR) leads to neuronal degeneration, defined as excitotoxicity. The hippocampus is especially vulnerable to excitotoxic neuronal death, but its mechanism has remained incompletely known in the developing brain. Recently, signs of activation of inflammatory processes after epileptic seizures have been detected in the hippocampus. The purpose of this thesis was to study the inflammatory reaction and death mechanisms in excitoxic neurodegeneration induced by the glutamate analogue kainic acid (KA) in the developing hippocampus. Organotypic hippocampal slice cultures (OHCs), prepared from 6-7-day-old rats (P6-7) and treated with KA, served as an in vitro model. KA-induced status epilepticus in P9 and P21 rats was used as an in vivo model. The results showed that the pyramidal cell layers of the hippocampus were the most susceptible to irreversible and age-specific neurodegeneration, which occurred in the juvenile (P21), but not in the immature (P9), rat hippocampus. The primary death mechanism was necrosis as there were no significant changes in the expression of selected apoptosis markers and morphological cellular features of necrosis were found. Inflammatory response was similarly age-dependent after KA treatment as a rapid, fulminant and wide response was detected in the juvenile, but not in the immature, rat brain. An anti-inflammatory drug treatment, given before KA, was not neuroprotective in OHCs, possibly because of the timing of the treatment. In summary, the results suggest that KA induces an age-dependent inflammatory response and necrotic neurodegeneration, which may cause disturbances in hippocampal connectivity and promote epileptogenesis.

Behavioral and electroencephalographic analysis of seizures induced by intrahippocampal injection of granulitoxin, a neurotoxic peptide from the sea anemone Bunodosoma granulifera

In this study, the behavioral and electroencephalographic (EEG) analysis of seizures induced by the intrahippocampal injection in rats of granulitoxin, a neurotoxic peptide from the sea anemone Bunodosoma granulifera, was determined. The first alterations occurred during microinjection of granulitoxin (8 µg) into the dorsal hippocampus and consisted of seizure activity that began in the hippocampus and spread rapidly to the occipital cortex. This activity lasted 20-30 s, and during this period the rats presented immobility. During the first 40-50 min after its administration, three to four other similar short EEG seizure periods occurred and the rats presented the following behavioral alterations: akinesia, facial automatisms, head tremor, salivation, rearing, jumping, barrel-rolling, wet dog shakes and forelimb clonic movements. Within 40-50 min, the status epilepticus was established and lasted 8-12 h. These results are similar to those observed in the acute phase of the pilocarpine model of temporal lobe epilepsy and suggest that granulitoxin may be a useful tool not only to study the sodium channels, but also to develop a new experimental model of status epilepticus.

Absence-like seizures in adult rats following pilocarpine-induced status epilepticus early in life

Administration of pilocarpine causes epilepsy in rats if status epilepticus (SE) is induced at an early age. To determine in detail the electrophysiological patterns of the epileptogenic activity in these animals, 46 Wistar rats, 7-17 days old, were subjected to SE induced by pilocarpine and electro-oscillograms from the cortex, hippocampus, amygdala, thalamus and hypothalamus, as well as head, rostrum and vibrissa, eye, ear and forelimb movements, were recorded 120 days later. Six control animals of the same age range did not show any signs of epilepsy. In all the rats subjected to SE, iterative spike-wave complexes (8.1 ± 0.5 Hz in frequency, 18.9 ± 9.1 s in duration) were recorded from the frontal cortex during absence fits. However, similar spike-wave discharges were always found also in the hippocampus and, less frequently, in the amygdala and in thalamic nuclei. Repetitive or single spikes were also detected in these same central structures. Clonic movements and single jerks were recorded from all the rats, either concomitantly with or independently of the spike-wave complexes and spikes. We conclude that rats made epileptic with pilocarpine develop absence seizures also occurring during paradoxical sleep, showing the characteristic spike-wave bursts in neocortical areas and also in the hippocampus. This is in contrast to the well-accepted statement that one of the main characteristics of absence-like fits in the rat is that spike-wave discharges are never recorded from the hippocampal fields.

Anticonvulsant and antiarrhythmic effects of nifedipine in rats prone to audiogenic seizures

Calcium ion participates in the regulation of neural transmission and the presynaptic release of neurotransmitters. It is also involved in epileptic events, cardiac arrhythmias and abnormal conduction of stimuli. The purpose of the present study was to evaluate the effects of nifedipine, a calcium channel blocker, on epileptic seizures and on reperfusion arrhythmias in rats prone to audiogenic epileptic seizures (Wistar audiogenic rats, WAR) and in normal Wistar rats (N = 6/group). The seizure severity index was applied after an intraperitoneal injection of 20 or 40 mg/kg nifedipine (N20 and N40 groups, respectively). The Langendorff technique was used to analyze cardiac function, as well as the incidence and severity of the reperfusion arrhythmias after ligature and release of the left coronary artery in rats treated or not with nifedipine. We found that nifedipine treatment decreased seizure severity (0.94 ± 0.02 for WAR; 0.70 ± 0.10 for WAR + N20; 0.47 ± 0.08 for WAR + N40) and increased the latent period (13 ± 2 s for WAR; 35 ± 10 s for WAR + N20; 48 ± 7 s for WAR + N40) for the development of seizures in WAR. Furthermore, the incidence and severity of the reperfusion arrhythmias were lower in WAR and normal Wistar rats injected with nifedipine. In WAR, these effects were mediated, at least in part, by a decrease in heart rate. Thus, our results indicate that nifedipine may be considered to be a potential adjuvant drug for epilepsy treatment, especially in those cases associated with cardiac rhythm abnormalities.

Montelukast reduces seizures in pentylenetetrazol-kindled mice

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Impact du genre et du modèle sur les mécanismes d’épileptogénèse dans le cerveau immature

Les modèles kainate et pentylènetétrazole représentent deux modèles d’épilepsie du lobe temporal dont les conséquences à long terme sont différentes. Le premier est un modèle classique d’épileptogénèse avec crises récurrentes spontanées tandis que le second se limite aux crises aigües. Nous avons d’abord caractérisé les différents changements survenant dans les circuits excitateurs et inhibiteurs de l’hippocampe adulte de rats ayant subi des crises à l’âge immature. Ensuite, ayant observé dans le modèle fébrile une différence du pronostic lié au genre, nous avons voulu savoir si cette différence était aussi présente dans des modèles utilisant des neurotoxines. L’étude électrophysiologique a démontré que les rats KA et PTZ, mâles comme femelles, présentaient une hyperactivité des récepteurs NMDA au niveau des cellules pyramidales du CA1, CA3 et DG. Les modifications anatomiques sous-tendant cette hyperexcitabilité ont été étudiées et les résultats ont montré une perte sélective des interneurones GABAergiques contenant la parvalbumine dans les couches O/A du CA1 des mâles KA et PTZ. Chez les femelles, seul le DG était légèrement affecté pour les PTZ tandis que les KA présentaient, en plus du DG, des pertes importantes au niveau de la couche O/A. Les évaluations cognitives ont démontré que seuls les rats PTZ accusaient un déficit spatial puisque les rats KA présentaient un apprentissage comparable aux rats normaux. Cependant, encore une fois, cette différence n’était présente que chez les mâles. Ainsi, nos résultats confirment qu’il y a des différences liées au genre dans les conséquences des convulsions lorsqu’elles surviennent chez l’animal immature.

Proyecto Colombia Slow Seizures

Teniendo en cuenta las tendencias del mercado de productos para el tratamiento de la Epilepsia Refractaria en Colombia, es necesario implementar estrategias de marketing para lograr la adherencia del producto y el seguimiento del tratamiento.

Cannabidiol exerts anti-convulsant effects in animal models of temporal lobe and partial seizures

Cannabis sativa has been associated with contradictory effects upon seizure states despite its medicinal use by numerous people with epilepsy. We have recently shown that the phytocannabinoid cannabidiol (CBD) reduces seizure severity and lethality in the well-established in vivo model of pentylenetetrazoleinduced generalised seizures, suggesting that earlier, small-scale clinical trials examining CBD effects in people with epilepsy warrant renewed attention. Here, we report the effects of pure CBD (1, 10 and 100 mg/kg) in two other established rodent seizure models, the acute pilocarpine model of temporal lobe seizure and the penicillin model of partial seizure. Seizure activity was video recorded and scored offline using model-specific seizure severity scales. In the pilocarpine model CBD (all doses) significantly reduced the percentage of animals experiencing the most severe seizures. In the penicillin model, CBD (�10 mg/kg) significantly decreased the percentage mortality as a result of seizures; CBD (all doses) also decreased the percentage of animals experiencing the most severe tonic–clonic seizures. These results extend the anticonvulsant profile of CBD; when combined with a reported absence of psychoactive effects, this evidence strongly supports CBD as a therapeutic candidate for a diverse range of human epilepsies.

Dissecting the illegal ivory trade: an analysis of ivory seizures data

Reliable evidence of trends in the illegal ivory trade is important for informing decision making for elephants but it is difficult to obtain due to the covert nature of the trade. The Elephant Trade Information System, a global database of reported seizures of illegal ivory, holds the only extensive information on illicit trade available. However inherent biases in seizure data make it difficult to infer trends; countries differ in their ability to make and report seizures and these differences cannot be directly measured. We developed a new modelling framework to provide quantitative evidence on trends in the illegal ivory trade from seizures data. The framework used Bayesian hierarchical latent variable models to reduce bias in seizures data by identifying proxy variables that describe the variability in seizure and reporting rates between countries and over time. Models produced bias-adjusted smoothed estimates of relative trends in illegal ivory activity for raw and worked ivory in three weight classes. Activity is represented by two indicators describing the number of illegal ivory transactions--Transactions Index--and the total weight of illegal ivory transactions--Weights Index--at global, regional or national levels. Globally, activity was found to be rapidly increasing and at its highest level for 16 years, more than doubling from 2007 to 2011 and tripling from 1998 to 2011. Over 70% of the Transactions Index is from shipments of worked ivory weighing less than 10 kg and the rapid increase since 2007 is mainly due to increased consumption in China. Over 70% of the Weights Index is from shipments of raw ivory weighing at least 100 kg mainly moving from Central and East Africa to Southeast and East Asia. The results tie together recent findings on trends in poaching rates, declining populations and consumption and provide detailed evidence to inform international decision making on elephants.

Coupling between gamma-band power and cerebral blood volume during recurrent acute neocortical seizures

Characterization of neural and hemodynamic biomarkers of epileptic activity that can be measured using noninvasive techniques is fundamental to the accurate identification of the epileptogenic zone (EZ) in the clinical setting. Recently, oscillations at gamma-band frequencies and above (N30 Hz) have been suggested to provide valuable localizing information of the EZ and track cortical activation associated with epileptogenic processes. Although a tight coupling between gamma-band activity and hemodynamic-based signals has been consistently demonstrated in non-pathological conditions, very little is known about whether such a relationship is maintained in epilepsy and the laminar etiology of these signals. Confirmation of this relationship may elucidate the underpinnings of perfusion-based signals in epilepsy and the potential value of localizing the EZ using hemodynamic correlates of pathological rhythms. Here, we use concurrent multi-depth electrophysiology and 2- dimensional optical imaging spectroscopy to examine the coupling between multi-band neural activity and cerebral blood volume (CBV) during recurrent acute focal neocortical seizures in the urethane-anesthetized rat. We show a powerful correlation between gamma-band power (25–90 Hz) and CBV across cortical laminae, in particular layer 5, and a close association between gamma measures and multi-unit activity (MUA). Our findings provide insights into the laminar electrophysiological basis of perfusion-based imaging signals in the epileptic state and may have implications for further research using non-invasive multi-modal techniques to localize epileptogenic tissue