Generalized Absence Epilepsy Research Articles

Combined epilepsy with generalized and focal seizures

<p>Combined epilepsy (with generalized and focal seizures) is a recently accepted and yet underreported epilepsy type. We intended to review the literature of combined epilepsy and to report the individual findings of the 31 combined epilepsy patients in our database. Thereafter, we investigated the characteristics of the patients at the group level.</p>. <p>The individual findings of the 31&nbsp;patients were tabulated. We characterized the group with special reference to epide&shy;miology, timing and the sequence of gene&shy;ralized and focal seizures, family history of seizures and severity of the electro-clinical phenotype. The variables were compared to those of the generalized epilepsy and the focal epilepsy groups of our database. We carried out statistical analyses by the two-sided Fishers&rsquo;s exact test and the Kruskal-Wallis and post-hoc Dunn tests.</p>. <p>The prevalence of combined epilepsy was 1.56% within the total sample of the classifiable epilepsy patients. Females were affected more often than males (67.7% and 32.3%, respectively). Statistically significant associations emerged firstly between the &ldquo;short interval&rdquo; subgroup (where the generalized and focal seizures occurred with short time difference) and the lack of other cerebral abnormality, and secondly between the &ldquo;long interval&rdquo; subgroup (where 4 to 37 years elapsed between the occurrence of the two seizure types) and the presence of other brain abnormality (p = 0.02). The proportion of patients with positive family history of seizures was greater in the combined epilepsy- than in the generalized epilepsy group (p = 0.03) and the focal epilepsy group (p &lt; 0.0001) of the database. The electro-clinical phenotype of the absence seizures showed more atypical findings (indicating poor prognosis) in combined epilepsy than in the generalized absence epilepsy patients of the database (p &lt; 0,0001).&nbsp;Despite dissimilar patient selection and study design, our main findings were in accord with those of prior studies. The dissection of the combined epilepsy group into the &ldquo;long interval&rdquo; and &ldquo;short interval&rdquo; subgroups was a novel approach that highlighted the dissimilar pathogenetic and clinical correlates of each.</p>. <p>The case reports might facilitate the spread of information about combined epilepsy in the medical community. Analyses of the patients at the group level resulted in clinically useful pieces of evidence.</p>.

Pain Modulation in WAG/Rij Epileptic Rats (A Genetic Model of Absence Epilepsy): Effects of Biological and Pharmacological Histone Deacetylase Inhibitors.

Epigenetic mechanisms are involved in epilepsy and chronic pain development. About that, we studied the effects of the natural histone deacetylase (HDAC) inhibitor sodium butyrate (BUT) in comparison with valproic acid (VPA) in a validated genetic model of generalized absence epilepsy and epileptogenesis. WAG/Rij rats were treated with BUT (30 mg/kg), VPA (300 mg/kg), and their combination (BUT + VPA) daily per os for 6 months. Rats were subjected at Randall–Selitto, von Frey, hot plate, and tail flick tests after 1, 3, and 6 months of treatment to evaluate hypersensitivity to noxious and non-noxiuous stimuli. Moreover, PPAR-γ (G3335 1 mg/kg), GABA-B (CGP35348 80 mg/kg), and opioid (naloxone 1 mg/kg) receptor antagonists were administrated to investigate the possible mechanisms involved in analgesic activity. The expression of NFkB, glutathione reductase, and protein oxidation (carbonylation) was also evaluated by Western blot analysis. WAG/Rij rats showed an altered pain threshold throughout the study (p < 0.001). BUT and BUT + VPA treatment reduced hypersensitivity (p < 0.01). VPA was significantly effective only after 1 month (p < 0.01). All the three receptors are involved in BUT + VPA effects (p < 0.001). BUT and BUT + VPA decreased the expression of NFkB and enhanced glutathione reductase (p < 0.01); protein oxidation (carbonylation) was reduced (p < 0.01). No effect was reported with VPA. In conclusion BUT, alone or in coadministration with VPA, is a valuable candidate for managing the epilepsy-related persistent pain.

Perspective: Is Cortical Hyperexcitability the Only Path to Generalized Absence Epilepsy?

Perspective: Is Cortical Hyperexcitability the Only Path to Generalized Absence Epilepsy?

A-58 Rare Case of Klinefelter Syndrome with 13/14 Balanced Translocation and Absence Epilepsy: Impact of Combined Genotypes on Cognitive Neuropsychological Phenotype

Abstract Objective Klinefelter syndrome (KS) and Robertsonian translocation of 13/14 [rob t(13;14)] are the most common sex-chromosome disorder and chromosome rearrangement, respectively (Engels et al., 2008; Skakkebæk, Wallentin, &amp; Gravholt, 2015). Both are associated with increased risk of cognitive/intellectual disability (ID). A case of KS and de novo (i.e., unbalanced) rob t(13;14) was previously reported (Gül &amp; Şayli, 1994). A case of KS with balanced rob t(13;14) and well-controlled generalized absence epilepsy will be presented with consideration for pediatric neuropsychological practice. Method Neuropsychological evaluation of a 12-year-old, right-handed boy diagnosed with comorbid KS, rob t(13;14), and generalized absence epilepsy. Particular attention was given to language given his KS diagnosis. The patient is in a 12:1:1 self-contained classroom with speech-language therapy and social skills groups in place. The patient’s mother is confirmed to have rob t(13;14), whereas paternal contribution is unknown. Results Adolescent with a history of language difficulties, especially comprehension. Recent school-based WISC-V FSIQ was in the extremely low range (SS = 53), with weaker verbal comprehension and working memory. Academic achievement was globally very low. Expressive and receptive language, visual perception and motor coordination were extremely low to low average. Verbal list learning and visual attention were near average to average. Conclusions This case contributes to the very limited body of pediatric neuropsychological data on the combined genotype of KS with rob t(13;14) and absence epilepsy. Both the KS and rob t(13;14) cognitive phenotypes have been characterized as highly variable, with the comorbidity a likely increased risk for ID.

Current Controversy: Spikes, Bursts, and Synchrony in Generalized Absence Epilepsy: Unresolved Questions Regarding Thalamocortical Synchrony in Absence Epilepsy.

Absence epilepsy is a disorder of thalamocortical networks. Animal models have provided detailed information regarding the core cellular, synaptic, and network features that contribute to the electroencephalogram spike and wave discharge characteristic of typical absence epilepsy. Understanding of seizure networks and dynamics is a critical step toward improving treatments, yet competing conceptual models have evolved to explain seizure initiation and propagation. Recent studies have questioned 2 key model concepts: (1) T-type Ca2+ channel-dependent burst firing in thalamic relay neurons may not be essential for seizure generation, bringing into question the proposed mechanism for the antiepileptic drug ethosuximide in reducing thalamic bursting and (2) widespread synchronized neural activity may not be a core feature of the seizures, indicating that reductions in synchrony would not be a productive therapeutic goal. In this review, I will discuss these current findings, highlight the innovative approaches that have enabled these insights, and provide a unified framework that incorporates these sometimes-conflicting ideas. Finally, I lay out future work that will be necessary to finally resolve the remaining issues.

Modelling Transition From Normal To Epileptic Eeg Signals: A Neuron-Astrocyte Mass Action Approach

Epileptic seizures occur intermittently as a result of complex dynamical interactions among many regions of the brain. The sudden and apparently unpredictable nature of refractory seizures is one of the most disabling aspects of the disease. Therefore, there is need for interdisciplinary research efforts directed at better understanding of the mechanisms involved in the emergence of epileptic seizures. Our research objective in this field is the use of applied methods from deterministic and nondeterministic dynamical systems modeling to study epilepsy. Dynamical systems refer to systems whose state variables evolve in time. By the assumption of deterministic system,the physiological system (the brain) can be treated as low dimensional without any random components. Nondeterministic assumption on the other hand allows randomness in some input components. We developed at the macroscopic level physiologically based mathematical models of parts of the brain believed to be eliciting the abnormal signals observed during Generalized Absence Epilepsy (GAE) and Temporal Lobe Epilepsy (TLE). In developing our models, we considered the activities of nerve cells, the surrounding astrocyte cells and the dynamics of extracellular neurotransmitters and conducted parameter sensitivity studies on our models. The models were then validated using Electroencephalogram (EEG) data of epileptic patients. The important conclusion from our findings is that the transition from normal to epileptic brain activity is critically dependent on small variations in few system parameters and/or the balance between a small number of system parameters, be it neural or astrocytes activity dependent

Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2

Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Cav2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Cav2.1 activity through protein misfolding and trafficking defects. To date, the role of this mechanism in the disease pathogenesis is unknown because no animal model exists. To address this issue, we have generated a mouse bearing the R1497X nonsense mutation in Cav2.1 (Cav2.1R1497X). Phenotypic analysis of heterozygous Cav2.1R1497X mice revealed ataxia associated with muscle weakness and generalized absence epilepsy. Electrophysiological studies of the cerebellar circuits in heterozygous Cav2.1R1497X mice highlighted severe dysregulations in synaptic transmission of the two major excitatory inputs as well as alteration of the spontaneous activity of Purkinje cells. Moreover, these neuronal dysfunctions were associated with a strong suppression of Cav2.1 channel expression in the cerebellum of heterozygous Cav2.1R1497X mice. Finally, the presence of Cav2.1 in cerebellar lipid raft microdomains was strongly impaired in heterozygous Cav2.1R1497X mice. Altogether, these results reveal a pathogenic mechanism for EA2 based on a dominant negative activity of mutant channels.

A Review of The Dynamical Systems Modeling of Epileptic Seizures For Onset Prediction

In this review, we present a critical appraisal of works that consider epilepsy as a dynamic disease and therefore presentable from the perspective of dynamic system theory. Epilepsy is an acute brain disorder characterized by recurrent seizures where parts of the brain elicit abnormally synchronous electrical activity. The most commonly encountered forms of epilepsy are generalized absence epilepsy and temporal lobe epilepsy. The electroencephalography (EEG) which is the recording of the fluctuating electric field of the brain is the major clinical diagnostic tool for epilepsy and also a vital source of data for epilepsy research. In majority of cases accurate diagnosis of the disease can be made and seizures are controlled by the regular use of anti-epileptic drugs (AEDs). However, approximately 30% of epileptic patients suffer from medically refractory epilepsy which has defied all existing treatment protocols. Understanding the mechanisms underlying these forms of epileptic seizures and the development of alternative effective treatment strategies is a fundamental challenge in modern epilepsy research. Experimental researches show that the mechanisms involved in refractory epilepsy are so diverse and complex that it is a formidable task to obtain a single framework that categorizes all the pathophysiological changes in the properties of the epileptic brain involved. There has evolved massive evidence that seizures do not occur abruptly as it has been earlier thought but develop over time even hours before the clinical symptoms, thus raising the hope for predictability of epileptic seizure occurrence. Thus, models of the epileptic brain can be postulated using concepts from deterministic and nondeterministic dynamical systems modelling. The main idea is that since the epileptic brain transitions into and out of seizures we can view it as a dynamical system. The deterministic and non-deterministic models are based on seizure onset detection algorithm for the design of a closed loop seizure warning/intervention system. The major focus being the stimulation of the epileptic brain by sending electrical pulses to it in order to disrupt seizure progression once its onset has been detected. Finally, we considered the essential issues in epileptic seizure prediction including the sceptism expressed in recent publications on the validity of nonlinear dynamical systems modelling to epileptic seizure prediction.

Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.

In this review article, we focus on the molecular pathogenic basis for genetic generalized epilepsies associated with mutations in the inhibitory γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2 (OMIM 137164), an established epilepsy gene. The γ-aminobutyric acid (GABAA) receptor γ2 subunit gene, GABRG2, is abundantly expressed in the mammalian brain, and its encoded γ2 subunit is assembled into αβγ2 receptors, which are the major GABAA receptor isoforms in the brain. The γ2 subunits have a critical role in GABAA receptor trafficking and clustering at synapses. They reside inside the endoplasmic reticulum after synthesis, where they oligomerize with other binding partners, such as α and β subunits, and further assemble into pentameric receptors. Only correctly assembled receptors can traffic beyond the endoplasmic reticulum and reach the cell surface and synapses, where they conduct chloride ion current when activated by GABA. Mutations in GABRG2 have been associated with simple febrile seizures and with genetic epilepsy syndromes, including childhood absence epilepsy, generalized epilepsy with febrile seizures plus, and Dravet syndrome or severe myoclonic epilepsy in infancy. The mutations include missense, nonsense, and frameshift mutations, as well as splice-site and deletion mutations. The mutations have been identified in both coding and noncoding sequences like splice sites. In the coding sequence, these mutations are found in multiple locations, including the extracellular N-terminus, transmembrane domains, and transmembrane 3-transmembrane 4 intracellular loop. All of these mutations reduced channel function but to different extents and by diverse mechanisms, including nonsense-mediated messenger RNA decay, endoplasmic reticulum-associated protein degradation, dominant negative suppression of partnering subunits, mutant subunit aggregation causing cell stress and cell death, and gating defects. We conclude that the epilepsy phenotypic heterogeneity associated with GABRG2 mutations may be related to the extent of the reduction of GABAA receptor channel function and the differential dominant negative suppression, as well to toxicity related to the metabolism of mutant subunit proteins resulting from each mutant γ2 subunit, in addition to different genetic backgrounds.

Regionally specific expression of high-voltage-activated calcium channels in thalamic nuclei of epileptic and non-epileptic rats.

The polygenic origin of generalized absence epilepsy results in dysfunction of ion channels that allows the switch from physiological asynchronous to pathophysiological highly synchronous network activity. Evidence from rat and mouse models of absence epilepsy indicates that altered Ca(2+) channel activity contributes to cellular and network alterations that lead to seizure activity. Under physiological circumstances, high voltage-activated (HVA) Ca(2+) channels are important in determining the thalamic firing profile. Here, we investigated a possible contribution of HVA channels to the epileptic phenotype using a rodent genetic model of absence epilepsy. In this study, HVA Ca(2+) currents were recorded from neurons of three different thalamic nuclei that are involved in both sensory signal transmission and rhythmic-synchronized activity during epileptic spike-and-wave discharges (SWD), namely the dorsal part of the lateral geniculate nucleus (dLGN), the ventrobasal thalamic complex (VB) and the reticular thalamic nucleus (NRT) of epileptic Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) and non-epileptic August Copenhagen Irish (ACI) rats. HVA Ca(2+) current densities in dLGN neurons were significantly increased in epileptic rats compared with non-epileptic controls while other thalamic regions revealed no differences between the strains. Application of specific channel blockers revealed that the increased current was carried by L-type Ca(2+) channels. Electrophysiological evidence of increased L-type current correlated with up-regulated mRNA and protein expression of a particular L-type channel, namely Cav1.3, in dLGN of epileptic rats. No significant changes were found for other HVA Ca(2+) channels. Moreover, pharmacological inactivation of L-type Ca(2+) channels results in altered firing profiles of thalamocortical relay (TC) neurons from non-epileptic rather than from epileptic rats. While HVA Ca(2+) channels influence tonic and burst firing in ACI and WAG/Rij differently, it is discussed that increased Cav1.3 expression may indirectly contribute to increased robustness of burst firing and thereby the epileptic phenotype of absence epilepsy.

The gamma-butyrolactone model of absence epilepsy: Acute and chronic effects in wistar rats.

Objectives: We studied the electroencephalographic (EEG) and behavioral changes of the chemical model of generalized absence epilepsy induced by acute and chronic administration of gamma-butrolactone (GBL), a prodrug of gamma-hydroxybutyric acid. Methods: Adult male Wistar rats under anesthesia were implanted with bilateral cortical recording electrodes. The rats were administered 30 intraperitoneal injections of GBL twice daily from Monday to Friday and EEG was recorded 20 min before and 40 min after GBL injections. In order to monitor spontaneous spike-and-wave discharges (SWDs), the baseline EEGs on the subsequent Monday mornings after the first, second and third weekends were recorded for 90 min. Results: The intraperitoneal administration of GBL caused a rapid onset of bilaterally synchronous SWDs in the cortical EEG accompanied by behavioral immobility, vacant-staring and vibrissal twitching. By repeated GBL injections, animals displayed spontaneous bilateral synchronous SWDs in the baseline EEG on the Monday morning session after the GBL-free weekend period (60 h after the Friday afternoon injection). Conclusion: The present study reports the acute and chronic effects of the systemic administration of GBL. The chronic systemic application of GBL may represent a model of epileptogenesis for absence epilepsy.

Age-dependent decline in learning and memory performances of WAG/Rij rat model of absence epilepsy

Recent clinical studies revealed emotional and cognitive impairments associated with absence epilepsy. Preclinical research with genetic models of absence epilepsy however have primarily focused on dysfunctional emotional processes and paid relatively less attention to cognitive impairment. In order to bridge this gap, we investigated age-dependent changes in learning and memory performance, anxiety-like behavior, and locomotor activity of WAG/Rij rats (a valid model of generalized absence epilepsy) using passive avoidance, Morris water maze, elevated plus maze, and locomotor activity cage. We tested 5 month-old and 13 month-old WAG/Rij rats and compared their performance to age-matched Wistar rats. Results revealed a decline in emotional and spatial memory of WAG/Rij rats compared to age-matched Wistar rats only at 13 months of age. Importantly, there were no significant differences between WAG/Rij and Wistar rats in terms of anxiety-like behavior and locomotor activity at either age. Results pointed at age-dependent learning and memory deficits in the WAG/Rij rat model of absence epilepsy.

Doxycycline could aggravate the absence-like epileptic seizures of WAG/Rij rats via matrix metalloproteinase inhibition

Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and elevated MMP-9 activity has been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we posed the question, whether MMP inhibitory dose of doxycycline (20mg/kg) could affect the spike-wave-discharges (SWDs) of the WAG/Rij rat. We found that intraperitoneal (i.p.) administration of 20mg/kg doxycycline significantly increased the incidence and duration of SWDs for 4h. As doxycycline has both MMP inhibitory and anti-inflammatory effects we also tested a lower dose of doxycycline (10mg/kg, i.p.) and a selective broad-spectrum MMP inhibitor GM6001 (N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-l-tryptophane methylamide) intracerebroventricularly (i.c.v., 10ng/rat). While 10mg/kg doxycycline significantly increased the SWD number for 1h, GM6001 significantly increased the SWD number during the whole 4-h recording period. Our results could indicate that the induction of MMPs in the epileptic brain, besides contributing to structural remodeling, would also be associated with such functions as homeostatic synaptic plasticity which might counteract epileptic seizures.

Doxycycline Increases Absence-like Epileptic Seizures in WAG/Rij Rats

Event Abstract Back to Event Doxycycline Increases Absence-like Epileptic Seizures in WAG/Rij Rats Z. Kovács1*, A. K. Kékesi2, G. Juhász2 and A. Czurkó3 1 University of West Hungary, Department of Zoology, Hungary 2 Eötvös Loránd University, Hungary 3 University of Szeged, Institute of Medical Chemistry, Hungary Epileptic seizures might activate matrix metalloproteinases (MMPs) in the brain and increased MMP-9 activity have been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we investigated the effect of subantimicrobial doses of MMP inhibitor doxycycline on spike-wave-discharges (SWDs) in WAG/Rij rats. A single dose of 20 mg/kg doxycycline were injected intraperitoneally (i.p.) into WAG/Rij rats and number and duration of SWDs were measured for 4 hours. We found that 20 mg/kg doxycycline significantly increased the incidence and duration of SWDs compared to the preceding three-day average control level during the whole four-hour recording period. Doxycycline at similar dosage inhibits also inflammation, e.g. systemic injection of 10 mg/kg of doxycycline blocks the increase of pro-inflammatory cytokines. While the role of inflammation in absence epilepsy is not elucidated yet, we also investigated the effect of 10 mg/kg doxycycline on the number of SWDs. We found that 10 mg/kg doxycycline also increased the number of SWD but only between 30-90 min after i.p. injection. Our results indicate that while in many epilepsy models the overexpression of MMP-9 could deteriorate the behavioral seizures and its consequences, in case of absence seizures MMP-9 may exert beneficial effects. Keywords: disorders, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Disorders Citation: Kovács Z, Kékesi AK, Juhász G and Czurkó A (2011). Doxycycline Increases Absence-like Epileptic Seizures in WAG/Rij Rats. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00163 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. Z. Kovács, University of West Hungary, Department of Zoology, Szombathely, Hungary, kovacs@koki.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Z. Kovács A. K Kékesi G. Juhász A. Czurkó Google Z. Kovács A. K Kékesi G. Juhász A. Czurkó Google Scholar Z. Kovács A. K Kékesi G. Juhász A. Czurkó PubMed Z. Kovács A. K Kékesi G. Juhász A. Czurkó Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague–Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death.

Spatiotemporal imaging of &amp;lsquo;generalized' seizure activity using MEG

Event Abstract Back to Event Spatiotemporal imaging of ‘generalized' seizure activity using MEG Pauly Ossenblok1*, Bert Kornips1, Hans Carpay2, Paul Boon1 and Gilles Van Luijtelaar3 1 Epilepsy Centre Kempenhaeghe, Netherlands 2 Tergooi Hospitals , Netherlands 3 Donders Center for Cognition, Netherlands Studies in the WAG/Rij rat [1] challenge the theory of primary generalized absence epilepsy by showing a crucial role for the cortex in generating the spike-and-wave discharges (SWDs). Association analysis of MEG signals recorded for children with absence epilepsy also demonstrated a focal onset region, followed by a recurrent pattern of regional activity during the spikes alternated by generalized activity during the slow-wave of the SWDs [2]. More recent findings of our study raised the question whether clinically distinct types of absence epilepsy differ by origin, while sharing a common corticothalamic network during the evolvement of the SWDs. The population studied (n=20; 6 – 14 years of age) ranges from patients with typical childhood absence epilepsy, who can be treated quite successfully with anti-epileptics, to more complex atypical forms and children who had absences and complex partial clinical features. For each of the seizures of these children the non-linear association analysis was performed, yielding both the dynamics of the SWDs and the regional distribution of the spikes, while the cortical origin of the SWDs was studied using advanced source analysis. The association analysis results of the SWDs indicated the involvement of mesiofrontal cortex and the bilateral frontal and temporoparietal regions during the spikes of the SWDs for each of the patients studied. However, the initial onset of the SWDs of the patients differing with regard to their clinical features may reflect either left or right frontal or temporoparietal regional activity or in case of complex partial semiology regional onset activity e.g. at the temporal lobe, a result which was in concordance with the dipole scan (MUSIC). If cortical structures activated before generalization can be identified for distinct subpopulations of absence epilepsy patients, this will change not only the concept of epilepsy, but also will improve the differential diagnosis of childhood absence epilepsy and may open new ways for treatment.

Maternal behavior in a genetic animal model of absence epilepsy.

In this study we quantified maternal behavior in genetic epileptic rats with deficiencies in the DA system known to be involved in maternal behavior in order to assess whether these rats have disturbances in maternal care. Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a genetic model for generalized absence epilepsy and Wistar rats were compared. Maternal behavior parameters and activity scores were quantified from post-natal day (PND) 4-6 in an open field in the presence of pups. WAG/Rij rats had less approaches to the pups and higher latencies of approaching them compared to Wistar, while locomotion showed a different pattern over days. This confirms the hypothesis that animals with absence epilepsy show more poor maternal behavior and that these effects cannot be solely attributed to differences in locomotor activity. It is proposed that the reduction in maternal care is attributed to low activity in the mesolimbic DA system.

SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy

SV2A, a synaptic vesicle protein, has been recently identified as a binding target for levetiracetam (Keppra ®). The specific mechanism by which SV2A binding leads to seizure protection has not yet been fully elucidated. However, a functional correlation between SV2A binding affinity and anticonvulsant potency has been observed in the mouse audiogenic seizure model. The present study was undertaken to test whether similar correlations exist in rodent models of partial and generalized epilepsies. As expected, there was a high degree of correlation between anticonvulsant potency and SV2A binding affinity in the mouse audiogenic seizure model ( r 2 = 0.77; p < 0.001). A similar correlation was also observed in the mouse corneal kindling ( r 2 = 0.80; p < 0.01) and in the rat model of generalized absence epilepsy (GAERS) ( r 2 = 0.72; p < 0.01). Moreover, there were no significant differences between the slopes and intercepts of regression lines in these models. Interestingly, the protective potencies in these three epilepsy models were also well correlated with each other. As such, protective doses of a given SV2A ligand in one model could be easily predicted based on the data obtained in another model. Taken together, these results support the concept that SV2A protein is an important target for both partial and generalized epilepsies and thereby relevant for the generation of new antiepileptic drugs with potential broad-spectrum efficacy.

Effects of non-competitive AMPA receptor antagonists injected into some brain areas of WAG/Rij rats, an animal model of generalized absence epilepsy

CFM-2 [1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one] and THIQ-10c [ N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline], are two non-competitive 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptor antagonists, which demonstrated to antagonize generalized tonic-clonic seizures in different animal models. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were focally microinjected into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs) and better characterize the role of AMPA neurotransmission in this animal model. The focal microinjection of the two AMPA antagonists into some thalamic nuclei (ventralis posteromedialis (VPM), reticularis (NRT), ventralis posterolateralis (VPL) and the primary somatosensory forelimb region (S1FL)) was, generally, not able to significantly modify the occurrence of SWDs. Whereas, both compounds were able to reduce the number and duration of SWDs dose-dependently when microinjected into the peri-oral region of the primary somatosensory cortex (S1po). These findings suggest that AMPA receptor antagonists might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.

The Mechanism of Carbamazepine Aggravation of Absence Seizures

Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood. GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures. The hypothesis that CBZ aggravates absence seizures by acting at the VB thalamus via a GABA(A) receptor-mediated mechanism was investigated in a genetic rat model, generalized absence epilepsy rats from Strasbourg (GAERS). Seizure activity was quantified by a 90-min electroencephalogram recording postdrug injection. Intracerebroventricular injections of CBZ (15 microg in 4 microl) resulted in seizure aggravation versus vehicle treatment, with a mean increase in seizure time of 40%. This indicates that CBZ acts directly, rather than via a metabolite, on the brain to aggravate seizures. Seizure aggravation also occurred following bilateral microinjection of CBZ (0.75 microg in 0.2 microl) into the VB (53%) but not following injection into the Rt (-9%). However, seizure aggravation was blocked when the GABA(A) receptor antagonist, bicuculline (BIC, 0.04 microg in 0.2 microl), was coinjected with CBZ into the VB. Injection of BIC alone (versus vehicle) into the VB also blocked seizure aggravation following systemic administration of CBZ (15 mg/kg i.p.). In vitro studies in Xenopus oocytes expressing recombinant GABA(A) receptors demonstrated that CBZ produced a dose-dependent potentiation of the GABA current at a physiological relevant concentration range (1-100 microM). These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABA(A) receptors is critical to this effect.