Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: An animal model of petit mal epilepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vadasz, C.; Fleischer, A.; Carpi, D.

1995-02-27

Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of themore » spike-and-wave pattern. We propose that both genetic and developmental - environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges. 67 refs., 3 figs., 5 tabs.« less

Improving your genetic literacy in epilepsy-A new series.

PubMed

Tan, Nigel C K; Lowenstein, Daniel H

2015-11-01

Advances in epilepsy genetics have been rapid, and it is challenging for clinicians on the ground to keep pace with these advances. The International League Against Epilepsy (ILAE) Genetics Commission has thus crafted a new Genetic Literacy series targeted at busy clinicians. Our goal is to help provide a concise, accessible resource on epilepsy genetics for the busy, on-the-ground clinician so that he/she can apply that knowledge at point-of-care to help patients. This new series is grounded in educational theories and evidence to ensure that learning is effective and efficient. We hope that by promoting and encouraging continuing medical education in epilepsy genetics, this eventually translates to better patient management and therefore better patient health outcomes. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Genetic Causal Attribution of Epilepsy and its Implications for Felt Stigma

PubMed Central

Sabatello, Maya; Phelan, Jo C.; Hesdorffer, Dale C.; Shostak, Sara; Goldsmith, Jeff; Sorge, Shawn T.; Winawer, Melodie R.; Chung, Wendy K.; Ottman, Ruth

2015-01-01

Summary Objective Research in other disorders suggests that genetic causal attribution of epilepsy might be associated with increased stigma. We investigated this hypothesis in a unique sample of families containing multiple individuals with epilepsy. Methods 181 people with epilepsy and 178 biological relatives without epilepsy completed a self-administered survey. In people with epilepsy, felt stigma was assessed through the Epilepsy Stigma Scale (ESS), scored 1 to 7 with higher scores indicating more stigma and >4 indicating some felt stigma. Felt stigma related to having epilepsy in the family was assessed through the Family Epilepsy Stigma Scale (FESS), created by replacing “epilepsy” with “epilepsy in my family” in each ESS item. Genetic attribution was assessed through participants’ perceptions of the (1) role of genetics in causing epilepsy in the family, (2) chance they had an epilepsy-related mutation, and (3) (in people with epilepsy) influence of genetics in causing their epilepsy. Results Among people with epilepsy, 22% met criteria for felt stigma (ESS score >4). Scores were increased among individuals who were aged ≥60 years, were unemployed, reported epilepsy-related discrimination, or had seizures within the last year or >100 seizures in their lifetime. Adjusting for other variables, ESS scores in people with epilepsy were significantly higher among those who perceived genetics played a “medium” or “big” role in causing epilepsy in the family than in others (3.4 vs. 2.7, p=0.025). Only 4% of relatives without epilepsy had felt stigma. Scores in relatives were unrelated to genetic attribution. Significance In these unusual families, predictors of felt stigma in individuals with epilepsy are similar to those in other studies, and stigma levels are low in relatives without epilepsy. Felt stigma may be increased in people with epilepsy who believe epilepsy in the family has a genetic cause, emphasizing the need for sensitive

Describing the genetic architecture of epilepsy through heritability analysis.

PubMed

Speed, Doug; O'Brien, Terence J; Palotie, Aarno; Shkura, Kirill; Marson, Anthony G; Balding, David J; Johnson, Michael R

2014-10-01

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Genetic variations and associated pathophysiology in the management of epilepsy.

PubMed

Mulley, John C; Dibbens, Leanne M

2011-01-01

The genomic era has enabled the application of molecular tools to the solution of many of the genetic epilepsies, with and without comorbidities. Massively parallel sequencing has recently reinvigorated gene discovery for the monogenic epilepsies. Recurrent and novel copy number variants have given much-needed impetus to the advancement of our understanding of epilepsies with complex inheritance. Superimposed upon that is the phenotypic blurring by presumed genetic modifiers scattering the effects of the primary mutation. The genotype-first approach has uncovered associated syndrome constellations, of which epilepsy is only one of the syndromes. As the molecular genetic basis for the epilepsies unravels, it will increasingly influence the classification and diagnosis of the epilepsies. The ultimate goal of the molecular revolution has to be the design of treatment protocols based on genetic profiles, and cracking the 30% of epilepsies refractory to current medications, but that still lies well into the future. The current focus is on the scientific basis for epilepsy. Understanding its genetic causes and biophysical mechanisms is where we are currently positioned: prizing the causes of epilepsy "out of the shadows" and exposing its underlying mechanisms beyond even the ion-channels.

Recent advances in the molecular genetics of epilepsy.

PubMed

Hildebrand, Michael S; Dahl, Hans-Henrik M; Damiano, John Anthony; Smith, Richard J H; Scheffer, Ingrid E; Berkovic, Samuel F

2013-05-01

Recent advances in molecular genetics have translated into the increasing utilisation of genetic testing in the routine clinical practice of neurologists. There has been a steady, incremental increase in understanding the genetic variation associated with epilepsies. Genetic testing in the epilepsies is not yet widely practiced, but the advent of new screening technologies promises to exponentially expand both knowledge and clinical utility. To maximise the value of this new genetic insight we need to rapidly extrapolate genetic findings to inform patients of their diagnosis, prognosis, recurrence risk and the clinical management options available for their specific genetic condition. Comprehensive, highly specific and sensitive genetic test results improve the management of patients by neurologists and clinical geneticists. Here we discuss the latest developments in clinical genetic testing for epilepsy and describe new molecular genetics platforms that will transform both genetic screening and novel gene discovery.

Genetic screening and diagnosis in epilepsy?

PubMed

Sisodiya, Sanjay M

2015-04-01

Genetic discovery has been extremely rapid over the last year, with many new discoveries illuminating novel mechanisms and pathways. In particular, the application of whole exome and whole genome sequencing has identified many new genetic causes of the epilepsies. As such methods become increasingly available, it will be critical for practicing neurologists to be acquainted with them. This review surveys some important developments over the last year. The range of tests available to the clinician is wide, and likely soon to be dominated by whole exome and whole genome sequencing. Both whole exome and whole genome sequencing have usually proven to be more powerful than most existing tests. Many new genes have been implicated in the epilepsies, with emerging evidence of the involvement of particular multigene pathways. For the practicing clinician, it will be important to appreciate progress in the field, and to prepare for the application of novel genetic testing in clinical practice, as genetic data are likely to contribute importantly for many people with epilepsy.

Genetics of human epilepsies: Continuing progress.

PubMed

Szepetowski, Pierre

2018-03-01

Numerous epilepsy genes have been identified in the last years, mostly in the (rare) monogenic forms and thanks to the increased availability and the decreased cost of next-generation sequencing approaches. Besides the somehow expected group of epilepsy genes encoding various ion channel subunits (e.g. sodium or potassium channel subunits, or GABA receptors, or glutamate-gated NMDA receptors), more diversity has emerged recently, with novel epilepsy genes encoding proteins playing a wide range of physiological roles at the cellular and molecular levels, such as synaptic proteins, members of the mTOR pathway, or proteins involved in chromatin remodeling. The overall picture is somehow complicated: one given epilepsy gene can be associated with more than one epileptic phenotype, and with variable degrees of severity, from the benign to the severe forms (e.g. epileptic encephalopathies), and with various comorbid conditions such as migraine or autism spectrum of disorders. Conversely, one given epileptic syndrome may be associated with different genes, some of which have obvious links with each other (e.g. encoding different subunits of the same receptor) while other ones have no clear relationships. Also genomic copy number variations have been detected, some of which, albeit rare, may confer high risk to epilepsy. Whereas translation from gene identification to targeted medicine still remains challenging, progress in epilepsy genetics is currently revolutionizing genetic-based diagnosis and genetic counseling. Epilepsy gene identification also represents a key entry point to start in deciphering the underlying pathophysiological mechanisms via the design and the study of the most pertinent cellular and animal models - which may in turn provide proofs-of-principle for future applications in human epilepsies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Decreased norepinephrine (NE) uptake in cerebral cortex and inferior colliculus of genetically epilepsy prone (GEP) rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Browning, R.A.; Rigler-Daugherty, S.K.; Long, G.

1986-03-01

GEP rats are characterized by an enhanced susceptibility to seizures caused by a variety of stimuli, most notably sound. Pharmacological treatments that reduce the synaptic concentration of NE increase seizure severity in GEP rats while elevations in NE have the opposite effect. GEP rats also display a widespread deficit in brain NE concentration suggesting that their increased seizure susceptibility is related to a deficit in noradrenergic transmission. The authors have compared the kinetics of /sup 3/H-NE uptake in the P/sub 2/ synaptosomal fraction isolated from the cerebral cortex of normal and GEP-rats. Although the apparent Kms were not significantly differentmore » (Normal +/- SEM:0.37 +/- 0.13..mu..M; GEP +/- SEM: 0.29 +/- 0.07..mu..M), the Vmax for GEP rats was 48% lower than that of normal rats (Normal +/- SEM: 474 +/- 45 fmole/mg/4min; GEP +/- SEM: 248 +/- 16 fmole/mg/4min). Because of the possible role of the inferior colliculus (IC) in the initiation of sound-induced seizures in GEP rats, the authors measured synaptosomal NE uptake in the IC using a NE concentration of 50 nM. The IC synaptosomal NE uptake was found to be 35% lower in GEP than in normal rats. These findings are consistent with the hypothesis that a deficit in noradrenergic transmission is related to the increased seizure susceptibility of GEP rats.« less

Clinical Application of Epilepsy Genetics in Africa: Is Now the Time?

PubMed Central

Esterhuizen, Alina I.; Carvill, Gemma L.; Ramesar, Rajkumar S.; Kariuki, Symon M.; Newton, Charles R.; Poduri, Annapurna; Wilmshurst, Jo M.

2018-01-01

Over 80% of people with epilepsy live in low- to middle-income countries where epilepsy is often undiagnosed and untreated due to limited resources and poor infrastructure. In Africa, the burden of epilepsy is exacerbated by increased risk factors such as central nervous system infections, perinatal insults, and traumatic brain injury. Despite the high incidence of these etiologies, the cause of epilepsy in over 60% of African children is unknown, suggesting a possible genetic origin. Large-scale genetic and genomic research in Europe and North America has revealed new genes and variants underlying disease in a range of epilepsy phenotypes. The relevance of this knowledge to patient care is especially evident among infants with early-onset epilepsies, where early genetic testing can confirm the diagnosis and direct treatment, potentially improving prognosis and quality of life. In Africa, however, genetic epilepsies are among the most under-investigated neurological disorders, and little knowledge currently exists on the genetics of epilepsy among African patients. The increased diversity on the continent may yield unique, important epilepsy-associated genotypes, currently absent from the North American or European diagnostic testing protocols. In this review, we propose that there is strong justification for developing the capacity to offer genetic testing for children with epilepsy in Africa, informed mostly by the existing counseling and interventional needs. Initial simple protocols involving well-recognized epilepsy genes will not only help patients but will give rise to further clinically relevant research, thus increasing knowledge and capacity. PMID:29770117

Genetic and epigenetic mechanisms of epilepsy: a review

PubMed Central

Chen, Tian; Giri, Mohan; Xia, Zhenyi; Subedi, Yadu Nanda; Li, Yan

2017-01-01

Epilepsy is a common episodic neurological disorder or condition characterized by recurrent epileptic seizures, and genetics seems to play a key role in its etiology. Early linkage studies have localized multiple loci that may harbor susceptibility genes to epilepsy, and mutational analyses have detected a number of mutations involved in both ion channel and nonion channel genes in patients with idiopathic epilepsy. Genome-wide studies of epilepsy have found copy number variants at 2q24.2-q24.3, 7q11.22, 15q11.2-q13.3, and 16p13.11-p13.2, some of which disrupt multiple genes, such as NRXN1, AUTS2, NLGN1, CNTNAP2, GRIN2A, PRRT2, NIPA2, and BMP5, implicated for neurodevelopmental disorders, including intellectual disability and autism. Unfortunately, only a few common genetic variants have been associated with epilepsy. Recent exome-sequencing studies have found some genetic mutations, most of which are located in nonion channel genes such as the LGI1, PRRT2, EFHC1, PRICKLE, RBFOX1, and DEPDC5 and in probands with rare forms of familial epilepsy, and some of these genes are involved with the neurodevelopment. Since epigenetics plays a role in neuronal function from embryogenesis and early brain development to tissue-specific gene expression, epigenetic regulation may contribute to the genetic mechanism of neurodevelopment through which a gene and the environment interacting with each other affect the development of epilepsy. This review focused on the analytic tools used to identify epilepsy and then provided a summary of recent linkage and association findings, indicating the existence of novel genes on several chromosomes for further understanding of the biology of epilepsy. PMID:28761347

A Model Program for Translational Medicine in Epilepsy Genetics

PubMed Central

Smith, Lacey A.; Ullmann, Jeremy F. P.; Olson, Heather E.; El Achkar, Christelle M.; Truglio, Gessica; Kelly, McKenna; Rosen-Sheidley, Beth; Poduri, Annapurna

2017-01-01

Recent technological advances in gene sequencing have led to a rapid increase in gene discovery in epilepsy. However, the ability to assess pathogenicity of variants, provide functional analysis, and develop targeted therapies has not kept pace with rapid advances in sequencing technology. Thus, although clinical genetic testing may lead to a specific molecular diagnosis for some patients, test results often lead to more questions than answers. As the field begins to focus on therapeutic applications of genetic diagnoses using precision medicine, developing processes that offer more than equivocal test results is essential. The success of precision medicine in epilepsy relies on establishing a correct genetic diagnosis, analyzing functional consequences of genetic variants, screening potential therapeutics in the preclinical laboratory setting, and initiating targeted therapy trials for patients. We describe the structure of a comprehensive, pediatric Epilepsy Genetics Program that can serve as a model for translational medicine in epilepsy. PMID:28056630

The role of genetic testing in epilepsy diagnosis and management.

PubMed

Weber, Yvonne G; Biskup, Saskia; Helbig, Katherine L; Von Spiczak, Sarah; Lerche, Holger

2017-08-01

Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. More than 500 epilepsy-associated genes have been described in the literature. Most of these genes play an important role in neuronal excitability, cortical development or synaptic transmission. A growing number of genetic variations have implications on diagnosis and prognostic or therapeutic advice in terms of a personalized medicine. Area covered: The review presents the different forms of genetic epilepsies with respect to their underlying genetic and functional pathophysiology and aims to give advice for recommended genetic testing. Moreover, it discusses ethical and legal guidelines, costs and technical limitations which should be considered. Expert commentary: Genetic testing is an important component in the diagnosis and treatment of many forms of epilepsy.

Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry.

PubMed

Dufour, Franck; Koning, Estelle; Nehlig, Astrid

2003-08-01

The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are considered an isomorphic, predictive, and homologous model of human generalized absence epilepsy. It is characterized by the expression of spike-and-wave discharges in the thalamus and cortex. In this strain, basal regional rates of cerebral glucose utilization measured by the quantitative autoradiographic [(14)C]2-deoxyglucose technique display a widespread consistent increase compared to a selected strain of genetically nonepileptic rats (NE). In order to verify whether these high rates of glucose metabolism are paralleled by elevated activities of the enzymes of the glycolytic and tricarboxylic acid cycle pathways, we measured by histochemistry the regional activity of the two key enzymes of glucose metabolism, lactate dehydrogenase (LDH) for the anaerobic pathway and cytochrome oxidase (CO) for the aerobic pathway coupled to oxidative phosphorylation. CO and LDH activities were significantly higher in GAERS than in NE rats in 24 and 28 of the 30 brain regions studied, respectively. The differences in CO and LDH activity between both strains were widespread, affected all brain systems studied, and ranged from 12 to 63%. The data of the present study confirm the generalized increase in cerebral glucose metabolism in GAERS, occurring both at the glycolytic and at the oxidative step. However, they still do not allow us to understand why the ubiquitous mutation(s) generates spike-and-wave discharges only in the thalamocortical circuit.

Decreased ERp57 Expression in WAG/Rij Rats Thalamus and Cortex; Possible Correlation with Absence Epilepsy.

PubMed

Sahin, Deniz; Karadenizli, Sabriye; Kasap, Murat; Oztas, Berrin; Kir, Hale Maral; Akpinar, Gurler; Ates, Nurbay

2018-02-06

The role of intracellular proteins in the pathogenesis of absence epilepsy were mentioned. These proteins are thought to be related to energy generation, signal transduction, inflammation processes and membrane conductance. The investigation of protein profile of the genetically epileptic rat brains was the main subject of this study. For this, a 2D-gel electrophoresis based comparative proteome analysis was performed using thalamus tissue of genetic absence epileptic WAG/Rij and age matched Wistar rats. Regulated spots displaying differences in their abundance were identified using MALDI-TOF/TOF. Among the six spots (DHRS9, BR44, HINT1, CREM, SPRE and PDIA3/ERp57) the highest mascot score was attributed to ERp57 a neuroprotective/neurodegenerative system associated protein. Western Blot analyses were performed to validate changes occurring at ERp57 in thalamus and also identify changes in fronto-parietal cortex. Reductions in the expression levels of ERp57 were detected in the thalamic and the fronto-parietal brain regions of the WAG/Rij rats in comparison to Wistar rats. Such difference might be associated with the pathogenic mechanisms dictating the absence epilepsy. Lower levels of ERp57 may be playing an important role in the development of spontaneous seizures activity seen in the absence epileptic WAG/Rij rats strain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy.

PubMed

Löscher, Wolfgang; Ferland, Russell J; Ferraro, Thomas N

2017-08-01

It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing. Copyright © 2017 Elsevier Inc. All rights reserved.

Epilepsy genetics: the ongoing revolution.

PubMed

Lesca, G; Depienne, C

2015-01-01

Epilepsies have long remained refractory to gene identification due to several obstacles, including a highly variable inter- and intrafamilial expressivity of the phenotypes, a high frequency of phenocopies, and a huge genetic heterogeneity. Recent technological breakthroughs, such as array comparative genomic hybridization and next generation sequencing, have been leading, in the past few years, to the identification of an increasing number of genomic regions and genes in which mutations or copy-number variations cause various epileptic disorders, revealing an enormous diversity of pathophysiological mechanisms. The field that has undergone the most striking revolution is that of epileptic encephalopathies, for which most of causing genes have been discovered since the year 2012. Some examples are the continuous spike-and-waves during slow-wave sleep and Landau-Kleffner syndromes for which the recent discovery of the role of GRIN2A mutations has finally confirmed the genetic bases. These new technologies begin to be used for diagnostic applications, and the main challenge now resides in the interpretation of the huge mass of variants detected by these methods. The identification of causative mutations in epilepsies provides definitive confirmation of the clinical diagnosis, allows accurate genetic counselling, and sometimes permits the development of new appropriate and specific antiepileptic therapies. Future challenges include the identification of the genetic or environmental factors that modify the epileptic phenotypes caused by mutations in a given gene and the understanding of the role of somatic mutations in sporadic epilepsies. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Using recurrence plot for determinism analysis of EEG recordings in genetic absence epilepsy rats.

PubMed

Ouyang, Gaoxiang; Li, Xiaoli; Dang, Chuangyin; Richards, Douglas A

2008-08-01

Understanding the transition of brain activity towards an absence seizure is a challenging task. In this paper, we use recurrence quantification analysis to indicate the deterministic dynamics of EEG series at the seizure-free, pre-seizure and seizure states in genetic absence epilepsy rats. The determinism measure, DET, based on recurrence plot, was applied to analyse these three EEG datasets, each dataset containing 300 single-channel EEG epochs of 5-s duration. Then, statistical analysis of the DET values in each dataset was carried out to determine whether their distributions over the three groups were significantly different. Furthermore, a surrogate technique was applied to calculate the significance level of determinism measures in EEG recordings. The mean (+/-SD) DET of EEG was 0.177+/-0.045 in pre-seizure intervals. The DET values of pre-seizure EEG data are significantly higher than those of seizure-free intervals, 0.123+/-0.023, (P<0.01), but lower than those of seizure intervals, 0.392+/-0.110, (P<0.01). Using surrogate data methods, the significance of determinism in EEG epochs was present in 25 of 300 (8.3%), 181 of 300 (60.3%) and 289 of 300 (96.3%) in seizure-free, pre-seizure and seizure intervals, respectively. Results provide some first indications that EEG epochs during pre-seizure intervals exhibit a higher degree of determinism than seizure-free EEG epochs, but lower than those in seizure EEG epochs in absence epilepsy. The proposed methods have the potential of detecting the transition between normal brain activity and the absence seizure state, thus opening up the possibility of intervention, whether electrical or pharmacological, to prevent the oncoming seizure.

Elevation of naloxone-sensitive /sup 3/H-dihydromorphine binding in hippocampal formation of genetically epilepsy-prone rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savage, D.D.; Mills, S.A.; Jobe, P.C.

1988-01-01

/sup 3/H-Dihydromorphine (DHM) binding sites were measured in the brain of non-epileptic control and GEPR rats using in vitro autoradiographic techniques. The number of naloxone-sensitive /sup 3/H-DHM binding sites was increased 38-57% in the pyramidal cell layer of ventral hippocampal CA/sub 3/ and CA/sub 1/ of GEPR-3 and GEPR-9 rats compared to non-epileptic controls. No significant differences in /sup 3/H-DHM binding were observed in dorsal hippocampal formation, lateral entorhinal cortex, lateral geniculate or cerebellum. The results suggest that an increase in the number of opioid receptors in ventral hippocampus of GEPR rats may be one factor contributing to the enhancedmore » sensitivity of GEPR-9 rats to the proconvulsant effects of morphine.« less

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

PubMed Central

2014-01-01

Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the

Genetics of reflex seizures and epilepsies in humans and animals.

PubMed

Italiano, Domenico; Striano, Pasquale; Russo, Emilio; Leo, Antonio; Spina, Edoardo; Zara, Federico; Striano, Salvatore; Gambardella, Antonio; Labate, Angelo; Gasparini, Sara; Lamberti, Marco; De Sarro, Giovambattista; Aguglia, Umberto; Ferlazzo, Edoardo

2016-03-01

Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. This comprehensive narrative review focuses on the role of genetic determinants in humans and animal models of reflex seizures and epilepsies. References were mainly identified through MEDLINE searches until August 2015 and backtracking of references in pertinent studies. Autosomal dominant inheritance with reduced penetrance was proven in several families with photosensitivity. Molecular genetic studies on EEG photoparoxysmal response identified putative loci on chromosomes 6, 7, 13 and 16 that seem to correlate with peculiar seizure phenotype. No specific mutation has been found in Papio papio baboon, although a genetic etiology is likely. Mutation in synaptic vesicle glycoprotein 2A was found in another animal model of photosensitivity (Fayoumi chickens). Autosomal dominant inheritance with incomplete penetrance overlapping with a genetic background for IGE was proposed for some families with primary reading epilepsy. Musicogenic seizures usually occur in patients with focal symptomatic or cryptogenic epilepsies, but they have been reported in rare genetic epilepsies such as Dravet syndrome. A single LGI1 mutation has been described in a girl with seizures evoked by auditory stimuli. Interestingly, heterozygous knockout (Lgi1(+/-)) mice show susceptibility to sound-triggered seizures. Moreover, in Frings and Black Swiss mice, the spontaneous mutations of MASS1 and JAMS1 genes, respectively, have been linked to audiogenic seizures. Eating seizures usually occur in symptomatic epilepsies but evidences for a genetic susceptibility were mainly provided by family report from Sri Lanka. Eating seizures were also reported in rare patients with MECP2 duplication or mutation. Hot water seizures are genetically heterogeneous but two loci at chromosomes 4 and 10 were identified in families with likely autosomal dominant inheritance. Startle-induced seizures usually occur in

Alterations in hippocampal and cortical densities of functionally different interneurons in rat models of absence epilepsy.

PubMed

Papp, Péter; Kovács, Zsolt; Szocsics, Péter; Juhász, Gábor; Maglóczky, Zsófia

2018-05-31

Recent data from absence epileptic patients and animal models provide evidence for significant impairments of attention, memory, and psychosocial functioning. Here, we outline aspects of the electrophysiological and structural background of these dysfunctions by investigating changes in hippocampal and cortical GABAergic inhibitory interneurons in two genetically absence epileptic rat strains: the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Using simultaneously recorded field potentials from the primary somatosensory cortex (S1 cortex, seizure focus) and the hippocampal hilus, we demonstrated that typical frequencies of spike-wave discharges (SWDs; 7-8 Hz, GAERS; 7-9 Hz, WAG/Rij) and their harmonics appeared and their EEG spectral power markedly increased on recordings not only from the S1 cortex, but also from the hilus in both GAERS and WAG/Rij rats during SWDs. Moreover, we observed an increased synchronization between S1 cortex and hilus at 7-8 Hz (GAERS) and 7-9 Hz (WAG/Rij) and at their harmonics when SWDs occurred in the S1 cortex in both rat strains. In addition, using immunohistochemistry we demonstrated changes in the densities of perisomatic (parvalbumin-immunopositive, PV+) and interneuron-selective (calretinin-immunopositive, CR+) GABAergic inhibitory interneuron somata. Specifically, GAERS and WAG/Rij rats displayed lower densities of PV-immunopositivity in the hippocampal hilus compared to non-epileptic control (NEC) and normal Wistar rats. GAERS and WAG/Rij rats also show a marked reduction in the density of CR + interneurons in the same region in comparison with NEC rats. Data from the S1 cortex reveals bidirectional differences in PV + density, with GAERS displaying a significant increase, whereas WAG/Rij a reduction compared to control rat strains. Our results suggest an enhanced synchronization and functional connections between the hippocampus and S1 cortex as well

Resistance Exercise Reduces Seizure Occurrence, Attenuates Memory Deficits and Restores BDNF Signaling in Rats with Chronic Epilepsy.

PubMed

de Almeida, Alexandre Aparecido; Gomes da Silva, Sérgio; Lopim, Glauber Menezes; Vannucci Campos, Diego; Fernandes, Jansen; Cabral, Francisco Romero; Arida, Ricardo Mario

2017-04-01

Epilepsy is a disease characterized by recurrent, unprovoked seizures. Cognitive impairment is an important comorbidity of chronic epilepsy. Human and animal model studies of epilepsy have shown that aerobic exercise induces beneficial structural and functional changes and reduces the number of seizures. However, little is yet understood about the effects of resistance exercise on epilepsy. We evaluated the effects of a resistance exercise program on the number of seizures, long-term memory and expression/activation of signaling proteins in rats with epilepsy. The number of seizures was quantified by video-monitoring and long-term memory was assessed by an inhibitory avoidance test. Using western blotting, multiplex and enzyme-linked immunosorbent assays, we determined the effects of a 4-week resistance exercise program on IGF-1 and BDNF levels and ERK, CREB, mTOR activation in the hippocampus of rats with epilepsy. Rats with epilepsy submitted to resistance exercise showed a decrease in the number of seizures compared to non-exercised epileptic rats. Memory deficits were attenuated by resistance exercise. Rats with epilepsy showed an increase in IGF-1 levels which were restored to control levels by resistance exercise. BDNF levels and ERK and mTOR activation were decreased in rats with epilepsy and resistance exercise restored these to control levels. In conclusion, resistance exercise reduced seizure occurrence and mitigated memory deficits in rats with epilepsy. These resistance exercise-induced beneficial effects can be related to changes in IGF-1 and BDNF levels and its signaling protein activation. Our findings indicate that the resistance exercise might be included as complementary therapeutic strategy for epilepsy treatment.

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

PubMed

Lee, Cha Gon; Lee, Jeehun; Lee, Munhyang

2018-01-01

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Genetic and forensic implications in epilepsy and cardiac arrhythmias: a case series.

PubMed

Partemi, Sara; Vidal, Monica Coll; Striano, Pasquale; Campuzano, Oscar; Allegue, Catarina; Pezzella, Marianna; Elia, Maurizio; Parisi, Pasquale; Belcastro, Vincenzo; Casellato, Susanna; Giordano, Lucio; Mastrangelo, Massimo; Pietrafusa, Nicola; Striano, Salvatore; Zara, Federico; Bianchi, Amedeo; Buti, Daniela; La Neve, Angela; Tassinari, Carlo Alberto; Oliva, Antonio; Brugada, Ramon

2015-05-01

Epilepsy affects approximately 3% of the world's population, and sudden death is a significant cause of death in this population. Sudden unexpected death in epilepsy (SUDEP) accounts for up to 17% of all these cases, which increases the rate of sudden death by 24-fold as compared to the general population. The underlying mechanisms are still not elucidated, but recent studies suggest the possibility that a common genetic channelopathy might contribute to both epilepsy and cardiac disease to increase the incidence of death via a lethal cardiac arrhythmia. We performed genetic testing in a large cohort of individuals with epilepsy and cardiac conduction disorders in order to identify genetic mutations that could play a role in the mechanism of sudden death. Putative pathogenic disease-causing mutations in genes encoding cardiac ion channel were detected in 24% of unrelated individuals with epilepsy. Segregation analysis through genetic screening of the available family members and functional studies are crucial tasks to understand and to prove the possible pathogenicity of the variant, but in our cohort, only two families were available. Despite further research should be performed to clarify the mechanism of coexistence of both clinical conditions, genetic analysis, applied also in post-mortem setting, could be very useful to identify genetic factors that predispose epileptic patients to sudden death, helping to prevent sudden death in patients with epilepsy.

Genetics Home Reference: SCN8A-related epilepsy with encephalopathy

MedlinePlus

... epilepsy with encephalopathy . This condition is estimated to account for 1 percent of all cases of epilepsy with encephalopathy. Related Information What information about a genetic condition can statistics ...

Time-frequency dynamics during sleep spindles on the EEG in rodents with a genetic predisposition to absence epilepsy (WAG/Rij rats)

NASA Astrophysics Data System (ADS)

Hramov, Alexander E.; Sitnikova, Evgenija Y.; Pavlov, Alexey N.; Grubov, Vadim V.; Koronovskii, Alexey A.; Khramova, Marina V.

2015-03-01

Sleep spindles are known to appear spontaneously in the thalamocortical neuronal network of the brain during slow-wave sleep; pathological processes in the thalamocortical network may be the reason of the absence epilepsy. The aim of the present work is to study developed changes in the time-frequency structure of sleep spindles during the progressive development of the absence epilepsy in WAG/Rij rats. EEG recordings were made at age 7 and 9 months. Automatic recognition and subsequent analysis of sleep spindles on the EEG were performed using the continuous wavelet transform. The duration of epileptic discharges and the total duration of epileptic activity were found to increase with age, while the duration of sleep spindles, conversely, decreased. In terms of the mean frequency, sleep spindles could be divided into three classes: `slow' (mean frequency 9.3Hz), `medium' (11.4Hz), and `fast' (13.5Hz). Slow and medium (transitional) spindles in five-month-old animals showed increased frequency from the beginning to the end of the spindle. The more intense the epilepsy is, the shorter are the durations of spindles of all types. The mean frequencies of `medium' and `fast' spindles were higher in rats with more intense signs of epilepsy. Overall, high epileptic activity in WAG/Rij rats was linked with significant changes in spindles of the transitional type, with less marked changes in the two traditionally identified types of spindle, slow and fast.

BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy.

PubMed

Foley, Jeannine; Burnham, Veronica; Tedoldi, Meghan; Danial, Nika N; Yellen, Gary

2018-01-01

Metabolic alteration, either through the ketogenic diet (KD) or by genetic alteration of the BAD protein, can produce seizure protection in acute chemoconvulsant models of epilepsy. To assess the seizure-protective role of knocking out (KO) the Bad gene in a chronic epilepsy model, we used the Kcna1 -/- model of epilepsy, which displays progressively increased seizure severity and recapitulates the early death seen in sudden unexplained death in epilepsy (SUDEP). Beginning on postnatal day 24 (P24), we continuously video monitored Kcna1 -/- and Kcna1 -/- Bad -/- double knockout mice to assess survival and seizure severity. We found that Kcna1 -/- Bad -/- mice outlived Kcna1 -/- mice by approximately 2 weeks. Kcna1 -/- Bad -/- mice also spent significantly less time in seizure than Kcna1 -/- mice on P24 and the day of death, showing that BadKO provides seizure resistance in a genetic model of chronic epilepsy. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Pre-existing differences and diet-induced alterations in striatal dopamine systems of obesity-prone rats.

PubMed

Vollbrecht, Peter J; Mabrouk, Omar S; Nelson, Andrew D; Kennedy, Robert T; Ferrario, Carrie R

2016-03-01

Interactions between pre-existing differences in mesolimbic function and neuroadaptations induced by consumption of fatty, sugary foods are thought to contribute to human obesity. This study examined basal and cocaine-induced changes in striatal neurotransmitter levels without diet manipulation and D2 /D3 dopamine receptor-mediated transmission prior to and after consumption of "junk-foods" in obesity-prone and obesity-resistant rats. Microdialysis and liquid chromatography-mass spectrometry were used to determine basal and cocaine-induced changes in neurotransmitter levels in real time with cocaine-induced locomotor activity. Sensitivity to the D2 /D3 dopamine receptor agonist quinpirole was examined before and after restricted junk-food exposure. Selectively bred obesity-prone and obesity-resistant rats were used. Cocaine-induced locomotion was greater in obesity-prone rats versus obesity-resistant rats prior to diet manipulation. Basal and cocaine-induced increases in dopamine and serotonin levels did not differ. Obesity-prone rats were more sensitive to the D2 receptor-mediated effects of quinpirole, and junk-food produced modest alterations in quinpirole sensitivity in obesity-resistant rats. These data show that mesolimbic systems differ prior to diet manipulation in susceptible versus resistant rats, and that consumption of fatty, sugary foods produce different neuroadaptations in these populations. These differences may contribute to enhanced food craving and an inability to limit food intake in susceptible individuals. © 2016 The Obesity Society.

Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats.

PubMed

Vogel, Heike; Kraemer, Maria; Rabasa, Cristina; Askevik, Kaisa; Adan, Roger A H; Dickson, Suzanne L

2017-06-15

Here we sought to define behavioural traits linked to anxiety, reward, and exploration in different strains of rats commonly used in obesity research. We hypothesized that genetic variance may contribute not only to their metabolic phenotype (that is well documented) but also to the expression of these behavioural traits. Rat strains that differ in their susceptibility to develop an obese phenotype (Sprague-Dawley, Obese Prone, Obese Resistant, and Zucker rats) were exposed to a number of behavioural tests starting at the age of 8 weeks. We found a similar phenotype in the obesity susceptible models, Obese Prone and Zucker rats, with a lower locomotor activity, exploratory activity, and higher level of anxiety-like behaviour in comparison to the leaner Obese Resistant strain. We did not find evidence that rat strains with a genetic predisposition to obesity differed in their ability to experience reward from chocolate (in a condition place preference task). However, Zucker rats show higher motivated behaviour for sucrose compared to Obese Resistant rats when the effort required to obtain palatable food is relatively low. Together our data demonstrate that rat strains that differ in their genetic predisposition to develop obesity also differ in their performance in behavioural tests linked to anxiety, exploration, and reward and that these differences are independent of body weight. We conclude that genetic variations which determine body weight and the aforementioned behaviours co-exist but that future studies are required to identify whether (and which) common genes are involved. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model.

PubMed

Bercum, Florencia M; Rodgers, Krista M; Benison, Alex M; Smith, Zachariah Z; Taylor, Jeremy; Kornreich, Elise; Grabenstatter, Heidi L; Dudek, F Edward; Barth, Daniel S

2015-12-02

Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome. Copyright © 2015 the authors 0270-6474/15/3515894-09$15.00/0.

Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy.

PubMed

Ren, Min; Li, Kunyi; Wang, Dan; Guo, Jiamei; Li, Jing; Yang, Guang; Long, Xianghua; Shen, Wenjing; Hu, Rong; Wang, Xuefeng; Zeng, Kebin

2016-11-01

Studies have shown that neurofibromin (NF1) restricts GABA release at inhibitory synapses and regulates dendritic spine formation, which may play an important role in temporal lobe epilepsy (TLE). NF1 expression was detected by double-label immunofluorescence, immunohistochemistry, and western blot analysis in the brains of pilocarpine-induced epilepsy model rats at 6 h, 24 h, 72 h, 7 days, 14 days, 30 days, and 60 days after kindling. NF1 was localized primarily in the nucleus and cytoplasm of neurons. NF1 protein levels significantly increased in the chronic phase (from 7 days until 60 days) in this epileptic rat model. After NF1 expression was knocked down by specific siRNA, the effects of kindling with pilocarpine were evaluated on the 7th day after kindling. The onset latencies of pilocarpine-induced seizures were elevated, and the seizure frequency and duration were reduced in these rats. Our study demonstrates that NF1 promoted seizure attacks in rats with pilocarpine-induced epilepsy.

E-learning courses in epilepsy--concept, evaluation, and experience with the e-learning course "genetics of epilepsies".

PubMed

Wehrs, Verena Hézser-V; Pfäfflin, Margarete; May, Theodor W

2007-05-01

To evaluate the efficacy of the e-learning course "Genetics of Epilepsies" and to assess the experiences of the participants and e-moderators with this new approach. Prospective, controlled study with waiting group (control group, n = 18) and e-learning group (n = 20). The control group got the same reference literature list as the e-learning group. Both groups were assessed twice: The e-learning group before and after the course; the control group was assessed at the same times. increase in knowledge about genetics of epilepsies using questionnaires based on items formulated by experts (internal consistency, Cronbach's alpha = 0.86). Main hypothesis: greater increase of knowledge in the e-learning group compared to control group. assessment of the educational course and learning environment by participants and by tutors/e-moderators. Significant time x group interaction and group effect (ANOVA, each p < 0.01) with regard to knowledge. At baseline, the groups did not differ with respect to knowledge about genetics of epilepsy. In contrast to the control group, the increase of knowledge in the e-learning group was highly significant (p < 0.001). The majority of the participants of the e-learning course was content with their personal learning process (75% agree, 15% strongly agree). Most of them reported a gain in competence in the treatment and counseling of people with epilepsy (38.9% agree, 50% strongly agree). All participants would recommend this course to others and all but one participant are interested in other e-learning courses. The study indicates e-learning courses are an appropriate tool to improve knowledge of physicians in genetics of epilepsy.

Expression of SHANK3 in the Temporal Neocortex of Patients with Intractable Temporal Epilepsy and Epilepsy Rat Models.

PubMed

Zhang, Yanke; Gao, Baobing; Xiong, Yan; Zheng, Fangshuo; Xu, Xin; Yang, Yong; Hu, Yida; Wang, Xuefeng

2017-07-01

SH3 and multiple ankyrin (ANK) repeat domain 3 (SHANK3) is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. SHANK3 plays an important role in the formation and maturation of excitatory synapses. In the brain, SHANK3 directly or indirectly interacts with various synaptic molecules including N-methyl-D-aspartate receptor, the metabotropic glutamate receptor (mGluR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Previous studies have shown that Autism spectrum disorder is a result of mutations of the main SHANK3 isoforms, which may be due to deficit in excitatory synaptic transmission and plasticity. Recently, accumulating evidence has demonstrated that overexpression of SHANK3 could induce seizures in vivo. However, little is known about the role of SHANK3 in refractory temporal lobe epilepsy (TLE). Therefore, we investigated the expression pattern of SHANK3 in patients with intractable temporal lobe epilepsy and in pilocarpine-induced models of epilepsy. Immunofluorescence, immunohistochemistry, and western blot analysis were used to locate and determine the expression of SHANK3 in the temporal neocortex of patients with epilepsy, and in the hippocampus and temporal lobe cortex of rats in a pilocarpine-induced epilepsy model. Double-labeled immunofluorescence showed that SHANK3 was mainly expressed in neurons. Western blot analysis confirmed that SHANK3 expression was increased in the neocortex of TLE patients and rats. These results indicate that SHANK3 participates in the pathology of epilepsy.

Up-regulated BAFF and BAFF receptor expression in patients with intractable temporal lobe epilepsy and a pilocarpine-induced epilepsy rat model.

PubMed

Ma, Limin; Li, Ruohan; Huang, Hao; Yuan, Jinxian; Ou, Shu; Xu, Tao; Yu, Xinyuan; Liu, Xi; Chen, Yangmei

2017-05-01

Some studies have suggested that BAFF and BAFFR are highly expressed in the central nervous system (CNS) and participate in inflammatory and immune associated diseases. However, whether BAFF and BAFFR are involved in the pathogenesis of epilepsy remains unknown. This study aimed to investigate the expression of BAFF and BAFFR proteins in the brains of patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model of TLE to identify possible roles of the BAFF-BAFFR signaling pathway in epileptogenesis. Real-time quantitative polymerase chain reaction (RT-qPCR), western blot, immunohistochemistry, and double-immunofluorescence were performed in this study. The results showed that BAFF and BAFFR expression levels were markedly up-regulated in intractable TLE patients and TLE rats. Moreover, BAFF and BAFFR proteins mainly highly expressed in the membranes and cytoplasms of the dendritic marker MAP2 in the cortex and hippocampus. Therefore, the significant increased in BAFF and BAFFR protein expression in both TLE patients and rats suggest that BAFF and BAFFR may play important roles in regulating the pathogenesis of epilepsy. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Pre-existing differences in motivation for food and sensitivity to cocaine-induced locomotion in obesity-prone rats.

PubMed

Vollbrecht, Peter J; Nobile, Cameron W; Chadderdon, Aaron M; Jutkiewicz, Emily M; Ferrario, Carrie R

2015-12-01

Obesity is a significant problem in the United States, with roughly one third of adults having a body mass index (BMI) over thirty. Recent evidence from human studies suggests that pre-existing differences in the function of mesolimbic circuits that mediate motivational processes may promote obesity and hamper weight loss. However, few preclinical studies have examined pre-existing neurobehavioral differences related to the function of mesolimbic systems in models of individual susceptibility to obesity. Here, we used selectively bred obesity-prone and obesity-resistant rats to examine 1) the effect of a novel "junk-food" diet on the development of obesity and metabolic dysfunction, 2) over-consumption of "junk-food" in a free access procedure, 3) motivation for food using instrumental procedures, and 4) cocaine-induced locomotor activity as an index of general mesolimbic function. As expected, eating a sugary, fatty, "junk-food" diet exacerbated weight gain and increased fasted insulin levels only in obesity-prone rats. In addition, obesity-prone rats continued to over-consume junk-food during discrete access testing, even when this same food was freely available in the home cage. Furthermore, when asked to press a lever to obtain food in an instrumental task, rates of responding were enhanced in obesity-prone versus obesity-resistant rats. Finally, obesity-prone rats showed a stronger locomotor response to 15 mg/kg cocaine compared to obesity-resistant rats prior to any diet manipulation. This enhanced sensitivity to this dose of cocaine is indicative of basal differences in the function of mesolimbic circuits in obesity-prone rats. We speculate that pre-existing differences in motivational systems may contribute to over-consumption and enhanced motivation in susceptible individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

Pre-existing differences in motivation for food and sensitivity to cocaine-induced locomotion in obesity-prone rats

PubMed Central

Vollbrecht, Peter J.; Nobile, Cameron W.; Chadderdon, Aaron M.; Jutkiewicz, Emily M.; Ferrario, Carrie R.

2015-01-01

Obesity is a significant problem in the United States, with roughly one third of adults having a body mass index (BMI) over thirty. Recent evidence from human studies suggests that pre-existing differences in the function of mesolimbic circuits that mediate motivational processes may promote obesity and hamper weight loss. However, few preclinical studies have examined pre-existing neurobehavioral differences related to the function of mesolimbic systems in models of individual susceptibility to obesity. Here, we used selectively bred obesity-prone and obesity-resistant rats to examine 1) the effect of a novel “junk-food” diet on the development of obesity and metabolic dysfunction, 2) over-consumption of “junk-food” in a free access procedure, 3) motivation for food using instrumental procedures, and 4) cocaine-induced locomotor activity as an index of general mesolimbic function. As expected, eating a sugary, fatty, “junk-food” diet exacerbated weight gain and increased fasted insulin levels only in obesity-prone rats. In addition, obesity-prone rats continued to over-consume junk-food during discrete access testing, even when this same food was freely available in the home cage. Furthermore, when asked to press a lever to obtain food in an instrumental task, rates of responding were enhanced in obesity-prone versus obesity-resistant rats. Finally, obesity-prone rats showed a stronger locomotor response to 15 mg/kg cocaine compared to obesity-resistant rats prior to any diet manipulation. This enhanced sensitivity to this dose of cocaine is indicative of basal differences in the function of mesolimbic circuits in obesity-prone rats. We speculate that pre-existing differences in motivational systems may contribute to over-consumption and enhanced motivation in susceptible individuals. PMID:26423787

Can mutation-mediated effects occurring early in development cause long-term seizure susceptibility in genetic generalized epilepsies?

PubMed

Reid, Christopher Alan; Rollo, Ben; Petrou, Steven; Berkovic, Samuel F

2018-05-01

Epilepsy has a strong genetic component, with an ever-increasing number of disease-causing genes being discovered. Most epilepsy-causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here we review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub-mesoscopic structural changes in GGE is also reviewed. Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub-mesoscopic structural changes occur in GGE. The existence of sub-mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. We also propose that presymptomatic treatment may be essential for limiting the long-term consequences of disease-causing mutations in genetic epilepsies. Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.

Management of genetic epilepsies: From empirical treatment to precision medicine.

PubMed

Striano, Pasquale; Vari, Maria Stella; Mazzocchetti, Chiara; Verrotti, Alberto; Zara, Federico

2016-05-01

Despite the over 20 antiepileptic drugs (AEDs) now licensed for epilepsy treatment, seizures can be effectively controlled in about ∼70% of patients. Thus, epilepsy treatment is still challenging in about one third of patients and this may lead to a severe medically, physically, and socially disabling condition. However, there is clear evidence of heterogeneity of response to existing AEDs and a significant unmet need for effective intervention. A number of studies have shown that polymorphisms may influence the poor or inadequate therapeutic response as well as the occurrence of adverse effects. In addition, the new frontier of genomic technologies, including chromosome microarrays and next-generation sequencing, improved our understanding of the genetic architecture of epilepsies. Recent findings in some genetic epilepsy syndromes provide insights into mechanisms of epileptogenesis, unrevealing the role of a number of genes with different functions, such as ion channels, proteins associated to the vesical synaptic cycle or involved in energy metabolism. The rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis are revolutionizing the practice and it is a fact that for some monogenic epilepsies the molecular confirmation may influence the choice of the treatment. Moreover, the novel genetic methods, that are able to analyze all known genes at a reasonable price, are of paramount importance to discover novel therapeutic avenues and individualized (or precision) medicine. Copyright © 2016 Elsevier Ltd. All rights reserved.

A spontaneous mutation of the Wwox gene and audiogenic seizures in rats with lethal dwarfism and epilepsy.

PubMed

Suzuki, H; Katayama, K; Takenaka, M; Amakasu, K; Saito, K; Suzuki, K

2009-10-01

The lde/lde rat is characterized by dwarfism, postnatal lethality, male hypogonadism, a high incidence of epilepsy and many vacuoles in the hippocampus and amygdala. We used a candidate approach to identify the gene responsible for the lde phenotype and assessed the susceptibility of lde/lde rats for audiogenic seizures. Following backcross breeding of lethal dwarfism with epilepsy (LDE) to Brown Norway rats, the lde/lde rats with an altered genetic background showed all pleiotropic phenotypes. The lde locus was mapped to a 1.5-Mbp region on rat chromosome 19 that included the latter half of the Wwox gene. Sequencing of the full-length Wwox transcript identified a 13-bp deletion in exon 9 in lde/lde rats. This mutation causes a frame shift, resulting in aberrant amino acid sequences at the C-terminal. Western blotting showed that both the full-length products of the Wwox gene and its isoform were present in normal testes and hippocampi, whereas both products were undetectable in the testes and hippocampi of lde/lde rats. Sound stimulation induced epileptic seizures in 95% of lde/lde rats, with starting as wild running (WR), sometimes progressing to tonic-clonic convulsions. Electroencephalogram (EEG) analysis showed interictal spikes, fast waves during WR and burst of spikes during clonic phases. The Wwox protein is expressed in the central nervous system (CNS), indicating that abnormal neuronal excitability in lde/lde rats may be because of a lack of Wwox function. The lde/lde rat is not only useful for understanding the multiple functions of Wwox but is also a unique model for studying the physiological function of Wwox in CNS.

Abnormal TNF-alpha production in diabetes-prone BB rats: enhanced TNF-alpha expression and defective PGE2 feedback inhibition.

PubMed Central

Rothe, H; Ongören, C; Martin, S; Rösen, P; Kolb, H

1994-01-01

Upon stimulation with lipopolysaccharide (LPS), peritoneal macrophages from diabetes-prone Bio-Breeding (BB) rats secrete more tumour necrosis factor-alpha (TNF-alpha) than macrophages from diabetes-resistant BB or normal Wistar rats. Enhanced transcription was demonstrated by Northern blot analysis and at the single cell level by mRNA: RNA hybridization. Cytofluorometry analysis showed 2-4 times more plasma membrane and total cell-associated TNF-alpha in macrophages of diabetes-prone BB rats. The analysis of fluorescence intensity showed a single peak, and TNF-alpha mRNA was found in > 90% of macrophages. These findings exclude TNF hypersecretion as being due to an abnormal subfraction of cells. TNF-alpha gene hyperexpression in diabetes-prone BB rats was not due to mutations in the regulatory regions of the promoter, which could be shown by cloning and sequencing of the TNF-alpha promoter in the three rat strains. When searching for other regulatory defects we found the production of prostaglandin E2 (PGE2) in response to LPS to be up to 10 times lower in macrophages from diabetes-prone BB rats than from Wistar rats. Furthermore, BB rats macrophages required significantly higher concentrations of PGE2 for suppression of TNF-alpha secretion. We conclude that abnormal TNF-alpha production in macrophages from diabetes-prone BB rats is due to enhanced gene transcription and translation and that this is associated with defective PGE2 feedback inhibition. Images Figure 1 Figure 2 PMID:8206514

Barriers to the use of genetic information for the development of new epilepsy treatments.

PubMed

Ferraro, Thomas N

2016-01-01

Genetic analysis is providing new information on the biological basis of epilepsy at a rapid pace; this article identifies factors acting as major barriers to use of these data for therapy development. Disease heterogeneity is a primary obstacle since so many genes can cause or predispose to epilepsy and the clinical presentation of epilepsy is so diverse, thus making it difficult to define the most therapeutically relevant targets. Further, many epilepsy genes affect brain development, an observation that represents a barrier unto itself given the challenge of reversing or preventing genetically mediated alterations of brain pathway formation. Finally, the lack of appropriate models for testing new therapies is also recognized as a fundamental limitation. Overcoming these barriers will be aided by full characterization of the genetic landscape of epilepsy, elucidation of key pathway points for therapeutic intervention and creation of unique experimental models to validate results.

Genetic (idiopathic) epilepsy with photosensitive seizures includes features of both focal and generalized seizures.

PubMed

Xue, Jiao; Gong, Pan; Yang, Haipo; Liu, Xiaoyan; Jiang, Yuwu; Zhang, Yuehua; Yang, Zhixian

2018-04-19

Clinically, some patients having genetic (idiopathic) epilepsy with photosensitive seizures were difficult to be diagnosed. We aimed to discuss whether the genetic (idiopathic) epilepsy with photosensitive seizures is a focal entity, a generalized entity or a continuum. Twenty-two patients with idiopathic epilepsies and photoconvulsive response (PCR) were retrospectively recruited. In the medical records, the seizure types included "generalized tonic-clonic seizures (GTCS)" in 15, "partial secondarily GTCS (PGTCS)" in 3, partial seizures (PS) in 3, myoclonic seizures in 2, eyelid myoclonus in one, and only febrile seizures in one. Seizure types of PCR included GTCS (1/22), PGTCS (6/22), PS (9/22), electrical seizures (ES) (3/22) and GTCS/PGTCS (3/22). Combined the medical history with PCR results, they were diagnosed as: idiopathic (photosensitive) occipital lobe epilepsy (I(P)OE) in 12, genetic (idiopathic) generalized epilepsy (GGE) in one, GGE/I(P)OE in 5, pure photosensitive seizure in one, and epilepsy with undetermined generalized or focal seizure in 3. So, the dichotomy between generalized and focal seizures might have been out of date regarding to pathophysiological advances in epileptology. To some extent, it would be better to recognize the idiopathic epilepsy with photosensitive seizures as a continuum between focal and generalized seizures.

Self-administered nicotine differentially impacts body weight gain in obesity-prone and obesity-resistant rats.

PubMed

Rupprecht, Laura E; Smith, Tracy T; Donny, Eric C; Sved, Alan F

2017-07-01

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown. In the current experiment, body weight gain of adult male rats maintained on a high energy diet (31.8% kcal from fat) distributed into obesity-prone (OP), obesity-resistant (OR) and an intermediate group, which was placed on standard rodent chow (Chow). These rats were surgically implanted with intravenous catheters and allowed to self-administer nicotine (0 or 60μg/kg/infusion, a standard self-administration dose) in 1-h sessions for 20 consecutive days. Self-administered nicotine significantly suppressed body weight gain but not food intake in OP and Chow rats. Self-administered nicotine had no effect on body weight gain in OR rats. These data suggest that: 1) OR rats are also resistant to nicotine-induced suppression of body weight gain; and 2) nicotine may reduce levels of obesity in a subset of smokers prone to obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

PubMed Central

Wang, Yimin; Du, Xiaonan; Bin, Rao; Yu, Shanshan; Xia, Zhezhi; Zheng, Guo; Zhong, Jianmin; Zhang, Yunjian; Jiang, Yong-hui; Wang, Yi

2017-01-01

Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children. PMID:28074849

Impaired central respiratory chemoreflex in an experimental genetic model of epilepsy

PubMed Central

Totola, Leonardo T.; Takakura, Ana C.; Oliveira, José Antonio C.

2016-01-01

Key points It is recognized that seizures commonly cause apnoea and oxygen desaturation, but there is still a lack in the literature about the respiratory impairments observed ictally and in the post‐ictal period.Respiratory disorders may involve changes in serotonergic transmission at the level of the retrotrapezoid nucleus (RTN).In this study, we evaluated breathing activity and the role of serotonergic transmission in the RTN with a rat model of tonic–clonic seizures, the Wistar audiogenic rat (WAR).We conclude that the respiratory impairment in the WAR could be correlated to an overall decrease in the number of neurons located in the respiratory column. Abstract Respiratory disorders may involve changes in serotonergic neurotransmission at the level of the chemosensitive neurons located in the retrotrapezoid nucleus (RTN). Here, we investigated the central respiratory chemoreflex and the role of serotonergic neurotransmission in the RTN with a rat model of tonic–clonic seizures, the Wistar audiogenic rat (WAR). We found that naive or kindled WARs have reduced resting ventilation and ventilatory response to hypercapnia (7% CO2). The number of chemically coded (Phox2b+/TH−) RTN neurons, as well as the serotonergic innervation to the RTN, was reduced in WARs. We detected that the ventilatory response to serotonin (1 mm, 50 nl) within the RTN region was significantly reduced in WARs. Our results uniquely demonstrated a respiratory impairment in a genetic model of tonic–clonic seizures, the WAR strain. More importantly, we demonstrated an overall decrease in the number of neurons located in the ventral respiratory column (VRC), as well as a reduction in serotonergic neurons in the midline medulla. This is an important step forward to demonstrate marked changes in neuronal activity and breathing impairment in the WAR strain, a genetic model of epilepsy. PMID:27633663

Genes, Seizures & Epilepsy

ERIC Educational Resources Information Center

Goldman, Alica M.

2006-01-01

The chance that someone will develop any disease is influenced by heredity and environment. Epilepsy is not an exception. Everybody inherits a unique degree of susceptibility to seizures. About 3 percent of the United States population is prone to seizures and will get epilepsy at some point of their lives (1). Two thirds of the people with…

Cognitive impairment and spontaneous epilepsy in rats with malformations of cortical development.

PubMed

Ye-wei, Xiao; Rong, Wang; Xun-tai, Ma; Shan, Zhang; Qian, Chen; Shi-hua, Huang; Fu-qun, Mao; Xiao-ming, Xiong

2015-12-01

To examine the cognition, spontaneous epilepsy, and electroencephalography (EEG) characteristics of rats with malformations of cortical development (MCD) and their use as an animal model for investigating the pathogenesis of intractable epilepsy and screening novel antiepileptic drugs. An epileptic rat model of MCD was established with the F1 generation of pregnant rats after X-irradiation with 175 cGy (Group L), 195 cGy (Group M), or 215 cGy (Group H). Long-term video-EEG monitoring was used to record the seizures in the rats with MCD. Cognition was assessed with the Morris water maze. The EEGs were recorded and analyzed in the frontal and parietal lobes and hippocampi of adult rats. Finally, the brain tissues were processed for Nissl staining. The model groups exhibited markedly prolonged escape latencies and distinct decrements in the percent distance traveled in the target quadrant and platform-crossing frequency. These findings were dose-dependent. Frequent interictal epileptiform discharges were observed in the frontal and parietal lobes and hippocampi of adult rats, and their incidences were markedly higher in the model groups compared with that in the normal controls, with Group M having the highest incidence. Spontaneous seizures were observed in the model groups (mean incidence, 46.7%). The daily mean frequency of seizures and the incidence of spontaneous seizures were highest in Group M. Nissl staining revealed a dose-dependent pattern of hippocampal abnormalities, cortical and subcortical nodular heterotopia, and callosal agenesis in the model groups. The 195 cGy dose was most appropriate for establishing an epileptic model of MCD with X-irradiation. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Neuronal zinc-α2-glycoprotein is decreased in temporal lobe epilepsy in patients and rats.

PubMed

Liu, Ying; Wang, Teng; Liu, Xi; Wei, Xin; Xu, Tao; Yin, Maojia; Ding, Xueying; Mo, Lijuan; Chen, Lifen

2017-08-15

Zinc-α2-glycoprotein (ZAG) is a 42-kDa protein encoded by the AZGP1 gene that is known as a lipid mobilizing factor and is highly homologous to major histocompatibility complex class I family molecules. Recently, transcriptomic research has shown that AZGP1 expression is reduced in the brain tissue of epilepsy patients. However, the cellular distribution and biological role of ZAG in the brain and epilepsy are unclear. Patients with refractory temporal lobe epilepsy (TLE) and brain trauma were included in this study, and pentylenetetrazole (PTZ)-kindled rats were also used. The existence and level of ZAG in the brain were identified using immunohistochemistry, double-labeled immunofluorescence and western blot, and the expression level of AZGP1 mRNA was determined with quantitative real-time polymerase chain reaction (qrt-PCR). To explore the potential biological role of ZAG in the brain, co-immunoprecipitation (Co-IP) of phosphorylated ERK (p-ERK), TGF-β1 and ZAG was also performed. ZAG was found in the cytoplasm of neurons in brain tissue from both patients and rats. The levels of AZGP1 mRNA and ZAG were lower in refractory TLE patients and PTZ-kindled rats than in controls. In addition, the ZAG level decreased as PTZ kindling continued. Co-IP identified direct binding between p-ERK, TGF-β1 and ZAG. ZAG was found to be synthesized in neurons, and both the AZGP1 mRNA and ZAG protein levels were decreased in epilepsy patients and rat models. The reduction in ZAG may participate in the pathogenesis and pathophysiology of epilepsy by interacting with p-ERK and TGF-β1, promoting inflammation, regulating the metabolism of ketone bodies, or affecting other epilepsy-related molecules. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Advancing epilepsy treatment through personalized genetic zebrafish models.

PubMed

Griffin, A; Krasniak, C; Baraban, S C

2016-01-01

With an increase in the number of disease causing genetic mutations identified from epilepsy cohorts, zebrafish are proving to be an attractive vertebrate model for functional analysis of these allele variants. Not only do zebrafish have conserved gene functions, but larvae harboring mutations in identified human epileptic genes show spontaneous seizure activity and mimic the convulsive behavioral movements observed in humans. With zebrafish being compatible with medium to high-throughput screening, they are also proving to be a unique and powerful system for early preclinical drug screening, including novel target identification, pharmacology, and toxicology. Additionally, with recent advances in genomic engineering technologies, it is now possible to study the precise pathophysiology of patient-specific gene mutations in zebrafish. The following sections highlight how the unique attributes of zebrafish, in combination with genetic modifications, are continuing to transform our understanding of epilepsy and help identify personalized therapeutics for specific patient cohorts. © 2016 Elsevier B.V. All rights reserved.

Inherited epilepsy in dogs.

PubMed

Ekenstedt, Kari J; Oberbauer, Anita M

2013-05-01

Epilepsy is the most common neurologic disease in dogs and many forms are considered to have a genetic basis. In contrast, some seizure disorders are also heritable, but are not technically defined as epilepsy. Investigation of true canine epilepsies has uncovered genetic associations in some cases, however, many remain unexplained. Gene mutations have been described for 2 forms of canine epilepsy: primary epilepsy (PE) and progressive myoclonic epilepsies. To date, 9 genes have been described to underlie progressive myoclonic epilepsies in several dog breeds. Investigations into genetic PE have been less successful, with only 1 causative gene described. Genetic testing as an aid to diagnosis, prognosis, and breeding decisions is available for these 10 forms. Additional studies utilizing genome-wide tools have identified PE loci of interest; however, specific genetic tests are not yet developed. Many studies of dog breeds with PE have failed to identify genes or loci of interest, suggesting that, similar to what is seen in many human genetic epilepsies, inheritance is likely complex, involving several or many genes, and reflective of environmental interactions. An individual dog's response to therapeutic intervention for epilepsy may also be genetically complex. Although the field of inherited epilepsy has faced challenges, particularly with PE, newer technologies contribute to further advances. © 2013 Elsevier Inc. All rights reserved.

American Epilepsy Society

MedlinePlus

... Epilepsy Society CLINICAL RESOURCES FAQs GUIDELINES IOM EPILEPSY MEDICAL MARIJUANA SUDEP SURGERY DEVICES GENETICS TREATMENTS Drug Alerts and ... RESOURCES Navigation CLINICAL RESOURCES FAQs GUIDELINES IOM EPILEPSY MEDICAL MARIJUANA SUDEP SURGERY DEVICES GENETICS TREATMENTS Drug Alerts and ...

Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.

PubMed

Marchese, Maria; Conti, Valerio; Valvo, Giulia; Moro, Francesca; Muratori, Filippo; Tancredi, Raffaella; Santorelli, Filippo M; Guerrini, Renzo; Sicca, Federico

2014-02-27

With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly. We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly. Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile ("extreme" macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with "extreme" macrocephaly, autism, intellectual disability and seizures. We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with "extreme" macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical

Ethnic variation of genetic (idiopathic) generalized epilepsy in Malaysia.

PubMed

Lim, Kheng Seang; Ng, Ching Ching; Chan, Chung Kin; Foo, Wee Shean; Low, Joyce Siew Yong; Tan, Chong Tin

2017-02-01

Ethnic variation in epilepsy classification was reported in the Epilepsy Phenome/Genome Project. This study aimed to determine the ethnic variation in the prevalence of genetic (idiopathic) generalized epilepsy (GGE) and GGE with family history in a multi-ethnic Asian population in Malaysia. In this cross-sectional study, 392 patients with a clinical diagnosis of GGE were recruited in the neurology outpatient clinic, University of Malaya Medical Centre (UMMC), from January 2011 till April 2016. In our epilepsy cohort (n=2100), 18.7% were diagnosed to have GGE. Of those, 28.6% >(N=112) had family history of epilepsy with a mean age of seizure onset of 16.5 years old, and 42.0% had myoclonic seizures (N=47). The lifetime prevalence of epilepsy among first-degree relative of those with GGE and positive family history was 15.0%. Analysis according to ethnicity showed that Malaysian Chinese had the lowest percentage of GGE among those with epilepsy (12.3%), as compared with Indian and Malay (25.3% and 21.3%, p<0.001). In addition, 32.1% of these Indian patients with GGE had positive family history, which is more than the Malay (26.4%) and Chinese (27.5%) ethnic groups. Consanguineous marriage was noted in 5 Indian families with positive family history (9.6%). There was ethnic variation in the prevalence of GGE, whereby the Malaysian Chinese had the lowest percentage of GGE as compared with Indian and Malay. A substantial proportion of GGE had positive family history among the three ethnics groups. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Might astrocytes play a role in maintaining the seizure-prone state?

PubMed

Vessal, Mani; Dugani, Chandrasagar B; Solomon, Dianand A; McIntyre Burnham, W; Ivy, Gwen O

2005-05-24

The amygdala-kindling model is used to study complex partial epilepsy with secondary generalization. The present study was designed to (A) quantify astrocytic changes in the piriform cortex of amygdala-kindled subjects over time and (B) investigate the role that astrocytes might play in maintaining the seizure-prone state. In Study A, once the experimental subjects reached five stage 5 seizures, stimulation was stopped, and both kindled and control rats were allowed to survive for the interval appropriate to their group (7, 18, 30, or 90 days). Following each interval, the kindled and control animals were given 10 intraperitoneal injections of bromodeoxyuridine (BrdU) and sacrificed 24 h following the last injection. Significantly higher numbers of dividing astrocytes (identified by co-labeling for BrdU and to one of the astrocytic intermediate filament proteins glial fibrillary acidic protein or vimentin) were found in the kindled brains. All kindled groups had significantly higher numbers of double-labeled cells on the side contralateral to the stimulation site, except for those in the 90 day survival group. In Study B, rats were implanted with chemotrodes, were kindled as in Study A, and were subsequently infused with either saline or with L alpha-AA (to lesion astrocytes) during a further 25 stimulations (1/day). L alpha-AA infused rats had significantly diminished levels of behavioral seizures, higher after discharge thresholds, lower after discharge durations, and decreased numbers of double-labeled astrocytes in piriform cortex than did saline infused rats. Together, the data indicate that astrocytes may play a role in maintaining the seizure-prone state.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

PubMed

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Centrally administered urocortin 2 decreases gorging on high-fat diet in in both diet induced obesity-prone and -resistant rats

PubMed Central

Cottone, Pietro; Sabino, Valentina; Nagy, Tim R.; Coscina, Donald V.; Levin, Barry E.; Zorrilla, Eric P.

2013-01-01

Objective Obesity is a costly, deadly public health problem for which new treatments are needed. Individual differences in meal pattern have been proposed to play a role in obesity risk. The present study tested the hypothesis that i) the microstructure of chronic high-fat diet intake differs between genetically selected Diet-Induced Obesity (DIO) and Diet Resistant (DR) rats, and ii) central administration of urocortin 2 (Ucn 2), a corticotropin-releasing factor type 2 (CRF2) agonist, decreases high-fat diet intake not only in lean DR rats, but also in obese DIO rats. Design Male, selectively bred DIO and DR rats (n=10/genotype) were chronically fed a high-fat diet. Food and water intake as well as ingestion microstructure were then compared under baseline conditions and following third intracerebroventricular injection of Ucn 2 (0, 0.1, 0.3, 1, 3 µg). Results Irrespective of genotype, Ucn 2 reduced nocturnal food intake with a minimum effective dose of 0.3 µg, suppressing high-fat diet intake by ~40% at the 3 µg dose. Ucn 2 also made rats of both genotypes eat smaller and briefer meals, including at doses that did not reduce drinking. Obese DIO rats ate fewer but larger meals than DR rats, which they ate more quickly and consumed with 2/3rd less water. Conclusions Unlike leptin and insulin, Ucn 2 retains its full central anorectic efficacy to reduce high-fat diet intake even in obese, genetically-prone DIO rats, which otherwise show a “gorging” meal pattern. These results open new opportunities of investigation towards treating some forms of diet-induced obesity. PMID:23478425

The gamma-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy.

PubMed

Smith, S E; Parvez, N S; Chapman, A G; Meldrum, B S

1995-02-06

The effects of i.p. administration of the gamma-aminobutyric acid (GABA) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nipecotic acid hydrochloride (tiagabine; molecular weight 412.0), (1-(2-(((diphenylmethylene)-amino)oxy)ethyl)-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid hydrochloride (NNC-711; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236.3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED50 value against clonic seizures (in mumol kg-1 at the time of maximal anticonvulsant effect) for tiagabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamazepine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg-1) was not anticonvulsant. High doses of NNC-711 (207-310 mumol kg-1) and of (+/-)-nipecotic acid (39-78 mmol kg-1) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myoclonic seizures and had similar therapeutic indices (locomotor deficit ED50/anticonvulsant ED50) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tiagabine (2.4 mumol kg-1 i.v.) accompanied with neurological impairment. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy.

Genetics of Temporal Lobe Epilepsy: A Review

PubMed Central

Salzmann, Annick; Malafosse, Alain

2012-01-01

Temporal lobe epilepsy (TLE) is usually regarded as a polygenic and complex disorder. To understand its genetic component, numerous linkage analyses of familial forms and association studies of cases versus controls have been conducted since the middle of the nineties. The present paper lists genetic findings for TLE from the initial segregation analysis to the most recent results published in May 2011. To date, no genes have been clearly related to TLE despite many efforts to do so. However, it is vital to continue replication studies and collaborative attempts to find significant results and thus determine which gene variant combination plays a definitive role in the aetiology of TLE. PMID:22957248

Early Activation of Ventral Hippocampus and Subiculum during Spontaneous Seizures in a Rat Model of Temporal Lobe Epilepsy

PubMed Central

Toyoda, Izumi; Bower, Mark R.; Leyva, Fernando

2013-01-01

Temporal lobe epilepsy is the most common form of epilepsy in adults. The pilocarpine-treated rat model is used frequently to investigate temporal lobe epilepsy. The validity of the pilocarpine model has been challenged based largely on concerns that seizures might initiate in different brain regions in rats than in patients. The present study used 32 recording electrodes per rat to evaluate spontaneous seizures in various brain regions including the septum, dorsomedial thalamus, amygdala, olfactory cortex, dorsal and ventral hippocampus, substantia nigra, entorhinal cortex, and ventral subiculum. Compared with published results from patients, seizures in rats tended to be shorter, spread faster and more extensively, generate behavioral manifestations more quickly, and produce generalized convulsions more frequently. Similarities to patients included electrographic waveform patterns at seizure onset, variability in sites of earliest seizure activity within individuals, and variability in patterns of seizure spread. Like patients, the earliest seizure activity in rats was recorded most frequently within the hippocampal formation. The ventral hippocampus and ventral subiculum displayed the earliest seizure activity. Amygdala, olfactory cortex, and septum occasionally displayed early seizure latencies, but not above chance levels. Substantia nigra and dorsomedial thalamus demonstrated consistently late seizure onsets, suggesting their unlikely involvement in seizure initiation. The results of the present study reveal similarities in onset sites of spontaneous seizures in patients with temporal lobe epilepsy and pilocarpine-treated rats that support the model's validity. PMID:23825415

Benign Occipital Epilepsies of Childhood: Clinical Features and Genetics

ERIC Educational Resources Information Center

Taylor, Isabella; Berkovic, Samuel F.; Kivity, Sara; Scheffer, Ingrid E.

2008-01-01

The early and late benign occipital epilepsies of childhood (BOEC) are described as two discrete electro-clinical syndromes, eponymously known as Panayiotopoulos and Gastaut syndromes. Our aim was to explore the clinical features, classification and clinical genetics of these syndromes using twin and multiplex family studies to determine whether…

GENETIC INFLUENCE ON THE DEVELOPMENT OF RENAL HYPERTENSION IN PARABIOTIC RATS

PubMed Central

Iwai, J.; Knudsen, K. D.; Dahl, L. K.; Heine, M.; Leitl, G.

1969-01-01

The effects of several renal manipulations including uninephrectomy, unilateral renal artery constriction, and a combination of these two (Goldblatt procedure) were studied in two strains of rats with opposite constitutional predispositions to experimental hypertension. The protective value of intact renal tissue to protect against hypertension was shown to be genetically determined. The Goldblatt procedure carried out on only one member of a parabiotic pair induced hypertension in this operated rat but significant hypertension developed in the intact partner only when the operated animal belonged to the strain predisposed to hypertension. It was speculated that there were qualitative differences in the pressor signals of the two strains of rats. In the strain genetically predisposed to hypertension there are at least two pressor principles: (a) one which is common to both strains, not transmittable via the parabiosis junction and presumably related to the renin-angiotensin system; and (b) a second which is specific for the hypertension-prone strain and can be transmitted through the parabiosis junction. This transmittable agent is probably identical with the factor that produces salt hypertension and is associated with the salt-excreting mechanism. PMID:4304137

Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.

PubMed Central

D’Amour, James; Magagna-Poveda, Alejandra; Moretto, Jillian; Friedman, Daniel; LaFrancois, John J.; Pearce, Patrice; Fenton, Andre A.; MacLusky, Neil J.; Scharfman, Helen E.

2015-01-01

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility. PMID:25864929

Genetic and environmental influences on the relationship between flow proneness, locus of control and behavioral inhibition.

PubMed

Mosing, Miriam A; Pedersen, Nancy L; Cesarini, David; Johannesson, Magnus; Magnusson, Patrik K E; Nakamura, Jeanne; Madison, Guy; Ullén, Fredrik

2012-01-01

Flow is a psychological state of high but subjectively effortless attention that typically occurs during active performance of challenging tasks and is accompanied by a sense of automaticity, high control, low self-awareness, and enjoyment. Flow proneness is associated with traits and behaviors related to low neuroticism such as emotional stability, conscientiousness, active coping, self-esteem and life satisfaction. Little is known about the genetic architecture of flow proneness, behavioral inhibition and locus of control--traits also associated with neuroticism--and their interrelation. Here, we hypothesized that individuals low in behavioral inhibition and with an internal locus of control would be more likely to experience flow and explored the genetic and environmental architecture of the relationship between the three variables. Behavioral inhibition and locus of control was measured in a large population sample of 3,375 full twin pairs and 4,527 single twins, about 26% of whom also scored the flow proneness questionnaire. Findings revealed significant but relatively low correlations between the three traits and moderate heritability estimates of .41, .45, and .30 for flow proneness, behavioral inhibition, and locus of control, respectively, with some indication of non-additive genetic influences. For behavioral inhibition we found significant sex differences in heritability, with females showing a higher estimate including significant non-additive genetic influences, while in males the entire heritability was due to additive genetic variance. We also found a mainly genetically mediated relationship between the three traits, suggesting that individuals who are genetically predisposed to experience flow, show less behavioral inhibition (less anxious) and feel that they are in control of their own destiny (internal locus of control). We discuss that some of the genes underlying this relationship may include those influencing the function of dopaminergic neural

A Functional-Genetic Scheme for Seizure Forecasting in Canine Epilepsy.

PubMed

Bou Assi, Elie; Nguyen, Dang K; Rihana, Sandy; Sawan, Mohamad

2018-06-01

The objective of this work is the development of an accurate seizure forecasting algorithm that considers brain's functional connectivity for electrode selection. We start by proposing Kmeans-directed transfer function, an adaptive functional connectivity method intended for seizure onset zone localization in bilateral intracranial EEG recordings. Electrodes identified as seizure activity sources and sinks are then used to implement a seizure-forecasting algorithm on long-term continuous recordings in dogs with naturally-occurring epilepsy. A precision-recall genetic algorithm is proposed for feature selection in line with a probabilistic support vector machine classifier. Epileptic activity generators were focal in all dogs confirming the diagnosis of focal epilepsy in these animals while sinks spanned both hemispheres in 2 of 3 dogs. Seizure forecasting results show performance improvement compared to previous studies, achieving average sensitivity of 84.82% and time in warning of 0.1. Achieved performances highlight the feasibility of seizure forecasting in canine epilepsy. The ability to improve seizure forecasting provides promise for the development of EEG-triggered closed-loop seizure intervention systems for ambulatory implantation in patients with refractory epilepsy.

Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention.

PubMed

Goldman, Alica M; Behr, Elijah R; Semsarian, Christopher; Bagnall, Richard D; Sisodiya, Sanjay; Cooper, Paul N

2016-01-01

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Genetics Home Reference: juvenile myoclonic epilepsy

MedlinePlus

... Home Health Conditions Juvenile myoclonic epilepsy Juvenile myoclonic epilepsy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Juvenile myoclonic epilepsy is a condition characterized by recurrent seizures (epilepsy). ...

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect

PubMed Central

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy. PMID:26309534

High dosage of cannabidiol (CBD) alleviates pentylenetetrazole-induced epilepsy in rats by exerting an anticonvulsive effect.

PubMed

Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

2015-01-01

The study was designed to investigate the effect of various concentrations of cannabidiol (CBD) in rats with chronic epilepsy. The chronic epilepsy rat model was prepared by intraperitoneally injecting pentylenetetrazole to the rats pre-treated with CBD (10, 20 and 50 mg/kg) for 28 consecutive days. Behavioral measurements of convulsion following pentylenetetrazole treatment and morphological changes of the hippocampal neurons with hematoxylin and eosin staining were used to observe the epileptic behaviour. Immunohistochemistry was used to detect the expression levels of glial fibrillary acidic protein and inducible nitric oxide synthase (iNOS) in the hippocampus. The mRNA expression of N-methyl-D-aspartic acid (NMDA) receptor subunits (NR1 and NR2B) was detected by reverse transcription polymerase chain reaction. The results revealed a significant decrease in the daily average grade of epileptic seizures on treatment with CBD (50 mg/kg). The neuronal loss and astrocyte hyperplasia in the hippocampal area were also decreased. CBD treatment did not affect the expression of iNOS in the hippocampus; however, the expression of NR1 was decreased significantly. Thus, CBD administration inhibited the effect of pentylenetetrazole in rats, decreased the astrocytic hyperplasia, decreased neuronal damage in the hippocampus caused by seizures and selectively reduced the expression of the NR1 subunit of NMDA. Therefore, CBD exhibits an anticonvulsive effect in the rats with chronic epilepsy.

Dietary resistant starch dose-dependently reduces adiposity in obesity-prone and obesity-resistant male rats.

PubMed

Belobrajdic, Damien P; King, Roger A; Christophersen, Claus T; Bird, Anthony R

2012-10-25

Animal studies show that diets containing resistant starch (RS) at levels not achievable in the human diet result in lower body weight and/or adiposity in rodents. We aimed to determine whether RS dose-dependently reduces adiposity in obesity-prone (OP) and obesity-resistant (OR) rats. Male Sprague-Dawley rats (n=120) were fed a moderate-fat, high-energy diet for 4 wk. Rats that gained the most weight (40%) were classified as obesity-prone (OP) and obesity-resistant (OR) rats were the 40% that gained the least weight. OP and OR rats were randomly allocated to one of six groups (n=8 for each phenotype). One group was killed for baseline measurements, the other five groups were allocated to AIN-93 based diets that contained 0, 4, 8, 12 and 16% RS (as high amylose maize starch) for 4 wk. These diets were matched for total carbohydrate content. At 0, 4 and 7 wk from the start of the study insulin sensitivity was calculated by homeostasis model assessment of insulin resistance (HOMA-IR) and adiposity was determined by dual-energy X-ray absorptiometry (DXA). At 8 wk, rats were euthanized and fat pad weights, intestinal digesta short chain fatty acid (SCFA) pools and plasma gut hormone levels were determined. Obesity prone rats gained less weight with 4, 12 and 16% RS compared to 0% RS, but the effect in OR animals was significant only at 16% RS. Irrespective of phenotype, diets containing ≥8% RS reduced adiposity compared to 0% RS. Energy intake decreased by 9.8 kJ/d for every 4% increase in RS. All diets containing RS increased total SCFA pools in the caecum and lowered plasma GIP concentrations compared to the 0% RS, whereas plasma GLP-1 and PYY were increased when the diet contained at least 8% RS. Insulin sensitivity was not affected by RS. RS in amounts that could be potentially consumed by humans were effective in reducing adiposity and weight gain in OP and OR rats, due in part to a reduction in energy intake, and changes in gut hormones and large bowel

Fish Oil Supplementation Reduces Heart Levels of Interleukin-6 in Rats with Chronic Inflammation due to Epilepsy

PubMed Central

Nejm, Mariana Bocca; Haidar, André Abou; Hirata, Aparecida Emiko; Oyama, Lila Missae; de Almeida, Antonio-Carlos Guimarães; Cysneiros, Roberta Monterazzo; Cavalheiro, Esper Abrão; Scorza, Carla Alessandra; Scorza, Fulvio Alexandre

2017-01-01

Sudden unexpected death in epilepsy (SUDEP) is a major cause of premature death related to epilepsy. The causes of SUDEP remain unknown, but cardiac arrhythmias and asphyxia have been suggested as a major mechanism of this event. Inflammation has been implicated in the pathogenesis of both epilepsy and ventricular arrhythmia, with interleukin-6 (IL-6) being recognized as a crucial orchestrator of inflammatory states. Our group previously reported that levels of IL-6 were increased in the hearts of epileptic rats. In this scenario, anti-inflammatory actions are among the beneficial effects of fish oil dietary supplementation. This investigation revealed that elevated levels of IL-6 in the heart were markedly reduced in epileptic rats that were treated in the long-term with fish oil, suggesting protective anti-inflammatory actions against dangerously high levels of IL-6. Based on these findings, our results suggest beneficial effects of long-term intake of fish oil in reducing the inflammation associated with chronic epilepsy. PMID:28649227

Impairment of exploratory behavior and spatial memory in adolescent rats in lithium-pilocarpine model of temporal lobe epilepsy.

PubMed

Kalemenev, S V; Zubareva, O E; Frolova, E V; Sizov, V V; Lavrentyeva, V V; Lukomskaya, N Ya; Kim, K Kh; Zaitsev, A V; Magazanik, L G

2015-01-01

Cognitive impairment in six-week -old rats has been studied in the lithium-pilocarpine model of adolescent temporal lobe epilepsy in humans. The pilocarpine-treated rats (n =21) exhibited (a) a decreased exploratory activity in comparison with control rats (n = 20) in the open field (OP) test and (b) a slower extinction of exploratory behavior in repeated OP tests. The Morris Water Maze (MWM) test showed that the effect of training was less pronounced in the pilocarpine-treated rats, which demonstrated disruption of predominantly short-term memory. Therefore, our study has shown that lithium-pilocarpine seizures induce substantial changes in exploratory behavior and spatial memory in adolescent rats. OP and MWM tests can be used in the search of drugs reducing cognitive impairments associated with temporal lobe epilepsy.

Taste-aversion-prone (TAP) rats and taste-aversion-resistant (TAR) rats differ in ethanol self-administration, but not in ethanol clearance or general consumption.

PubMed

Orr, T Edward; Whitford-Stoddard, Jennifer L; Elkins, Ralph L

2004-05-01

Taste-aversion (TA)-prone (TAP) rats and TA-resistant (TAR) rats have been developed by means of bidirectional selective breeding on the basis of their behavioral responses to a TA conditioning paradigm. The TA conditioning involved the pairing of an emetic-class agent (cyclophosphamide) with a novel saccharin solution as the conditioned stimulus. Despite the absence of ethanol in the selective breeding process, these rat lines differ widely in ethanol self-administration. In the current study, blood alcohol concentrations (BACs) were determined after 9 days of limited (2 h per day) access to a simultaneous, two-bottle choice of a 10% ethanol in water solution [volume/volume (vol./vol.)] or plain water. The BACs correlated highly with ethanol intake among TAR rats, but an insufficient number of TAP rats yielded measurable BACs to make the same comparison within this rat line. The same rats were subsequently exposed to 24-h access of a two-bottle choice (10% ethanol or plain water) for 8 days. Ethanol consumption during the 24-h access period correlated highly with that seen during limited access. Subsequent TA conditioning with these rats yielded line-typical differences in saccharin preferences. In a separate group of rats, ethanol clearance was determined by measuring BACs at 1, 4, and 7 h after injection of a 2.5-g/kg dose of ethanol. Ethanol clearance was not different between the two lines. Furthermore, the lines did not differ with respect to food and water consumption. Therefore, the TAP rat-TAR rat differences in ethanol consumption cannot be attributed to line differences in ethanol metabolism or in general consummatory behavior. The findings support our contention that the line differences in ethanol consumption are mediated by differences in TA-related mechanisms. The findings are discussed with respect to genetically based differences in the subjective experience of ethanol.

Addiction-prone Lewis but not Fischer rats develop compulsive running that coincides with downregulation of nerve growth factor inducible-B and neuron-derived orphan receptor 1.

PubMed

Werme, M; Thorén, P; Olson, L; Brené, S

1999-07-15

We have examined the effects of chronic voluntary running for 30 d on the levels of nerve growth factor inducilble-B (NGFI-B) and neuron-derived orphan receptor 1 (NOR1) mRNAs in Fischer and Lewis rats. The aim was to compare the addiction-prone Lewis rat strain to the Fischer strain in a plausible model for natural reward. The Lewis strain ran markedly more than the Fischer strain, as indicated by the length of running per day when given free access to running wheels. Both strains progressively increased their amount of daily running. By day 14, Lewis rats had reached a maximal level corresponding to 10 km/d, which slowly decreased to approximately 8 km/d. Fischer rats ran considerably less, averaging approximately 1. 5 km/d by day 30. After 30 d of running, levels of mRNA encoding NGFI-B and Nor1 were decreased in cerebral cortex in Lewis but not Fischer rats. The downregulation of NGFI-B mRNA in Lewis rats could not be attenuated by the opioid receptor antagonist naloxone. Instead, naloxone by itself downregulated NGFI-B in striatum and cerebral cortex in both strains. In contrast, naloxone had no effect on Nor1 mRNA levels, although the running-induced downregulation of Nor1 was, in most cases, attenuated by naloxone. Data from the present study suggest that the same genetic factors contributing to the drug addiction-prone behavior of Lewis rats also control the excessive running behavior and that this coincides with downregulation of transcription factors of the NGFI-B family.

Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines.

PubMed

Shir, Y; Zeltser, R; Vatine, J J; Carmi, G; Belfer, I; Zangen, A; Overstreet, D; Raber, P; Seltzer, Z

2001-02-01

In some rat strains, total hindpaw denervation triggers autotomy, a behavior of self mutilation presumably related to neuropathic pain. Partial sciatic ligation (PSL) in rats produces tactile allodynia and heat hyperalgesia but not autotomy. Our aims in this study were to examine: (1) whether sensibility of intact rats to noxious and non-noxious stimuli is strain-dependent; (2) whether sensibility of intact rats could predict levels of autotomy, or of allodynia and hyperalgesia in the PSL model; and (3) whether autotomy levels are correlated with levels of allodynia or hyperalgesia. Here we report that in two inbred rat strains (Lewis and Fisher 344), two outbred rat strains (Sabra and Sprague-Dawley) and four selection lines of rats (Genetically Epilepsy-Prone Rats, High Autotomy, Low Autotomy and Flinders Sensitive Line), tactile sensitivity and response duration to noxious heat of intact animals were strain-dependent. Levels of autotomy following hindpaw denervation and of allodynia and hyperalgesia in the PSL model were also strain-dependent. Thus, these traits are determined in part by genetic factors. Sensory sensibility of intact rats was not correlated with levels of autotomy following total denervation, or allodynia and hyperalgesia following partial denervation. We suggest that preoperative sensibility of intact rats is not a predictor of levels of neuropathic disorders following nerve injury. Likewise, no correlation was found between autotomy, allodynia and hyperalgesia, suggesting that neuropathic pain behaviors triggered by nerve injury of different etiologies are mediated by differing mechanisms.

Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat

PubMed Central

Eastman, Clifford L.; Fender, Jason S.; Temkin, Nancy R.; D’Ambrosio, Raimondo

2015-01-01

Conventionally developed antiseizure drugs fail to control epileptic seizures in about 30% of patients, and no treatment prevents epilepsy. New etiologically realistic, syndrome-specific epilepsy models are expected to identify better treatments by capturing currently unknown ictogenic and epileptogenic mechanisms that operate in the corresponding patient populations. Additionally, the use of electrocorticography permits better monitoring of epileptogenesis and the full spectrum of acquired seizures, including focal nonconvulsive seizures that are typically difficult to treat in humans. Thus, the combined use of etiologically realistic models and electrocorticography may improve our understanding of the genesis and progression of epilepsy, and facilitate discovery and translation of novel treatments. However, this approach is labor intensive and must be optimized. To this end, we used an etiologically realistic rat model of posttraumatic epilepsy, in which the initiating fluid percussion injury closely replicates contusive closed-head injury in humans, and has been adapted to maximize epileptogenesis and focal non-convulsive seizures. We obtained week-long 5-electrode electrocorticography 1 month post-injury, and used a Monte-Carlo-based non-parametric bootstrap strategy to test the impact of electrode montage design, duration-based seizure definitions, group size and duration of recordings on the assessment of posttraumatic epilepsy, and on statistical power to detect antiseizure and antiepileptogenic treatment effects. We found that use of seizure definition based on clinical criteria rather than event duration, and of recording montages closely sampling the activity of epileptic foci, maximize the power to detect treatment effects. Detection of treatment effects was marginally improved by prolonged recording, and 24 h recording epochs were sufficient to provide 80% power to detect clinically interesting seizure control or prevention of seizures with small groups

Genetics of Severe Early Onset Epilepsies

ClinicalTrials.gov

2017-08-24

Epilepsy; Epileptic Encephalopathy; Ohtahara Syndrome; Infantile Spasms; Dravet Syndrome; Malignant Migrating Partial Epilepsy of Infancy; Early Myoclonic Epileptic Encephalopathy; PCDH19-related Epilepsy and Related Conditions

Dissociative experiences in patients with epilepsy.

PubMed

Özdemir, Osman; Cilingir, Vedat; Özdemir, Pınar Güzel; Milanlioglu, Aysel; Hamamci, Mehmet; Yilmaz, Ekrem

2016-03-01

A few studies have explored dissociative experiences in epilepsy patients. We investigated dissociative experiences in patients with epilepsy using the dissociative experiences scale (DES). Ninety-eight patients with epilepsy and sixty healthy controls were enrolled in this study. A sociodemographic questionnaire and the Dissociative Experiences Scale (DES), Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were administered to the participants. The DES scores were significantly higher for the patients with epilepsy than the healthy individuals. The number of individuals with pathological dissociation (DES ≥ 30) was higher in the epilepsy group (n = 28) than in the control group (n = 8). Also, higher levels of dissociation were significantly associated with frequency of seizures, but were not associated with duration of epilepsy and age at onset of the disorder. These findings demonstrate that patients with epilepsy are more prone to dissociation than controls. The high rate of dissociative experiences among patients with epilepsy suggest that some epilepsy-related factors are present.

Behavioral and hormonal responses to stress in binge-like eating prone female rats.

PubMed

Calvez, Juliane; Timofeeva, Elena

2016-04-01

Binge eating episodes are frequently stimulated by stress. We developed a model of binge eating proneness based on individual sensitivity of young female Sprague Dawley rats to significantly increase sucrose consumption in response to stress. The rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. After the stabilization of sucrose intake, rats were assessed for consistency of higher (for binge-like eating prone, BEP) or lower (for binge-like eating resistant, BER) sucrose intake in response to unpredictable episodes of foot-shock stress. The objectives of this study included demonstrating face validity of the BEP model and determining if some of the features of this model were pre-existing before exposure to intermittent access to sucrose and repeated stress. The BEP rats consumed a larger (20%>BER) amount of sucrose in a discrete (1-h) period of time compared to the BER phenotype in non-stressful conditions and significantly increased sucrose intake (50%>BER) under stress. Conversely, stress did not affect sucrose intake in BER rats. BEP rats showed higher sucrose intake compared to BER rats at the beginning of darkness as well as during the light period when they were sated and not physically hungry. Analyses of the sucrose licking microstructure revealed that BEP rats had a high motivational drive to consume sucrose in non-stressful condition and an increased hedonic value of sucrose when they were exposed to stressful conditions. BEP rats consumed sucrose much more rapidly under stressful conditions compared to BER rats. Finally, BEP rats demonstrated compulsive-like intake of sucrose (assessed in the light-dark box) and a blunted stress-induced increase in plasma corticosterone levels. Body weight and chow intake were not different between the phenotypes. Before exposure to intermittent access to sucrose and repeated stress, the BEP rats showed no clear evidence for compulsive sucrose intake. However, from the first 1-h access to

Genetics Home Reference: pyridoxine-dependent epilepsy

MedlinePlus

... Home Health Conditions Pyridoxine-dependent epilepsy Pyridoxine-dependent epilepsy Printable PDF Open All Close All Enable Javascript ... view the expand/collapse boxes. Description Pyridoxine-dependent epilepsy is a condition that involves seizures beginning in ...

Assessment of trichloroethylene (TCE) exposure in murine strains genetically-prone and non-prone to develop autoimmune disease.

PubMed

Keil, Deborah E; Peden-Adams, Margie M; Wallace, Stacy; Ruiz, Phillip; Gilkeson, Gary S

2009-04-01

There is increasing laboratory and epidemiologic evidence relating exposure to trichloroethylene (TCE) with autoimmune disease including scleroderma and lupus. New Zealand Black/New Zealand White (NZBWF1) and B6C3F1 mice were exposed to TCE (0, 1, 400 or 14,000 ppb) via drinking water for 27 or 30 weeks, respectively. NZBWF1 mice spontaneously develop autoimmune disease while B6C3F1 mice, a standard strain used in immunotoxicology testing, are not genetically prone to develop autoimmune disease. During the TCE exposure period, serum levels of total IgG, and autoantibodies (anti-ssDNA, -dsDNA, and -glomerular antigen [GA]) were monitored. At the termination of the study, renal pathology, natural killer (NK) cell activity, total IgG levels, autoantibody production, T-cell activation, and lymphocytic proliferative responses were evaluated. TCE did not alter NK cell activity, or T- and B-cell proliferation in either strain. Numbers of activated T-cells (CD4+/CD44+) were increased in the B6C3F1 mice but not in the NZBWF1 mice. Renal pathology, as indicated by renal score, was significantly increased in the B6C3F1, but not in the NZBWF1 mice. Serum levels of autoantibodies to dsDNA and ssDNA were increased at more time points in B6C3F1, as compared to the NZBWF1 mice. Anti-GA autoantibodies were increased by TCE treatment in early stages of the study in NZBWF1 mice, but by 23 weeks of age, control levels were comparable to those of TCE-exposed animals. Serum levels anti-GA autoantibodies in B6C3F1 were not affected by TCE exposure. Overall, these data suggest that TCE did not contribute to the progression of autoimmune disease in autoimmune-prone mice during the period of 11-36 weeks of age, but rather lead to increased expression of markers associated with autoimmune disease in a non-genetically prone mouse strain.

Amygdala kindling-resistant (SLOW) or -prone (FAST) rat strains show differential fear responses.

PubMed

Mohapel, P; McIntyre, D C

1998-12-01

The authors compared two rat strains, selectively bred for their susceptibility to amygdala kindling, with respect to their performance on various behavioral and learning tasks that are associated with fear and anxiety. The two rat strains differed significantly in measurements of exploration of novel and familiar environments, as well as in reactivity to footshock and fear-based learning. The kindling-resistant (SLOW) strain exhibited a lower ratio of open- to closed-arm entries in the elevated plus-maze, less activity over days in the open field, greater behavioral suppression in the open-field if previously footshocked, greater freezing in the inhibitory avoidance task, and slower acquisition and poorer retention in the one-way avoidance task than did the kindling-prone (FAST) strain. These experiments suggest that the SLOW rats are more expressively fearful than the FAST rats, particularly with respect to environmentally triggered freezing or immobility. Further, these observations imply that the relatively constrained excitability of the amygdala network in the SLOW rats might mediate their relatively greater expression of fear and anxiety compared with the FAST rats.

Pediatric epilepsy: The Indian experience

PubMed Central

Gadgil, Pradnya; Udani, Vrajesh

2011-01-01

Epilepsy is a common clinical entity in neurology clinics. The understanding of the genetics of epilepsy has undergone a sea change prompting re-classification by the International league against epilepsy recently. The prevalence rates of epilepsy in India are similar to those of developed nations. However, the large treatment gap is a major challenge to our public health system. Perinatal injuries are a major causative factor in pediatric group. We have discussed a few common etiologies such as neurocysticercosis and newer genetic epilepsy syndromes. We have also briefly touched upon the Indian experience in pediatric epilepsy surgery. PMID:22069423

Pediatric epilepsy: The Indian experience.

PubMed

Gadgil, Pradnya; Udani, Vrajesh

2011-10-01

Epilepsy is a common clinical entity in neurology clinics. The understanding of the genetics of epilepsy has undergone a sea change prompting re-classification by the International league against epilepsy recently. The prevalence rates of epilepsy in India are similar to those of developed nations. However, the large treatment gap is a major challenge to our public health system. Perinatal injuries are a major causative factor in pediatric group. We have discussed a few common etiologies such as neurocysticercosis and newer genetic epilepsy syndromes. We have also briefly touched upon the Indian experience in pediatric epilepsy surgery.

Diesel Exhaust-Induced Cardiac Dysfunction Is Mediated by Sympathetic Dominance in Heart Failure-Prone Rats

EPA Science Inventory

Short-term exposure to vehicular emissions is associated with adverse cardiac events. Diesel exhaust (DE) may provoke cardiac events through defective co-ordination of the two main autonomic nervous system (ANS) branches. We exposed heart failure-prone rats once to DE (500 g/m3 ...

Integrative properties and transfer function of cortical neurons initiating absence seizures in a rat genetic model

PubMed Central

Williams, Mark S.; Altwegg‐Boussac, Tristan; Chavez, Mario; Lecas, Sarah; Mahon, Séverine

2016-01-01

Key points Absence seizures are accompanied by spike‐and‐wave discharges in cortical electroencephalograms. These complex paroxysmal activities, affecting the thalamocortical networks, profoundly alter cognitive performances and preclude conscious perception.Here, using a well‐recognized genetic model of absence epilepsy, we investigated in vivo how information processing was impaired in the ictogenic neurons, i.e. the population of cortical neurons responsible for seizure initiation.In between seizures, ictogenic neurons were more prone to generate bursting activity and their firing response to weak depolarizing events was considerably facilitated compared to control neurons.In the course of seizures, information processing became unstable in ictogenic cells, alternating between an increased and a decreased responsiveness to excitatory inputs, depending on the spike and wave patterns.The state‐dependent modulation in the excitability of ictogenic neurons affects their inter‐seizure transfer function and their time‐to‐time responsiveness to incoming inputs during absences. Abstract Epileptic seizures result from aberrant cellular and/or synaptic properties that can alter the capacity of neurons to integrate and relay information. During absence seizures, spike‐and‐wave discharges (SWDs) interfere with incoming sensory inputs and preclude conscious experience. The Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well‐established animal model of absence epilepsy, allows exploration of the cellular basis of this impaired information processing. Here, by combining in vivo electrocorticographic and intracellular recordings from GAERS and control animals, we investigated how the pro‐ictogenic properties of seizure‐initiating cortical neurons modify their integrative properties and input–output operation during inter‐ictal periods and during the spike (S‐) and wave (W‐) cortical patterns alternating during seizures. In addition to a

Effects of aniracetam on impaired sleep patterns in stroke-prone spontaneously hypertensive rats.

PubMed

Kimura, M; Okano, S; Inoué, S

2000-06-01

The aim of the present study was to determine the pattern of sleep disturbances and the effects on sleep of aniracetam, a cognitive enhancer, in stroke-prone spontaneously hypertensive rats (SHRSP). Compared with normotensive control rats, SHRSP exhibited an impaired sleep pattern characterized by suppressed diurnal rapid eye movement (REM) sleep and excessive nocturnal non-REM sleep. At a dose of 30 mg/kg per day p.o., aniracetam increased REM sleep in the light period after administration for 5 consecutive days. Consequently, suppressed REM sleep in SHRSP was restored by repeated treatment with aniracetam. Aniracetam could be useful in improving REM sleep impairment associated with vascular dementia.

Phenotypic characterization of spontaneously mutated rats showing lethal dwarfism and epilepsy.

PubMed

Suzuki, Hiroetsu; Takenaka, Motoo; Suzuki, Katsushi

2007-08-01

We have characterized the phenotype of spontaneously mutated rats, found during experimental inbreeding in a closed colony of Wistar Imamichi rats. Mutant rats showed severe dwarfism, short lifespan (early postnatal lethality), and high incidence of epileptic seizures. Mutant rats showed growth retardation after 3 d of age, and at 21 d their weight was about 56% that of normal rats. Most mutant rats died without reaching maturity, and 95% of the mutant rats had an ataxic gait. About 34% of the dwarf rats experienced epileptic seizures, most of which started as 'wild running' convulsions, progressing to generalized tonic-clonic convulsions. At age 28 d, the relative weight of the testes was significantly lower, and the relative weight of the brain was significantly higher, in mutant than in normal rats. Histologically, increased apoptotic germ cells, lack of spermatocytes, and immature Leydig cells were found in the mutant testes, and extracellular vacuoles of various sizes were present in the hippocampus and amygdala of the mutant brain. Mutant rats had significantly increased concentrations of plasma urea nitrogen, creatinine, and inorganic phosphate, as well as decreased concentrations of plasma growth hormone. Hereditary analysis showed that the defects were inherited as a single recessive trait. We have named the hypothetically mutated gene as lde (lethal dwarfism with epilepsy).

Genetic investigation of sudden unexpected death in epilepsy cohort by panel target resequencing.

PubMed

Coll, Monica; Allegue, Catarina; Partemi, Sara; Mates, Jesus; Del Olmo, Bernat; Campuzano, Oscar; Pascali, Vincenzo; Iglesias, Anna; Striano, Pasquale; Oliva, Antonio; Brugada, Ramon

2016-03-01

Sudden unexpected death in epilepsy (SUDEP) is defined as the abrupt, no traumatic, witnessed or unwitnessed death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥ 30 min or seizures without recovery), and in which postmortem examination does not reveal a cause of death. Although the physiopathological mechanisms that underlie SUDEP remain to be clarified, the genetic background has been described to play a role in this disorder. Pathogenic variants in genes associated with epilepsy and encoding cardiac ion channels could explain the SUDEP phenotype. To test this we use the next-generation sequencing technology to sequence a cohort of SUDEP cases and its translation into clinical and forensic fields. A panel target resequencing was used to study 14 SUDEP cases from both postmortem (2 cases) and from living patients (12 cases). Genes already associated with SUDEP and also candidate genes had been investigated. Overall, 24 rare genetic variants were identified in 13 SUDEP cases. Four cases showed rare variants with complete segregation in the SCN1A, FBN1, HCN1, SCN4A, and EFHC1 genes, and one case with a rare variant in KCNQ1 gene showed incomplete pattern of inheritance. In four cases, rare variants were detected in CACNA1A, SCN11A and SCN10A, and KCNQ1 genes, but familial segregation was not possible due to lack of DNA from relatives. Finally, in the four remaining cases, the rare variants did not segregate in the family. This study confirms the link between epilepsy, sudden death, and cardiac disease. In addition, we identified new potential candidate genes for SUDEP: FBN1, HCN1, SCN4A, EFHC1, CACNA1A, SCN11A, and SCN10A. Further confirmation in larger cohorts will be necessary especially if genetic screening for SUDEP is applied to forensic and clinical medicine. Nevertheless, this study supports the emerging concept of a genetically

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

PubMed

Cohen, Joshua L; Glover, Matthew E; Pugh, Phyllis C; Fant, Andrew D; Simmons, Rebecca K; Akil, Huda; Kerman, Ilan A; Clinton, Sarah M

2015-01-01

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

Idiopathic generalized epilepsies with pure grand mal: clinical data and genetics.

PubMed

Unterberger, I; Trinka, E; Luef, G; Bauer, G

2001-04-01

To analyze the clinical features and family history of patients with idiopathic generalized epilepsy (IGE), with pure grand mal (GM), divided into epilepsies with GM occurring exclusively on awakening (GMA) and random GM (RGM). We studied retrospectively 98 patients from a large epilepsy outpatient clinic. All patients had a full clinical examination and computed cerebral tomography scans (CCT) or magnetic resonance imaging (MRI) when feasible. We analyzed seizure type, seizure frequency, provocative factors, prognosis, electroencephalography (EEG) findings and family history. Sixty-eight patients had GMA and 30 had RGM. The mean age at seizure onset was 16.6 years (+/-6.3 S.D., range: 5-41) and 16.7 years in those with RGM (+/-7.5 S.D., range: 4-42, NSD). Patients with GMA had a longer course of active epilepsy (median 8.5 years) compared to RGM (median 2 years). Seizure-provoking factors, especially sleep deprivation, were significantly (P=0.001) more common in patients with GMA (52/68, 77%) than in the group with RGM (13/30, 43%). Of all patients, 23% (23/98) reported first degree relatives with seizures or epilepsy. Pure GM was found in 41% (12/29) of affected first degree relatives, other idiopathic generalized epilepsy syndromes were less frequently observed (4/29, 14%). The concordance rate was high within the syndrome - none of the patients with RGM had an affected relative with GMA and vice versa only two of affected relatives of GMA patients had RGM. GMA seems to be associated with a longer duration of active epilepsy, a higher relapse rate and a stronger tendency to be precipitated by seizure provoking factors. The different concordance rates between the syndromes suggest a genetically different background.

Increased impulsive behavior and risk proneness following lentivirus-mediated dopamine transporter over-expression in rats' nucleus accumbens.

PubMed

Adriani, W; Boyer, F; Gioiosa, L; Macrì, S; Dreyer, J-L; Laviola, G

2009-03-03

Multiple theories have been proposed for sensation seeking and vulnerability to impulse-control disorders [Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: Common biosocial factors. J Pers 68:999-1029], and many of these rely on a dopamine system deficit. Available animal models reproduce only some behavioral symptoms and seem devoid of construct validity. We used lentivirus tools for over-expressing or silencing the dopamine transporter (DAT) and we evaluated the resulting behavioral profiles in terms of motivation and self-control. Wistar adult rats received stereotaxic inoculation of a lentivirus that allowed localized intra-accumbens delivery of a DAT gene enhancer/silencer, or the green fluorescent protein, GFP. These animals were studied for intolerance to delay, risk proneness and novelty seeking. As expected, controls shifted their demanding from a large reward toward a small one when the delivery of the former was increasingly delayed (or uncertain). Interestingly, in the absence of general locomotor effects, DAT over-expressing rats showed increased impulsivity (i.e. a more marked shift of demanding from the large/delayed toward the small/soon reward), and increased risk proneness (i.e. a less marked shift from the large/uncertain toward the small/sure reward), compared with controls. Rats with enhanced or silenced DAT expression did not show any significant preference for a novel environment. In summary, consistent with literature on comorbidity between attention-deficit/hyperactivity disorder and pathological gambling, we demonstrate that DAT over-expression in rats' nucleus accumbens leads to impulsive and risk prone phenotype. Thus, a reduced dopaminergic tone following altered accumbal DAT function may subserve a sensation-seeker phenotype and the vulnerability to impulse-control disorders.

Protective Effect of Resveratrol on the Brain in a Rat Model of Epilepsy.

PubMed

Li, Zhen; You, Zhuyan; Li, Min; Pang, Liang; Cheng, Juan; Wang, Liecheng

2017-06-01

Accumulating evidence has suggested resveratrol as a promising drug candidate for the treatment of epilepsy. To validate this, we tested the protective effect of resveratrol on a kainic acid (KA)-induced epilepsy model in rats and investigated the underlying mechanism. We found that acute resveratrol application partially inhibited evoked epileptiform discharges in the hippocampal CA1 region. During acute, silent and chronic phases of epilepsy, the expression of hippocampal kainate glutamate receptor (GluK2) and the GABA A receptor alpha1 subunit (GABA A R-alpha1) was up-regulated and down-regulated, respectively. Resveratrol reversed these effects and induced an antiepileptic effect. Furthermore, in the chronic phase, resveratrol treatment inhibited the KA-induced increased glutamate/GABA ratio in the hippocampus. The antiepileptic effects of resveratrol may be partially attributed to the reduction of glutamate-induced excitotoxicity and the enhancement in GABAergic inhibition.

Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

PubMed

Sarkisova, Karine Yu; Fedotova, Irina B; Surina, Natalia M; Nikolaev, Georgy M; Perepelkina, Olga V; Kostina, Zoya A; Poletaeva, Inga I

2017-03-01

Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel genetic linkage of rat Sp6 mutation to Amelogenesis imperfecta

PubMed Central

2012-01-01

Background Amelogenesis imperfecta (AI) is an inherited disorder characterized by abnormal formation of tooth enamel. Although several genes responsible for AI have been reported, not all causative genes for human AI have been identified to date. AMI rat has been reported as an autosomal recessive mutant with hypoplastic AI isolated from a colony of stroke-prone spontaneously hypertensive rat strain, but the causative gene has not yet been clarified. Through a genetic screen, we identified the causative gene of autosomal recessive AI in AMI and analyzed its role in amelogenesis. Methods cDNA sequencing of possible AI-candidate genes so far identified using total RNA of day 6 AMI rat molars identified a novel responsible mutation in specificity protein 6 (Sp6). Genetic linkage analysis was performed between Sp6 and AI phenotype in AMI. To understand a role of SP6 in AI, we generated the transgenic rats harboring Sp6 transgene in AMI (Ami/Ami + Tg). Histological analyses were performed using the thin sections of control rats, AMI, and Ami/Ami + Tg incisors in maxillae, respectively. Results We found the novel genetic linkage between a 2-bp insertional mutation of Sp6 gene and the AI phenotype in AMI rats. The position of mutation was located in the coding region of Sp6, which caused frameshift mutation and disruption of the third zinc finger domain of SP6 with 11 cryptic amino acid residues and a stop codon. Transfection studies showed that the mutant protein can be translated and localized in the nucleus in the same manner as the wild-type SP6 protein. When we introduced the CMV promoter-driven wild-type Sp6 transgene into AMI rats, the SP6 protein was ectopically expressed in the maturation stage of ameloblasts associated with the extended maturation stage and the shortened reduced stage without any other phenotypical changes. Conclusion We propose the addition of Sp6 mutation as a new molecular diagnostic criterion for the autosomal recessive AI patients

Epilepsy Genetics—Past, Present, and Future

PubMed Central

Poduri, Annapurna; Lowenstein, Daniel

2014-01-01

Human epilepsy is a common and heterogeneous condition in which genetics play an important etiological role. We begin by reviewing the past history of epilepsy genetics, a field that has traditionally included studies of pedigrees with epilepsy caused by defects in ion channels and neurotransmitters. We highlight important recent discoveries that have expanded the field beyond the realm of channels and neurotransmitters and that have challenged the notion that single genes produce single disorders. Finally, we project toward an exciting future for epilepsy genetics as large-scale collaborative phenotyping studies come face to face with new technologies in genomic medicine. PMID:21277190

Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.

PubMed

von Stülpnagel, C; Ensslen, M; Møller, R S; Pal, D K; Masnada, S; Veggiotti, P; Piazza, E; Dreesmann, M; Hartlieb, T; Herberhold, T; Hughes, E; Koch, M; Kutzer, C; Hoertnagel, K; Nitanda, J; Pohl, M; Rostásy, K; Haack, T B; Stöhr, K; Kluger, G; Borggraefe, I

2017-05-01

To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment. Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire. 7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion). Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome. Copyright © 2017 European Paediatric Neurology Society. All rights reserved.

Self and informant report ratings of psychopathology in genetic generalized epilepsy.

PubMed

Loughman, Amy; Bowden, Stephen C; D'Souza, Wendyl J

2017-02-01

The psychological sequelae of genetic generalized epilepsies (GGE) is of growing research interest, with up to a third of all adults with GGE experiencing significant psychiatric comorbidity according to a recent systematic review. A number of unexplored questions remain. Firstly, there is insufficient evidence to determine relative prevalence of psychopathology between GGE syndromes. Secondly, the degree to which self-report and informant-report questionnaires accord in adults with epilepsy is unknown. Finally, while epilepsy severity is one likely predictor of worse psychopathology in GGE, evidence regarding other possible contributing factors such as epilepsy duration and antiepileptic drugs (AEDs) has been equivocal. The potential impact of subclinical epileptiform discharges remains unexplored. Self-report psychopathology symptoms across six DSM-Oriented Subscales were prospectively measured in 60 adults with GGE, with informant-report provided for a subset of 47. We assessed the burden of symptoms from both self- and informant-report, and the relationship between clinical epilepsy variables and self-reported symptoms. Results showed elevated symptoms in almost half of the sample overall. Depression and anxiety were the most commonly reported types of symptoms. There was a trend towards greater symptoms endorsement by self-report, and relatively modest interrater agreement. Symptoms of ADHD were significantly positively associated with number of AEDs currently prescribed. Other psychopathology symptoms were not significantly predicted by epilepsy duration, seizure-free duration or total duration of epileptiform discharges over a 24-hour period. The high prevalence of psychological needs suggests that routine screening of psychopathology and provision of psychoeducation may be essential to improving patient care and outcomes. Further investigation is required to better understand predictive and causal factors for psychopathology in GGE. Copyright © 2016

Genetics Home Reference: STXBP1 encephalopathy with epilepsy

MedlinePlus

... Conditions STXBP1 encephalopathy with epilepsy STXBP1 encephalopathy with epilepsy Printable PDF Open All Close All Enable Javascript ... the expand/collapse boxes. Description STXBP1 encephalopathy with epilepsy is a condition characterized by recurrent seizures (epilepsy), ...

Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy.

PubMed

Hellier, J L; Patrylo, P R; Buckmaster, P S; Dudek, F E

1998-06-01

Human temporal lobe epilepsy is associated with complex partial seizures that can produce secondarily generalized seizures and motor convulsions. In some patients with temporal lobe epilepsy, the seizures and convulsions occur following a latent period after an initial injury and may progressively increase in frequency for much of the patient's life. Available animal models of temporal lobe epilepsy are produced by acute treatments that often have high mortality rates and/or are associated with a low proportion of animals developing spontaneous chronic motor seizures. In this study, rats were given multiple low-dose intraperitoneal (i.p.) injections of kainate in order to minimize the mortality rate usually associated with single high-dose injections. We tested the hypothesis that these kainate-treated rats consistently develop a chronic epileptic state (i.e. long-term occurrence of spontaneous, generalized seizures and motor convulsions) following a latent period after the initial treatment. Kainate (5 mg/kg per h, i.p.) was administered to rats every hour for several hours so that class III-V seizures were elicited for > or = 3 h, while control rats were treated similarly with saline. This treatment protocol had a relatively low mortality rate (15%). After acute treatment, rats were observed for the occurrence of motor seizures for 6-8 h/week. Nearly all of the kainate-treated rats (97%) had two or more spontaneous motor seizures months after treatment. With this observation protocol, the average latency for the first spontaneous motor seizure was 77+/-38 (+/-S.D.) days after treatment. Although variability was observed between rats, seizure frequency initially increased with time after treatment, and nearly all of the kainate-treated rats (91%) had spontaneous motor seizures until the time of euthanasia (i.e. 5-22 months after treatment). Therefore, multiple low-dose injections of kainate, which cause recurrent motor seizures for > or = 3 h, lead to the

Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats.

PubMed

Halliday, Amy J; Campbell, Toni E; Nelson, Timothy S; McLean, Karen J; Wallace, Gordon G; Cook, Mark J

2013-01-01

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site. Copyright © 2012 Elsevier Ltd. All rights reserved.

Familial mesial temporal lobe epilepsy (FMTLE) : a clinical and genetic study of 15 Italian families.

PubMed

Striano, Pasquale; Gambardella, Antonio; Coppola, Antonietta; Di Bonaventura, Carlo; Bovo, Giorgia; Diani, Erica; Boaretto, Francesca; Egeo, Gabriella; Ciampa, Clotilde; Labate, Angelo; Testoni, Stefania; Passarelli, Daniela; Manna, Ida; Sferro, Caterina; Aguglia, Umberto; Caranci, Ferdinando; Giallonardo, Anna Teresa; Striano, Salvatore; Nobile, Carlo; Michelucci, Roberto

2008-01-01

Familial mesial temporal lobe epilepsy (FMTLE) is characterized by prominent psychic and autonomic seizures, often without hippocampal sclerosis (HS) or a previous history of febrile seizures (FS), and good prognosis. The genetics of this condition is largely unknown.We present the electroclinical and genetic findings of 15 MTLE Italian families. FMTLE was defined when two or more first-degree relatives had epilepsy suggesting a mesial temporal lobe origin. The occurrence of seizures with auditory auras was considered an exclusion criterion. Patients underwent video-EEG recordings, 1.5-Tesla MRI particularly focused on hippocampal analysis, and neuropsychological evaluation. Genetic study included genotyping and linkage analysis of candidate loci at 4q, 18q, 1q, and 12q as well as screening for LGI1/Epitempin mutations. Most of the families showed an autosomal dominant inheritance pattern with incomplete penetrance. Fifty-four (32 F) affected individuals were investigated. Twenty-one (38.8 %) individuals experienced early FS. Forty-eight individuals fulfilled the criteria for MTLE. Epigastric/visceral sensation (72.9 %) was the most common type of aura, followed by psychic symptoms (35.4 %), and déjà vu (31.2 %). HS occurred in 13.8% of individuals, three of whom belonged to the same family. Prognosis of epilepsy was generally good. Genetic study failed to show LGI1/Epitempin mutations or significative linkage to the investigated loci. FMTLE may be a more common than expected condition, clinically and genetically heterogeneous. Some of the reported families, grouped on the basis of a specific aura, may represent an interesting subgroup on whom to focus future linkage studies.

Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid).

PubMed

Chapman, A G; Yip, P K; Yap, J S; Quinn, L P; Tang, E; Harris, J R; Meldrum, B S

1999-02-26

We have studied the effects in three rodent models of generalised convulsive or absence epilepsy of two antagonists of group I metabotropic glutamate receptors that are selective for the mGlu1 receptor. LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid) have been administered intracerebroventricularly (i.c.v.) to DBA/2 mice and lethargic mice (lh/lh), and focally into the inferior colliculus of genetically epilepsy prone rats (GEPR). In DBA/2 mice both compounds produce a rapid, transient suppression of sound-induced clonic seizures (LY 367385: ED50 = 12 nmol, i.c.v., 5 min; AIDA: ED50 = 79 nmol, i.c.v., 15 min). In lethargic mice both compounds significantly reduce the incidence of spontaneous spike and wave discharges on the electroencephalogram, from <30 to >150 min after the administration of AIDA, 500 nmol, i.c.v., and from 30 to >150 min after the administration of LY 367385, 250 nmol, i.c.v. LY 367385, 50 nmol, suppresses spontaneous spike and wave discharges from 30 to 60 min. In genetically epilepsy prone rats both compounds reduce sound-induced clonic seizures. LY 367385, 160 nmol bilaterally, fully suppresses clonic seizures after 2-4 h. AIDA is fully effective 30 min after 100 nmol bilaterally. It is concluded that antagonists of mGlu1 receptors are potential anticonvulsant agents and that activation of mGlu1 receptors probably contributes to a variety of epileptic syndromes.

Multiplex families with epilepsy

PubMed Central

Afawi, Zaid; Oliver, Karen L.; Kivity, Sara; Mazarib, Aziz; Blatt, Ilan; Neufeld, Miriam Y.; Helbig, Katherine L.; Goldberg-Stern, Hadassa; Misk, Adel J.; Straussberg, Rachel; Walid, Simri; Mahajnah, Muhammad; Lerman-Sagie, Tally; Ben-Zeev, Bruria; Kahana, Esther; Masalha, Rafik; Kramer, Uri; Ekstein, Dana; Shorer, Zamir; Wallace, Robyn H.; Mangelsdorf, Marie; MacPherson, James N.; Carvill, Gemma L.; Mefford, Heather C.; Jackson, Graeme D.; Scheffer, Ingrid E.; Bahlo, Melanie; Gecz, Jozef; Heron, Sarah E.; Corbett, Mark; Mulley, John C.; Dibbens, Leanne M.; Korczyn, Amos D.

2016-01-01

Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. Conclusion: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies. PMID:26802095

Familial clustering of epilepsy and behavioral disorders: Evidence for a shared genetic basis

PubMed Central

Hesdorffer, Dale C.; Caplan, Rochelle; Berg, Anne T.

2011-01-01

Purpose To examine whether family history of unprovoked seizures is associated with behavioral disorders in epilepsy probands, thereby supporting the hypothesis of shared underlying genetic susceptibility to these disorders. Methods We conducted an analysis of the 308 probands with childhood onset epilepsy from the Connecticut Study of Epilepsy with information on first degree family history of unprovoked seizures and of febrile seizures whose parents completed the Child Behavior Checklist (CBCL) at the 9-year follow-up. Clinical cut-offs for CBCL problem and DSM-Oriented scales were examined. The association between first degree family history of unprovoked seizure and behavioral disorders was assessed separately in uncomplicated and complicated epilepsy and separately for first degree family history of febrile seizures. A subanalysis, accounting for the tendency for behavioral disorders to run in families, adjusted for siblings with the same disorder as the proband. Prevalence ratios were used to describe the associations. Key findings In probands with uncomplicated epilepsy, first degree family history of unprovoked seizure was significantly associated with clinical cut-offs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cut-offs for Withdrawn/Depressed, and DSM-Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cut-offs for Aggressive Behavior and Delinquent Behavior, and DSM-Oriented scales for Conduct Disorder and Oppositional Defiant Disorder were significantly associated with family history of unprovoked seizure. Adjustment for siblings with the same disorder revealed significant associations for the relationship between first degree family history of unprovoked seizure and Total Problems and Agressive Behavior in probands with uncomplicated epilepsy; marginally significant results were seen for Internalizing Disorder

Heredity in epilepsy: neurodevelopment, comorbidity, and the neurological trait.

PubMed

Johnson, Michael R; Shorvon, Simon D

2011-11-01

The genetic bases of common, nonmendelian epilepsy have been difficult to elucidate. In this article, we argue for a new approach to genetic inquiry in epilepsy. In the latter part of the 19th century, epilepsy was universally acknowledged to be part of a wider "neurological trait" that included other neuropsychiatric conditions. In recent years, studies of comorbidity have shown clear links between epilepsy and various neuropsychiatric disorders including psychosis and depression, and genetic studies of copy number variants (CNVs) have shown that in some cases, the same CNV underpins neuropsychiatric illness and epilepsy. Functional annotation analysis of the sets of genes impacted by epilepsy CNVs shows enrichment for genes involved with neural development, with gene ontological (GO) categories including "neurological system process" (P=0.006), "synaptic transmission" (P=0.009), and "learning or memory" (P=0.01). These data support the view that epilepsy and some neuropsychiatric conditions share pathogenic neurodevelopmental pathways, and that epilepsy should be included in the spectrum of neurodevelopmental disorders. Yet, most current genetic research in epilepsy has restricted samples to specific types of epilepsy categorized according to the clinical classification schemes on the basis of seizure type, anatomical location, or epilepsy syndrome. These schemes are, to an extent, arbitrary and do not necessarily align with biological reality. We propose an alternative approach that makes no phenotypic assumptions beyond including epilepsy in the neurodevelopmental spectrum. A "'value-free" strategy of reverse phenotyping may be worth exploring, starting with genetic association and looking backward at the phenotype. Finally, it should be noted that there are societal implications to associating epilepsy with other neuropsychiatric disorders, and it is vital to ensure research in this area does not result in increased stigma for patients with epilepsy. Copyright

Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus.

PubMed

Puranam, Ram S; He, Xiao Ping; Yao, Lijun; Le, Tri; Jang, Wonjo; Rehder, Catherine W; Lewis, Darrell V; McNamara, James O

2015-06-10

We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability. Copyright © 2015 the authors 0270-6474/15/358866-16$15.00/0.

Genetically Epilepsy-Prone Rats Have Increased Brain Regional Activity of an Enzyme Which Liberates Glutamate from N-acetyl-aspartyl-glutamate

DTIC Science & Technology

1992-01-01

DISTRIBUTION C OOt .APPROVED FOR PUPLIC RELEASE: DISTRIBUTION UNLIMITED Ii. A STRA T (Minls.m200oids N-Acetylated-a- 1 n (’ed acidic dip cpL,2ase (N...aspartate (NAA) and the excitatory amino acid , glutamate (CLU). Although there is evidence that NAAG might be a neurotransmitter, this dipoptide could...Genetics; Itippocampus: E-ctlsatlltmt pilepsy-, Glutamate: N-Acetylated-o-1 inked acidic dipeptidasc-: Enrniatic: IIrosz:NAAG: Aspartalc N-Acetylated-a

Familial clustering of epilepsy and behavioral disorders: evidence for a shared genetic basis.

PubMed

Hesdorffer, Dale C; Caplan, Rochelle; Berg, Anne T

2012-02-01

To examine whether family history of unprovoked seizures is associated with behavioral disorders in epilepsy probands, thereby supporting the hypothesis of shared underlying genetic susceptibility to these disorders. We conducted an analysis of the 308 probands with childhood onset epilepsy from the Connecticut Study of Epilepsy with information on first-degree family history of unprovoked seizures and of febrile seizures whose parents completed the Child Behavior Checklist (CBCL) at the 9-year follow-up. Clinical cutoffs for CBCL problem and Diagnostic and Statistical Manual of Mental Disorders (DSM)-Oriented scales were examined. The association between first-degree family history of unprovoked seizure and behavioral disorders was assessed separately in uncomplicated and complicated epilepsy and separately for first-degree family history of febrile seizures. A subanalysis, accounting for the tendency for behavioral disorders to run in families, was adjusted for siblings with the same disorder as the proband. Prevalence ratios were used to describe the associations. In probands with uncomplicated epilepsy, first-degree family history of unprovoked seizure was significantly associated with clinical cutoffs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cutoffs for Withdrawn/Depressed, and DSM-Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cutoffs for Aggressive Behavior and Delinquent Behavior, and DSM-Oriented scales for Conduct Disorder and Oppositional Defiant Disorder were significantly associated with family history of unprovoked seizure. Adjustment for siblings with the same disorder revealed significant associations for the relationship between first-degree family history of unprovoked seizure and Total Problems and Aggressive Behavior in probands with uncomplicated epilepsy; marginally significant results were seen for

Theory of Mind and social competence in children and adolescents with genetic generalised epilepsy (GGE): Relationships to epilepsy severity and anti-epileptic drugs.

PubMed

Stewart, Elizabeth; Catroppa, Cathy; Gill, Deepak; Webster, Richard; Lawson, John; Mandalis, Anna; Sabaz, Mark; Barton, Belinda; Lah, Suncica

2018-06-18

This study aimed to examine Theory of Mind (ToM) and social competence in children and adolescents with genetic generalised epilepsy (GGE), and explore how they relate to neurocognitive and epilepsy variables. Twenty-two children and adolescents with GGE (8-16 years old) and 22 typically developing controls completed two behavioural tasks (faux-pas, strange stories) assessing cognitive and affective ToM, and a battery of standardised neuropsychological tests. Parents completed questionnaires assessing ToM and social competence. Neurologists completed the Global Assessment Severity of Epilepsy (GASE) scale to measure of epilepsy severity. Children and adolescents with GGE were impaired in both cognitive and affective ToM, and had reduced social competence compared to controls, which was not attributable to low intellectual functioning or impaired executive skills (working memory, inhibition). Lower ToM correlated with reduced social competence in children and adolescents with GGE. Clinical variables identified included: (i) higher daily dosage of valproate, which was correlated with reduced affective ToM, (ii) higher daily dosages of ethosuximide and lamotrigine, which were correlated with reduced social competence, and (iii) overall epilepsy severity on the GASE, which was correlated with reduced social competence. Our study revealed cognitive and affective ToM impairments in children and adolescents with GGE, which correlated with everyday social problems. Moreover, higher dosages of commonly prescribed anti-epileptic drugs and overall epilepsy severity were related to ToM impairments and social competence problems. Although preliminary, these findings provide critical information for detection and screening procedures for social difficulties in children and adolescents with GGE, which are currently lacking. Copyright © 2018 British Epilepsy Association. All rights reserved.

Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats

PubMed Central

Sinclair, Elaine B.; Culbert, Kristen M.; Gradl, Dana R.; Richardson, Kimberlei A.; Klump, Kelly L.; Sisk, Cheryl L.

2017-01-01

Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague–Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1 h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial pre-frontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal

Unraveling Genetic Modifiers in the Gria4 Mouse Model of Absence Epilepsy

PubMed Central

Frankel, Wayne N.; Mahaffey, Connie L.; McGarr, Tracy C.; Beyer, Barbara J.; Letts, Verity A.

2014-01-01

Absence epilepsy (AE) is a common type of genetic generalized epilepsy (GGE), particularly in children. AE and GGE are complex genetic diseases with few causal variants identified to date. Gria4 deficient mice provide a model of AE, one for which the common laboratory inbred strain C3H/HeJ (HeJ) harbors a natural IAP retrotransposon insertion in Gria4 that reduces its expression 8-fold. Between C3H and non-seizing strains such as C57BL/6, genetic modifiers alter disease severity. Even C3H substrains have surprising variation in the duration and incidence of spike-wave discharges (SWD), the characteristic electroencephalographic feature of absence seizures. Here we discovered extensive IAP retrotransposition in the C3H substrain, and identified a HeJ-private IAP in the Pcnxl2 gene, which encodes a putative multi-transmembrane protein of unknown function, resulting in decreased expression. By creating new Pcnxl2 frameshift alleles using TALEN mutagenesis, we show that Pcnxl2 deficiency is responsible for mitigating the seizure phenotype – making Pcnxl2 the first known modifier gene for absence seizures in any species. This finding gave us a handle on genetic complexity between strains, directing us to use another C3H substrain to map additional modifiers including validation of a Chr 15 locus that profoundly affects the severity of SWD episodes. Together these new findings expand our knowledge of how natural variation modulates seizures, and highlights the feasibility of characterizing and validating modifiers in mouse strains and substrains in the post-genome sequence era. PMID:25010494

Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.

PubMed

Khan, Shanzana I; Andrews, Karen L; Jackson, Kristy L; Memon, Basimah; Jefferis, Ann-Maree; Lee, Man K S; Diep, Henry; Wei, Zihui; Drummond, Grant R; Head, Geoffrey A; Jennings, Garry L; Murphy, Andrew J; Vinh, Antony; Sampson, Amanda K; Chin-Dusting, Jaye P F

2018-05-01

The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.

Familial mesial temporal lobe epilepsy: a benign epilepsy syndrome showing complex inheritance.

PubMed

Crompton, Douglas E; Scheffer, Ingrid E; Taylor, Isabella; Cook, Mark J; McKelvie, Penelope A; Vears, Danya F; Lawrence, Kate M; McMahon, Jacinta M; Grinton, Bronwyn E; McIntosh, Anne M; Berkovic, Samuel F

2010-11-01

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T₂ signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands' relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be

Evaluation of an automated spike-and-wave complex detection algorithm in the EEG from a rat model of absence epilepsy.

PubMed

Bauquier, Sebastien H; Lai, Alan; Jiang, Jonathan L; Sui, Yi; Cook, Mark J

2015-10-01

The aim of this prospective blinded study was to evaluate an automated algorithm for spike-and-wave discharge (SWD) detection applied to EEGs from genetic absence epilepsy rats from Strasbourg (GAERS). Five GAERS underwent four sessions of 20-min EEG recording. Each EEG was manually analyzed for SWDs longer than one second by two investigators and automatically using an algorithm developed in MATLAB®. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the manual (reference) versus the automatic (test) methods. The results showed that the algorithm had specificity, sensitivity, PPV and NPV >94%, comparable to published methods that are based on analyzing EEG changes in the frequency domain. This provides a good alternative as a method designed to mimic human manual marking in the time domain.

Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

PubMed Central

Trucks, Holger; Schulz, Herbert; de Kovel, Carolien G.; Kasteleijn-Nolst Trenité, Dorothée; Sonsma, Anja C. M.; Koeleman, Bobby P.; Lindhout, Dick; Weber, Yvonne G.; Lerche, Holger; Kapser, Claudia; Schankin, Christoph J.; Kunz, Wolfram S.; Surges, Rainer; Elger, Christian E.; Gaus, Verena; Schmitz, Bettina; Helbig, Ingo; Muhle, Hiltrud; Stephani, Ulrich; Klein, Karl M.; Rosenow, Felix; Neubauer, Bernd A.; Reinthaler, Eva M.; Zimprich, Fritz; Feucht, Martha; Møller, Rikke S.; Hjalgrim, Helle; De Jonghe, Peter; Suls, Arvid; Lieb, Wolfgang; Franke, Andre; Strauch, Konstantin; Gieger, Christian; Schurmann, Claudia; Schminke, Ulf; Nürnberg, Peter; Sander, Thomas

2015-01-01

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes. PMID:25950944

Effect of Diet on Preference and Intake of Sucrose in Obese Prone and Resistant Rats

PubMed Central

Duca, Frank A.; Swartz, Timothy D.; Covasa, Mihai

2014-01-01

Increased orosensory stimulation from palatable diets and decreased feedback from gut signals have been proposed as contributing factors to obesity development. Whether altered taste functions associated with obesity are common traits or acquired deficits to environmental factors, such as a high-energy (HE)-diet, however, is not clear. To address this, we examined preference and sensitivity of increasing concentrations of sucrose solutions in rats prone (OP) and resistant (OR) to obesity during chow and HE feeding and measured lingual gene expression of the sweet taste receptor T1R3. When chow-fed, OP rats exhibited reduced preference and acceptance of dilute sucrose solutions, sham-fed less sucrose compared to OR rats, and had reduced lingual T1R3 gene expression. HE-feeding abrogated differences in sucrose preference and intake and lingual T1R3 expression between phenotypes. Despite similar sucrose intakes however, OP rats consumed significantly more total calories during 48-h two-bottle testing compared to OR rats. The results demonstrate that OP rats have an innate deficit for sweet taste detection, as illustrated by a reduction in sensitivity to sweets and reduced T1R3 gene expression; however their hyperphagia and subsequent obesity during HE-feeding is most likely not due to altered consumption of sweets. PMID:25329959

Seizure classification key to epilepsy management.

PubMed

Davidson, Louise; Derry, Chris

2015-09-01

The diagnosis of epilepsy carries significant implications for physical, psychosocial and financial wellbeing as well as a small but significant increased risk of mortality. The diagnosis is often incorrect, potentially in up to 20% of cases, so should be revisited if seizures are not responding to treatment. Evidence indicates that misdiagnosis is significantly more common among nonspecialists. SIGN recommends that the diagnosis of epilepsy should be made by an epilepsy specialist, ideally in the setting of a dedicated first seizure or epilepsy clinic. An incorrect diagnosis of epilepsy can be harmful. There is an exhaustive list of epilepsy mimics that can result in misdiagnosis and expose patients to unnecessary treatment with antiepileptic drugs. Diagnosis relies primarily on the history. Investigations can support the diagnosis but cannot make it in isolation, and negative investigation findings are common in epilepsy. Brain imaging will be undertaken in most patients with epilepsy, but is not routinely required in those with a definite diagnosis of genetic generalised epilepsy. The EEG has limitations and can sometimes cloud rather than clarify the diagnostic picture. Distinguishing between a genetic generalised epilepsy and a focal epilepsy is vital as this influences investigation, treatment and prognosis. Generally medication should not be started following a single seizure except in specific circumstances or in cases where the risk of recurrence is high.

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy.

PubMed

Campbell, John N; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later.

Adverse effects of high-intensity sweeteners on energy intake and weight control in male and obesity-prone female rats

PubMed Central

Swithers, Susan E.; Sample, Camille H.; Davidson, T.L.

2014-01-01

The use of high-intensity sweeteners has been proposed as a method to combat increasing rates of overweight and obesity in the human population. However, previous work with male rats suggests that consumption of such sweeteners might contribute to, rather than ameliorate, weight gain. The goals of the present experiments were to assess whether intake of high-intensity sweeteners is associated with increased food intake and body weight gain in female rats; to evaluate whether this effect depends on composition of the maintenance diet (i.e., standard chow compared to diets high in energy, fat and sugar [HE diets]); and to determine whether the phenotype of the rats with regard to propensity to gain weight on HE diets affects the consequences of consuming high-intensity sweeteners. The data demonstrated that female rats fed a low-fat, standard laboratory chow diet did not gain extra weight when fed yogurt dietary supplements sweetened with saccharin compared to those fed glucose-sweetened dietary supplements. However, female rats maintained on a “Westernized” diet high in fat and sugar (HE diet) showed significant increases in energy intake, weight gain and adiposity when given saccharin-sweetened compared to glucose-sweetened yogurt supplements. These differences were most pronounced in female rats known to be prone to obesity prior to the introduction of the yogurt diets. Both selectively-bred Crl:OP[CD] rats, and outbred Sprague-Dawley rats fed an HE diet showing high levels of weight gain (DIO rats) had increased weight gain in response to consuming saccharin-sweetened compared to glucose-sweetened supplements. However, in male rats fed an HE diet, saccharin-sweetened supplements produced extra weight gain regardless of obesity phenotype. These results suggest that the most negative consequences of consuming high-intensity sweeteners may occur in those most likely to use them for weight control, females consuming a “Westernized” diet and already prone to

PSYCHOSIS IN RELATION TO EPILEPSY - A CLINICAL MODEL OF NEURO - PSYCHIATRY

PubMed Central

Shrivastava, Amresh Kumar

1996-01-01

Psychosis occurring in epileptics has always been an area of research interest, particularly, because of possible link of mental illness, organic lesions, convulsive process and behavioural abnormlity, all occuring together in the same subject. Vast amount of investigation on this subject has been done with a view to understand something more fundamental in ‘Brain-Behaviour Connection’. Occurance of interictal phase of psychosis long after cessation of seizure has driven investigators to conclude the two being unrelated, which has brought important issues of brain pathology and behavioural abnormality into focus of research from dimensions of genetics, neuroendocrine and environmental influences. The aspects of behavioural neurology, behavioural genetics, genetics of epilepsy and ‘shared common genetic diathesis for development of psychosis, possibly converge in the neuropsychiatric model of psychosis in relation to epilepsy’. E.E.G.- spiking and regional slow waves in inter - ictal phase are emerging as correlates determining behaviour. Status of prolactin - dopamine relationship and its correlation to neuro - cognition may be another pointer in guiding some of these complex issues. It is expected that current focus of research should be able to develop on the profile of ‘psychotic brain’ also. One of the major clinical issue is identifying epileptic subjects prone to develop psychosis with precision of nature and type, not only because such developments jeopardises and compromises the state of art treatment done for epilepsy, but also because of devastating deterioration in quality of life of patients and relatives, besides having pharmacoeconmic devaluations. Studies have revealed that more detailed work up in the beginning may possibly identify high risk groups based upon clinical phenomenlogy, E.E.G. topography, endocrine status, regional brain damage, etc. The presention attempts to focus some of the relevant clinical issues with reference to a

Clinical utility of genetic testing in pediatric drug-resistant epilepsy: a pilot study.

PubMed

Ream, Margie A; Mikati, Mohamad A

2014-08-01

The utility of genetic testing in pediatric drug-resistant epilepsy (PDRE), its yield in "real life" clinical practice, and the practical implications of such testing are yet to be determined. To start to address the above gaps in our knowledge as they apply to a patient population seen in a tertiary care center. We retrospectively reviewed our experience with the use of clinically available genetic tests in the diagnosis and management of PDRE in one clinic over one year. Genetic testing included, depending on clinical judgment, one or more of the following: karyotype, chromosomal microarray, single gene sequencing, gene sequencing panels, and/or whole exome sequencing (WES). We were more likely to perform genetic testing in patients with developmental delay, epileptic encephalopathy, and generalized epilepsy. In our unique population, the yield of specific genetic diagnosis was relatively high: karyotype 14.3%, microarray 16.7%, targeted single gene sequencing 15.4%, gene panels 46.2%, and WES 16.7%. Overall yield of diagnosis from at least one of the above tests was 34.5%. Disease-causing mutations that were not clinically suspected based on the patients' phenotypes and representing novel phenotypes were found in 6.9% (2/29), with an additional 17.2% (5/29) demonstrating pharmacologic variants. Three patients were incidentally found to be carriers of recessive neurologic diseases (10.3%). Variants of unknown significance (VUSs) were identified in 34.5% (10/29). We conclude that genetic testing had at least some utility in our patient population of PDRE, that future similar larger studies in various populations are warranted, and that clinics offering such tests must be prepared to address the complicated questions raised by the results of such testing. Copyright © 2014. Published by Elsevier Inc.

The concept of symptomatic epilepsy and the complexities of assigning cause in epilepsy.

PubMed

Shorvon, Simon

2014-03-01

The concept of symptomatic epilepsy and the difficulties in assigning cause in epilepsy are described. A historical review is given, emphasizing aspects of the history which are relevant today. The historical review is divided into three approximately semicentenial periods (1860-1910, 1910-1960, 1960-present). A definition of symptomatic epilepsy and this is followed by listing of causes of symptomatic epilepsy. The fact that not all the causes of idiopathic epilepsy are genetic is discussed. A category of provoked epilepsy is proposed. The complexities in assigning cause include the following: the multifactorial nature of epilepsy, the distinction between remote and proximate causes, the role of nongenetic factors in idiopathic epilepsy, the role of investigation in determining the range of causes, the fact that not all symptomatic epilepsy is acquired, the nosological position of provoked epilepsy and the view of epilepsy as a process, and the differentiation of new-onset and established epilepsy. The newly proposed ILAE classification of epilepsy and its changes in terminologies and the difficulties in the concept of acute symptomatic epilepsy are discussed, including the inconsistencies and gray areas and the distinction between idiopathic, symptomatic, and provoked epilepsies. Points to be considered in future work are listed. Copyright © 2013 Elsevier Inc. All rights reserved.

Aniracetam enhances glutamatergic transmission in the prefrontal cortex of stroke-prone spontaneously hypertensive rats.

PubMed

Togashi, Hiroko; Nakamura, Kazuo; Matsumoto, Machiko; Ueno, Ken-ichi; Ohashi, Satoshi; Saito, Hideya; Yoshioka, Mitsuhiro

2002-03-08

The effects of aniracetam, a cognition enhancer, on extracellular levels of glutamate (Glu), gamma-aminobutyric acid (GABA) and nitric oxide metabolites (NOx) were examined in the prefrontal cortex (PFC) and the basolateral amygdala (AMG) in stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal release of Glu, was lower in the AMG of SHRSP than in normotensive Wistar Kyoto rats, whereas no difference in GABA and NOx was noted. Aniracetam (100 mg/kg, p.o.) significantly increased the area under the curve of Glu levels in the PFC, but not in the AMG, of SHRSP. Aniracetam failed to exert any remarkable effects on GABA or NOx levels in either brain region. Our findings suggest that aniracetam enhances cortical glutamatergic release, which may be the mechanism involved in the ameliorating effects of aniracetam on various neuronal dysfunctions.

Differential mesocorticolimbic responses to palatable food in binge eating prone and binge eating resistant female rats.

PubMed

Sinclair, Elaine B; Culbert, Kristen M; Gradl, Dana R; Richardson, Kimberlei A; Klump, Kelly L; Sisk, Cheryl L

2015-12-01

Binge eating is a key symptom of many eating disorders (e.g. binge eating disorder, bulimia nervosa, anorexia nervosa binge/purge type), yet the neurobiological underpinnings of binge eating are poorly understood. The mesocorticolimbic reward circuit, including the nucleus accumbens and the medial prefrontal cortex, is likely involved because this circuit mediates the hedonic value and incentive salience of palatable foods (PF). Here we tested the hypothesis that higher propensity for binge eating is associated with a heightened response (i.e., Fos induction) of the nucleus accumbens and medial prefrontal cortex to PF, using an animal model that identifies binge eating prone (BEP) and binge eating resistant (BER) rats. Forty adult female Sprague-Dawley rats were given intermittent access to PF (high fat pellets) 3×/week for 3 weeks. Based on a pattern of either consistently high or consistently low PF consumption across these feeding tests, 8 rats met criteria for categorization as BEP, and 11 rats met criteria for categorization as BER. One week after the final feeding test, BEP and BER rats were either exposed to PF in their home cages or were given no PF in their home cages for 1h prior to perfusion, leading to three experimental groups for the Fos analysis: BEPs given PF, BERs given PF, and a No PF control group. The total number of Fos-immunoreactive (Fos-ir) cells in the nucleus accumbens core and shell, and the cingulate, prelimbic, and infralimbic regions of the medial prefrontal cortex was estimated by stereological analysis. PF induced higher Fos expression in the nucleus accumbens shell and core and in the prelimbic and infralimbic cortex of BEP rats compared to No PF controls. Throughout the nucleus accumbens and medial prefrontal cortex, PF induced higher Fos expression in BEP than in BER rats, even after adjusting for differences in PF intake. Differences in the neural activation pattern between BEP and BER rats were more robust in prefrontal cortex

Reprint of: The new approach to epilepsy classification: Cognition and behavior in adult epilepsy syndromes.

PubMed

Baxendale, Sallie; Thompson, Pamela

2016-11-01

The revised terminology and concepts for the organization of seizures and epilepsy proposed by the ILAE Commission on Classification and Terminology in 2010 allows for a number of new opportunities in the study of cognition and behavior in adults. This review examines the literature that has looked for behavioral and cognitive correlates of the newly recognized genetic epilepsies in adults. While some studies report clear cognitive phenotypes associated with specific genetic mutations in adults with epilepsy, others report remarkable clinical heterogeneity. In the second part of this review, we discuss some of the factors that may influence the findings in this literature. Cognitive function is the product of both genetic and environmental influences. Neuropsychological phenotypes under direct genetic influence may be wider and more subtle than specific deficits within discreet cognitive domains and may be reflected in broader, multidimensional measures of cognitive function than those tapped by scores on standardized tests of function. Future studies must be carefully designed to reflect these factors. It is also imperative that studies with negative findings are assigned as much value as those with positive results and published accordingly. This article is part of a Special Issue titled "The new approach to classification: Rethinking cognition and behavior in epilepsy". Copyright © 2016 Elsevier Inc. All rights reserved.

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction

PubMed Central

Cadoni, Cristina

2016-01-01

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

PubMed

Cadoni, Cristina

2016-01-01

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

ENU mutagenesis to generate genetically modified rat models.

PubMed

van Boxtel, Ruben; Gould, Michael N; Cuppen, Edwin; Smits, Bart M G

2010-01-01

The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach for generating genetically modified rats has been the target-selected N-ethyl-N-nitrosourea (ENU) mutagenesis-based technology. Here, we describe the detailed protocols for ENU mutagenesis and mutant retrieval in the rat model organism.

Differential response of rat strains to obesogenic diets underlines the importance of genetic makeup of an individual towards obesity.

PubMed

Mn, Muralidhar; Smvk, Prasad; Battula, Kiran Kumar; Nv, Giridharan; Kalashikam, Rajender Rao

2017-08-22

Obesity, a multifactorial disorder, results from a chronic imbalance of energy intake vs. expenditure. Apart from excessive consumption of high calorie diet, genetic predisposition also seems to be equally important for the development of obesity. However, the role of genetic predisposition in the etiology of obesity has not been clearly delineated. The present study addresses this problem by selecting three rat strains (WNIN, F-344, SD) with different genetic backgrounds and exposing them to high calorie diets. Rat strains were fed HF, HS, and HFS diets and assessed for physical, metabolic, biochemical, inflammatory responses, and mRNA expression. Under these conditions: significant increase in body weight, visceral adiposity, oxidative stress and systemic pro-inflammatory status; the hallmarks of central obesity were noticed only in WNIN. Further, they developed altered glucose and lipid homeostasis by exhibiting insulin resistance, impaired glucose tolerance, dyslipidemia and fatty liver condition. The present study demonstrates that WNIN is more prone to develop obesity and associated co-morbidities under high calorie environment. It thus underlines the cumulative role of genetics (nature) and diet (nurture) towards the development of obesity, which is critical for understanding this epidemic and devising new strategies to control and manage this modern malady.

Traumatic Brain Injury Causes a Tacrolimus-Sensitive Increase in Non-Convulsive Seizures in a Rat Model of Post-Traumatic Epilepsy

PubMed Central

Campbell, John N.; Gandhi, Anandh; Singh, Baljinderjit; Churn, Severn B.

2014-01-01

Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later. PMID:25580467

A developmental study of glutamatergic neuron populations in the ventrobasal and the lateral geniculate nucleus of the thalamus: Comparing Genetic Absence Rats from Strasbourg (GAERS) and normal control wistar rats.

PubMed

Kirazlı, Özlem; Çavdar, Safiye; Yıldızel, Sercan; Onat, Filiz; Kaptanoğlu, Erkan

2017-02-01

An imbalance of GABAergic inhibition and glutamatergic excitation is suspected to be the cause of absence epileptic seizures. Absence seizures are known to be generated in thalamocortical circuitry. In the present study we used light microscopy immunohistochemistry to quantify the density of glutamate+ve neurons at two developmental stages (P10 and P60) in two thalamic nuclei, the ventrobasal (VB) and lateral geniculate nucleus (LGN) in Wistar rats and compared the results with similar data obtained from genetic absence epilepsy rats from Strasbourg (GAERS). Rats were perfused transcardially with glutaraldehyde and paraformaldehyde fixative, then samples from VB and LGN were removed from each animal and sectioned. The glutamatergic neurons were labelled using light-microscopic glutamate immunohistochemistry. The disector method was used to quantify the glutamate+ve neurons in VB and LGN of GAERS and Wistar rats. The data were statistically analyzed. The distribution of the glutamate+ve neurons in the VB thalamic nucleus showed a significant reduction in the neuronal profiles per unit thalamic area from P10 to P60 in both Wistar and GAERS. The decrease was greater in the GAERS compared to the Wistar animals. However, in the LGN no reduction was observed either in the Wistar or in the GAERS. Comparing the density of glutamate+ve neurons in the VB thalamic nucleus of P10 of Wistar animals with of P10 GAERS showed statistically significant greater densities of these neurons in GAERS than in the Wistar rats. However no significant difference was present at P60 between the Wistar and GAERS animals. The disproportional decrease in GAERS may be related to the onset of absence seizures or may be related to neurogenesis of absence epilepsy. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

[Epilepsy: incidens, prevalens and causes].

PubMed

Forsgren, Lars; Sundelin, Heléne; Sveinsson, Olafur

2018-05-21

Epilepsy affects people in all ages with the highest incidence in small children, particularly before age one year, and in elderly aged 65 years and older. In Sweden, between 4500-5000 persons develop epilepsy annually. Based on studies from North America and Europe, including the Nordic countries, the number of people with active epilepsy in Sweden is between 60000-70000. The lifetime risk for epilepsy up to age 85 years is 4-5 %, i.e. approximately every 25th person. The new epilepsy classification divides etiology into the following groups: structural, genetic, infectious, metabolic, immune and unknown. The majority (70%) of people with epilepsy eventually become seizure free. Epilepsy increases the risk of psychosocial problems and accidents. People with epilepsy have up to a 3-fold increase in mortality, mainly due to the underlying causes and epilepsy related deaths, e.g. status epilepticus, SUDEP and accidents. Somatic, psychiatric and neuropsychiatric comorbidities are common in epilepsy.

Role of oxidative stress in epileptic seizures

PubMed Central

Shin, Eun-Joo; Jeong, Ji Hoon; Chung, Yoon Hee; Kim, Won-Ki; Ko, Kwang-Ho; Bach, Jae-Hyung; Hong, Jau-Shyong; Yoneda, Yukio; Kim, Hyoung-Chun

2013-01-01

Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of epilepsy. Therefore, antioxidant therapies aimed at reducing oxidative stress have received considerable attention in epilepsy treatment. However, much evidence suggests that oxidative stress does not always have the same pattern in all seizures models. Thus, this review provides an overview aimed at achieving a better understanding of this issue. We summarize work regarding seizure models (i.e., genetically epilepsy-prone rats, kainic acid, pilocarpine, pentylenetetrazol, and trimethyltin), oxidative stress as an etiologic factor in epileptic seizures (i.e., impairment of antioxidant systems, mitochondrial dysfunction, involvement of redox-active metals, arachidonic acid pathway activation, and aging), and antioxidant strategies for seizure treatment. Combined, this review highlights pharmacological mechanisms associated with oxidative stress in epileptic seizures and the potential for neuroprotection in epilepsy that targets oxidative stress and is supported by effective antioxidant treatment. PMID:21672578

Prevalence and etiology of epilepsy in a Norwegian county-A population based study.

PubMed

Syvertsen, Marte; Nakken, Karl Otto; Edland, Astrid; Hansen, Gunnar; Hellum, Morten Kristoffer; Koht, Jeanette

2015-05-01

Epilepsy represents a substantial personal and social burden worldwide. When addressing the multifaceted issues of epilepsy care, updated epidemiologic studies using recent guidelines are essential. The aim of this study was to find the prevalence and causes of epilepsy in a representative Norwegian county, implementing the new guidelines and terminology suggested by the International League Against Epilepsy (ILAE). Included in the study were all patients from Buskerud County in Norway with a diagnosis of epilepsy at Drammen Hospital and the National Center for Epilepsy at Oslo University Hospital. The study period was 1999-2014. Patients with active epilepsy were identified through a systematic review of medical records, containing information about case history, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), genetic tests, blood samples, treatment, and other investigations. Epilepsies were classified according to the revised terminology suggested by the ILAE in 2010. In a population of 272,228 inhabitants, 1,771 persons had active epilepsy. Point prevalence on January 1, 2014 was 0.65%. Of the subjects registered with a diagnostic code of epilepsy, 20% did not fulfill the ILAE criteria of the diagnosis. Epilepsy etiology was structural-metabolic in 43%, genetic/presumed genetic in 20%, and unknown in 32%. Due to lack of information, etiology could not be determined in 4%. Epilepsy is a common disorder, affecting 0.65% of the subjects in this cohort. Every fifth subject registered with a diagnosis of epilepsy was misdiagnosed. In those with a reliable epilepsy diagnosis, every third patient had an unknown etiology. Future advances in genetic research will probably lead to an increased identification of genetic and hopefully treatable causes of epilepsy. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Low-frequency electroacupuncture suppresses focal epilepsy and improves epilepsy-induced sleep disruptions.

PubMed

Yi, Pei-Lu; Lu, Chin-Yu; Jou, Shuo-Bin; Chang, Fang-Chia

2015-07-07

The positive effects of acupuncture at Feng-Chi acupoints on treating epilepsy and insomnia have been well-documented in ancient Chinese literature. However, there is a lack of scientific evidence to elucidate the underlying mechanisms behind these effects. Our previous study demonstrated that high-frequency (100 Hz) electroacupuncture (EA) at Feng-Chi acupoints deteriorates both pilocarpine-induced focal epilepsy and sleep disruptions. This study investigated the effects of low-frequency (10 Hz) EA on epileptic activities and epilepsy-induced sleep disruptions. In rats, the Feng-Chi acupoint is located 3 mm away from the center of a line between the two ears. Rats received 30 min of 10 Hz EA stimuli per day before each day's dark period for three consecutive days. Our results indicated that administration of pilocarpine into the left CeA at the beginning of the dark period induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep during the consequent light period. Low-frequency (10 Hz) EA at Feng-Chi acupoints suppressed pilocarpine-induced epileptiform EEGs, and this effect was in turn blocked by naloxone (a broad-spectrum opioid receptor antagonist), but not by naloxonazine (a μ-receptor antagonist), naltrindole (a δ-receptor antagonist) and nor-binaltorphimine (a κ-receptor antagonist). Ten Hz EA enhanced NREM sleep during the dark period, and this enhancement was blocked by all of the opioid receptor antagonists. On the other hand, 10 Hz EA reversed pilocarpine-induced NREM suppression during the light period, and the EA's effect on the sleep disruption was only blocked by naloxonazine. These results indicate that low-frequency EA stimulation of Feng-Chi acupoints is beneficial in improving epilepsy and epilepsy-induced sleep disruptions, and that opioid receptors in the CeA mediate EA's therapeutic effects.

Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats.

PubMed

Louis, Xavier L; Thandapilly, Sijo J; MohanKumar, Suresh K; Yu, Liping; Taylor, Carla G; Zahradka, Peter; Netticadan, Thomas

2012-09-01

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation. Copyright © 2012 Elsevier Inc. All rights reserved.

Progressive myoclonic epilepsies

PubMed Central

Michelucci, Roberto; Canafoglia, Laura; Striano, Pasquale; Gambardella, Antonio; Magaudda, Adriana; Tinuper, Paolo; La Neve, Angela; Ferlazzo, Edoardo; Gobbi, Giuseppe; Giallonardo, Anna Teresa; Capovilla, Giuseppe; Visani, Elisa; Panzica, Ferruccio; Avanzini, Giuliano; Tassinari, Carlo Alberto; Bianchi, Amedeo; Zara, Federico

2014-01-01

Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized. PMID:24384641

Potassium Channels in Epilepsy

PubMed Central

Köhling, Rüdiger; Wolfart, Jakob

2016-01-01

This review attempts to give a concise and up-to-date overview on the role of potassium channels in epilepsies. Their role can be defined from a genetic perspective, focusing on variants and de novo mutations identified in genetic studies or animal models with targeted, specific mutations in genes coding for a member of the large potassium channel family. In these genetic studies, a demonstrated functional link to hyperexcitability often remains elusive. However, their role can also be defined from a functional perspective, based on dynamic, aggravating, or adaptive transcriptional and posttranslational alterations. In these cases, it often remains elusive whether the alteration is causal or merely incidental. With ∼80 potassium channel types, of which ∼10% are known to be associated with epilepsies (in humans) or a seizure phenotype (in animals), if genetically mutated, a comprehensive review is a challenging endeavor. This goal may seem all the more ambitious once the data on posttranslational alterations, found both in human tissue from epilepsy patients and in chronic or acute animal models, are included. We therefore summarize the literature, and expand only on key findings, particularly regarding functional alterations found in patient brain tissue and chronic animal models. PMID:27141079

Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

MedlinePlus

... myoclonic epilepsy Spinal muscular atrophy with progressive myoclonic epilepsy Printable PDF Open All Close All Enable Javascript ... boxes. Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: Changes in LC3, P62, Beclin-1 and Bcl-2 levels.

PubMed

Li, Qinrui; Han, Ying; Du, Junbao; Jin, Hongfang; Zhang, Jing; Niu, Manman; Qin, Jiong

2018-05-01

Current studies have indicated that apoptotic and autophagic signaling pathways are triggered by epileptic seizures, but the precise roles of these processes in epilepsy-induced neuronal loss remain unclear. Identifying a concrete molecular mechanism may help researchers develop relevant epilepsy therapies that are more effective than existing treatments. Autophagy is a type of conserved degradation that contributes to cellular homeostasis. The involved signaling pathways allow us to observe alterations in autophagy and apoptosis during epileptic seizures over time. This study investigated the time-dependent changes in autophagy, apoptosis and neuronal morphology in developing brain of epilepsy model rats. At 48h after epileptic seizure onset, the number of neurons in neocortex decreased, and the number of apoptotic cells in neocortex increased. The ratio of microtubule-associated protein 1 light chain 3 (LC3) II to LC3 I and Beclin-1 protein levels increased from 12h to 48h after epileptic seizure onset. P62 protein and Bcl-2 protein levels decreased from 24h to 48h after epileptic seizure onset. The changes in the levels of these autophagy and apoptosis markers indicate that autophagy starts before apoptosis in rats with epilepsy, demonstrating a potential role of autophagy in epilepsy-induced neuronal loss in developing brain. Copyright © 2017. Published by Elsevier B.V.

Left hemisphere predominance of pilocarpine-induced rat epileptiform discharges

PubMed Central

2009-01-01

Background The left cerebral hemisphere predominance in human focal epilepsy has been observed in a few studies, however, there is no related systematic study in epileptic animal on hemisphere predominance. The main goal of this paper is to observe if the epileptiform discharges (EDs) of Pilocarpine-induced epileptic rats could present difference between left hemisphere and right hemisphere or not. Methods The electrocorticogram (ECoG) and electrohippocampogram (EHG) from Pilocarpine-induced epileptic rats were recorded and analyzed using Synchronization likelihood (SL) in order to determine the synchronization relation between different brain regions, then visual check and cross-correlation analysis were adopted to evaluate if the EDs were originated more frequently from the left hemisphere than the right hemisphere. Results The data show that the synchronization between left-EHG and right-EHG, left-ECoG and left-EHG, right-ECoG and right-EHG, left-ECoG and right-ECoG, are significantly strengthened after the brain functional state transforms from non-epileptiform discharges to continuous-epileptiform discharges(p < 0.05). When the state transforms from continuous EDs to periodic EDs, the synchronization is significantly weakened between left-ECoG and left-EHG, left-EHG and right-EHG (p < 0.05). Visual check and the time delay (τ) based cross-correlation analysis finds that 10 out of 13 EDs have a left predominance (77%) and 3 out of 13 EDs are right predominance (23%). Conclusion The results suggest that the left hemisphere may be more prone to EDs in the Pilocarpine-induced rat epilepsy model and implicate that the left hemisphere might play an important role in epilepsy states transition. PMID:19948024

The epilepsy phenome/genome project.

PubMed

Abou-Khalil, Bassel; Alldredge, Brian; Bautista, Jocelyn; Berkovic, Sam; Bluvstein, Judith; Boro, Alex; Cascino, Gregory; Consalvo, Damian; Cristofaro, Sabrina; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael; Fahlstrom, Robyn; Fiol, Miguel; Fountain, Nathan; Fox, Kristen; French, Jacqueline; Freyer Karn, Catharine; Friedman, Daniel; Geller, Eric; Glauser, Tracy; Glynn, Simon; Haas, Kevin; Haut, Sheryl; Hayward, Jean; Helmers, Sandra; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi; Knowlton, Robert; Kossoff, Eric; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel; McGuire, Shannon; Motika, Paul; Nesbitt, Gerard; Novotny, Edward; Ottman, Ruth; Paolicchi, Juliann; Parent, Jack; Park, Kristen; Poduri, Annapurna; Risch, Neil; Sadleir, Lynette; Scheffer, Ingrid; Shellhaas, Renee; Sherr, Elliott; Shih, Jerry J; Shinnar, Shlomo; Singh, Rani; Sirven, Joseph; Smith, Michael; Sullivan, Joe; Thio, Liu Lin; Venkat, Anu; Vining, Eileen; von Allmen, Gretchen; Weisenberg, Judith; Widdess-Walsh, Peter; Winawer, Melodie

2013-08-01

Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies. Study design The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype-genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy. EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants. EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

Familial risk of epilepsy: a population-based study

PubMed Central

Peljto, Anna L.; Barker-Cummings, Christie; Vasoli, Vincent M.; Leibson, Cynthia L.; Hauser, W. Allen; Buchhalter, Jeffrey R.

2014-01-01

probands with focal epilepsy, standardized incidence ratios were 1.0 (95% confidence interval 0.00–2.19) for generalized epilepsy and 2.6 (95% confidence interval 1.19–4.26) for focal epilepsy. Epilepsy incidence was greater in offspring of female probands than in offspring of male probands, and this maternal effect was restricted to offspring of probands with focal epilepsy. The results suggest that risks for epilepsies of unknown and prenatal/developmental cause may be influenced by shared genetic mechanisms. They also suggest that some of the genetic influences on generalized and focal epilepsies are distinct. However, the similar increase in risk for focal epilepsy among relatives of probands with either generalized (2.5-fold) or focal epilepsy (2.6-fold) may reflect some coexisting shared genetic influences. PMID:24468822

Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats

PubMed Central

D’Amore, V.; Santolini, I.; van Rijn, C.M.; Biagioni, F.; Molinaro, G.; Prete, A.; Conn, P.J.; Lindsley, C.W.; Zhou, Y.; Vinson, P.N.; Rodriguez, A.L.; Jones, C.K.; Stauffer, S.R.; Nicoletti, F.; van Luijtelaar, G.; Ngomba, R.T.

2013-01-01

Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. PMID:22705340

The impact of marital status on epilepsy-related health concerns.

PubMed

Elliott, John O; Charyton, Christine; McAuley, James W; Shneker, Bassel F

2011-08-01

Social support from marriage has been linked with better health outcomes. Persons with epilepsy (PWE) are significantly less likely to be married than persons without epilepsy. No previous studies have examined the impact of marriage on epilepsy-related health concerns. Outpatient PWE (n=267) were asked to identify their top five concerns on the Epilepsy Foundation Concerns Index. After controlling for clinical factors (seizure frequency, age of epilepsy diagnosis and disability status) PWE who were married were significantly less likely to report "Fear of being injured during a seizure" Odds Ratio (OR) 0.33, "Holding down a job" OR 0.29, "Getting the work or education you want" OR 0.29, "Medical costs of your epilepsy" OR 0.21 and "Lack of people's understanding of epilepsy" OR 0.27. Once we controlled for both clinical factors and demographic factors only one concern "Medical costs of your epilepsy" OR 0.24 remained significant. Our findings support several theories examining the health benefits of marriage related to selection, protection and economic resources. PWE are particularly prone to economic disparities due to lower educational attainment and unemployment. Earlier intervention especially for those with childhood onset epilepsy may help mitigate these disparities and their impact on social relationships and marriage. Copyright © 2011 Elsevier B.V. All rights reserved.

Down-regulation of Long Noncoding RNA MALAT1 Protects Hippocampal Neurons Against Excessive Autophagy and Apoptosis via the PI3K/Akt Signaling Pathway in Rats with Epilepsy.

PubMed

Wu, Qiang; Yi, Xuewei

2018-06-01

Epilepsy is a common chronic brain disorder and is characterized by an enduring predisposition to generate seizures. The hippocampus is especially vulnerable to seizure-induced damage. In this study, we explore the ability of long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) to influence the autophagy and apoptosis of hippocampal neurons in epilepsy and the underlying mechanism involving the PI3K/Akt signaling pathway. Seventy-two Sprague-Dawley rats were assigned to normal, sham, Ep, Ep + si-NC, Ep + si-MALAT1, and Ep + si-MALAT1 + LY groups. Fluorescence in situ hybridization kit was employed to determine the MALAT1 in the brain tissues. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were performed to determine the expression of MALAT1, mRNAs, and proteins. The autophagy of hippocampal neurons was evaluated under a transmission electron microscope and their apoptosis was evaluated using TUNEL staining. We found that MALAT1 and c-Met were enriched while microRNA-101 (miR-101) decreased in rats with epilepsy. The demonstration showed that MALAT1 binds to miR-101, thus regulating c-Met. In rats with epilepsy, MALAT1 depletion mediated by anti-MALAT1 siRNA resulted in activation of PI3K/Akt signaling pathway and loss of hippocampal neurons. LY294002, an inhibitor of PI3K/Akt signaling pathway, could reverse the events caused by MALAT1 knockdown. Taken together, these findings indicate that down-regulation of MALAT1 activates the PI3K/Akt signaling pathway to protect hippocampal neurons against autophagy and apoptosis in rats with epilepsy.

Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance.

PubMed

Balan, Shabeesh; Bharathan, Sumitha Prameela; Vellichiramal, Neetha Nanoth; Sathyan, Sanish; Joseph, Vijai; Radhakrishnan, Kurupath; Banerjee, Moinak

2014-01-01

Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency for MTLE

Genetic Association Analysis of ATP Binding Cassette Protein Family Reveals a Novel Association of ABCB1 Genetic Variants with Epilepsy Risk, but Not with Drug-Resistance

PubMed Central

Balan, Shabeesh; Bharathan, Sumitha Prameela; Vellichiramal, Neetha Nanoth; Sathyan, Sanish; Joseph, Vijai; Radhakrishnan, Kurupath; Banerjee, Moinak

2014-01-01

Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with

Intravenous lacosamide for treatment of absence status epilepticus in genetic generalized epilepsy: A case report and review of literature.

PubMed

Reif, P S; Männer, A; Willems, L M; Kay, L; Zöllner, J P; Klein, K M; Rosenow, F; Strzelczyk, A

2018-04-06

Nearly 10 years after its introduction into the market, the significance of lacosamide in genetic generalized epilepsies is still unclear. Its new mode of action may qualify lacosamide as a therapeutic agent in this entity, but only a limited number of cases have been published so far. To describe the efficacy of lacosamide as treatment in a patient with the absence status epilepticus. We report on a 28-year-old woman with genetic generalized epilepsy who suffered recurrent absence status epilepticus during video-EEG-monitoring. After treatment failure of first- and second-line medication, lacosamide was administered. The outcome in this patient was evaluated, and a systematic literature review was performed for the use of lacosamide in the absence status epilepticus. After application of 400 mg lacosamide intravenously, the absence status epilepticus terminated within 30 minutes. No further seizures or epileptiform discharges reoccurred until the end of video-EEG-Monitoring 3 days later. The role of lacosamide as a therapeutic option in patients with the absence status epilepticus is unclear. Only two cases have been reported so far with conflicting results. Further randomized controlled studies are required to validate the relevance of lacosamide as treatment for status epilepticus in genetic generalized and the absence epilepsy. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pulmonary Transcriptional Response to Ozone in Healthy and Cardiovascular Compromised Rat Models

EPA Science Inventory

The genetic cardiovascular disease (CVD) and associated metabolic impairments can influence the lung injury from inhaled pollutants. We hypothesized that comparative assessment of global pulmonary expression profile of healthy and CVD-prone rat models will provide mechanistic ins...

Translational Advancement of Somatostatin Gene Delivery for Disease Modification and Cognitive Sparing in Intractable Epilepsy

DTIC Science & Technology

2014-09-01

delivery persistently reduces seizure severity in a rat model of temporal lobe epilepsy ," Session number: 314, Session title: Non-pharmacological...delivery persistently reduces seizure severity in a rat model of temporal lobe epilepsy Location: WCC Hall A-C Presentation time: Monday, Nov 17, 2014...therapeutic potential administered prior to last-resort neurosurgical resections in pharmacoresistant cases of temporal lobe epilepsy . Disclosures: G. Natarajan

Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications.

PubMed

Prontera, P; Sarchielli, P; Caproni, S; Bedetti, C; Cupini, L M; Calabresi, P; Costa, C

2018-02-01

Objective We performed a systematic review on the comorbidities of familial/sporadic hemiplegic migraine (F/SHM) with seizure/epilepsy in patients with CACNA1A, ATP1A2 or SCN1A mutations, to identify the genotypes associated and investigate for the presence of mutational hot spots. Methods We performed a search in MEDLINE and in the Human Gene Mutation and Leiden Open Variation Databases for mutations in the CACNA1A, ATP1A2 and SCN1A genes. After having examined the clinical characteristics of the patients, we selected those having HM and seizures, febrile seizures or epilepsy. For each gene, we determined both the frequency and the positions at protein levels of these mutations, as well as the penetrance of epilepsy within families. Results Concerning F/SHM-Epilepsy1 (F/SHME1) and F/SHME2 endophenotypes, we observed a prevalent involvement of the transmembrane domains, and a strong correlation in F/SHME1 when the positively charged amino acids were involved. The penetrance of epilepsy within the families was highest for patients carrying mutation in the CACNA1A gene (60%), and lower in those having SCN1A (33.3%) and ATP1A2 (30.9%) mutations. Conclusion Among the HM cases with seizure/epilepsy, we observed mutational hot spots in the transmembrane domains of CACNA1A and ATP1A2 proteins. These findings could lead to a better understanding of the pathological mechanisms underlying migraine and epilepsy, therein guaranteeing the most appropriate therapeutic approach.

Canine epilepsy: an underutilized model.

PubMed

Patterson, Edward E

2014-01-01

The mainstay of comparative research for epilepsy has been rodent models of induced epilepsy. This rodent basic science is essential, but it does not always translate to similar results in people, likely because induced epilepsy is not always similar enough to naturally occurring epilepsy. A good large animal, intermediate model would be very helpful to potentially bridge this translational gap. Epilepsy is the most common medical neurologic disease of dogs. It has been proposed since the 1970s that dogs with naturally occurring epilepsy could potentially be used as a comparative model for people of the underlying basis and therapy of epilepsy. There have been sporadic studies in the decades since then, with a relative surge in the last 10 years. These canine studies in the areas of genetics, drug therapy, dietary therapy, electroencelphalogram research, and devices for epilepsy show proof of concept that canine epilepsy can be a very good model for comparative research for many, but not all, facets of epilepsy. Results of research in canine epilepsy can and have benefited the improvement of treatment for both people and dogs. © The Author 2014. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Molecular diagnosis of patients with epilepsy and developmental delay using a customized panel of epilepsy genes.

PubMed

Ortega-Moreno, Laura; Giráldez, Beatriz G; Soto-Insuga, Victor; Losada-Del Pozo, Rebeca; Rodrigo-Moreno, María; Alarcón-Morcillo, Cristina; Sánchez-Martín, Gema; Díaz-Gómez, Esther; Guerrero-López, Rosa; Serratosa, José M

2017-01-01

Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness.

Identification of 29 Rat Genetic Markers by Arbitrarily Primed Polymerase Chain Reaction

PubMed Central

Canzian, Federico; Toyota, Minoru; Hosoya, Yoko; Sugimura, Takashi; Nagao, Minako

1996-01-01

The number of genetic markers for the rat is still limited, in spite of its wide use in cancer research. To facilitate accurate mapping of both established and novel rat genetic markers, we constructed a linkage map by genotyping 105 F2 rats from ACI/N (ACI) and BUF/Nac (BUF) crosses. This map consists of 120 genetic markers that had been previously reported, mainly by two research groups, but had not been integrated. To find new genetic markers, the arbitrarily primed polymerase chain reaction (AP‐PCR) was applied to detect polymorphic bands between ACI and BUF rats. After testing 56 single primers and 12 combinations of primers, we found 36 bands produced by 16 single primers and two combinations to be reliably polymorphic between ACI and BUF rats. The 36 bands were typed in the 105 F2 rats, and 29 of them could be linkage‐mapped. AP‐PCR is thus useful to detect new genetic markers in laboratory strains of rats. PMID:8698613

Changes in calcium and iron levels in the brains of rats during kainate induced epilepsy

NASA Astrophysics Data System (ADS)

Ren, Min-Qin; Ong, Wei-Yi; Makjanic, Jagoda; Watt, Frank

1999-10-01

Epilepsy is a recurrent disorder of cerebral function characterised by sudden brief attacks of altered consciousness, motor activity or sensory phenomena, and affects approximately 1% of the population. Kainic acid injection induces neuronal degeneration in rats, is associated with glial hypertrophy and proliferation in the CA3-CA4 fields of hippocampal complex, and is a model for temporal lobe epilepsy. In this study we have applied Nuclear Microscopy to the investigation of the elemental changes within the hippocampus and the cortex areas of the rat brain following kainate injection. Analyses of unstained freeze dried tissue sections taken at 1 day and 1, 2, 3 and 4 weeks following injection were carried out using the Nuclear Microscopy facility at the Research Centre for Nuclear Microscopy, National University of Singapore. Quantitative analysis and elemental mapping indicates that there are significant changes in the calcium levels and distributions in the hippocampus as early as 1 day following injection. Preliminary results indicate a rapid increase in cellular calcium. High levels of calcium can activate calcium dependent proteins and phospholipases. Activation of phospholipase A 2 can be harmful to surrounding neurons through free radical damage. In addition to observed increases in calcium, there was evidence of increases in iron levels. This is consistent with measurements in other degenerative brain disorders, and may signal a late surge in free radical production.

Genetic testing in the epilepsies—Report of the ILAE Genetics Commission

PubMed Central

Ottman, Ruth; Hirose, Shinichi; Jain, Satish; Lerche, Holger; Lopes-Cendes, Iscia; Noebels, Jeffrey L.; Serratosa, José; Zara, Federico; Scheffer, Ingrid E.

2010-01-01

SUMMARY In this report, the International League Against Epilepsy (ILAE) Genetics Commission discusses essential issues to be considered with regard to clinical genetic testing in the epilepsies. Genetic research on the epilepsies has led to the identification of more than 20 genes with a major effect on susceptibility to idiopathic epilepsies. The most important potential clinical application of these discoveries is genetic testing: the use of genetic information, either to clarify the diagnosis in people already known or suspected to have epilepsy (diagnostic testing), or to predict onset of epilepsy in people at risk because of a family history (predictive testing). Although genetic testing has many potential benefits, it also has potential harms, and assessment of these potential benefits and harms in particular situations is complex. Moreover, many treating clinicians are unfamiliar with the types of tests available, how to access them, how to decide whether they should be offered, and what measures should be used to maximize benefit and minimize harm to their patients. Because the field is moving rapidly, with new information emerging practically every day, we present a framework for considering the clinical utility of genetic testing that can be applied to many different syndromes and clinical contexts. Given the current state of knowledge, genetic testing has high0020clinical utility in few clinical contexts, but in some of these it carries implications for daily clinical practice. PMID:20100225

Rational management of epilepsy.

PubMed

Viswanathan, Venkataraman

2014-09-01

Management of epilepsies in children has improved considerably over the last decade, all over the world due to the advances seen in the understanding of the patho-physiology of epileptogenesis, availability of both structural and functional imaging studies along with better quality EEG/video-EEG recordings and the availability of a plethora of newer anti-epileptic drugs which are tailormade to act on specific pathways. In spite of this, there is still a long way to go before one is able to be absolutely rational about which drug to use for which type of epilepsy. There have been a lot of advances in the area of epilepsy surgery and is certainly gaining ground for specific cases. Better understanding of the genetic basis of epilepsies will hopefully lead to a more rational treatment plan in the future. Also, a lot of work needs to be done to dispel various misunderstandings and myths about epilepsy which still exists in our country.

Accelerated cognitive decline in a rodent model for temporal lobe epilepsy.

PubMed

Schipper, Sandra; Aalbers, Marlien W; Rijkers, Kim; Lagiere, Melanie; Bogaarts, Jan G; Blokland, Arjan; Klinkenberg, Sylvia; Hoogland, Govert; Vles, Johan S H

2016-12-01

Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy. Neurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance. Rats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits. The effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy. Copyright © 2016 Elsevier Inc. All rights reserved.

Altered Expression of CXCL13 and CXCR5 in Intractable Temporal Lobe Epilepsy Patients and Pilocarpine-Induced Epileptic Rats.

PubMed

Li, Ruohan; Ma, Limin; Huang, Hao; Ou, Shu; Yuan, Jinxian; Xu, Tao; Yu, Xinyuan; Liu, Xi; Yang, Juan; Chen, Yangmei; Peng, Xi

2017-02-01

The mechanisms that underlie the pathogenesis of epilepsy are still unclear. Recent studies have indicated that inflammatory processes occurring in the brain are involved in a common and crucial mechanism in epileptogenesis. C-X-C motif chemokine ligand 13 (CXCL13) and its only receptor, C-X-C motif chemokine receptor 5 (CXCR5), are highly expressed in the central nervous system (CNS) and participate in inflammatory responses. The present study aimed to assess the expression of CXCL13 and CXCR5 in the brain tissues of both patients with intractable epilepsy (IE) and a rat model (lithium-pilocarpine) of temporal lobe epilepsy (TLE) to identify possible roles of the CXCL13-CXCR5 signaling pathway in epileptogenesis. Real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemical, double-labeled immunofluorescence and Western blot analyses were performed in this study. CXCL13 and CXCR5 mRNA expression and protein levels were found to be significantly up-regulated in the TLE patients and TLE rats. Further, CXCL13 and CXCR5 protein levels were altered during the different epileptic phases after onset of status epilepticus (SE) in the pilocarpine model rats, including the acute phase (6, 24, and 72 h), latent phase (7 and 14 days) and chronic phase (30 and 60 days groups). Moreover, double-labeled immunofluorescence analysis revealed that CXCL13 was mainly expressed in the cytomembranes and cytoplasm of neurons and astrocytes, while CXCR5 was mainly expressed in the cytomembranes and cytoplasm of neurons. Thus, the CXCL13-CXCR5 signaling pathway may play a possible pathogenic role in IE. CXCL13 and CXCR5 may represent potential biomarkers of brain inflammation in epileptic patients.

Emerging Antiepileptic Drugs for Severe Pediatric Epilepsies.

PubMed

Mudigoudar, Basanagoud; Weatherspoon, Sarah; Wheless, James W

2016-05-01

The medical management of the epilepsy syndromes of early childhood (eg, infantile spasms, Dravet syndrome, and Lennox-Gastaut syndrome) is challenging; and requires careful evaluation, classification, and treatment. Pharmacologic therapy continues to be the mainstay of management for these children, and as such it is important for the clinician to be familiar with the role of new antiepileptic drugs. This article reports the clinical trial data and personal experience in treating the severe epilepsies of childhood with the recently Food and Drug Administration-approved new antiepileptic drugs (vigabatrin, rufinamide, perampanel, and clobazam) and those in clinical trials (cannabidiol, stiripentol, and fenfluramine). Genetic research has also identified an increasing number of pediatric developmental and seizure disorders that are possibly treatable with targeted drug therapies, focused on correcting underlying neural dysfunction. We highlight recent genetic advances, and how they affect our treatment of some of the genetic epilepsies, and speculate on the use of targeted genetic treatment (precision medicine) in the future. Copyright © 2016 Elsevier Inc. All rights reserved.

Epilepsy and vaccinations: Italian guidelines.

PubMed

Pruna, Dario; Balestri, Paolo; Zamponi, Nelia; Grosso, Salvatore; Gobbi, Giuseppe; Romeo, Antonino; Franzoni, Emilio; Osti, Maria; Capovilla, Giuseppe; Longhi, Riccardo; Verrotti, Alberto

2013-10-01

Reports of childhood epilepsies in temporal association with vaccination have had a great impact on the acceptance of vaccination programs by health care providers, but little is known about this possible temporal association and about the types of seizures following vaccinations. For these reasons the Italian League Against Epilepsy (LICE), in collaboration with other Italian scientific societies, has decided to generate Guidelines on Vaccinations and Epilepsy. The aim of Guidelines on Vaccinations and Epilepsy is to present recent unequivocal evidence from published reports on the possible relationship between vaccines and epilepsy in order to provide information about contraindications and risks of vaccinations in patients with epilepsy. The following main issues have been addressed: (1) whether contraindications to vaccinations exist in patients with febrile convulsions, epilepsy, and/or epileptic encephalopathies; and (2) whether any vaccinations can cause febrile seizures, epilepsy, and/or epileptic encephalopathies. Diphtheria-tetanus-pertussis (DTP) vaccination and measles, mumps, and rubella vaccination (MMR) increase significantly the risk of febrile seizures. Recent observations and data about the relationships between vaccination and epileptic encephalopathy show that some cases of apparent vaccine-induced encephalopathy could in fact be caused by an inherent genetic defect with no causal relationship with vaccination. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Infections, inflammation and epilepsy

PubMed Central

Vezzani, Annamaria; Fujinami, Robert S.; White, H. Steve; Preux, Pierre-Marie; Blümcke, Ingmar; Sander, Josemir W.; Löscher, Wolfgang

2016-01-01

Epilepsy is the tendency to have unprovoked epileptic seizures. Anything causing structural or functional derangement of brain physiology may lead to seizures, and different conditions may express themselves solely by recurrent seizures and thus be labelled “epilepsy.” Worldwide, epilepsy is the most common serious neurological condition. The range of risk factors for the development of epilepsy varies with age and geographic location. Congenital, developmental and genetic conditions are mostly associated with the development of epilepsy in childhood, adolescence and early adulthood. Head trauma, infections of the central nervous system (CNS) and tumours may occur at any age and may lead to the development of epilepsy. Infections of the CNS are a major risk factor for epilepsy. The reported risk of unprovoked seizures in population-based cohorts of survivors of CNS infections from developed countries is between 6.8 and 8.3 %, and is much higher in resource-poor countries. In this review, the various viral, bacterial, fungal and parasitic infectious diseases of the CNS which result in seizures and epilepsy are discussed. The pathogenesis of epilepsy due to brain infections, as well as the role of experimental models to study mechanisms of epileptogenesis induced by infectious agents, is reviewed. The sterile (non-infectious) inflammatory response that occurs following brain insults is also discussed, as well as its overlap with inflammation due to infections, and the potential role in epileptogenesis. Furthermore, autoimmune encephalitis as a cause of seizures is reviewed. Potential strategies to prevent epilepsy resulting from brain infections and non-infectious inflammation are also considered. PMID:26423537

A model of posttraumatic epilepsy after penetrating brain injuries: effect of lesion size and metal fragments.

PubMed

Kendirli, M Tansel; Rose, Dominique T; Bertram, Edward H

2014-12-01

Penetrating brain injury (PBI) has the highest risk for inducing posttraumatic epilepsy, and those PBIs with retained foreign materials such as bullet fragments carry the greatest risk. This study examines the potential contribution of copper, a major component of bullets, to the development of epilepsy following PBI. Anesthetized adult male rats received a penetrating injury from the dorsal cortex to the ventral hippocampus from a high speed small bit drill. In one group of animals, copper wire was inserted into the lesion. Control animals had only the lesion or the lesion plus stainless steel wire (biologically inert foreign body). From 6 to up to 11 months following the injury the rats were monitored intermittently for the development of epilepsy with video-electroencephalography (EEG). A separate set of animals was examined for possible acute seizures in the week following the injury. Twenty-two of the 23 animals with copper wire developed chronic epilepsy, compared to three of the 20 control rats (lesion and lesion with stainless steel). Copper was associated with more extensive injury. The control rats with epilepsy had larger lesions. In the acute injury group, there was no difference in the incidence of seizures (83% lesion plus stainless steel, 70% lesion plus copper). Copper increases the risk for epilepsy and may increase damage over time, but there were no differences between the groups in the incidence of acute postinjury seizures. Lesion size may contribute to epilepsy development in lesion-only animals. Copper may be an independent risk factor for the development of epilepsy and possible secondary injury, but lesion size also contributes to the development of epilepsy. The consequences of prolonged exposure of the brain to copper observed in these animals may have clinical implications that require further evaluation. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

DEPDC5 as a potential therapeutic target for epilepsy.

PubMed

Myers, Kenneth A; Scheffer, Ingrid E

2017-06-01

Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.

Effects of rapamycin and curcumin treatment on the development of epilepsy after electrically induced status epilepticus in rats.

PubMed

Drion, Cato M; Borm, Lars E; Kooijman, Lieneke; Aronica, Eleonora; Wadman, Wytse J; Hartog, Aloysius F; van Vliet, Erwin A; Gorter, Jan A

2016-05-01

Inhibition of the mammalian target of rapamycin (mTOR) pathway has been suggested as a possible antiepileptogenic strategy in temporal lobe epilepsy (TLE). Here we aim to elucidate whether mTOR inhibition has antiepileptogenic and/or antiseizure effects using different treatment strategies in the electrogenic post-status epilepticus (SE) rat model. Effects of mTOR inhibitor rapamycin were tested using the following three treatment protocols: (1) "stop-treatment"-post-SE treatment (6 mg/kg/day) was discontinued after 3 weeks; rats were monitored for 5 more weeks thereafter, (2) "pretreatment"-rapamycin (3 mg/kg/day) was applied during 3 days preceding SE; and (3) "chronic phase-treatment"-5 days rapamycin treatment (3 mg/kg/day) in the chronic phase. We also tested curcumin, an alternative mTOR inhibitor with antiinflammatory and antioxidant effects, using chronic phase treatment. Seizures were continuously monitored using video-electroencephalography (EEG) recordings; mossy fiber sprouting, cell death, and inflammation were studied using immunohistochemistry. Blood was withdrawn regularly to assess rapamycin and curcumin levels with high performance liquid chromatography (HPLC). Stop-treatment led to a strong reduction of seizures during the 3-week treatment and a gradual reappearance of seizures during the following 5 weeks. Three days pretreatment did not prevent seizure development, whereas 5-day rapamycin treatment in the chronic phase reduced seizure frequency. Washout of rapamycin was slow and associated with a gradual reappearance of seizures. Rapamycin treatment (both 3 and 6 mg/kg) led to body growth reduction. Curcumin treatment did not reduce seizure frequency or lead to a decrease in body weight. The present study indicates that rapamycin cannot prevent epilepsy in the electrical stimulation post-SE rat model but has seizure-suppressing properties as long as rapamycin blood levels are sufficiently high. Oral curcumin treatment had no effect on chronic

A comprehensive assessment of cognitive function in the common genetic generalized epilepsy syndromes.

PubMed

Loughman, A; Bowden, S C; D'Souza, W J

2017-03-01

Considered to be benign conditions, the common genetic generalized epilepsy (GGE) syndromes are now known to be frequently accompanied by cognitive dysfunction. However, unresolved issues impede clinical management of this common comorbidity, including which cognitive abilities are most affected, whether there are differences between syndromes and how seizure type and mood symptoms affect cognitive dysfunction. We provide a detailed description of cognitive ability and evaluate factors contributing to cognitive dysfunction. A total of 76 adults with GGE were assessed with the Woodcock Johnson III Tests of Cognitive Abilities. Scores on tests of overall cognitive ability, acquired knowledge, long-term retrieval and speed of information processing were significantly below the normative mean. Long-term retrieval was a pronounced weakness with a large reduction in scores (d = 0.84). GGE syndrome, seizure type and the presence of recent psychopathology symptoms were not significantly associated with cognitive function. This study confirms previous meta-analytic findings with a prospective study, offers new insights into the cognitive comorbidity of these common epilepsy syndromes and reinforces the need for cognitive interventions in people with GGE. © 2016 EAN.

Clonic Seizures in GAERS Rats after Oral Administration of Enrofloxacin

PubMed Central

Bauquier, Sebastien H; Jiang, Jonathan L; Lai, Alan; Cook, Mark J

2016-01-01

The aim of this study was to evaluate the effect of oral enrofloxacin on the epileptic status of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). Five adult female GAERS rats, with implanted extradural electrodes for EEG monitoring, were declared free of clonic seizures after an 8-wk observation period. Enrofloxacin was then added to their drinking water (42.5 mg in 750 mL), and rats were observed for another 3 days. The number of spike-and-wave discharges and mean duration of a single discharge did not differ before and after treatment, but 2 of the 5 rats developed clonic seizures after treatment. Enrofloxacin should be used with caution in GAERS rats because it might induce clonic seizures. PMID:27298247

Effects of a herbal medicine, Hippophae rhamnoides, on cardiovascular functions and coronary microvessels in the spontaneously hypertensive stroke-prone rat.

PubMed

Koyama, Tomiyasu; Taka, Akira; Togashi, Hiroko

2009-01-01

The dry fruits of Hippophae rhamnoides (so-called "Saji" or "Sea buckthorn") are used in China as a herbal medicine. The present work studied the effects on microvessels in the left ventricular wall, hematological parameters, cardiovascular performance and plasma constituents in spontaneously hypertensive stroke-prone rats (SHRSP/EZO) treated with Hippophae for 60 days. Analyses showed that the powder made of dry Hippophae fruits contains the vitamins C, B1, B2 and E, provitamin A, rutin, serotonin, cytosterol, selenium and zinc, among other constituents. The experimental rats were fed ad libitum with blocks of rat chow supplemented with Hippophae powder at a concentration of 0.7 g/kg in rat powder chow, while control rats were unsupplemented chow. The mean arterial blood pressure, heart rate, total plasma cholesterol, triglycerides, and glycated hemoglobin were significantly decreased by the Hippophae treatment. The arteriolar capillary portions of microvessels expressing alkaline phosphatase decreased, but there was a trend for an increase in the total capillary density. It was concluded that Hippophae fruits improved the metabolic processes accompanied by reduction of hypertensive stress on the ventricular microvessels.

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

PubMed

Leu, Costin; de Kovel, Carolien G F; Zara, Federico; Striano, Pasquale; Pezzella, Marianna; Robbiano, Angela; Bianchi, Amedeo; Bisulli, Francesca; Coppola, Antonietta; Giallonardo, Anna Teresa; Beccaria, Francesca; Trenité, Dorothée Kasteleijn-Nolst; Lindhout, Dick; Gaus, Verena; Schmitz, Bettina; Janz, Dieter; Weber, Yvonne G; Becker, Felicitas; Lerche, Holger; Kleefuss-Lie, Ailing A; Hallman, Kerstin; Kunz, Wolfram S; Elger, Christian E; Muhle, Hiltrud; Stephani, Ulrich; Møller, Rikke S; Hjalgrim, Helle; Mullen, Saul; Scheffer, Ingrid E; Berkovic, Samuel F; Everett, Kate V; Gardiner, Mark R; Marini, Carla; Guerrini, Renzo; Lehesjoki, Anna-Elina; Siren, Auli; Nabbout, Rima; Baulac, Stephanie; Leguern, Eric; Serratosa, Jose M; Rosenow, Felix; Feucht, Martha; Unterberger, Iris; Covanis, Athanasios; Suls, Arvid; Weckhuysen, Sarah; Kaneva, Radka; Caglayan, Hande; Turkdogan, Dilsad; Baykan, Betul; Bebek, Nerses; Ozbek, Ugur; Hempelmann, Anne; Schulz, Herbert; Rüschendorf, Franz; Trucks, Holger; Nürnberg, Peter; Avanzini, Giuliano; Koeleman, Bobby P C; Sander, Thomas

2012-02-01

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31

Variability in Ozone-Induced Pulmonary Injury and Inflammation in Healthy and Cardiovascular Compromised Rat Models

EPA Science Inventory

The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure depe...

Association of ABCB1 C3435T polymorphism with phenobarbital resistance in Thai patients with epilepsy.

PubMed

Keangpraphun, T; Towanabut, S; Chinvarun, Y; Kijsanayotin, P

2015-06-01

One-third of patients with epilepsy are resistant to anti-epileptic drugs (AEDs). Drug-resistant epilepsy is believed to be multifactorial involving both genetic and non-genetic factors. Genetic variations in the ABCB1 gene encoding the drug efflux transporter, p-glycoprotein (p-gp), may influence the interindividual variability in AED response by limiting drugs from reaching their target. Phenobarbital (PB), one of the most cost-effective and widely used AEDs in developing countries, has been reported to be transported by p-gp. This study aimed to investigate the association of a genetic variant, ABCB1 3435C>T, and non-genetic factors with phenobarbital response in Thai patients with epilepsy. One hundred and ten Thai patients with epilepsy who were treated with PB maintenance doses were enrolled in this study. Two phenotypic groups, PB-responsive epilepsy and PB-resistant epilepsy, were defined according to the International League Against Epilepsy (ILAE) criteria. Subjects were genotyped for ABCB1 3435C>T (rs1045642). Multiple logistic regression analysis was tested for the association of ABCB1 3435C>T polymorphism and non-genetic factors with PB response. Sixty-two PB-responsive epilepsy subjects and 48 PB-resistant epilepsy subjects were identified. All genotype frequencies of the ABCB1 3435C>T SNP were consistent with the Hardy-Weinberg equilibrium (P > 0·05). The ABCB1 3435C>T polymorphism and type of epilepsy were associated with response to PB. Patients with PB-resistant epilepsy had a significantly higher frequency of ABCB1 3435CC genotype and had focal epilepsy more often than patients with PB-responsive epilepsy (adjusted OR = 3·962, 95% CI = 1·075-14·610, P-value = 0·039; adjusted OR = 5·936, 95% CI = 2·272-15·513, P-value < 0·001, respectively). The model explained 25·5% of the variability in response to PB (R(2)  = 0·255). Thai patients of ABCB1 3435CC genotype and with focal epilepsy were more often PB resistant. Those two

Autism, epilepsy, and synaptopathies: a not rare association.

PubMed

Keller, Roberto; Basta, Roberta; Salerno, Luana; Elia, Maurizio

2017-08-01

Autism spectrum disorders (ASD) are neurodevelopmental disorders typically diagnosed in childhood, characterized by core social dysfunction, rigid and repetitive behaviors, restricted interests, and abnormal sensorial sensitivity. ASD belong to multifactorial diseases: both genetic and environmental factors have been considered as potential risk factors for their onset. ASD are often associated with neurological conditions: the co-occurrence of epilepsy is well documented and there is also evidence of a higher prevalence of EEG abnormalities with 4-86% of individuals with ASD presenting epileptiform or not epileptiform EEG abnormalities. The presence of epilepsy in people with ASD may be determined by several structural alterations, genetic conditions, or metabolic dysfunctions, known to play a role in the emergence of both epilepsy and autism. The purpose of this article is to discuss precisely such latter cause of the autism-epilepsy association, focusing specifically on those "synaptic genes," whose mutation predisposes to both the diseases.

Genetics Home Reference: autosomal dominant partial epilepsy with auditory features

MedlinePlus

... Twitter Home Health Conditions ADPEAF Autosomal dominant partial epilepsy with auditory features Printable PDF Open All Close ... the expand/collapse boxes. Description Autosomal dominant partial epilepsy with auditory features ( ADPEAF ) is an uncommon form ...

Lingual CD36 and nutritional status differentially regulate fat preference in obesity-prone and obesity-resistant rats.

PubMed

Douglas Braymer, H; Zachary, Hannah; Schreiber, Allyson L; Primeaux, Stefany D

2017-05-15

Lingual fatty acid receptors (i.e. CD36) mediate the orosensory perception of fat/fatty acids and may contribute to the susceptibility to develop obesity. The current study tested the hypothesis that fat/fatty acid preference in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats is mediated by nutritional status and lingual CD36. To determine if nutritional status affected linoleic acid (LA) preference in OP and OR rats, rats were either fasted overnight or fed a high fat diet (60% kcal from fat). In OR rats, fasting increased the preference for higher concentrations of LA (1.0%), while consumption of a high fat diet decreased LA preference. In OP rats, fasting increased the preference for lower concentrations of LA (0.25%), however high fat diet consumption did not alter LA preference. To determine if lingual CD36 mediated the effects of an overnight fast on LA preference, the expression of lingual CD36 mRNA was assessed and the effect of lingual application of CD36 siRNA on LA preference was determined. Fasting increased lingual CD36 mRNA expression in OR rats, but failed to alter lingual CD36 mRNA in OP rats. Following an overnight fast, application of lingual CD36 siRNA led to a decrease in LA preference in OR, but not OP rats. Lingual application of CD36 siRNA was also used to determine if lingual CD36 mediated the intake and preference for a high fat diet in OP and OR rats. CD36 siRNA decreased the preference and intake of high fat diet in OR rats, but not OP rats. The results from this study suggest that the dysregulation of lingual CD36 in OP rats is a potential factor leading to increased fat intake and fat preference and an enhanced susceptibility to develop obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

Lingual CD36 and nutritional status differentially regulate fat preference in obesity-prone and obesity-resistant rats

PubMed Central

Braymer, H. Douglas; Zachary, Hannah; Schreiber, Allyson L.; Primeaux, Stefany D.

2017-01-01

Lingual fatty acid receptors (i.e. CD36) mediate the orosensory perception of fat/fatty acids and may contribute to the susceptibility to develop obesity. The current study tested the hypothesis that fat/fatty acid preference in obesity-prone (OP, Osborne-Mendel) and obesity-resistant (OR, S5B/Pl) rats is mediated by nutritional status and lingual CD36. To determine if nutritional status affected linoleic acid (LA) preference in OP and OR rats, rats were either fasted overnight or fed a high fat diet (60% kcal from fat). In OR rats, fasting increased the preference for higher concentrations of LA (1.0%), while consumption of a high fat diet decreased LA preference. In OP rats, fasting increased the preference for lower concentrations of LA (0.25%), however high fat diet consumption did not alter LA preference. To determine if lingual CD36 mediated the effects of an overnight fast on LA preference, the expression of lingual CD36 mRNA was assessed and the effect of lingual application of CD36 siRNA on LA preference was determined. Fasting increased lingual CD36 mRNA expression in OR rats, but failed to alter lingual CD36 mRNA in OP rats. Following an overnight fast, application of lingual CD36 siRNA led to a decrease in LA preference in OR, but not OP rats. Lingual application of CD36 siRNA was also used to determine if lingual CD36 mediated the intake and preference for a high fat diet in OP and OR rats. CD36 siRNA decreased the preference and intake of high fat diet in OR rats, but not OP rats. The results from this study suggest that the dysregulation of lingual CD36 in OP rats is a potential factor leading to increased fat intake and fat preference and an enhanced susceptibility to develop obesity. PMID:28302572

Neuroimaging in epilepsy.

PubMed

Sidhu, Meneka Kaur; Duncan, John S; Sander, Josemir W

2018-05-17

Epilepsy neuroimaging is important for detecting the seizure onset zone, predicting and preventing deficits from surgery and illuminating mechanisms of epileptogenesis. An aspiration is to integrate imaging and genetic biomarkers to enable personalized epilepsy treatments. The ability to detect lesions, particularly focal cortical dysplasia and hippocampal sclerosis, is increased using ultra high-field imaging and postprocessing techniques such as automated volumetry, T2 relaxometry, voxel-based morphometry and surface-based techniques. Statistical analysis of PET and single photon emission computer tomography (STATISCOM) are superior to qualitative analysis alone in identifying focal abnormalities in MRI-negative patients. These methods have also been used to study mechanisms of epileptogenesis and pharmacoresistance.Recent language fMRI studies aim to localize, and also lateralize language functions. Memory fMRI has been recommended to lateralize mnemonic function and predict outcome after surgery in temporal lobe epilepsy. Combinations of structural, functional and post-processing methods have been used in multimodal and machine learning models to improve the identification of the seizure onset zone and increase understanding of mechanisms underlying structural and functional aberrations in epilepsy.

Epilepsy in twins: insights from unique historical data of William Lennox.

PubMed

Vadlamudi, L; Andermann, E; Lombroso, C T; Schachter, S C; Milne, R L; Hopper, J L; Andermann, F; Berkovic, S F

2004-04-13

To classify the Lennox twin pairs according to modern epilepsy classifications, use the classic twin model to identify which epilepsy syndromes have an inherited component, search for evidence of syndrome-specific genes, and compare concordances from Lennox's series with a contemporary Australian series. Following review of Lennox's original files describing twins with seizures from 1934 through 1958, the International League Against Epilepsy classifications of seizures and epileptic syndromes were applied to 169 pairs. Monozygous (MZ) and dizygous (DZ) pairs were subdivided into epilepsy syndromes and casewise concordances estimated. The authors excluded 26 pairs, with 71 MZ and 72 DZ pairs remaining. Seizure analysis demonstrated strong parallels between contemporary seizure classification and Lennox's terminology. Epilepsy syndrome diagnoses were made in 75%. The MZ and DZ casewise concordance estimates gave strong evidence for a major genetic influence in idiopathic generalized epilepsies (0.80 versus 0.00; n = 23). High MZ casewise concordances also supported a genetic etiology in symptomatic generalized epilepsies and febrile seizures. The pairs who were concordant for seizures usually had the same syndromic diagnoses in both twins (86% in MZ, 60% in DZ), suggesting syndrome-specific genes. Apart from partial epilepsies, the MZ casewise concordances were similar to those derived from Australian twin data. The authors were able to apply contemporary classifications to Lennox's twins. The data confirm genetic bases for common generalized epilepsies as well as febrile seizures and provide further support for syndrome-specific genes. Finally, comparable results to our Australian series were obtained, verifying the value of twin studies.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy.

PubMed

Helbig, Katherine L; Farwell Hagman, Kelly D; Shinde, Deepali N; Mroske, Cameron; Powis, Zöe; Li, Shuwei; Tang, Sha; Helbig, Ingo

2016-09-01

To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy. In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis. Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%). A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications. DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.Genet Med 18 9, 898-905.

WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities.

PubMed

Ravizza, Teresa; Onat, Filiz Y; Brooks-Kayal, Amy R; Depaulis, Antoine; Galanopoulou, Aristea S; Mazarati, Andrey; Numis, Adam L; Sankar, Raman; Friedman, Alon

2017-03-01

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate

The Spanish Society of Neurology's official clinical practice guidelines for epilepsy. Special considerations in epilepsy: comorbidities, women of childbearing age, and elderly patients.

PubMed

Mauri Llerda, J A; Suller Marti, A; de la Peña Mayor, P; Martínez Ferri, M; Poza Aldea, J J; Gomez Alonso, J; Mercadé Cerdá, J M

2015-10-01

The characteristics of some population groups (patients with comorbidities, women of childbearing age, the elderly) may limit epilepsy management. Antiepileptic treatment in these patients may require adjustments. We searched articles in Pubmed, clinical practice guidelines for epilepsy, and recommendations by the most relevant medical societies regarding epilepsy in special situations (patients with comorbidities, women of childbearing age, the elderly). Evidence and recommendations are classified according to the prognostic criteria of Oxford Centre of Evidence-Based Medicine (2001) and the European Federation of Neurological Societies (2004) for therapeutic interventions. Epilepsy treatment in special cases of comorbidities must be selected properly to improve efficacy with the fewest side effects. Adjusting antiepileptic medication and/or hormone therapy is necessary for proper seizure management in catamenial epilepsy. Exposure to antiepileptic drugs (AED) during pregnancy increases the risk of birth defects and may affect fetal growth and/or cognitive development. Postpartum breastfeeding is recommended, with monitoring for adverse effects if sedative AEDs are used. Finally, the elderly are prone to epilepsy, and diagnostic and treatment characteristics in this group differ from those of other age groups. Although therapeutic limitations may be more frequent in older patients due to comorbidities, they usually respond better to lower doses of AEDs than do other age groups. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy.

PubMed

Reddy, Doodipala Samba

2016-01-01

Catamenial epilepsy is a type of refractory epilepsy characterized by seizure clusters around perimenstrual or periovulatory period. The pathophysiology of catamenial epilepsy still remains unclear, yet there are few animal models to study this gender-specific disorder. The pathophysiology of perimenstrual catamenial epilepsy involves the withdrawal of the progesterone-derived GABAergic neurosteroids due to the decline in progesterone level at the time of menstruation. These manifestations can be faithfully reproduced in rodents by specific neuroendocrine manipulations. Since mice and rats, like humans, have ovarian cycles with circulating hormones, they appear to be suitable animal models for studies of perimenstrual seizures. Recently, we created specific experimental models to mimic perimenstrual seizures. Studies in rat and mouse models of catamenial epilepsy show enhanced susceptibility to seizures or increased seizure exacerbations following neurosteroid withdrawal. During such a seizure exacerbation period, there is a striking decrease in the anticonvulsant effect of commonly prescribed antiepileptics, such as benzodiazepines, but an increase in the anticonvulsant potency of exogenous neurosteroids. We discovered an extrasynaptic molecular mechanism of catamenial epilepsy. In essence, extrasynaptic δGABA-A receptors are upregulated during perimenstrual-like neuroendocrine milieu. Consequently, there is enhanced antiseizure efficacy of neurosteroids in catamenial models because δGABA-A receptors confer neurosteroid sensitivity and greater seizure protection. Molecular mechanisms such as these offer a strong rationale for the clinical development of a neurosteroid replacement therapy for catamenial epilepsy.

Longitudinal study of accelerated long-term forgetting in children with genetic generalized epilepsy: Evidence of ongoing deficits.

PubMed

Grayson-Collins, Jasmin; Gascoigne, Michael B; Barton, Belinda; Webster, Richard; Gill, Deepak; Lah, Suncica

2017-09-15

Accelerated long-term forgetting (ALF) is a recently described memory disorder characterised by adequate recall after short, but not long delays. Currently, the prevailing conceptualisation of ALF is of a seizure related phenomenon. The main aim of this study was to assess whether ALF subsides as epilepsy severity and seizures abate in children with genetic generalized epilepsy (GGE). Eighteen children with GGE were compared over time to 29 healthy controls on a range of cognitive measures. The primary outcome was a modified version of the California Verbal Learning Test for Children with a long delay (seven day) recall component. At approximately two years follow up, ALF was apparent, although epilepsy severity subsided and seizures resolved in many children. This result contrasts with the dominant conceptualisation of ALF being a seizure related phenomenon. Moreover, at follow-up, worse recall at the long delay was related to greater epilepsy severity at baseline and earlier age of seizure onset, but not to being seizure free at follow-up. While at follow-up worse recall at the long delay related to the worse baseline recall at the long delay, this recall did not relate to scores obtained on standardised memory tests at baseline. Our study suggests that ALF may not be seizure related and identifies factors associated with risk of ALF in children with GGE. Copyright © 2017 Elsevier Ltd. All rights reserved.

Inherent vulnerabilities in monoaminergic pathways predict the emergence of depressive impairments in an animal model of chronic epilepsy.

PubMed

Medel-Matus, Jesús-Servando; Shin, Don; Sankar, Raman; Mazarati, Andrey

2017-08-01

The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus (RN)-prefrontal cortex (PFC) and dopaminergic ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathways were interrogated by fast scan cyclic voltammetry (FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN-PFC and seven rats for VTA-NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN-PFC invariably developed despair, and rats with deviations in VTA-NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to obese-prone rats impairs glucose and insulin tolerance.

PubMed

Hamilton, Melissa; Hopkins, Loren E; AlZahal, Ousama; MacDonald, Tara L; Cervone, Daniel T; Wright, David C; McBride, Brian W; Dyck, David J

2015-09-28

We recently demonstrated that feeding a natural CLAt10,c12-enriched butter to lean female rats resulted in small, but significant increases in fasting glucose and insulin concentrations, and impaired insulin tolerance. Our goal was to extend these findings by utilizing the diabetes-prone female fatty Zucker rat. Rats were fed custom diets containing 45 % kcal of fat derived from control and CLAt10,c12-enriched butter for 8 weeks. CLA t10,c12-enriched butter was prepared from milk collected from cows fed a high fermentable carbohydrate diet to create subacute rumen acidosis (SARA); control (non-SARA) butter was collected from cows fed a low grain diet. Female fatty Zucker rats (10 weeks old) were randomly assigned to one of four diet treatments: i) low fat (10 % kcal), ii) 45 % kcal lard, iii) 45 % kcal SARA butter, or iv) 45 % kcal non-SARA butter. A low fat fed lean Zucker group was used as a control group. After 8 weeks, i) glucose and insulin tolerance tests, ii) insulin signaling in muscle, adipose and liver, and iii) metabolic caging measurements were performed. Glucose and insulin tolerance were significantly impaired in all fatty Zucker groups, but to the greatest extent in the LARD and SARA conditions. Insulin signaling (AKT phosphorylation) was impaired in muscle, visceral (perigonadal) adipose tissue and liver in fatty Zucker rats, but was generally similar across dietary groups. Physical activity, oxygen consumption, food intake and weight gain were also similar amongst the various fatty Zucker groups. Increasing the consumption of a food naturally enriched with CLAt10,c12 significantly worsens glucose and insulin tolerance in a diabetes-prone rodent model. This outcome is not explained by changes in tissue insulin signaling, physical activity, energy expenditure, food intake or body mass.

Oxidative stress as a mechanism of diabetes in diabetic BB prone rats: effect of secoisolariciresinol diglucoside (SDG).

PubMed

Prasad, K

2000-06-01

Secoisolariciresinol diglucoside (SDG) isolated from flaxseed has antioxidant activity and has been shown to prevent hypercholesterolemic atherosclerosis. An investigation was made of the effects of SDG on the development of diabetes in diabetic prone BioBreeding rats (BBdp rats), a model of human type I diabetes [insulin dependent diabetes mellitus (IDDM)] to determine if this type of diabetes is due to oxidative stress and if SDG can prevent the incidence of diabetes. The rats were divided into three groups: Group I, BioBreeding normal rats (BBn rats) (n = 10); group II, BBdp untreated (n = 11); and group III, BBdp treated with SDG 22 mg/kg body wt, orally) (n = 14). Oxidative stress was determined by measuring lipid peroxidation product malondialdehyde (MDA) an index of level of reactive oxygen species in blood and pancreas; and pancreatic chemiluminescence (Pancreatic-CL), a measure of antioxidant reserve. Incidence of diabetes was 72.7% in untreated and 21.4% in SDG-treated group as determined by glycosuria and hyperglycemia. SDG prevented the development of diabetes by approximately 71%. Development of diabetes was associated with an increase in serum and pancreatic MDA and a decrease in antioxidant reserve. Prevention in development of diabetes by SDG was associated with a decrease in serum and pancreatic-MDA and an increase in antioxidant reserve. These results suggest that IDDM is mediated through oxidative stress and that SDG prevents the development of diabetes.

Electroencephalography in the Diagnosis of Genetic Generalized Epilepsy Syndromes

PubMed Central

Seneviratne, Udaya; Cook, Mark J.; D’Souza, Wendyl Jude

2017-01-01

Genetic generalized epilepsy (GGE) consists of several syndromes diagnosed and classified on the basis of clinical features and electroencephalographic (EEG) abnormalities. The main EEG feature of GGE is bilateral, synchronous, symmetric, and generalized spike-wave complex. Other classic EEG abnormalities are polyspikes, epileptiform K-complexes and sleep spindles, polyspike-wave discharges, occipital intermittent rhythmic delta activity, eye-closure sensitivity, fixation-off sensitivity, and photoparoxysmal response. However, admixed with typical changes, atypical epileptiform discharges are also commonly seen in GGE. There are circadian variations of generalized epileptiform discharges. Sleep, sleep deprivation, hyperventilation, intermittent photic stimulation, eye closure, and fixation-off are often used as activation techniques to increase the diagnostic yield of EEG recordings. Reflex seizure-related EEG abnormalities can be elicited by the use of triggers such as cognitive tasks and pattern stimulation during the EEG recording in selected patients. Distinct electrographic abnormalities to help classification can be identified among different electroclinical syndromes. PMID:28993753

Experimental Treatment Options in Absence Epilepsy.

PubMed

Luijtelaar, Gilles van; Zobeiri, Mehrnoush; Lüttjohann, Annika; Depaulis, Antoine

2017-01-01

The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy per se but also for other genetic - previously called idiopathic - forms of epilepsy. The recent discovery of a highly excitable cortical zone in these models is considered as a new therapeutic target area. Here, we provide an overview regarding the search for new therapeutical options as has been investigated in the genetic rodent models (mainly WAG/Rij and GAERS) including drugs and whether antiepileptogenesis can be achieved, various types of electrical and optogenetical invasive stimulations, different types of noninvasive stimulation and finally whether absence seizures can be predicted and prevented. Many factors determine either the cortical and or thalamic excitability or the interaction between cortex and thalamus and offer new possibilities for new anti-absence drugs, among others metabotropic glutamatergic positive and negative allosteric modulators. The inhibition of epileptogenesis by various drugs with its widespread consequences seems feasible, although its mechanisms remain obscure and seems different from the antiabsence action. Surgical intervention on the cortical zone initiating seizures, either with radiosurgery using synchrotron- generated microbeams, or ablation techniques might reduce spike-and-wave discharges in the rodent models. High frequency electrical subcortical or cortical stimulation might be a good way to abort ongoing spikeand- wave discharges. In addition, possibilities for prevention with real-time EEG analyses in combination with

Comparative genetics of longevity and cancer: insights from long-lived rodents

PubMed Central

Gorbunova, Vera; Seluanov, Andrei; Zhang, Zhengdong; Gladyshev, Vadim N.; Vijg, Jan

2015-01-01

Mammals have evolved a dramatic diversity of aging rates. Within the single order of Rodentia maximum lifespans differ from four years in mice to 32 years in naked mole rats. Cancer rates also differ significantly, from cancer-prone mice to virtually cancer-proof naked and blind mole rats. Recent progress in rodent comparative biology, in combination with the emergence of whole genome sequence information, has opened opportunities for the discovery of genetic factors controlling longevity and cancer susceptibility. PMID:24981598

The Effects of Prone Position Ventilation on Experimental Mild Acute Lung Injury Induced by Intraperitoneal Lipopolysaccharide Injection in Rats.

PubMed

Bianchi, Aydra Mendes Almeida; Reboredo, Maycon Moura; Lucinda, Leda Marília Fonseca; Reis, Fernando Fonseca; Silva, Manfrinni Vinícius Alves; Rabelo, Maria Aparecida Esteves; Holanda, Marcelo Alcantara; Oliveira, Júlio César Abreu; Lorente, José Ángel; Pinheiro, Bruno do Valle

2016-04-01

The benefits of prone position ventilation are well demonstrated in the severe forms of acute respiratory distress syndrome, but not in the milder forms. We investigated the effects of prone position on arterial blood gases, lung inflammation, and histology in an experimental mild acute lung injury (ALI) model. ALI was induced in Wistar rats by intraperitoneal Escherichia coli lipopolysaccharide (LPS, 5 mg/kg). After 24 h, the animals with PaO2/FIO2 between 200 and 300 mmHg were randomized into 2 groups: prone position (n = 6) and supine position (n = 6). Both groups were compared with a control group (n = 5) that was ventilated in the supine position. All of the groups were ventilated for 1 h with volume-controlled ventilation mode (tidal volume = 6 ml/kg, respiratory rate = 80 breaths/min, positive end-expiratory pressure = 5 cmH2O, inspired oxygen fraction = 1) RESULTS: Significantly higher lung injury scores were observed in the LPS-supine group compared to the LPS-prone and control groups (0.32 ± 0.03; 0.17 ± 0.03 and 0.13 ± 0.04, respectively) (p < 0.001), mainly due to a higher neutrophil infiltration level in the interstitial space and more proteinaceous debris that filled the airspaces. Similar differences were observed when the gravity-dependent lung regions and non-dependent lung regions were analyzed separately (p < 0.05). The BAL neutrophil content was also higher in the LPS-supine group compared to the LPS-prone and control groups (p < 0.05). There were no significant differences in the wet/dry ratio and gas exchange levels. In this experimental extrapulmonary mild ALI model, prone position ventilation for 1 h, when compared with supine position ventilation, was associated with lower lung inflammation and injury.

Genetic profiling of two phenotypically distinct outbred rats derived from a colony of the Zucker fatty rats maintained at Tokyo Medical University

PubMed Central

Nakanishi, Satoshi; Kuramoto, Takashi; Kashiwazaki, Naomi; Yokoi, Norihide

2016-01-01

The Zucker fatty (ZF) rat is an outbred rat and a well-known model of obesity without diabetes, harboring a missense mutation (fatty, abbreviated as fa) in the leptin receptor gene (Lepr). Slc:Zucker (Slc:ZF) outbred rats exhibit obesity while Hos:ZFDM-Leprfa (Hos:ZFDM) outbred rats exhibit obesity and type 2 diabetes. Both outbred rats have been derived from an outbred ZF rat colony maintained at Tokyo Medical University. So far, genetic profiles of these outbred rats remain unknown. Here, we applied a simple genotyping method using Ampdirect reagents and FTA cards (Amp-FTA) in combination with simple sequence length polymorphisms (SSLP) markers to determine genetic profiles of Slc:ZF and Hos:ZFDM rats. Among 27 SSLP marker loci, 24 loci (89%) were fixed for specific allele at each locus in Slc:ZF rats and 26 loci (96%) were fixed in Hos:ZFDM rats, respectively. This indicates the low genetic heterogeneity in both colonies of outbred rats. Nine loci (33%) showed different alleles between the two outbred rats, suggesting considerably different genetic profiles between the two outbred rats in spite of the same origin. Additional analysis using 72 SSLP markers further supported these results and clarified the profiles in detail. This study revealed that genetic profiles of the Slc:ZF and Hos:ZFDM outbred rats are different for about 30% of the SSLP marker loci, which is the underlying basis for the phenotypic difference between the two outbred rats. PMID:27795491

A Model of Post-Traumatic Epilepsy After Penetrating Brain Injuries: Effect of Lesion Size and Metal Fragments

PubMed Central

Kendirli, M. Tansel; Rose, Dominique T.; Bertram, Edward H.

2014-01-01

Objective Penetrating brain injury (PBI) has the highest risk for inducing post-traumatic epilepsy and retained foreign materials such as bullet fragments carry the greatest risk. This study examines the potential contribution of copper, a major component of bullets, to the development of epilepsy following PBI. Methods Anesthetized adult male rats received a penetrating injury from the dorsal cortex to the ventral hippocampus from a high speed small bit drill. In one group of animals, copper wire was inserted into the lesion. Control animals had only the lesion or the lesion plus stainless steel wire (biologically inert foreign body). From 6 to up to 11 months following the injury the rats were monitored intermittently for the development of epilepsy with video-EEG. A separate set of animals was examined for possible acute seizures in the week following the injury. Results 22 of the 23 animals with copper wire developed chronic epilepsy compared to 3 of the 20 control rats (lesion and lesion with stainless steel). Copper was associated with more extensive injury. The control rats with epilepsy had larger lesions. In the acute injury group, there was no difference in the incidence of seizures (83% lesion plus stainless steel, 70% lesion plus copper). Conclusions Copper increases the risk for epilepsy and may increase damage over time, but there were no differences between the groups in the incidence of acute post-injury seizures. Lesion size may contribute to epilepsy development in lesion only animals. Copper maybe an independent risk factor for the development of epilepsy and possible secondary injury, but lesion size also contributes to the development of epilepsy. The consequences of prolonged exposure of the brain to copper observed in these animals may have clinical implications that require further evaluation. PMID:25470332

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

PubMed Central

Rudolf, Gabrielle; Lesca, Gaetan; Mehrjouy, Mana M; Labalme, Audrey; Salmi, Manal; Bache, Iben; Bruneau, Nadine; Pendziwiat, Manuela; Fluss, Joel; de Bellescize, Julitta; Scholly, Julia; Møller, Rikke S; Craiu, Dana; Tommerup, Niels; Valenti-Hirsch, Maria Paola; Schluth-Bolard, Caroline; Sloan-Béna, Frédérique; Helbig, Katherine L; Weckhuysen, Sarah; Edery, Patrick; Coulbaut, Safia; Abbas, Mohamed; Scheffer, Ingrid E; Tang, Sha; Myers, Candace T; Stamberger, Hannah; Carvill, Gemma L; Shinde, Deepali N; Mefford, Heather C; Neagu, Elena; Huether, Robert; Lu, Hsiao-Mei; Dica, Alice; Cohen, Julie S; Iliescu, Catrinel; Pomeran, Cristina; Rubenstein, James; Helbig, Ingo; Sanlaville, Damien; Hirsch, Edouard; Szepetowski, Pierre

2016-01-01

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5–10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures. PMID:27352968

Left Ventricular Gene Expression Profile of Healthy and Cardiovascular Compromised Rat Models Used in Air Pollution Studies

EPA Science Inventory

The link between pollutant exposure and cardiovascular disease (CVD) has prompted mechanistic research with animal models of CVD. We hypothesized that the cardiac gene expression patterns of healthy and genetically compromised, CVD-prone rat models, with or without metabolic impa...

Unmasking of myoclonus by lacosamide in generalized epilepsy.

PubMed

Birnbaum, Daniel; Koubeissi, Mohamad

2017-01-01

Lacosamide is a new-generation antiseizure medication that is approved for use as an adjunctive treatment and monotherapy in focal epilepsy. Its use in generalized epilepsy, however, has not been adequately evaluated in controlled trials. We report a 67-year-old woman who experienced new-onset myoclonic seizures after initiation of lacosamide. We presume that she had an undiagnosed generalized epilepsy syndrome, likely juvenile myoclonic epilepsy. Myoclonic seizures were not reported before introducing lacosamide and completely resolved after lacosamide was discontinued. This suggests that lacosamide may have the potential to worsen myoclonus, similar to what has been reported with another sodium channel agent, lamotrigine, in some individuals with genetic generalized epilepsy (GGE).

Up-regulated ephrinB3/EphB3 expression in intractable temporal lobe epilepsy patients and pilocarpine induced experimental epilepsy rat model.

PubMed

Huang, Hao; Li, Ruohan; Yuan, Jinxian; Zhou, Xin; Liu, Xi; Ou, Shu; Xu, Tao; Chen, Yangmei

2016-05-15

EphB family receptor tyrosine kinases, in cooperation with cell surface-bound ephrinB ligands, play a critical role in maintenance of dendritic spine morphogenesis, axons guidance, synaptogenesis, synaptic reorganization and plasticity in the central nervous system (CNS). However, the expression pattern of ephrinB/EphB in intractable temporal lobe epilepsy (TLE) and the underlying molecular mechanisms during epileptogenesis remain poorly understood. Here we investigated the expression pattern and cellular distribution of ephrinB/EphB in intractable TLE patients and lithium chloride-pilocarpine induced TLE rats using real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry, double-labeled immunofluorescence and Western blot analysis. Compared to control groups, ephrinB3 and EphB3 mRNA expression were significantly up-regulated in intractable TLE patients and TLE rats, while the mRNA expression trend of ephrinB1/2 and EphB1/2/4/6 in intractable TLE patients and TLE rats were inconsistent. Western blot analysis and semi-quantitative immunohistochemistry confirmed that ephrinB3 and EphB3 protein level were up-regulated in intractable TLE patients and TLE rats. At the same time, double-labeled immunofluorescence indicate that ephrinB3 was expressed mainly in the cytoplasm and protrusions of glia and neurons, while EphB3 was expressed mainly in the cytoplasm of neurons. Taken together, up-regulated expression of ephrinB3/EphB3 in intractable TLE patients and experimental TLE rats suggested that ephrinB3/EphB3 might be involved in the pathogenesis of TLE. Copyright © 2016 Elsevier B.V. All rights reserved.

Dendritic ion channelopathy in acquired epilepsy

PubMed Central

Poolos, Nicholas P.; Johnston, Daniel

2012-01-01

Summary Ion channel dysfunction or “channelopathy” is a proven cause of epilepsy in the relatively uncommon genetic epilepsies with Mendelian inheritance. But numerous examples of acquired channelopathy in experimental animal models of epilepsy following brain injury have also been demonstrated. Our understanding of channelopathy has grown due to advances in electrophysiology techniques that have allowed the study of ion channels in the dendrites of pyramidal neurons in cortex and hippocampus. The apical dendrites of pyramidal neurons comprise the vast majority of neuronal surface membrane area, and thus the majority of the neuronal ion channel population. Investigation of dendritic ion channels has demonstrated remarkable plasticity in ion channel localization and biophysical properties in epilepsy, many of which produce hyperexcitability and may contribute to the development and maintenance of the epileptic state. Here we review recent advances in dendritic physiology and cell biology, and their relevance to epilepsy. PMID:23216577

Optogenetic approaches to treat epilepsy.

PubMed

Wykes, Robert C; Kullmann, Dimitri M; Pavlov, Ivan; Magloire, Vincent

2016-02-15

Novel treatments for drug-resistant epilepsy are required. Optogenetics is a combination of optical and genetic methods used to control the activity of specific populations of excitable cells using light with high temporal and spatial resolution. Derived from microbial organisms, 'opsin' genes encode light-activated ion channels and pumps. Opsins can be genetically targeted to well-defined neuronal populations in mammalian brains using viral vectors. When exposed to light of an appropriate wavelength, the excitability of neurons can be increased or decreased optically on a millisecond timescale. Alternative treatments for drug-resistant epilepsy such as vagal, cortical or subcortical stimulation, focal cooling, callosotomy, or ketogenic diet have met with limited success, whereas optogenetic approaches have shown considerable pre-clinical promise. Several groups have reported that optogenetic approaches successfully attenuated epileptiform activity in different rodent models of epilepsy, providing proof of the principle that this approach may translate to an effective treatment for epilepsy patients. However, further studies are required to determine the optimal opsin, in which types (or subtypes) of neurons it should be expressed, and what are the most efficient temporal profiles of photostimulation. Although invasive due to the need to inject a viral vector into the brain and implant a device to deliver light to opsin-transduced neurons, this approach has the potential to be effective in suppressing spontaneous seizures while avoiding the side-effects of anti-epileptic drugs (AEDs) or the need to permanently excise regions of the brain. Optogenetic approaches may treat drug-refractory epilepsies. Copyright © 2015 Elsevier B.V. All rights reserved.

Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).

PubMed

Mishra, Vikas; Karumuri, Bharat K; Gautier, Nicole M; Liu, Rui; Hutson, Timothy N; Vanhoof-Villalba, Stephanie L; Vlachos, Ioannis; Iasemidis, Leonidas; Glasscock, Edward

2017-06-01

People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Silencing miR-181a produces neuroprotection against hippocampus neuron cell apoptosis post-status epilepticus in a rat model and in children with temporal lobe epilepsy.

PubMed

Ren, L; Zhu, R; Li, X

2016-02-22

Epilepsy is one of the most frequent neurological disorders. Recently, the regulation of microRNAs was found to be associated with epilepsy, but the molecular mechanism by which microRNA influences epilepsy process remains to be unveiled and the development of microRNA-based therapy requires more intensive research. In this study, five microRNAs with potential relevance to epilepsy were initially chosen: miR-132, miR-146a, miR-181a, miR-34a, and miR-124. Twenty-five children who were patients with epilepsy were selected as subjects to obtain tissue samples for the study. The miRNA-181a, which represented the most increased fold-changes in clinical samples, were then selected for further function study in mouse model. The temporal lobe epilepsy (TLE) model, along with lithium-pilocarpine-induced status epilepticus (SE), was established in Sprague-Dawley rats. The antagomir of miR-181a was used to determine the role of miR-181a in cell apoptosis. Analyses were conducted to determine the expression levels of miR-181a, neuronal apoptosis in post-SE, and activated caspase-3. We found evidence of significant time dependent up-regulation of miR-181a amongst post-SE rats and TLE on 24 h (4.47 ± 0.35), 7 days (4.85 ± 0.53), and 2 weeks (5.66 ± 0.64). Experiments with the miR-181a antagomir showed that this particular miRNA led to the inhibition of the protein expression of caspase-3, and was up-regulated in the course of seizure-induced neuronal apoptosis. This study provided evidence that targeting miR-181a leads to a neuroprotective response and is linked to an increase in the activation of the caspase-3 protein. These findings suggest that miR-181a may serve as a promising therapeutic target for epilepsy.

Epilepsy in Institutionalized Patients with Encephalopathy: Clinical Aspects and Nosological Considerations.

ERIC Educational Resources Information Center

Mariani, Emilio; And Others

1993-01-01

The prevalence of epilepsy was correlated with the severity and type of encephalopathy of 1,023 individuals with mental retardation. A total of 326 individuals were diagnosed with epilepsy. Results indicated a low percentage of epilepsy in chromosomic-genetic and young adult encephalopathies and a high prevalence when the neurodeficit was…

A Road Map for Precision Medicine in the Epilepsies

PubMed Central

2015-01-01

Summary Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well-suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in vitro and in vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug screening platforms, and the establishment of collaborative research groups. Moving forward, it is critical that we strengthen these collaborations, particularly through integrated research platforms to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice. PMID:26416172

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

PubMed Central

Clossen, Bryan L.; Reddy, Doodipala Samba

2017-01-01

This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy. PMID:28179120

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy.

PubMed

Clossen, Bryan L; Reddy, Doodipala Samba

2017-06-01

This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982-2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Antiepileptic effect of fisetin in iron-induced experimental model of traumatic epilepsy in rats in the light of electrophysiological, biochemical, and behavioral observations.

PubMed

Das, Jharana; Singh, Rameshwar; Sharma, Deepak

2017-05-01

Traumatic epilepsy is defined by episodes of recurring seizures secondary to severe brain injury. Though drugs are found effective to control seizures, their long-term use have been observed to increase reactive oxygen species in animals. Flavonoid fisetin, a natural bioactive phytonutrient reported to exert anticonvulsive effect in experimental seizure models. But, trauma-induced seizures could not be prevented by anticonvulsants was reported in some clinical studies. To study the effect of fisetin on epileptiform electrographic activity in iron-induced traumatic epilepsy and also the probable reason behind the effect in rats. Fisetin pretreatment (20 mg/kg body wt., p.o.) of rats for 12 weeks were chosen followed by injecting iron (5 µl, 100 mM) stereotaxically to generate iron-induced epilepsy. Experimental design include electrophysiological study (electroencephalograph in correlation with multiple unit activity (MUA) in the cortex and CA1 subfield of the hippocampus; spectral analysis of seizure and seizure-associated behavioral study (Morris water maze for spatial learning, open-field test for anxiety) and biochemical study (lipid peroxidation, Na + ,K + -ATPase activity) in both the cortex and the hippocampus. Fisetin pretreatment was found to prevent the development of iron-induced electrical seizure and decrease the corresponding MUA in the cortex (*P˂0.05) as well as in the hippocampus (***P˂0.001). Fisetin pretreatment decreased the lipid peroxides (*P˂0.05) and retained the Na + ,K + -ATPase activity (*P˂0.05) which was found altered in the epileptic animals and also found to attenuate the seizure-associated cognitive dysfunctions. This study demonstrated the antiepileptic action of fisetin in iron-induced model of epileptic rats by inhibiting oxidative stress.

Familial temporal lobe epilepsy due to focal cortical dysplasia type IIIa.

PubMed

Fabera, Petr; Krijtova, Hana; Tomasek, Martin; Krysl, David; Zamecnik, Josef; Mohapl, Milan; Jiruska, Premysl; Marusic, Petr

2015-09-01

Focal cortical dysplasia (FCD) represents a common cause of refractory epilepsy. It is considered a sporadic disorder, but its occasional familial occurrence suggests the involvement of genetic mechanisms. Siblings with intractable epilepsy were referred for epilepsy surgery evaluation. Both patients were examined using video-EEG monitoring, MRI examination and PET imaging. They underwent left anteromedial temporal lobe resection. Electroclinical features pointed to left temporal lobe epilepsy and MRI examination revealed typical signs of left-sided hippocampal sclerosis and increased white matter signal intensity in the left temporal pole. PET examination confirmed interictal hypometabolism in the left temporal lobe. Histopathological examination of resected tissue demonstrated the presence FCD type IIIa, i.e. hippocampal sclerosis and focal cortical dysplasia in the left temporal pole. We present a unique case of refractory mesial temporal lobe epilepsy in siblings, characterized by an identical clinical profile and histopathology of FCD type IIIa, who were successfully treated by epilepsy surgery. The presence of such a high concordance between the clinical and morphological data, together with the occurrence of epilepsy and febrile seizures in three generations of the family pedigree points towards a possible genetic nature of the observed FCD type IIIa. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy.

PubMed

Barker-Haliski, Melissa L; Johnson, Kristina; Billingsley, Peggy; Huff, Jennifer; Handy, Laura J; Khaleel, Rizvana; Lu, Zhenmei; Mau, Matthew J; Pruess, Timothy H; Rueda, Carlos; Saunders, Gerald; Underwood, Tristan K; Vanegas, Fabiola; Smith, Misty D; West, Peter J; Wilcox, Karen S

2017-07-01

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

Interview: the National Institute of Neurological Diseases and Stroke/American Epilepsy Society benchmarks and research priorities for epilepsy research.

PubMed

Lowenstein, Daniel H

2011-10-01

Daniel H Lowenstein, MD, is the Robert B and Ellinor Aird Professor and Vice-Chairman of Neurology, Director of the Epilepsy Center, and Director of Physician-Scientist Education and Training at the University of California, San Francisco (UCSF). He received his BA in Mathematics from the University of Colorado and MD from Harvard Medical School. He completed his neurology residency training at UCSF. Dr Lowenstein is a clinician-scientist who has studied both basic science and clinical aspects of epilepsy. In recent years, he has been an organizer of a large-scale, international effort to study the complex genetics of epilepsy, known as the Epilepsy Phenome/Genome Project. He has been actively involved in advancing the cause of epilepsy at the national and international level. Dr Lowenstein served as President of the American Epilepsy Society from 2003 to 2004 and the National Institute of Neurological Diseases and Stroke (NINDS) Advisory Council from 2000 to 2004, and has overseen the development of the NINDS Epilepsy Research Benchmarks since their inception in 2000.

Glycine Transporter 1 is a Target for the Treatment of Epilepsy

PubMed Central

Shen, Hai-Ying; van Vliet, Erwin; Bright, Kerry-Ann; Hanthorn, Marissa; Lytle, Nikki; Gorter, Jan; Aronica, Eleonora; Boison, Detlev

2015-01-01

Glycine is the major inhibitory neurotransmitter in brainstem and spinal cord, whereas in hippocampus glycine exerts dual modulatory roles on strychnine-sensitive glycine receptors and on the strychnine-insensitive glycineB site of the N-methyl-D-aspartate receptor (NMDAR). In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1). Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy. Using two different rodent models of temporal lobe epilepsy (TLE) – the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE – we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy. Overexpression of GlyT1 in the hippocampal formation was corroborated in human TLE samples by quantitative real time PCR. In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice. Importantly, chronic seizures in the mouse model of TLE were robustly suppressed by systemic administration of the GlyT1 inhibitor LY2365109. We conclude that GlyT1 overexpression in the epileptic brain constitutes a new target for therapeutic intervention, and that GlyT1 inhibitors constitute a new class of antiictogenic drugs. These findings are of translational value since GlyT1 inhibitors are already in clinical development to treat cognitive symptoms in schizophrenia. PMID:26302655

Computer modeling of Epilepsy

PubMed Central

Lytton, William W.

2009-01-01

Preface Epilepsy is a complex set of disorders that can involve many areas of cortex as well as underlying deep brain systems. The myriad manifestations of seizures, as varied as déjà vu and olfactory hallucination, can thereby give researchers insights into regional functions and relations. Epilepsy is also complex genetically and pathophysiologically, involving microscopic (ion channels, synaptic proteins), macroscopic (brain trauma and rewiring) and intermediate changes in a complex interplay of causality. It has long been recognized that computer modeling will be required to disentangle causality, to better understand seizure spread and to understand and eventually predict treatment efficacy. Over the past few years, substantial progress has been made modeling epilepsy at levels ranging from the molecular to the socioeconomic. We review these efforts and connect them to the medical goals of understanding and treating this disorder. PMID:18594562

The human epilepsy mutation GABRG2(Q390X) causes chronic subunit accumulation and neurodegeneration.

PubMed

Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen; Xu, Dong; Macdonald, Robert L

2015-07-01

Genetic epilepsy and neurodegenerative diseases are two common neurological disorders that are conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies who have impaired development and often go on to die of their disease respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations result in protein misfolding and abnormal receptor trafficking. We have now developed a model of a severe human genetic epileptic encephalopathy, the Gabrg2(+/Q390X) knock-in mouse. We found that, in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. Our results have far-reaching relevance for the identification of conserved pathological cascades and mechanism-based therapies that are shared between genetic epilepsies and neurodegenerative diseases.

The Human Epilepsy Mutation GABRG2(Q390X) Causes Chronic Subunit Accumulation and Neurodegeneration

PubMed Central

Kang, Jing-Qiong; Shen, Wangzhen; Zhou, Chengwen; Xu, Dong; Macdonald, Robert L.

2015-01-01

Genetic epilepsy and neurodegenerative diseases are two common neurological disorders conventionally viewed as being unrelated. A subset of patients with severe genetic epilepsies with impaired development and often death respond poorly to anticonvulsant drug therapy, suggesting a need for new therapeutic targets. Previously, we reported that multiple GABAA receptor epilepsy mutations caused protein misfolding and abnormal receptor trafficking. Here we establish in a novel model of a severe human genetic epileptic encephalopathy, the Gabrg2+/Q390X knock-in mouse, that in addition to impairing inhibitory neurotransmission, mutant GABAA receptor γ2(Q390X) subunits accumulated and aggregated intracellularly, activated caspase 3 and caused widespread, age-dependent neurodegeneration. These novel findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant γ2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration. The study has far-reaching significance for identification of conserved pathological cascades and mechanism-based therapies that overlap genetic epilepsies and neurodegenerative diseases. PMID:26005849

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy.

PubMed

Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen; Michel, Cole R; Gomez, Joe; Vassilopoulos, Athanassios; Reisdorph, Nichole; Fritz, Kristofer S; Patel, Manisha

2018-08-01

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy.

PubMed

Shen, Chunhong; Zhang, Bijun; Liu, Zhirong; Tang, Yelei; Zhang, Yinxi; Wang, Shan; Guo, Yi; Ding, Yao; Wang, Shuang; Ding, Meiping

2017-10-01

The aim of the study is to investigate the effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on plasma oxcarbazepine (OXC) concentrations and therapeutic efficacy in Han Chinese patients with epilepsy. We recruited 116 Han Chinese patients with epilepsy who were receiving OXC monotherapy. Blood samples were taken and OXC levels were measured. The polymorphisms of ABCB1 rs1045642, ABCC2 rs2273697, UGT2B7 rs7439366, and HNF4α rs2071197 were determined. The therapeutic efficacy of OXC at the 1-year time-point was assessed. Data analysis was performed using IBM SPSS Statistics 22.0. The genetic polymorphism of ABCB1 rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05). As for UGT2B7 rs7439366, the allele polymorphism exhibited a correlation with treatment outcome, but not OXC concentration. The polymorphisms of ABCC2 rs2273697 and HNF4α rs2071197 was not associated with OXC concentrations and therapeutic efficacy. These results suggested that ABCB1 rs1045642 and UGT2B7 rs7439366 may affect OXC pharmacokinetics and therapeutic efficacy in Han Chinese patients with epilepsy. However, further studies in larger populations and other ethnic groups are required. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance.

PubMed

Zara, Federico; Specchio, Nicola; Striano, Pasquale; Robbiano, Angela; Gennaro, Elena; Paravidino, Roberta; Vanni, Nicola; Beccaria, Francesca; Capovilla, Giuseppe; Bianchi, Amedeo; Caffi, Lorella; Cardilli, Viviana; Darra, Francesca; Bernardina, Bernardo Dalla; Fusco, Lucia; Gaggero, Roberto; Giordano, Lucio; Guerrini, Renzo; Incorpora, Gemma; Mastrangelo, Massimo; Spaccini, Luigina; Laverda, Anna Maria; Vecchi, Marilena; Vanadia, Francesca; Veggiotti, Pierangelo; Viri, Maurizio; Occhi, Guya; Budetta, Mauro; Taglialatela, Maurizio; Coviello, Domenico A; Vigevano, Federico; Minetti, Carlo

2013-03-01

To dissect the genetics of benign familial epilepsies of the first year of life and to assess the extent of the genetic overlap between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). Families with at least two first-degree relatives affected by focal seizures starting within the first year of life and normal development before seizure onset were included. Families were classified as BFNS when all family members experienced neonatal seizures, BFNIS when the onset of seizures in family members was between 1 and 4 months of age or showed both neonatal and infantile seizures, and BFIS when the onset of seizures was after 4 months of age in all family members. SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. A total of 46 families including 165 affected members were collected. Eight families were classified as BFNS, 9 as BFNIS, and 29 as BFIS. Genetic analysis led to the identification of 41 mutations, 14 affecting KCNQ2, 1 affecting KCNQ3, 5 affecting SCN2A, and 21 affecting PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS two genes are involved (KCNQ2, six families; SCN2A, two families). BFIS families are the most genetically heterogeneous, with all four genes involved, although about 70% of them carry a PRRT2 mutation. Our data highlight the important role of KCNQ2 in the entire spectrum of disorders, although progressively decreasing as the age of onset advances. The occurrence of afebrile seizures during follow-up is associated with KCNQ2 mutations and may represent a predictive factor. In addition, we showed that KCNQ3 mutations might be also involved in families with infantile seizures. Taken together our data indicate an important

Aging models of acute seizures and epilepsy.

PubMed

Kelly, Kevin M

2010-01-01

Aged animals have been used by researchers to better understand the differences between the young and the aged brain and how these differences may provide insight into the mechanisms of acute seizures and epilepsy in the elderly. To date, there have been relatively few studies dedicated to the modeling of acute seizures and epilepsy in aged, healthy animals. Inherent challenges to this area of research include the costs associated with the purchase and maintenance of older animals and, at times, the unexpected and potentially confounding comorbidities associated with aging. However, recent studies using a variety of in vivo and in vitro models of acute seizures and epilepsy in mice and rats have built upon early investigations in the field, all of which has provided an expanded vision of seizure generation and epileptogenesis in the aged brain. Results of these studies could potentially translate to new and tailored interventional approaches that limit or prevent the development of epilepsy in the elderly.

Cortical interneuron dysfunction in epilepsy associated with autism spectrum disorders.

PubMed

Jacob, John

2016-02-01

Autism and epilepsy are two associated disorders that are highly prevalent, share common developmental origins, and demonstrate substantial heritability. In this review, cross-disciplinary data in a rapidly evolving field that bridges neurology and psychiatry are synthesized to identify shared biologic mechanisms. The relationship between these debilitating, lifelong conditions is examined at the clinical, genetic, and neurophysiologic levels in humans and in animal models. Scopus and PubMed searches were used to identify relevant literature. Clinical observations have prompted speculation about the interdependence of autism and epilepsy, but causal relationships have proved difficult to determine. Despite their heritability, the genetic basis of autism spectrum disorder (ASD) and epilepsy has remained largely elusive until the advent of next-generation sequencing. This approach has revealed that mutations that are either causal or confer an increased disease risk are found in numerous different genes, any one of which accounts for only a small percentage of cases. Conversely, even cases with identical clinical phenotypes can be genetically heterogeneous. Candidate gene identification has facilitated the development of mouse genetic models, which in parallel with human studies have implicated shared brain regions and circuits that mediate disease expression. Diverse genetic causes of ASD and epilepsy converge on cortical interneuron circuits as one important mediator of both disorders. Cortical interneurons are among the most diverse cell types in the brain and their unique chemical and electrical coupling exert a powerful inhibitory influence on excitatory neurons via the release of the neurotransmitter, γ-aminobutyric acid (GABA). These multifaceted approaches have validated theories derived from the field of developmental neurobiology, which propose that the neurologic and neuropsychiatric manifestations are caused by an altered ratio of excitation to

Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy.

PubMed

Han, Chun-Lei; Ge, Ming; Liu, Yun-Peng; Zhao, Xue-Min; Wang, Kai-Liang; Chen, Ning; Hu, Wei; Zhang, Jian-Guo; Li, Liang; Meng, Fan-Gang

2018-05-23

Temporal lobe epilepsy (TLE) is one of the most common types of intractable epilepsy, characterized by hippocampal neuron damage and hippocampal sclerosis. Long noncoding RNAs (lncRNAs) have been increasingly recognized as posttranscriptional regulators. However, their expression levels and functions in TLE remain largely unknown. In the present study, TLE rat model is used to explore the expression profiles of lncRNAs in the hippocampus of epileptic rats using microarray analysis. Our results demonstrate that H19 is the most pronouncedly differentiated lncRNA, significantly upregulated in the latent period of TLE. Moreover, the in vivo studies using gain- and loss-of-function approaches reveal that the overexpression of H19 aggravates SE-induced neuron apoptosis in the hippocampus, while inhibition of H19 protects the rats from SE-induced cellular injury. Finally, we show that H19 might function as a competing endogenous RNA to sponge microRNA let-7b in the regulation of cellular apoptosis. Overall, our study reveals a novel lncRNA H19-mediated mechanism in seizure-induced neural damage and provides a new target in developing lncRNA-based strategies to reduce seizure-induced brain injury.

The causes of epilepsy: changing concepts of etiology of epilepsy over the past 150 years.

PubMed

Shorvon, Simon D

2011-06-01

This paper provides a survey of the changing concepts of the etiology of epilepsy from 1860 to 2010, focusing on the first two 50-year periods and outlining more briefly major developments in the past 50 years. Among the concepts reviewed in the first 100 years are: the division between predisposing and exciting causes, idiopathic and genuine epilepsy, organic epilepsy, the concept of "cause" being equivalent to "causal mechanism," Russell Reynolds etiological classification, the neurological taint and theories of degeneration, the self-perpetuating nature of seizures, reflex theories of etiology, autointoxication, heredity and eugenics, epilepsy due to brain disorders, the role of EEG and of hippocampal sclerosis, psychological theories of causation, and the multifactorial view of epilepsy etiology. In the past 50 years, the major advances in studying causation in epilepsy have been: clinical biochemistry, neuroimaging, molecular genetics, studies of mechanisms of epilepsy, better statistical methodologies and classification. A number of general observations can be made: the identification of "cause" is not as simple as it might at first appear; progress in the study of causation has been often erratic and travelled up many cul-de-sacs; theories of causation are heavily influenced by societal influences and fashion, and is also heavily dependent on applied methodologies; the recently explored possibility that the underlying inherited mechanisms of epilepsy are shared with other neuropsychiatric conditions is in effect a reinvention of the concept of the neurological trait, and this has ethical and social implications. Considering and classifying cause in terms of causal mechanism, as was suggested by Hughlings Jackson, is an ultimate goal. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats.

PubMed

Ghazizadeh, Vahid; Nazıroğlu, Mustafa

2014-09-01

Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

Progressive myoclonic epilepsies: definitive and still undetermined causes.

PubMed

Franceschetti, Silvana; Michelucci, Roberto; Canafoglia, Laura; Striano, Pasquale; Gambardella, Antonio; Magaudda, Adriana; Tinuper, Paolo; La Neve, Angela; Ferlazzo, Edoardo; Gobbi, Giuseppe; Giallonardo, Anna Teresa; Capovilla, Giuseppe; Visani, Elisa; Panzica, Ferruccio; Avanzini, Giuliano; Tassinari, Carlo Alberto; Bianchi, Amedeo; Zara, Federico

2014-02-04

To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Neurodevelopmental Malformations of the Cerebellar Vermis in Genetically Engineered Rats.

PubMed

Ramos, Raddy L; Van Dine, Sarah E; Gilbert, Mary E; Leheste, Joerg R; Torres, German

2015-12-01

The cerebellar vermis is particularly vulnerable to neurodevelopmental malformations in humans and rodents. Sprague-Dawley, and Long-Evans rats exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis. Malformations are almost exclusively found along the primary fissure and are indicative of deficits of neuronal migration during cerebellar development. In the present report, we test the prediction that genetically engineered rats on Sprague-Dawley or Long-Evans backgrounds will also exhibit the same cerebellar malformations. Consistent with our hypothesis, we found that three different transgenic lines on two different backgrounds had cerebellar malformations. Heterotopia in transgenic rats had identical cytoarchitecture as that observed in wild-type rats including altered morphology of Bergmann glia. In light of the possibility that heterotopia could affect results from behavioral studies, these data suggest that histological analyses be performed in studies of cerebellar function or development when using genetically engineered rats on these backgrounds in order to have more careful interpretation of experimental findings.

Epilepsy and violence: case series concerning physical trauma in children of persons with epilepsy

PubMed Central

Gauffin, Helena; Landtblom, Anne-Marie

2014-01-01

Historically, epilepsy has been associated with violence, but more recent studies have emphasized genetic and psychosocial factors as more important. The case series presented here aim to highlight the difficult situation the affected children are in. We report on three cases when children have been traumatized and, in one case, even been killed by their parent who was diagnosed with epilepsy. In the first case, we describe a woman with juvenile myoclonic epilepsy who was sentenced to forensic psychiatry care for killing her child. She lived under difficult psychosocial circumstances and a suicide attempt contributed to what happened. The second case describes a man with post-traumatic seizures who was sentenced for child abuse. Ictal or postictal violence was considered in these two cases but a causal link between the violence and epilepsy has not been established. In the third case, we describe a woman with focal epilepsy and psychogenic non-epileptic seizures (PNESs). Her child was hurt and frightened in relation to violent seizures, which were regarded as PNESs. This case series demonstrates that children of parents with epilepsy can be in a vulnerable situation. No causality has been established between the seizures and these events, so consequently other factors such as psychosocial stress, low cognitive function, and a suicide attempt must also be considered as important. When a child is hurt by a parent with epilepsy the patient must be closely examined to determine the role of the seizures. Children can also be affected by PNESs. It is essential to notice especially those children of parents with epilepsy who live under difficult psychosocial circumstances and offer extra support when necessary. PMID:25484586

Oxotremorine-induced cerebral hyperemia does not predict infarction volume in spontaneously hypertensive or stroke-prone rats.

PubMed

Harukuni, I; Takahashi, H; Traystman, R J; Bhardwaj, A; Kirsch, J R

2000-01-01

We tested the following hypotheses: a) spontaneously hypertensive stroke-prone rats (SHR-SP) have more brain injury than spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto rats [WKY]) when exposed to transient focal ischemia; b) infarction size is not correlated with baseline blood pressure; and c) infarction size is inversely related to the cerebral hyperemic response to oxotremorine, a muscarinic agonist that increases cerebral blood flow (CBF) by stimulating endothelial nitric oxide synthase. In vivo study. Animal laboratory in a university teaching hospital. Adult age-matched male WKY, SHR, and SHR-SP. Rats were instrumented under halothane anesthesia. Transient focal cerebral ischemia was produced for 2 hrs with the intravascular suture technique. Cerebral perfusion, estimated with laser Doppler flowmetry (LD-CBF), in response to intravenous oxotremorine, was measured in one cohort of rats to estimate endothelial nitric oxide synthase function. Infarction volume was measured at 22 hrs of reperfusion with 2,3,5-triphenyltetrazolium chloride staining. Infarction volume in the striatum of SHR-SP (42+/-4 mm3) was greater than in SHR (29+/-6 mm3) or WKY (1+/-1 mm3) (n = 9 rats/strain). Resting (unanesthetized) mean arterial blood pressure was similar in SHR-SP (177+/-5 mm Hg) and SHR (170+/-5 mm Hg) despite a greater infarction volume in SHR-SP (n = 4) compared with SHR (n = 5). The percentage increase in LD-CBF signal in response to oxotremorine was similar for both groups (SHR, 64%+/-22% [n = 10]; SHR-SP, 69%+/-22% [n = 8]). However, in this cohort, cortical infarction volume was less in SHR (30%+/-4% of ipsilateral cortex) than in SHR-SP (49%+/-2% of ipsilateral cortex). Although SHR-SP have greater infarction volume than SHR, the mechanism of injury does not appear to be related to a difference in unanesthetized baseline mean arterial blood pressure or to an alteration in endothelium-produced nitric oxide.

Autistic traits in epilepsy models: Why, when and how?

PubMed

Velíšková, Jana; Silverman, Jill L; Benson, Melissa; Lenck-Santini, Pierre-Pascal

2018-05-18

Autism spectrum disorder (ASD) is a common comorbidity of epilepsy and seizures and/or epileptiform activity are observed in a significant proportion of ASD patients. Current research also implies that autistic traits can be observed to a various degree in mice and rats with seizures. This suggests that there are shared mechanisms in both ASD and epilepsy syndromes. Here, we first review the standard, validated methods used to assess autistic traits in animal models as well as their limitations with regards to epilepsy models. We then discuss two of the potential pathological processes that could be shared between ASD and epilepsy. We first focus on functional implications of neuroinflammation including changes to excitable networks mediated by inflammatory regulators. Finally we examine mechanisms at the cellular and network level involved in neuronal excitability, timing and network coordination that may directly lead to behavioral disturbances present in both epilepsy and ASD. This mini-review summarizes the work first presented at an Investigators Workshop at the 2016 American Epilepsy Society meeting. Copyright © 2018. Published by Elsevier B.V.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.

PubMed

Leu, Costin; Balestrini, Simona; Maher, Bridget; Hernández-Hernández, Laura; Gormley, Padhraig; Hämäläinen, Eija; Heggeli, Kristin; Schoeler, Natasha; Novy, Jan; Willis, Joseph; Plagnol, Vincent; Ellis, Rachael; Reavey, Eleanor; O'Regan, Mary; Pickrell, William O; Thomas, Rhys H; Chung, Seo-Kyung; Delanty, Norman; McMahon, Jacinta M; Malone, Stephen; Sadleir, Lynette G; Berkovic, Samuel F; Nashef, Lina; Zuberi, Sameer M; Rees, Mark I; Cavalleri, Gianpiero L; Sander, Josemir W; Hughes, Elaine; Helen Cross, J; Scheffer, Ingrid E; Palotie, Aarno; Sisodiya, Sanjay M

2015-09-01

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10(- 3)) and non-epilepsy disease controls (P = 1.2 × 10(- 3)). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy

PubMed Central

Leu, Costin; Balestrini, Simona; Maher, Bridget; Hernández-Hernández, Laura; Gormley, Padhraig; Hämäläinen, Eija; Heggeli, Kristin; Schoeler, Natasha; Novy, Jan; Willis, Joseph; Plagnol, Vincent; Ellis, Rachael; Reavey, Eleanor; O'Regan, Mary; Pickrell, William O.; Thomas, Rhys H.; Chung, Seo-Kyung; Delanty, Norman; McMahon, Jacinta M.; Malone, Stephen; Sadleir, Lynette G.; Berkovic, Samuel F.; Nashef, Lina; Zuberi, Sameer M.; Rees, Mark I.; Cavalleri, Gianpiero L.; Sander, Josemir W.; Hughes, Elaine; Helen Cross, J.; Scheffer, Ingrid E.; Palotie, Aarno; Sisodiya, Sanjay M.

2015-01-01

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10− 3) and non-epilepsy disease controls (P = 1.2 × 10− 3). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patient's risk of SUDEP. PMID:26501104

Neurocysticercosis as an infectious acquired epilepsy worldwide.

PubMed

Reddy, Doodipala Samba; Volkmer, Randy

2017-11-01

Aside from brain injury and genetic causes, there is emerging information on brain infection and inflammation as a common cause of epilepsy. Neurocysticercosis (NCC), the most common cause of epilepsy worldwide, is caused by brain cysts from the Taenia solium tapeworm. In this article, we provide a critical analysis of current and emerging information on the relationship between NCC infection and epilepsy occurrence. We searched PubMed and other databases for reports on the prevalence of NCC and incidence of epilepsy in certain regions worldwide. NCC is caused by brain cysts from the T. solium and related tapeworms. Many people with NCC infection may develop epilepsy but the rates are highly variable. MRI imaging shows many changes including localization of cysts as well as the host response to treatment. Epilepsy, in a subset of NCC patients, appears to be due to hippocampal sclerosis. Serologic and brain imaging profiles are likely diagnostic biomarkers of NCC infection and are also used to monitor the course of treatments. Limited access to these tools is a key limitation to identify and treat NCC-related epilepsy in places with high prevalence of this parasite infestation. Overall, NCC is a common infection in many patients with epilepsy worldwide. Additional clinical and animal studies could confirm common pathology of NCC as a postinfectious epilepsy that is curable. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

The effect of Vitamin E on learning and memory deficits in intrahippocampal kainate-induced temporal lobe epilepsy in rats.

PubMed

Kiasalari, Zahra; Khalili, Mohsen; Shafiee, Samaneh; Roghani, Mehrdad

2016-01-01

Since temporal lobe epilepsy (TLE) is associated with learning and memory impairment, we investigated the beneficial effect of Vitamin E on the impaired learning and memory in the intrahippocampal kainate model of TLE in rats. Rats were divided into sham, Vitamin E-treated sham, kainate, and Vitamin E-treated kainate. Intrahippocampal kainate was used for induction of epilepsy. Vitamin E was injected intraperitoneal (i.p.) at a dose of 200 mg/kg/day started 1 week before surgery until 1 h presurgery. Initial and step-through latencies in the passive avoidance test and alternation behavior percentage in Y-maze were finally determined in addition to measurement of some oxidative stress markers. Kainate injection caused a higher severity and rate of seizures and deteriorated learning and memory performance in passive avoidance paradigm and spontaneous alternation as an index of spatial recognition memory in Y-maze task. Intrahippocampal kainate also led to the elevation of malondialdehyde (MDA) and nitrite and reduced activity of superoxide dismutase (SOD). Vitamin E pretreatment significantly attenuated severity and incidence rate of seizures, significantly improved retrieval and recall in passive avoidance, did not ameliorate spatial memory deficit in Y-maze, and lowered MDA and enhanced SOD activity. Vitamin E improves passive avoidance learning and memory and part of its beneficial effect is due to its potential to mitigate hippocampal oxidative stress.

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy.

PubMed

Barker-Haliski, Melissa L; Löscher, Wolfgang; White, H Steve; Galanopoulou, Aristea S

2017-07-01

Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy.

PubMed

Vari, Maria Stella; Traverso, Monica; Bellini, Tommaso; Madia, Francesca; Pinto, Francesca; Minetti, Carlo; Striano, Pasquale; Zara, Federico

2017-08-01

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. We report a de novo duplication of the long arm of chromosome 12. We confirm that 12q22-q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Differential Stiffening between the Abdominal and Thoracic Aorta: Effect of Salt Loading in Stroke-Prone Hypertensive Rats.

PubMed

Lindesay, George; Bézie, Yvonnick; Ragonnet, Christophe; Duchatelle, Véronique; Dharmasena, Chandima; Villeneuve, Nicole; Vayssettes-Courchay, Christine

2018-06-08

Central artery stiffening is recognized as a cardiovascular risk. The effects of hypertension and aging have been shown in human and animal models but the effect of salt is still controversial. We studied the effect of a high-salt diet on aortic stiffness in salt-sensitive spontaneously hypersensitive stroke-prone rats (SHRSP). Distensibility, distension, and β-stiffness were measured at thoracic and abdominal aortic sites in the same rats, using echotracking recording of the aortic diameter coupled with blood pressure (BP), in SHRSP-salt (5% salted diet, 5 weeks), SHRSP, and normotensive Wistar-Kyoto (WKY) rats. Hemodynamic parameters were measured at BP matched to that of WKY. Histological staining and immunohistochemistry were used for structural analysis. Hemodynamic isobaric parameters in SHRSP did not differ from WKY and only those from the abdominal aorta of SHRSP-salt presented decreased distensibility and increased stiffness compared with WKY and SHRSP. The abdominal and thoracic aortas presented similar thickening, increased fibrosis, and remodeling with no change in collagen content. SHRSP-salt presented a specific increased elastin disarray at the abdominal aorta level but a decrease in elastin content in the thoracic aorta. This study demonstrates the pro-stiffening effect of salt in addition to hypertension; it shows that only the abdominal aorta presents a specific pressure-independent stiffening, in which elastin disarray is likely a key mechanism. © 2018 S. Karger AG, Basel.

Ketogenic Diet Based on Extra Virgin Coconut Oil Has No Effects in Young Wistar Rats With Pilocarpine-Induced Epilepsy.

PubMed

Melo, Isabelle T; M Rêgo, Elisabete; Bueno, Nassib B; Gomes, Tâmara C; Oliveira, Suzana L; Trindade-Filho, Euclides M; Cabral, Cyro R; Machado, Tacy S; Galvão, Jaqueline A; R Ataide, Terezinha

2018-02-01

This study evaluated the effects of a ketogenic diet (KD) based on extra virgin coconut oil (Cocos nucifera L., VCO), on the treatment of epileptic rats. Two sets of experiments were conducted. First, male Wistar rats underwent induction of status epilepticus (SE) with the administration of pilocarpine intraperitoneally 21 animals reached spontaneous recurrent seizures (SRS) and were randomly allocated to the dietary regimens and video-monitored for 19 days. In the second experiment, 24 animals were randomized immediately after the induction of SE and followed for 67 days. Diets were as follows: Control (AIN-93G; 7% lipid), KetoTAGsoya (KD based on soybean oil; 69.79% lipid), and KetoTAGcoco (KD based on VCO; 69.79% lipid). There were no differences in the latency to the first crisis, total frequency, and duration of the SRS between groups in 2 experiments. The data suggest no effects of KD, with or without VCO, in rats with pilocarpine-induced epilepsy. © 2018 AOCS.

Computer modelling of epilepsy.

PubMed

Lytton, William W

2008-08-01

Epilepsy is a complex set of disorders that can involve many areas of the cortex, as well as underlying deep-brain systems. The myriad manifestations of seizures, which can be as varied as déjà vu and olfactory hallucination, can therefore give researchers insights into regional functions and relations. Epilepsy is also complex genetically and pathophysiologically: it involves microscopic (on the scale of ion channels and synaptic proteins), macroscopic (on the scale of brain trauma and rewiring) and intermediate changes in a complex interplay of causality. It has long been recognized that computer modelling will be required to disentangle causality, to better understand seizure spread and to understand and eventually predict treatment efficacy. Over the past few years, substantial progress has been made in modelling epilepsy at levels ranging from the molecular to the socioeconomic. We review these efforts and connect them to the medical goals of understanding and treating the disorder.

A Nerve Growth Factor Peptide Retards Seizure Development and Inhibits Neuronal Sprouting in a Rat Model of Epilepsy

NASA Astrophysics Data System (ADS)

Rashid, Kashif; van der Zee, Catharina E. E. M.; Ross, Gregory M.; Chapman, C. Andrew; Stanisz, Jolanta; Riopelle, Richard J.; Racine, Ronald J.; Fahnestock, Margaret

1995-10-01

Kindling, an animal model of epilepsy wherein seizures are induced by subcortical electrical stimulation, results in the upregulation of neurotrophin mRNA and protein in the adult rat forebrain and causes mossy fiber sprouting in the hippocampus. Intraventricular infusion of a synthetic peptide mimic of a nerve growth factor domain that interferes with the binding of neurotrophins to their receptors resulted in significant retardation of kindling and inhibition of mossy fiber sprouting. These findings suggest a critical role for neurotrophins in both kindling and kindling-induced synaptic reorganization.

Whole-Genome Sequencing Reveals Genetic Variation in the Asian House Rat.

PubMed

Teng, Huajing; Zhang, Yaohua; Shi, Chengmin; Mao, Fengbiao; Hou, Lingling; Guo, Hongling; Sun, Zhongsheng; Zhang, Jianxu

2016-07-07

Whole-genome sequencing of wild-derived rat species can provide novel genomic resources, which may help decipher the genetics underlying complex phenotypes. As a notorious pest, reservoir of human pathogens, and colonizer, the Asian house rat, Rattus tanezumi, is successfully adapted to its habitat. However, little is known regarding genetic variation in this species. In this study, we identified over 41,000,000 single-nucleotide polymorphisms, plus insertions and deletions, through whole-genome sequencing and bioinformatics analyses. Moreover, we identified over 12,000 structural variants, including 143 chromosomal inversions. Further functional analyses revealed several fixed nonsense mutations associated with infection and immunity-related adaptations, and a number of fixed missense mutations that may be related to anticoagulant resistance. A genome-wide scan for loci under selection identified various genes related to neural activity. Our whole-genome sequencing data provide a genomic resource for future genetic studies of the Asian house rat species and have the potential to facilitate understanding of the molecular adaptations of rats to their ecological niches. Copyright © 2016 Teng et al.

Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy.

PubMed

Bagnall, Richard D; Crompton, Douglas E; Petrovski, Slavé; Lam, Lien; Cutmore, Carina; Garry, Sarah I; Sadleir, Lynette G; Dibbens, Leanne M; Cairns, Anita; Kivity, Sara; Afawi, Zaid; Regan, Brigid M; Duflou, Johan; Berkovic, Samuel F; Scheffer, Ingrid E; Semsarian, Christopher

2016-04-01

The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of <0.1% and predicted to be pathogenic with multiple in silico tools. The 61 SUDEP cases were categorized as definite SUDEP (n = 54), probable SUDEP (n = 5), and definite SUDEP plus (n = 2). We identified de novo mutations, previously reported pathogenic mutations, or candidate pathogenic variants in 28 of 61 (46%) cases. Four SUDEP cases (7%) had mutations in common genes responsible for the cardiac arrhythmia disease, long QT syndrome (LQTS). Nine cases (15%) had candidate pathogenic variants in dominant cardiac arrhythmia genes. Fifteen cases (25%) had mutations or candidate pathogenic variants in dominant epilepsy genes. No gene reached genome-wide significance with rare variant collapsing analysis; however, DEPDC5 (p = 0.00015) and KCNH2 (p = 0.0037) were among the top 30 genes, genome-wide. A sizeable proportion of SUDEP cases have clinically relevant mutations in cardiac arrhythmia and epilepsy genes. In cases with an LQTS gene mutation, SUDEP may occur as a result of a predictable and preventable cause. Understanding the genetic basis of SUDEP may inform cascade testing of at-risk family members. © 2016 American Neurological Association.

A systematic review of the risks factors associated with the onset and natural progression of epilepsy.

PubMed

Walsh, Stephanie; Donnan, Jennifer; Fortin, Yannick; Sikora, Lindsey; Morrissey, Andrea; Collins, Kayla; MacDonald, Don

2017-07-01

Epilepsy is a neurological condition that affects more than 50 million individuals worldwide. It presents as unpredictable, temporary and recurrent seizures often having negative physical, psychological and social consequences. To inform disease prevention and management strategies, a comprehensive systematic review of the literature on risk factors for the onset and natural progression of epilepsy was conducted. Computerized bibliographic databases for systematic reviews, meta-analyses, observational studies and genetic association studies published between 1990 and 2013 describing etiological risk factors for epilepsy was searched. The quality of systematic reviews was validated using the AMSTAR tool and articles were reviewed by two referees. A total of 16,958 articles went through stage one review of abstracts and titles. A total of 76 articles on genetic and non-genetic risk factors for the onset and progression of epilepsy met the eligibility criteria for data extraction. Dozens of risk factors were significantly associated with onset of epilepsy. Inconsistent levels of evidence for risk of onset included family history of epilepsy, history of febrile seizures, alcohol consumption, CNS and other infections, brain trauma, head injury, perinatal stroke, preterm birth and three genetic markers. Limited evidence showed that symptomatic epilepsy, focal seizures/syndromes, slow waves on EEG, higher seizure frequency, high stress or anxiety, and lack of sleep decreased the odds of seizure remission. High quality studies were rare and while a large body of work exists, relatively few systematic reviews were found. Copyright © 2016. Published by Elsevier B.V.

Current controversies in the relationships between autism and epilepsy.

PubMed

Besag, Frank M C

2015-06-01

The controversies that have arisen in endeavoring to establish the nature of the relationships between autism and epilepsy might be summarized in a few simple questions, most of which do not yet have clear, complete answers. Does epilepsy cause autism? Does autism cause epilepsy? Are there underlying brain mechanisms that predispose to both conditions? What is the role of genetics in this regard? What is the importance of prenatal, perinatal, and postnatal environmental factors? Do any of the proposed relationships between autism and epilepsy provide insight into useful management or treatment? Is the prognosis of either autism or epilepsy different when the other condition is also present? What is the role of additional comorbidities, such as intellectual impairment or attention deficit hyperactivity disorder, in the relationship between the two conditions and in influencing treatment choices? From the evidence currently available, it would appear that epilepsy can rarely be the cause of autistic features but is not the cause of autism in most cases. There is currently no credible mechanism for suggesting that autism might cause epilepsy. There is strong evidence for an underlying predisposition for both conditions, particularly arising from genetic investigations. However, many issues remain unresolved. Considering the amount of research that has been published in this area, it is surprising that so few definitive answers have been established. The papers in this issue's special section provide additional insights into the relationships between autism and epilepsy; while they do not provide answers to all the questions, they represent considerable progress in this area and, at the very least, give some strong indication of what research might, in the future, provide such answers. Copyright © 2015. Published by Elsevier Inc.

From Classification to Epilepsy Ontology and Informatics

PubMed Central

Zhang, Guo-Qiang; Sahoo, Satya S; Lhatoo, Samden D

2012-01-01

Summary The 2010 International League Against Epilepsy (ILAE) classification and terminology commission report proposed a much needed departure from previous classifications to incorporate advances in molecular biology, neuroimaging, and genetics. It proposed an interim classification and defined two key requirements that need to be satisfied. The first is the ability to classify epilepsy in dimensions according to a variety of purposes including clinical research, patient care, and drug discovery. The second is the ability of the classification system to evolve with new discoveries. Multi-dimensionality and flexibility are crucial to the success of any future classification. In addition, a successful classification system must play a central role in the rapidly growing field of epilepsy informatics. An epilepsy ontology, based on classification, will allow information systems to facilitate data-intensive studies and provide a proven route to meeting the two foregoing key requirements. Epilepsy ontology will be a structured terminology system that accommodates proposed and evolving ILAE classifications, the NIH/NINDS Common Data Elements, the ICD systems and explicitly specifies all known relationships between epilepsy concepts in a proper framework. This will aid evidence based epilepsy diagnosis, investigation, treatment and research for a diverse community of clinicians and researchers. Benefits range from systematization of electronic patient records to multi-modal data repositories for research and training manuals for those involved in epilepsy care. Given the complexity, heterogeneity and pace of research advances in the epilepsy domain, such an ontology must be collaboratively developed by key stakeholders in the epilepsy community and experts in knowledge engineering and computer science. PMID:22765502

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

PubMed Central

Kasperavičiūtė, Dalia; Catarino, Claudia B.; Matarin, Mar; Leu, Costin; Novy, Jan; Tostevin, Anna; Leal, Bárbara; Hessel, Ellen V. S.; Hallmann, Kerstin; Hildebrand, Michael S.; Dahl, Hans-Henrik M.; Ryten, Mina; Trabzuni, Daniah; Ramasamy, Adaikalavan; Alhusaini, Saud; Doherty, Colin P.; Dorn, Thomas; Hansen, Jörg; Krämer, Günter; Steinhoff, Bernhard J.; Zumsteg, Dominik; Duncan, Susan; Kälviäinen, Reetta K.; Eriksson, Kai J.; Kantanen, Anne-Mari; Pandolfo, Massimo; Gruber-Sedlmayr, Ursula; Schlachter, Kurt; Reinthaler, Eva M.; Stogmann, Elisabeth; Zimprich, Fritz; Théâtre, Emilie; Smith, Colin; O’Brien, Terence J.; Meng Tan, K.; Petrovski, Slave; Robbiano, Angela; Paravidino, Roberta; Zara, Federico; Striano, Pasquale; Sperling, Michael R.; Buono, Russell J.; Hakonarson, Hakon; Chaves, João; Costa, Paulo P.; Silva, Berta M.; da Silva, António M.; de Graan, Pierre N. E.; Koeleman, Bobby P. C.; Becker, Albert; Schoch, Susanne; von Lehe, Marec; Reif, Philipp S.; Rosenow, Felix; Becker, Felicitas; Weber, Yvonne; Lerche, Holger; Rössler, Karl; Buchfelder, Michael; Hamer, Hajo M.; Kobow, Katja; Coras, Roland; Blumcke, Ingmar; Scheffer, Ingrid E.; Berkovic, Samuel F.; Weale, Michael E.; Delanty, Norman; Depondt, Chantal; Cavalleri, Gianpiero L.; Kunz, Wolfram S.

2013-01-01

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures

An Exploration of Gardens in Maycoba, Mexico: Change in the Environment of a Population Genetically Prone to Diabetes

PubMed Central

Begay, R. Cruz; Chaudhari, Lisa S.; Esparza-Romero, Julian; Romero, Rene Urquidez; Schulz, Leslie O.

2013-01-01

Gardens are an important part of the environment as they play multiple roles and are central to the lifestyle and economy of many communities. The investigators use qualitative methods to explore patterns and perceptions about changes in gardening and cultivation in the community of Maycoba, Mexico. Maycoba is home to a large community of Pima Indians, an Indigenous population genetically prone to diabetes. Pima Indians living in the United States have been shown to have an extremely high prevalence of diabetes, but the genetically comparable Pimas in Maycoba, Mexico, were found to have little diabetes in the early 1990s. The authors examine home gardens and other cultivation in the area as an element of a changing environment and lifestyle during the past 15 years. Methods include interviews and focus groups. Preliminary findings are presented in this paper. PMID:25364623

The Physiopathogenesis of the Epilepsies.

ERIC Educational Resources Information Center

Gastaut, Henri; And Others

Material is discussed in articles by 40 contributors. Concerning physiopathogenesis of epilepsies there are introductory notes, two articles on genetics, one on neurophysiological and metabolic mechanisms, two on renal failure, a discussion of convulsive seizure and water intoxication, three articles on hypoglycemia, one on electroclinical…

A Population-Based Study of Long-term Outcomes of Cryptogenic Focal Epilepsy in Childhood: Cryptogenic Epilepsy is NOT Probably Symptomatic Epilepsy

PubMed Central

Wirrell, Elaine C; Grossardt, Brandon R; So, Elson L; Nickels, Katherine C

2011-01-01

Purpose To compare long-term outcome in a population-based group of children with cryptogenic vs symptomatic focal epilepsy diagnosed from 1980–2004 and to define the course of epilepsy in the cryptogenic group. Methods We identified all children residing in Olmsted County, MN, 1 month through 17 years with newly diagnosed, non-idiopathic focal epilepsy from 1980–2004. Children with idiopathic partial epilepsy syndromes were excluded. Medical records were reviewed to determine etiology, results of imaging and EEG studies, treatments used, and long-term outcome. Children were defined as having symptomatic epilepsy if they had a known genetic or structural/metabolic etiology, and as cryptogenic if they did not. Key Findings Of 359 children with newly-diagnosed epilepsy, 215 (60%) had non-idiopathic focal epilepsy. Of these, 206 (96%) were followed for more than 12 months. Ninety five children (46%) were classified as symptomatic. Median follow-up from diagnosis was similar in both groups, being 157 months (25%ile, 75%ile 89, 233) in the cryptogenic group vs 134 months (25%ile, 75%ile 78, 220) in the symptomatic group (p=0.26). Of 111 cryptogenic cases, 66% had normal cognition. Long-term outcome was significantly better in those with cryptogenic vs symptomatic etiology (intractable epilepsy at last follow-up, 7% vs 40%, p<0.001; seizure-freedom at last follow-up, 81% vs 55%, p<0.001). Of those who achieved seizure-freedom at final follow-up, 68% of the cryptogenic group versus only 46% of the symptomatic group were off antiepileptic medications (p=0.01). One third of the cryptogenic group had a remarkably benign disorder, with no seizures seen after initiation of medication, or in those who were untreated, after the second afebrile seizure. A further 5% had seizures within the first year but remained seizure-free thereafter. With the exception of perinatal complications, which predicted against seizure remission, no other factors were found to significantly

Racial and ethnic differences in epilepsy classification among probands in the Epilepsy Phenome/Genome Project (EPGP).

PubMed

Friedman, Daniel; Fahlstrom, Robyn

2013-12-01

Little is known about the ethnic and racial differences in the prevalence of generalized and focal epilepsy among patients with non-acquired epilepsies. In this study, we examined epilepsy classification and race/ethnicity in 813 probands from sibling or parent-child pairs with epilepsy enrolled in the Epilepsy Genome/Phenome Project (EPGP). Subjects were classified as generalized epilepsy (GE), non-acquired focal epilepsy (NAFE), mixed epilepsy syndrome (both generalized and focal), and unclassifiable, based on consensus review of semiology and available clinical, electrophysiology, and neuroimaging data. In this cohort, 628 (77.2%) subjects identified exclusively as Caucasian/white and 65 (8.0%) subjects reported African ancestry, including subjects of mixed-race. Of the Caucasian/white subjects, 357 (56.8%) had GE, 207 (33.0%) had NAFE, 32 (5.1%) had a mixed syndrome, and 32 (5.1%) were unclassifiable. Among subjects of African ancestry, 28 (43.1%) had GE, 27 (41.5%) had NAFE, 2 (3.1%) had a mixed syndrome, and 8 (12.3%) were unclassifiable. There was a higher proportion of subjects with GE compared to other syndromes among Caucasians/whites compared to subjects with African ancestry (OR 1.74, 95% CI: 1.04-2.92, two-tailed Fisher's exact test, p=0.036). There was no difference in the rate of GE among subjects reporting Hispanic ethnicity (7.6% of total) when adjusted for race (Caucasian/white vs non-Caucasian/white; OR 0.65, 95% CI: 0.40-1.06, p>0.05). The proportion of participants with unclassifiable epilepsy was significantly greater in those of African-American descent. In a group of patients with epilepsy of unknown etiology and an affected first degree relative, GE is more common among Caucasian/white subjects than among those with African ancestry. These findings suggest there may be geographical differences in the distribution of epilepsy susceptibility genes and an effect of genetic background on epilepsy phenotype. However, the results should be

Epilepsy

MedlinePlus

... Staying Safe Videos for Educators Search English Español Epilepsy KidsHealth / For Kids / Epilepsy What's in this article? ... Epilepsy Different? Print en español Epilepsia What Is Epilepsy? Epilepsy comes from a Greek word meaning "to ...

P-gp Protein Expression and Transport Activity in Rodent Seizure Models and Human Epilepsy.

PubMed

Hartz, Anika M S; Pekcec, Anton; Soldner, Emma L B; Zhong, Yu; Schlichtiger, Juli; Bauer, Bjoern

2017-04-03

A cure for epilepsy is currently not available, and seizure genesis, seizure recurrence, and resistance to antiseizure drugs remain serious clinical problems. Studies show that the blood-brain barrier is altered in animal models of epilepsy and in epileptic patients. In this regard, seizures increase expression of blood-brain barrier efflux transporters such as P-glycoprotein (P-gp), which is thought to reduce brain uptake of antiseizure drugs, and thus, contribute to antiseizure drug resistance. The goal of the current study was to assess the viability of combining in vivo and ex vivo preparations of isolated brain capillaries from animal models of seizures and epilepsy as well as from patients with epilepsy to study P-gp at the blood-brain barrier. Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy. Moreover, the fold-increase in P-gp protein expression seen in animal models is consistent with the fold-increase in P-gp observed in human brain capillaries isolated from patients with epilepsy compared to age-matched control individuals. Overall, the in vivo/ex vivo approach presented here allows detailed analysis of the mechanisms underlying seizure-induced changes of P-gp expression and transport activity at the blood-brain barrier. This approach can be extended to other blood-brain barrier proteins that might contribute to drug-resistant epilepsy or other CNS disorders as well.

LP-211, a selective 5-HT7 receptor agonist, increases novelty-preference and promotes risk-prone behavior in rats.

PubMed

Beaudet, G; Paizanis, E; Zoratto, F; Lacivita, E; Leopoldo, M; Freret, T; Laviola, G; Boulouard, M; Adriani, W

2017-12-01

Gambling disorder is associated to an increased impulsivity, a high level of novelty-seeking and a dysregulation of the forebrain neurotransmission systems. However, the neurobiological mechanisms of this addictive disorder are not fully understood and no valid pharmacological approach has yet been approved. The present study aimed to investigate the effect of 5-HT7 receptor (5-HT 7 R) stimulation with a brain penetrant and selective agonist, LP-211 (0.25 and 0.50 mg kg -1 i.p.) during post-experience consolidation, (i) acutely in a novelty-preference test (Exp. 1) or (ii) sub-chronically in the Probabilistic-Delivery Task (rPDT, commonly used to measure individual differences in risk proneness of rats; Exp. 2). Results of Exp. 1 showed that 5-HT 7 R activation improves consolidation of chamber-shape memory in the novelty-preference test, leading to significant novelty-induced hyperactivity and recognition, in conditions where controls displayed a null-preference. These results suggest that 5-HT 7 Rs may be involved in the consolidation of information inherent to spatial environments, facilitating the recognition of novelty. Furthermore, in the operant rPDT (Exp. 2), 5-HT 7 R activation shifts the choice towards a larger yet unlikely reward and turns the propensity of rats towards risk-prone behavior. Thus, 5-HT 7 Rs stimulation apparently strengthens the consideration of future, bigger rewards, also enhancing the seeking of it by operant pokes. These effects may well be explained by LP-211 actions on hippocampal versus prefrontal cortex-mediated regulations, leading to improved (though suboptimal) strategy formation. However, further experiments are necessary to determine more in depth the serotonergic pathways involved. © 2017 Wiley Periodicals, Inc.

Isometric elbow extensors strength in supine- and prone-lying positions.

PubMed

Abdelzaher, Ibrahim E; Ababneh, Anas F; Alzyoud, Jehad M

2013-01-01

The purpose of this study was to compare isometric strength of elbow extensors measured in supine- and prone-lying positions at elbow flexion angles of 45 and 90 degrees. Twenty-two male subjects under single-blind procedures participated in the study. Each subject participated in both supine-lying and prone-lying measuring protocols. Calibrated cable tensiometer was used to measure isometric strength of the right elbow extensors and a biofeedback electromyography was used to assure no substitution movements from shoulder girdle muscles. The mean values of isometric strength of elbow extensors measured from supine-lying position at elbow flexion angles of 45 and 90 degrees were 11.1  ±  4.2 kg and 13.1  ±  4.6 kg, while those measured from prone-lying position were 9.9  ±  3.6 kg and 12  ±  4.2 kg, respectively. There is statistical significant difference between the isometric strength of elbow extensors measured from supine-lying position at elbow flexion angles of 45 and 90 degrees compared to that measured from prone-lying position (p  <  0.05). The results suggest that in manual muscle testing starting position can affect the isometric strength of elbow extensors since supine-lying starting position is better than prone-lying starting position.

Epilepsy: Transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.

PubMed

Andrade, Danielle M; Bassett, Anne S; Bercovici, Eduard; Borlot, Felippe; Bui, Esther; Camfield, Peter; Clozza, Guida Quaglia; Cohen, Eyal; Gofine, Timothy; Graves, Lisa; Greenaway, Jon; Guttman, Beverly; Guttman-Slater, Maya; Hassan, Ayman; Henze, Megan; Kaufman, Miriam; Lawless, Bernard; Lee, Hannah; Lindzon, Lezlee; Lomax, Lysa Boissé; McAndrews, Mary Pat; Menna-Dack, Dolly; Minassian, Berge A; Mulligan, Janice; Nabbout, Rima; Nejm, Tracy; Secco, Mary; Sellers, Laurene; Shapiro, Michelle; Slegr, Marie; Smith, Rosie; Szatmari, Peter; Tao, Leeping; Vogt, Anastasia; Whiting, Sharon; Carter Snead, O

2017-09-01

The transition from a pediatric to adult health care system is challenging for many youths with epilepsy and their families. Recently, the Ministry of Health and Long-Term Care of the Province of Ontario, Canada, created a transition working group (TWG) to develop recommendations for the transition process for patients with epilepsy in the Province of Ontario. Herein we present an executive summary of this work. The TWG was composed of a multidisciplinary group of pediatric and adult epileptologists, psychiatrists, and family doctors from academia and from the community; neurologists from the community; nurses and social workers from pediatric and adult epilepsy programs; adolescent medicine physician specialists; a team of physicians, nurses, and social workers dedicated to patients with complex care needs; a lawyer; an occupational therapist; representatives from community epilepsy agencies; patients with epilepsy; parents of patients with epilepsy and severe intellectual disability; and project managers. Three main areas were addressed: (1) Diagnosis and Management of Seizures; 2) Mental Health and Psychosocial Needs; and 3) Financial, Community, and Legal Supports. Although there are no systematic studies on the outcomes of transition programs, the impressions of the TWG are as follows. Teenagers at risk of poor transition should be identified early. The care coordination between pediatric and adult neurologists and other specialists should begin before the actual transfer. The transition period is the ideal time to rethink the diagnosis and repeat diagnostic testing where indicated (particularly genetic testing, which now can uncover more etiologies than when patients were initially evaluated many years ago). Some screening tests should be repeated after the move to the adult system. The seven steps proposed herein may facilitate transition, thereby promoting uninterrupted and adequate care for youth with epilepsy leaving the pediatric system. Wiley

Lessons learned from gene identification studies in Mendelian epilepsy disorders

PubMed Central

Hardies, Katia; Weckhuysen, Sarah; De Jonghe, Peter; Suls, Arvid

2016-01-01

Next-generation sequencing (NGS) technologies are now routinely used for gene identification in Mendelian disorders. Setting up cost-efficient NGS projects and managing the large amount of variants remains, however, a challenging job. Here we provide insights in the decision-making processes before and after the use of NGS in gene identification studies. Genetic factors are thought to have a role in ~70% of all epilepsies, and a variety of inheritance patterns have been described for seizure-associated gene defects. We therefore chose epilepsy as disease model and selected 35 NGS studies that focused on patients with a Mendelian epilepsy disorder. The strategies used for gene identification and their respective outcomes were reviewed. High-throughput NGS strategies have led to the identification of several new epilepsy-causing genes, enlarging our knowledge on both known and novel pathomechanisms. NGS findings have furthermore extended the awareness of phenotypical and genetic heterogeneity. By discussing recent studies we illustrate: (I) the power of NGS for gene identification in Mendelian disorders, (II) the accelerating pace in which this field evolves, and (III) the considerations that have to be made when performing NGS studies. Nonetheless, the enormous rise in gene discovery over the last decade, many patients and families included in gene identification studies still remain without a molecular diagnosis; hence, further genetic research is warranted. On the basis of successful NGS studies in epilepsy, we discuss general approaches to guide human geneticists and clinicians in setting up cost-efficient gene identification NGS studies. PMID:26603999

Autosomal dominant cortical tremor, myoclonus and epilepsy.

PubMed

Striano, Pasquale; Zara, Federico

2016-09-01

The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.

Top 100 cited articles on epilepsy and status epilepticus: A bibliometric analysis.

PubMed

Park, Kang Min; Kim, Sung Eun; Lee, Byung In; Kim, Hyung Chan; Yoon, Dae Young; Song, Hong Ki; Bae, Jong Seok

2017-08-01

The purpose of this study is to identify the top 100-cited articles dedicated to epilepsy and status epilepticus published in journals from January, 1950 through February, 2016 that have made key contributions in the field. We performed a search of journals and selected the top 100-cited articles on epilepsy and status epilepticus, respectively, by utilizing the Institute for Scientific Information database available under the banner of the Web of Science. The top-cited articles on epilepsy and status epilepticus were all published in 24 journals, respectively. In both fields of epilepsy and status epilepticus, the most frequently cited journal was Epilepsia (26 articles on epilepsy and 19 articles on status epilepticus). The 100 most-cited articles in the field of both epilepsy and status epilepticus mainly originated from institutions in the United States of America. The articles on epilepsy included 25 laboratory studies, 15 pharmacotherapy studies, 13 general review studies, 12 surgery studies, 11 neuroimaging studies, eight epidemiology studies, eight neuropsychiatry studies, six genetic studies, and two electrophysiology studies, whereas 41 laboratory studies, 21 epidemiology studies, 16 pharmacotherapy studies, nine electrophysiology studies, nine general review studies, and four neuroimaging studies were included in the field of status epilepticus. We demonstrate that neuroimaging, genetics, and surgery are emerging topics in the field of epilepsy over the past decades. Moreover, we found that the majority of top-cited articles on epilepsy and status epilepticus originated from institutions in the United States of America and most were published in Epilepsia. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Prediction Algorithm for Drug Response in Patients with Mesial Temporal Lobe Epilepsy Based on Clinical and Genetic Information

PubMed Central

Carvalho, Benilton S.; Bilevicius, Elizabeth; Alvim, Marina K. M.; Lopes-Cendes, Iscia

2017-01-01

Mesial temporal lobe epilepsy is the most common form of adult epilepsy in surgical series. Currently, the only characteristic used to predict poor response to clinical treatment in this syndrome is the presence of hippocampal sclerosis. Single nucleotide polymorphisms (SNPs) located in genes encoding drug transporter and metabolism proteins could influence response to therapy. Therefore, we aimed to evaluate whether combining information from clinical variables as well as SNPs in candidate genes could improve the accuracy of predicting response to drug therapy in patients with mesial temporal lobe epilepsy. For this, we divided 237 patients into two groups: 75 responsive and 162 refractory to antiepileptic drug therapy. We genotyped 119 SNPs in ABCB1, ABCC2, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 genes. We used 98 additional SNPs to evaluate population stratification. We assessed a first scenario using only clinical variables and a second one including SNP information. The random forests algorithm combined with leave-one-out cross-validation was used to identify the best predictive model in each scenario and compared their accuracies using the area under the curve statistic. Additionally, we built a variable importance plot to present the set of most relevant predictors on the best model. The selected best model included the presence of hippocampal sclerosis and 56 SNPs. Furthermore, including SNPs in the model improved accuracy from 0.4568 to 0.8177. Our findings suggest that adding genetic information provided by SNPs, located on drug transport and metabolism genes, can improve the accuracy for predicting which patients with mesial temporal lobe epilepsy are likely to be refractory to drug treatment, making it possible to identify patients who may benefit from epilepsy surgery sooner. PMID:28052106

Connectomics and graph theory analyses: Novel insights into network abnormalities in epilepsy.

PubMed

Gleichgerrcht, Ezequiel; Kocher, Madison; Bonilha, Leonardo

2015-11-01

The assessment of neural networks in epilepsy has become increasingly relevant in the context of translational research, given that localized forms of epilepsy are more likely to be related to abnormal function within specific brain networks, as opposed to isolated focal brain pathology. It is notable that variability in clinical outcomes from epilepsy treatment may be a reflection of individual patterns of network abnormalities. As such, network endophenotypes may be important biomarkers for the diagnosis and treatment of epilepsy. Despite its exceptional potential, measuring abnormal networks in translational research has been thus far constrained by methodologic limitations. Fortunately, recent advancements in neuroscience, particularly in the field of connectomics, permit a detailed assessment of network organization, dynamics, and function at an individual level. Data from the personal connectome can be assessed using principled forms of network analyses based on graph theory, which may disclose patterns of organization that are prone to abnormal dynamics and epileptogenesis. Although the field of connectomics is relatively new, there is already a rapidly growing body of evidence to suggest that it can elucidate several important and fundamental aspects of abnormal networks to epilepsy. In this article, we provide a review of the emerging evidence from connectomics research regarding neural network architecture, dynamics, and function related to epilepsy. We discuss how connectomics may bring together pathophysiologic hypotheses from conceptual and basic models of epilepsy and in vivo biomarkers for clinical translational research. By providing neural network information unique to each individual, the field of connectomics may help to elucidate variability in clinical outcomes and open opportunities for personalized medicine approaches to epilepsy. Connectomics involves complex and rich data from each subject, thus collaborative efforts to enable the

A role for the preoptic sleep-promoting system in absence epilepsy.

PubMed

Suntsova, N; Kumar, S; Guzman-Marin, R; Alam, M N; Szymusiak, R; McGinty, D

2009-10-01

Absence epilepsy (AE) in humans and the genetic AE model in WAG/Rij rats are both associated with abnormalities in sleep architecture that suggest insufficiency of the sleep-promoting mechanisms. In this study we compared the functionality of sleep-active neuronal groups within two well-established sleep-promoting sites, the ventrolateral and median preoptic nuclei (VLPO and MnPN, respectively), in WAG/Rij and control rats. Neuronal activity was assessed using c-Fos immunoreactivity and chronic single-unit recording techniques. We found that WAG/Rij rats exhibited a lack of sleep-associated c-Fos activation of GABAergic MnPN and VLPO neurons, a lower percentage of MnPN and VLPO cells increasing discharge during sleep and reduced firing rates of MnPN sleep-active neurons, compared to non-epileptic rats. The role of sleep-promoting mechanisms in pathogenesis of absence seizures was assessed in non-epileptic rats using electrical stimulation and chemical manipulations restricted to the MnPN. We found that fractional activation of the sleep-promoting system in waking was sufficient to elicit absence-like seizures. Given that reciprocally interrelated sleep-promoting and arousal neuronal groups control thalamocortical excitability, we hypothesize that malfunctioning of sleep-promoting system results in impaired ascending control over thalamocortical rhythmogenic mechanisms during wake-sleep transitions thus favoring aberrant thalamocortical oscillations. Our findings suggest a pathological basis for AE-associated sleep abnormalities and a mechanism underlying association of absence seizures with wake-sleep transitions.

Prehypertensive treatment with losartan, however not amlodipine, leads to long-term effects on blood pressure and reduces the risk of stroke in spontaneously hypertensive stroke-prone rats.

PubMed

Zhang, Liangmin; He, Dehua; Lin, Jinxiu

2016-02-01

The current study investigated the efficacy of losartan and amlodipine in protecting spontaneously hypertensive stroke-prone (SHRSP) rats against the risk of stroke. SHRSP rats were administered losartan, amlodipine or the vehicle for 6 weeks. There were no significant differences in systolic blood pressure (SBP) in rats treated with losartan or amlodipine, however, following drug withdrawal, rats treated with losartan maintained reduced SBP for a longer time compared with rats treated with amlodipine. In addition, rats treated with losartan exhibited thinner vascular walls and improved systolic and diastolic function. Clinical stroke scores in the losartan group were significantly reduced compared with those in the amlodipine and vehicle groups. However, rats treated with losartan exhibited higher levels of angiotensin II and lower levels of aldosterone in the serum and brain cortex compared with the vehicle and amlodipine-treated rats. Furthermore, losartan significantly reduced the abnormal expression of angiotensin II receptors type 1 and 2 in SHRSP rats, whilst amlodipine did not. These results suggest that losartan may be more efficacious than amlodipine in ameliorating blood pressure deterioration and reducing stroke risk in SHRSP rats via regulation of the renin angiotensin system.

Astaxanthin inhibits thrombosis in cerebral vessels of stroke-prone spontaneously hypertensive rats.

PubMed

Sasaki, Yasuto; Kobara, Nozomi; Higashino, Saori; Giddings, John C; Yamamoto, Junichiro

2011-10-01

It is known that vitamin E and some carotenoids have antioxidant activities that alleviate endothelial dysfunction and play a protective role against cardiovascular disease. The current study was designed to examine the hypothesis that astaxanthin, a red pigment carotenoid found in salmonid and crustacean aquaculture, protects stroke-prone spontaneously hypertensive rats (SHRSP) from vascular oxidative damage, hypertension, and cerebral thrombosis. Male 6-week-old SHRSP were classified into 4 groups: a control group, 2 astaxanthin groups, and a vitamin E group. The treated animals were given either astaxanthin or vitamin E for 3 weeks. Body weights in each group were not significantly different from control group during the treatment period, but the usual increase in systolic blood pressure in SHRSP observed with age was significantly suppressed by treatment. Thrombogenesis, assessed using a helium-neon (He-Ne) laser technique in pial blood vessels, together with antioxidant activity, assessed by measuring urinary 8-OHdG levels, were significantly moderated. Urinary nitric oxide (NO) metabolites were increased after treatment. These results supported our hypothesis and strongly suggested that the antithrombotic and antihypertensive effects of astaxanthin or vitamin E may be related to an increase in bioavailable NO, possibly mediated by decreased inactivation of NO by reactive oxygen species. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

PubMed

Klein, Brian D; Jacobson, Catherine A; Metcalf, Cameron S; Smith, Misty D; Wilcox, Karen S; Hampson, Aidan J; Kehne, John H

2017-07-01

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED 50 164 mg/kg), mouse MES (ED 50 83.5 mg/kg) and rat MES (ED 50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED 50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment.

PubMed

Shrot, Shai; Ramaty, Erez; Biala, Yoav; Bar-Klein, Guy; Daninos, Moshe; Kamintsky, Lyn; Makarovsky, Igor; Statlender, Liran; Rosman, Yossi; Krivoy, Amir; Lavon, Ophir; Kassirer, Michael; Friedman, Alon; Yaari, Yoel

2014-09-02

Poisoning with organophosphates (OPs) may induce status epilepticus (SE), leading to severe brain damage. Our objectives were to investigate whether OP-induced SE leads to the emergence of spontaneous recurrent seizures (SRSs), the hallmark of chronic epilepsy, and if so, to assess the efficacy of benzodiazepine therapy following SE onset in preventing the epileptogenesis. We also explored early changes in hippocampal pyramidal cells excitability in this model. Adult rats were poisoned with the paraoxon (450μg/kg) and immediately treated with atropine (3mg/kg) and obidoxime (20mg/kg) to reduce acute mortality due to peripheral acetylcholinesterase inhibition. Electrical brain activity was assessed for two weeks during weeks 4-6 after poisoning using telemetric electrocorticographic intracranial recordings. All OP-poisoned animals developed SE, which could be suppressed by midazolam. Most (88%) rats which were not treated with midazolam developed SRSs, indicating that they have become chronically epileptic. Application of midazolam 1min following SE onset had a significant antiepileptogenic effect (only 11% of the rats became epileptic; p=0.001 compared to non-midazolam-treated rats). Applying midazolam 30min after SE onset did not significantly prevent chronic epilepsy. The electrophysiological properties of CA1 pyramidal cells, assessed electrophysiologically in hippocampal slices, were not altered by OP-induced SE. Thus we show for the first time that a single episode of OP-induced SE in rats leads to the acquisition of chronic epilepsy, and that this epileptogenic outcome can be largely prevented by immediate, but not delayed, administration of midazolam. Extrapolating these results to humans would suggest that midazolam should be provided together with atropine and an oxime in the immediate pharmacological treatment of OP poisoning. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy

PubMed Central

Speed, Doug; Hoggart, Clive; Petrovski, Slave; Tachmazidou, Ioanna; Coffey, Alison; Jorgensen, Andrea; Eleftherohorinou, Hariklia; De Iorio, Maria; Todaro, Marian; De, Tisham; Smith, David; Smith, Philip E.; Jackson, Margaret; Cooper, Paul; Kellett, Mark; Howell, Stephen; Newton, Mark; Yerra, Raju; Tan, Meng; French, Chris; Reuber, Markus; Sills, Graeme E.; Chadwick, David; Pirmohamed, Munir; Bentley, David; Scheffer, Ingrid; Berkovic, Samuel; Balding, David; Palotie, Aarno; Marson, Anthony; O'Brien, Terence J.; Johnson, Michael R.

2014-01-01

We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 106 imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta < 5.0 × 10−7) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, Pmeta = 2.1 × 10−7, OR[G] = 0.57), 9p23 (rs72700966, Pmeta = 3.1 × 10−7, OR[C] = 2.70) and 15q13.2 (rs143536437, Pmeta = 3.2 × 10−7, OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories ‘calcium signaling pathway’ and ‘phosphatidylinositol signaling pathway’. Through a series of power curves, we conclude that it is unlikely any single common variant explains >4.4% of the variation in the outcome of newly treated epilepsy. PMID:23962720

When the face says it all: dysmorphology in identifying syndromic causes of epilepsy.

PubMed

Dixit, Abhijit; Suri, Mohnish

2016-04-01

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A Murine Model to Study Epilepsy and SUDEP Induced by Malaria Infection

PubMed Central

Ssentongo, Paddy; Robuccio, Anna E.; Thuku, Godfrey; Sim, Derek G.; Nabi, Ali; Bahari, Fatemeh; Shanmugasundaram, Balaji; Billard, Myles W.; Geronimo, Andrew; Short, Kurt W.; Drew, Patrick J.; Baccon, Jennifer; Weinstein, Steven L.; Gilliam, Frank G.; Stoute, José A.; Chinchilli, Vernon M.; Read, Andrew F.; Gluckman, Bruce J.; Schiff, Steven J.

2017-01-01

One of the largest single sources of epilepsy in the world is produced as a neurological sequela in survivors of cerebral malaria. Nevertheless, the pathophysiological mechanisms of such epileptogenesis remain unknown and no adjunctive therapy during cerebral malaria has been shown to reduce the rate of subsequent epilepsy. There is no existing animal model of postmalarial epilepsy. In this technical report we demonstrate the first such animal models. These models were created from multiple mouse and parasite strain combinations, so that the epilepsy observed retained universality with respect to genetic background. We also discovered spontaneous sudden unexpected death in epilepsy (SUDEP) in two of our strain combinations. These models offer a platform to enable new preclinical research into mechanisms and prevention of epilepsy and SUDEP. PMID:28272506

A genetic locus for sensory epilepsy precipitated by contact with hot water maps to chromosome 9p24.3-p23.

PubMed

Karan, Kalpita R; Satishchandra, Parthasarthy; Sinha, Sanjib; Anand, Anuranjan

2018-06-01

Hot water epilepsy (HWE) is a rare form of sensory epilepsy where seizures are precipitated by a stimulus of contact with hot water. While earlier studies have suggested causal role of genes for HWE, specific underpinnings are beginning to be explored only recently. We carried out a whole genome-based linkage analysis in a family where most of its members affected by HWE and found evidence of a previously unknown locus at chromosome 9p24.3-p23. Parametric two-point analysis suggested linkage with the greatest LOD score of 3.42 for the marker D9S286 at 9p24.1 at recombination fraction ( θ ) = 0, 90% penetrance value and 1% phenocopy rate. The highest multipoint LODscore of 3.42 was obtained for same marker at 9p24. The critical genetic interval of about 10 Mb of DNA was defined by the markers D9S917 and D9S168 corresponding to the centromere-distal and centromere-proximal recombination boundaries, respectively. This observation along with our previous findings of hot water genetic loci at 10q21.3-q22.3 (OMIM: 613339) and 4q24-q28 (OMIM: 613340), indicates unanticipated genetic heterogeneity for the disorder in families from a relatively small geographic region in the southern parts of India.

Delivery of epilepsy care to adults with intellectual and developmental disabilities

PubMed Central

Asato, Miya; Camfield, Peter; Geller, Eric; Kanner, Andres M.; Keller, Seth; Kerr, Michael; Kossoff, Eric H.; Lau, Heather; Kothare, Sanjeev; Singh, Baldev K.; Wirrell, Elaine

2015-01-01

Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E. PMID:26423430

Tetanus toxin as a tool for studying epilepsy.

PubMed

Mellanby, J; Hawkins, C; Mellanby, H; Rawlins, J N; Impey, M E

1984-01-01

The use of tetanus toxin, injected into the hippocampus of the rat, to produce an "animal model" of chronic limbic epilepsy is described. This model has yielded information complementary to that derived from other animal models and has several important advantages: while it involves spontaneous seizures, it occurs without gross damage to the brain ; it is eventually reversible in terms of fits and the overall reappearance of the EEG. It can therefore be used to look both at the effects of ongoing epilepsy and also at the long-term changes in brain function induced by previous epilepsy. Evidence is presented that the toxin probably remains localised at the site of injection. The information which has so far been obtained with this model on the relation between epilepsy and abnormal behaviour is summarised. In particular, it appears that the epilepsy produces long-term deficits in the animals' ability to learn and remember of a sort which suggest that an enduring malfunction has been induced in the hippocampus. The significance of the findings for clinical research and for future investigation of the nature of epilepsy are described. It is emphasised that the neurotoxins may be usefully exploited not only for investigating the molecular basis of neuronal mechanisms but also for inducing long-lasting plastic changes in integrated brain function.

Manipulations in Maternal Environment Reverse Periodontitis in Genetically Predisposed Rats

PubMed Central

Sluyter, Frans; Breivik, Torbjørn; Cools, Alexander

2002-01-01

The predisposition to develop periodontitis is partly genetically determined in humans as well as in animals. Here we demonstrate, however, that early manipulations in the maternal environment of an animal (rat) model of periodontitis can fully reverse the genetic predisposition to develop periodontitis at adult age. PMID:12093700

Localization of a locus for juvenile myoclonic epilepsy on chromosome 6p11-21.2 and evidence for genetic heterogeneity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, A.W.; Delgado-Escueta, A.V.; Alonso, V.M.E.

1994-09-01

Juvenile myoclonic epilepsy (JME) is a common form of primary idiopathic generalized epilepsy characterized by myoclonias, tonic-clonic or clonic tonic-clonic convulsions and absences. Ictal electroencephalograms (EEGs) show high amplitude multispikes folowed by slow waves and interictal EEGs manifest 3.5-6 Hz diffuse multispike wave complexes. JME affected about 7-10% of patients with epilepsies and its onset peaks between 13-15 years of age. We recently mapped a JME locus on chromosome 6p21.1-6p11 by linkage analysis of one relatively large JME family from Los Angeles and Belize. Assuming autosomal dominant inheritance with 70% penetrance, pairwise analyses tightly linked JME to D6S257 (Z =more » 3.67), D6S428 (Z = 3.08) and D6S272 (Z = 3.56) at {theta} = 0, m = f. Recombination and multipoints linkage analysis also suggested a locus is between markers D6S257 and D6S272. We then screened three relatively larger Mexican JME pedigrees with D6S257, D6S272, D6S282, TNF, D6S276, D6S273, D6S105 and F13A1 on chromosome 6p. Assuming autosomal dominant inheritance with incomplete penetrance, linkage to chromosome 6p DNA markers are excluded. Our findings underline the genetic heterogeneity of juvenile myoclonic epilepsy.« less

Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

PubMed Central

van den Ende, Tom; Sharifi, Sarvi; van der Salm, Sandra M. A.; van Rootselaar, Anne-Fleur

2018-01-01

Background Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings. Methods We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria. Results Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A “benign” phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam. Several genes have been identified, which differ in potential pathogenicity. Discussion Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes. PMID:29416935

[Eponyms and epilepsy (history of Eastern civilizations)].

PubMed

Janković, S M; Sokić, D V; Lević, Z M; Susić, V; Drulović, J; Stojsavljević, N; Veskov, R; Ivanus, J

1996-01-01

The history of eponyms for epilepsy in the lands of the Eastern globe present the portrait of the attitudes of both the laymen and skilled people towards the disease and patient, as well as to the Nature itself. As opposed to the West which during the Middle ages changed its concepts of epilepsy as the organic brain disease for the sublime 'alchemic' position, the people of the East were more prone to consider from the beginning of their civilization till the XIX century that epilepsy is the consequence of the evanescent spiritual and extracorporal forces which by themselves were out of their reach. As compared to the western civilization, the historical resources are, often as a consequence of a linguistic barriers, more scarce-as consequently is the number of eponyms, but are nevertheless picturesque. The medical science from Babylonian period presumed that epileptic manifestations are the consequence of the demonic or ill spiritual actions. There existed an attitude that at the beginning of an epileptic attack the patient was possessed by a demon (the Akkadic, i.e., Babylonian verb "sibtu" denoting epilepsy, had the meaning "to seize" or "to be obsessed"); at the end of the clonic phase the demon departed from the body. Different demons were responsible for different forms of epilepsy such as nocturnal and children epilepsy, absence epilepsy and pure convulsions, simple and complex automatisms, and gelastic epilepsy. Thus, the doctors from the period of Babylon aside from making primordial classification of epilepsies, knew about their clinical picture (prodromal symptoms and aura, Jackson's epilepsy. Todd's paralysis), postictal phenomena and intericatl emotional instability; provocative factors were also known (sleep deprivation, emotions, as well as alcohol, albeit in a negative sense-as a cure for epilepsy). There is no doubt than in the period of Babylon the clinical picture of serial fits and its progress to status epilepticus were clearly recognized and

Epilepsy

MedlinePlus

... Staying Safe Videos for Educators Search English Español Epilepsy KidsHealth / For Teens / Epilepsy What's in this article? ... embarrass himself or scare his friends. What Is Epilepsy? Epilepsy is a condition of the nervous system ...

Medical management of children with epilepsy.

PubMed

Ackermann, S; Wilmshurst, J M

2015-02-01

Epilepsy is a common neurological condition presenting to the pediatrician. There are many seizure mimics and the differential diagnosis of paroxysmal events is wide which may make a definitive diagnosis challenging. Epilepsy is a heterogeneous condition with marked variability in presentation, underlying etiologies, associated comorbidities and outcomes. The reorganization of epilepsies in 2010 reflects an increasing understanding of the neuropathological and etiological mechanisms as a result of rapid technological advances in neuroimaging techniques and molecular genetics in particular. An increasing number of treatment options are available although high quality evidence, applicable to children, is lacking. Choices should be tailored to the individual patient applying knowledge of adverse drug effects, including the potential for seizure exacerbation in certain syndromes. Neurobehavioral and psychiatric comorbidities occur in up to 80% of children and frequently remain unrecognized. Screening for these conditions should form part of holistic management, along with awareness of the psychosocial and educational needs of the child from the time of initial diagnosis. The management of individual children with epilepsy therefore presents a myriad challenges. Early referral to a specialist with expertise in the management of pediatric epilepsy should be sought whenever there is diagnostic uncertainty or a poor response to therapy.

Electric stimulation of the tuberomamillary nucleus affects epileptic activity and sleep-wake cycle in a genetic absence epilepsy model.

PubMed

Blik, Vitaliya

2015-01-01

Deep brain stimulation (DBS) is a promising approach for epilepsy treatment, but the optimal targets and parameters of stimulation are yet to be investigated. Tuberomamillary nucleus (TMN) is involved in EEG desynchronization-one of the proposed mechanisms for DBS action. We studied whether TMN stimulation could interfere with epileptic spike-wave discharges (SWDs) in WAG/Rij rats with inherited absence epilepsy and whether such stimulation would affect sleep-wake cycle. EEG and video registration were used to determine SWD occurrence and stages of sleep and wake during three-hours recording sessions. Stimulation (100Hz) was applied in two modes: closed-loop (with previously determined interruption threshold intensity) or open-loop mode (with 50% or 70% threshold intensity). Closed-loop stimulation successfully interrupted SWDs but elevated their number by 148 ± 54% compared to baseline. It was accompanied by increase in number of episodes but not total duration of both active and passive wakefulness. Open-loop stimulation with amplitude 50% threshold did not change measured parameters, though 70% threshold stimulation reduced SWDs number by 40 ± 9%, significantly raised the amount of active wakefulness and decreased the amount of both slow-wave and rapid eye movement sleep. These results suggest that the TMN is unfavorable as a target for DBS as its stimulation may cause alterations in sleep-wake cycle. A careful choosing of parameters and control of sleep-wake activity is necessary when applying DBS in epilepsy. Copyright © 2014 Elsevier B.V. All rights reserved.

Usefulness of Ilae 2010 classification in Mexican epilepsy patients.

PubMed

Leyva, Ildefonso Rodríguez; Gómez, Juan Francisco Hernández; Enríquez, Fernando Cortés; Sierra, Juan Francisco Hernández

2017-05-15

Advances in neuroimaging, genomics, and molecular biology have improved the understanding of the pathogenesis of epilepsy. That is why the International League Against Epilepsy (ILAE) has created a new classification system. The present study aims to evaluate the association between epilepsy cases classified by the ILAE 2010 classification proposal, electroencephalography (EEG), and magnetic resonance imaging brain findings (MRI). Prospective cross-sectional design of 277 cases of epilepsy seen at the Epilepsy Clinic, Hospital Central "Dr. Ignacio Morones Prieto", were compared with the ILAE classification based on the etiology and clinical manifestations and their MRI and EEG findings. Cochran, Mantell, Haenzel test with significance p<0.05. MRI findings were associated with the etiology of the ILAE classification. According to EEG findings, the structural-metabolic etiology patients had more dysfunctional reports than genetic or unknown etiology patients (p<0.05). The adoption of the ILAE classification is recommended, as it can provide useful guidance towards the etiology of cases of epilepsy even when brain MRIs and EEGs are not available. Copyright © 2017 Elsevier B.V. All rights reserved.

Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy.

PubMed

Rempe, Ralf G; Hartz, Anika M S; Soldner, Emma L B; Sokola, Brent S; Alluri, Satya R; Abner, Erin L; Kryscio, Richard J; Pekcec, Anton; Schlichtiger, Juli; Bauer, Björn

2018-05-02

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo / ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A 2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage. SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A 2 , which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden. Copyright © 2018 the

Shame and Guilt-Proneness in Adolescents: Gene-Environment Interactions.

PubMed

Szentágotai-Tătar, Aurora; Chiș, Adina; Vulturar, Romana; Dobrean, Anca; Cândea, Diana Mirela; Miu, Andrei C

2015-01-01

Rooted in people's preoccupation with how they are perceived and evaluated, shame and guilt are self-conscious emotions that play adaptive roles in social behavior, but can also contribute to psychopathology when dysregulated. Shame and guilt-proneness develop during childhood and adolescence, and are influenced by genetic and environmental factors that are little known to date. This study investigated the effects of early traumatic events and functional polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the serotonin transporter gene promoter (5-HTTLPR) on shame and guilt in adolescents. A sample of N = 271 healthy adolescents between 14 and 17 years of age filled in measures of early traumatic events and proneness to shame and guilt, and were genotyped for the BDNF Val66Met and 5-HTTLPR polymorphisms. Results of moderator analyses indicated that trauma intensity was positively associated with guilt-proneness only in carriers of the low-expressing Met allele of BDNF Val66Met. This is the first study that identifies a gene-environment interaction that significantly contributes to guilt proneness in adolescents, with potential implications for developmental psychopathology.

Effect of tempol and tempol plus catalase on intra-renal haemodynamics in spontaneously hypertensive stroke-prone (SHSP) and Wistar rats.

PubMed

Ahmeda, Ahmad F; Rae, Mark G; Al Otaibi, Mohammed F; Anweigi, Lamyia M; Johns, Edward J

2017-05-01

Vasoconstriction within the renal medulla contributes to the development of hypertension. This study investigated the role of reactive oxygen species (ROS) in regulating renal medullary and cortical blood perfusion (MBP and CBP respectively) in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar rats. CBP and MBP were measured using a laser-Doppler flow meter before and after intra-renal infusion of tempol, the superoxide dismutase (SOD) mimetic or tempol plus catalase, the hydrogen peroxide-degrading enzyme. Tempol infusion significantly elevated blood perfusion within the renal medulla (MBP) in both SHRSP (by 43 ± 7%, P < 0.001) and Wistar rats (by 17 ± 2%, P < 0.05) but the magnitude of the increase was significantly greater in the SHRSP (P < 0.01). When the enzyme catalase and tempol were co-infused, MBP was again significantly increased in SHRSP (by 57 ± 6%, P < 0.001) and Wistar rats (by 33 ± 6%, P < 0.001), with a significantly greater increase in perfusion being induced in the SHRSP relative to the Wistar rats (P < 0.01). Notably, this increase was significantly greater than in those animals infused with tempol alone (P < 0.01). These results suggest that ROS plays a proportionally greater role in reducing renal vascular compliance, particularly within the renal medulla, in normotensive and hypertensive animals, with effects being greater in the hypertensive animals. This supports the hypothesis that SHRSP renal vasculature might be subjected to elevated level of oxidative stress relative to normotensive animals.

Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

PubMed Central

Seppälä, Eija H.; Koskinen, Lotta L. E.; Gulløv, Christina H.; Jokinen, Päivi; Karlskov-Mortensen, Peter; Bergamasco, Luciana; Baranowska Körberg, Izabella; Cizinauskas, Sigitas; Oberbauer, Anita M.; Berendt, Mette; Fredholm, Merete; Lohi, Hannes

2012-01-01

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10−10, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10−8, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10−11, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a

Genetics Home Reference: autosomal dominant nocturnal frontal lobe epilepsy

MedlinePlus

... brain are involved in many critical functions, including reasoning, planning, judgment, and problem-solving. It is unclear ... E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain. ...

Genetic linkage studies in familial partial epilepsy: Exclusion of the human chromosome regions syntenic to the El-1 mouse locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lopes-Cendes, I.; Mulley, J.C.; Andermann, E.

1994-09-01

Recently, six families with a familial form of partial epilepsy were described. All pedigrees showed autosomal dominant inheritance with incomplete penetrance. Affected individuals present with predominantly nocturnal seizures with frontal lobe semiology. In 1959, a genetic mouse model for partial epilepsy, the El mouse, was reported. In the El mouse, a major seizure susceptibility gene, El-1, segregates in an autosomal dominant fashion and has been localized to a region distal to the centromere of mouse chromosome 9. Comparative genetic maps between man and mouse have been used for prediction of localization of several human disease genes. Because the region ofmore » mouse chromosome 9 that is the most likely to contain the El-1 locus is syntenic to regions on human chromosomes 3q21-p22, 3q21-q23.3, 6q12 and 15q24, we adopted the candidate gene approach as an initial linkage strategy. Twenty-two polymorphic microsatellite markers covering these regions were used for genotyping individuals in the three larger families ascertained, two of which are Australian and one French-Canadian. Negative two-point lod scores were obtained separately for each family. The analysis of all three families combined significantly excludes the candidate regions on chromosomes 3, 6 and 15.« less

Proposed International League Against Epilepsy Classification 2010: new insights.

PubMed

Udani, Vrajesh; Desai, Neelu

2014-09-01

The International League Against Epilepsy (ILAE) Classification of Seizures in 1981 and the Classification of the Epilepsies, in 1989 have been widely accepted the world over for the last 3 decades. Since then, there has been an explosive growth in imaging, genetics and other fields in the epilepsies which have changed many of our concepts. It was felt that a revision was in order and hence the ILAE commissioned a group of experts who submitted the initial draft of this revised classification in 2010. This review focuses on what are the strengths and weaknesses of this new proposed classification, especially in the context of a developing country.

Efficacy and safety of a video-EEG protocol for genetic generalized epilepsies.

PubMed

De Marchi, Luciana Rodrigues; Corso, Jeana Torres; Zetehaku, Ana Carolina; Uchida, Carina Gonçalves Pedroso; Guaranha, Mirian Salvadori Bittar; Yacubian, Elza Márcia Targas

2017-05-01

Video-EEG has been used to characterize genetic generalized epilepsies (GGE). For best performance, sleep recording, photic stimulation, hyperventilation, and neuropsychological protocols are added to the monitoring. However, risks and benefits of these video-EEG protocols are not well established. The aim of this study was to analyze the efficacy and safety of a video-EEG neuropsychological protocol (VNPP) tailored for GGE and compare its value with that of routine EEG (R-EEG). We reviewed the VNPP and R-EEG of patients with GGE. We considered confirmation of the clinical suspicion of a GGE syndrome and characterization of reflex traits as benefits; and falls, injuries, psychiatric and behavioral changes, generalized tonic-clonic (GTC) seizures, and status epilepticus (SE) as the main risks of the VNPP. The VNPPs of 113 patients were analyzed. The most common epileptic syndrome was juvenile myoclonic epilepsy (85.8%). The protocol confirmed a GGE syndrome in 97 patients and 62 had seizures. Sleep recording had a provocative effect in 51.2% of patients. The second task that showed highest efficacy was praxis (39.3%) followed by hyperventilation (31.3%). Among the risks, 1.8% had GTC seizures and another 1.8%, SE. Eighteen percent of patients had persistently normal R-EEG, 72.2% of them had discharges during VNPP. Generalized tonic-clonic seizures, myoclonic status epilepticus, and repeated seizures were the main risks of VNPP present in 6 (5.31%) patients while there were no complications during R-EEG. The VNPP in GGE is a useful tool in diagnosis and characterization of reflex traits, and is a safe procedure. Its use might preclude multiple R-EEG exams. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronobiology of epilepsy: diagnostic and therapeutic implications of chrono-epileptology.

PubMed

Loddenkemper, Tobias; Lockley, Steven W; Kaleyias, Joseph; Kothare, Sanjeev V

2011-04-01

The combination of chronobiology and epilepsy offers novel diagnostic and therapeutic management options. Knowledge of the interactions between circadian periodicity, entrainment, sleep patterns, and epilepsy may provide additional diagnostic options beyond sleep deprivation and extended release medication formulations. It may also provide novel insights into the physiologic, biochemical, and genetic regulation processes of epilepsy and the circadian clock, rendering new treatment options. Temporal fluctuations of seizure susceptibility based on sleep homeostasis and circadian phase in selected epilepsies may provide predictability based on mathematical models. Chrono-epileptology offers opportunities for individualized patient-oriented treatment paradigms based on chrono-pharmacology, differential medication dosing, chrono-drug delivery systems, and utilization of "zeitgebers" such as chronobiotics or light-therapy and desynchronization strategies among others.

Genetics Home Reference: familial focal epilepsy with variable foci

MedlinePlus

... SF, Dibbens LM. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. ... caused by mutation in the mammalian target of rapamycin regulator NPRL3. Ann Neurol. 2016 Jan;79(1): ...

Familiarity with, knowledge of, and attitudes toward epilepsy among teachers in Korean elementary schools.

PubMed

Lee, Haeyoung; Lee, Sang Kun; Chung, Chun Kee; Yun, Soon Nyung; Choi-Kwon, Smi

2010-02-01

We investigated familiarity with, knowledge of, and attitudes toward epilepsy among teachers in elementary schools in Korea, where there is profound prejudice against epilepsy. Most of the teachers thought that epilepsy is a genetic disease. They agreed that children with epilepsy (CWE) should attend regular classes (although with some restriction of school activities) because their academic achievement would be comparable to that of children without epilepsy. However, half of the teachers opposed having CWE in their own classes because they feared a child having a seizure during class and they felt they lacked knowledge of first-aid for seizures. Those teachers who had inaccurate clinical knowledge of epilepsy also demonstrated negative attitudes toward the marriage and employment of persons with epilepsy. We conclude that information about epilepsy should be included in teacher training programs so as to increase their level of knowledge of epilepsy and correct prejudices against epilepsy. (c) 2009 Elsevier Inc. All rights reserved.

Mother and daughter with adolescent-onset severe frontal lobe dysfunction and epilepsy

PubMed Central

dos Passos, Giordani Rodrigues; Fernández, Alonso Cuadrado; Vasques, Adriana Machado; Martins, William Alves; Palmini, André

2016-01-01

ABSTRACT Familial cases of early-onset prominent frontal lobe dysfunction associated with epilepsy have not been reported to date. We report a mother and her only daughter with incapacitating behavioral manifestations of frontal lobe dysfunction and epilepsy of variable severity. The possibility of a hitherto undescribed genetic condition is discussed. PMID:29213461

Losartan suppresses the kainate-induced changes of angiotensin AT1 receptor expression in a model of comorbid hypertension and epilepsy.

PubMed

Atanasova, Dimitrinka; Tchekalarova, Jana; Ivanova, Natasha; Nenchovska, Zlatina; Pavlova, Ekaterina; Atanassova, Nina; Lazarov, Nikolai

2018-01-15

Experimental and clinical studies have demonstrated that components of renin-angiotensin system are elevated in the hippocampus in epileptogenic conditions. In the present work, we explored the changes in the expression of angiotensin II receptor, type 1 (AT 1 receptor) in limbic structures, as well as the effect of the AT1 receptor antagonist losartan in a model of comorbid hypertension and epilepsy. The expression of AT 1 receptors was compared between spontaneously hypertensive rats (SHRs) and Wistar rats by using immunohistochemistry in the kainate (KA) model of temporal lobe epilepsy (TLE). The effect of losartan was studied on AT 1 receptor expression in epileptic rats that were treated for a period of 4weeks after status epilepticus. The naive and epileptic SHRs were characterized by stronger protein expression of AT 1 receptor than normotensive Wistar rats in the CA1, CA3a, CA3b, CA3c field and the hilus of the dentate gyrus of the dorsal hippocampus but fewer cells were immunostained in the piriform cortex. Increased AT 1 immunostaining was observed in the basolateral amygdala of epileptic SHRs but not of epileptic Wistar rats. Losartan exerted stronger and structure-dependent suppression of AT 1 receptor expression in SHRs compared to Wistar rats. Our results confirm the important role of AT 1 receptor in epilepsy and suggest that the AT 1 receptor antagonists could be used as a therapeutic strategy for treatment of comorbid hypertension and epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Perirhinal cortex and temporal lobe epilepsy

PubMed Central

Biagini, Giuseppe; D'Antuono, Margherita; Benini, Ruba; de Guzman, Philip; Longo, Daniela; Avoli, Massimo

2013-01-01

The perirhinal cortex—which is interconnected with several limbic structures and is intimately involved in learning and memory—plays major roles in pathological processes such as the kindling phenomenon of epileptogenesis and the spread of limbic seizures. Both features may be relevant to the pathophysiology of mesial temporal lobe epilepsy that represents the most refractory adult form of epilepsy with up to 30% of patients not achieving adequate seizure control. Compared to other limbic structures such as the hippocampus or the entorhinal cortex, the perirhinal area remains understudied and, in particular, detailed information on its dysfunctional characteristics remains scarce; this lack of information may be due to the fact that the perirhinal cortex is not grossly damaged in mesial temporal lobe epilepsy and in models mimicking this epileptic disorder. However, we have recently identified in pilocarpine-treated epileptic rats the presence of selective losses of interneuron subtypes along with increased synaptic excitability. In this review we: (i) highlight the fundamental electrophysiological properties of perirhinal cortex neurons; (ii) briefly stress the mechanisms underlying epileptiform synchronization in perirhinal cortex networks following epileptogenic pharmacological manipulations; and (iii) focus on the changes in neuronal excitability and cytoarchitecture of the perirhinal cortex occurring in the pilocarpine model of mesial temporal lobe epilepsy. Overall, these data indicate that perirhinal cortex networks are hyperexcitable in an animal model of temporal lobe epilepsy, and that this condition is associated with a selective cellular damage that is characterized by an age-dependent sensitivity of interneurons to precipitating injuries, such as status epilepticus. PMID:24009554

Epilepsy in patients with autism: links, risks and treatment challenges.

PubMed

Besag, Frank Mc

2018-01-01

Autism is more common in people with epilepsy, approximately 20%, and epilepsy is more common in people with autism with reported rates of approximately 20%. However, these figures are likely to be affected by the current broader criteria for autism spectrum disorder (ASD), which have contributed to an increased prevalence of autism, with the result that the rate for ASD in epilepsy is likely to be higher and the figure for epilepsy in ASD is likely to be lower. Some evidence suggests that there are two peaks of epilepsy onset in autism, in infancy and adolescence. The rate of autism in epilepsy is much higher in those with intellectual disability. In conditions such as the Landau-Kleffner syndrome and nonconvulsive status epilepticus, the epilepsy itself may present with autistic features. There is no plausible mechanism for autism causing epilepsy, however. The co-occurrence of autism and epilepsy is almost certainly the result of underlying factors predisposing to both conditions, including both genetic and environmental factors. Conditions such as attention deficit hyperactivity disorder, anxiety and sleep disorders are common in both epilepsy and autism. Epilepsy is generally not a contraindication to treating these conditions with suitable medication, but it is important to take account of relevant drug interactions. One of the greatest challenges in autism is to determine why early childhood regression occurs in perhaps 25%. Further research should focus on finding the cause for such regression. Whether epilepsy plays a role in the regression of a subgroup of children with autism who lose skills remains to be determined.

Cholinergic control over attention in rats prone to attribute incentive salience to reward cues

PubMed Central

Paolone, Giovanna; Angelakos, Christopher C.; Meyer, Paul J.; Robinson, Terry E.; Sarter, Martin

2013-01-01

Some rats (sign-trackers, ST) are especially prone to attribute incentive salience to reward cues, relative to others (goal-trackers, GT). Thus, reward cues are more likely to promote maladaptive reward-seeking behavior in ST than GT. Here, we asked whether ST and GT differ on another trait that can contribute to poor restraint over behavior evoked by reward cues. We report that, relative to GT, ST have poor control over attentional performance, due in part to insufficient cholinergic stimulation of cortical circuitry. We found that, relative to GT, ST showed poor performance on a sustained attention task (SAT). Furthermore, their performance fluctuated rapidly between periods of good to near-chance performance. This finding was reproduced using a separate cohort of rats. As demonstrated earlier, performance on the SAT was associated with increases in extracellular levels of cortical acetylcholine (ACh); however, SAT performance-associated increases in ACh levels were significantly attenuated in ST relative to GT. Consistent with the view that the modulatory effects of ACh involves stimulation of α4β2* nicotinic acetylcholine receptors (nAChRs), systemic administration of the partial nAChR agonist ABT-089 improved SAT performance in ST and abolished the difference between SAT-associated ACh levels in ST and GT. Neither the nonselective nAChR agonist nicotine nor the psychostimulant amphetamine improved SAT performance. These findings suggest that individuals who have a propensity to attribute high incentive salience to reward cues also exhibit relatively poor attentional control. A combination of these traits may render individuals especially vulnerable to disorders such as obesity and addiction. PMID:23658172

Causes of learning disability and epilepsy: a review.

PubMed

Prince, Elizabeth; Ring, Howard

2011-04-01

Although the association between learning disability and epilepsy is well known, until relatively recently specific processes underlying this association were relatively poorly understood. However, scientific advances in molecular biology are starting to guide researchers towards descriptions of genetic and pathophysiological processes that may explain why syndromes of epilepsy and learning disability often co-exist. This article will focus largely on three areas of advancing knowledge: insights gained from wider use of genome-wide array comparative genomic hybridization (aCGH), specific insights gained from detailed study of Rett syndrome and the role of abnormalities of astrocytic function in predisposing to both epilepsy and learning disability. The enormous complexity of the biological underpinnings of the co-occurrence of epilepsy and learning disability are becoming apparent. In the future it is likely that research into therapeutic approaches will include, amongst other approaches, investigations of gene structure and expression, the role of astrocytes and the stability of dendritic spines.

Parental and comorbid epilepsy in persons with bipolar disorder.

PubMed

Sucksdorff, Dan; Brown, Alan S; Chudal, Roshan; Jokiranta-Olkoniemi, Elina; Leivonen, Susanna; Suominen, Auli; Heinimaa, Markus; Sourander, Andre

2015-12-01

Population-based studies have demonstrated an overrepresentation of bipolar disorder (BPD) in individuals with epilepsy. However, few studies have examined the reverse association, i.e. comorbid epilepsy in individuals selected based on BPD diagnosis. No previous population-based study having examined the co-occurrence of BPD and epilepsy has adjusted for parental psychopathology. Such an adjustment is motivated by population-based studies reporting an overrepresentation of various types of parental psychiatric disorders in both BPD and epilepsy. Furthermore, an association between epilepsy in first-degree relatives and BPD has previously only been examined and demonstrated in a small clinical sample. The objective of this study is to examine the associations between parental and comorbid epilepsy and BPD, adjusting for parental psychopathology. This nested case-control study identified 1861 cases with BPD, age up to 25 years, 3643 matched controls, and their parents from Finnish national registers. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) and two-sided significance limits of p<0.05. BPD was associated with comorbid epilepsy (adjusted OR 2.53, 95% CI: 1.73-3.70) but not with parental epilepsy. Epilepsy was found in 3.33% of cases versus 1.29% of controls, 2.69% of cases' parents versus 2.53% of controls' parents. The diagnoses were register-based, not based on standardized procedures with direct ascertainment. An association between BPD and comorbid epilepsy persists even after adjusting for parental psychopathology. Lack of familial clustering of BPD and epilepsy would suggest that the elevated co-occurrence of these disorders is influenced by non-genetic factors. Copyright © 2015 Elsevier B.V. All rights reserved.

Low incidence of SCN1A genetic mutation in patients with hemiconvulsion-hemiplegia-epilepsy syndrome.

PubMed

Kim, Dong Wook; Lim, Byung Chan; Kim, Ki Joong; Chae, Jong Hee; Lee, Ran; Lee, Sang Kun

2013-10-01

Genetic mutations in SCN1A account for more than two-thirds of patients with classic Dravet syndrome. A role for SCN1A genetic mutations in the development of hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome was recently suggested based on the observation that HHE syndrome and classic Dravet syndrome share many clinical features. We previously identified a 2 bp-deletion mutation in SCN1A in a Dravet patient, and we found out the patient also had HHE syndrome upon clinical re-evaluation. We subsequently screened 10 additional HHE patients for SCN1A. Among the 11 patients who were diagnosed with HHE syndrome, six patients had no other etiology with the exception of prolonged febrile illness, therefore classified as idiopathic HHE syndrome, whereas five patients were classified as symptomatic HHE syndrome. Direct sequencing of all coding exons and flanking intronic sequences of the SCN1A gene was performed, but we failed to identify additional mutations in 10 patients. The patient with SCN1A mutation had the earliest onset of febrile convulsion and hemiparesis. Our study suggests that SCN1A genetic mutation is only a rare predisposing cause of HHE syndrome. Copyright © 2013 Elsevier B.V. All rights reserved.

Changes in alanine turnover rate due to nutritional and genetic obesity in the rat.

PubMed

Yebras, M; Salvadó, J; Arola, L; Remesar, X; Segués, T

1994-08-01

The changes in alanine turnover were determined in Zucker rats, which were either genetically obese (fa/fa) or rendered obese by dietary treatment (cafeteria fed). The whole body rate of alanine turnover was higher in genetically obese rats than in rats in which obesity was induced by diet (cafeteria). This is possibly due to variations in the rate of the amino acid incorporation into proteins, since the rate of whole body alanine degradation is the same for both groups. Thus, the different pattern followed by alanine turnover rate in these types of obese animals reflects the differences in the nitrogen economy of these animals, pointing to a higher alanine utilization in the genetically obese animals and a conservative management of alanine in the cafeteria-fed animals.

Hcn1 Is a Tremorgenic Genetic Component in a Rat Model of Essential Tremor

PubMed Central

Ohno, Yukihiro; Shimizu, Saki; Tatara, Ayaka; Imaoku, Takuji; Ishii, Takahiro; Sasa, Masashi; Serikawa, Tadao; Kuramoto, Takashi

2015-01-01

Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET. PMID:25970616

Polymerization-Incompetent Uromodulin in the Pregnant Stroke-Prone Spontaneously Hypertensive Rat

PubMed Central

Mary, Sheon; Small, Heather Yvonne; Siwy, Justyna; Mullen, William; Giri, Ashok

2017-01-01

The kidney is centrally involved in blood pressure regulation and undergoes extensive changes during pregnancy. Hypertension during pregnancy may result in an altered urinary peptidome that could be used to indicate new targets of therapeutic or diagnostic interest. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of maternal chronic hypertension. Capillary electrophoresis-mass spectrometry was conducted to interrogate the urinary peptidome in SHRSP and the control Wistar–Kyoto strain at three time points: prepregnancy and gestational days 12 and 18. The comparison within and between the Wistar–Kyoto and SHRSP peptidome at all time points detected 123 differentially expressed peptides (fold change >1.5; P<0.05). Sequencing of these peptides identified fragments of collagen α-chains, albumin, prothrombin, actin, serpin A3K, proepidermal growth factor, and uromodulin. Uromodulin peptides showed a pregnancy-specific alteration in SHRSP with a 7.8-fold (P<0.01) and 8.8-fold (P<0.05) increase at gestational days 12 and 18, respectively, relative to the Wistar–Kyoto. Further investigation revealed that these peptides belonged to the polymerization-inhibitory region of uromodulin. Two forms of uromodulin (polymerization competent and polymerization incompetent) were found in urine from both Wistar–Kyoto and SHRSP, where the polymerization-incompetent form was increased in a pregnancy-specific manner in SHRSP. Nifedipine-treated pregnant SHRSP showed only polymerization-competent uromodulin, indicating that calcium may be mechanistically involved in uromodulin polymerization. This study highlights, for the first time, a potential role of uromodulin and its polymerization in hypertensive pregnancy. PMID:28348009

Shame and Guilt-Proneness in Adolescents: Gene-Environment Interactions

PubMed Central

Szentágotai-Tătar, Aurora; Chiș, Adina; Vulturar, Romana; Dobrean, Anca; Cândea, Diana Mirela; Miu, Andrei C.

2015-01-01

Rooted in people’s preoccupation with how they are perceived and evaluated, shame and guilt are self-conscious emotions that play adaptive roles in social behavior, but can also contribute to psychopathology when dysregulated. Shame and guilt-proneness develop during childhood and adolescence, and are influenced by genetic and environmental factors that are little known to date. This study investigated the effects of early traumatic events and functional polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the serotonin transporter gene promoter (5-HTTLPR) on shame and guilt in adolescents. A sample of N = 271 healthy adolescents between 14 and 17 years of age filled in measures of early traumatic events and proneness to shame and guilt, and were genotyped for the BDNF Val66Met and 5-HTTLPR polymorphisms. Results of moderator analyses indicated that trauma intensity was positively associated with guilt-proneness only in carriers of the low-expressing Met allele of BDNF Val66Met. This is the first study that identifies a gene-environment interaction that significantly contributes to guilt proneness in adolescents, with potential implications for developmental psychopathology. PMID:26230319

Copy number variants are frequent in genetic generalized epilepsy with intellectual disability

PubMed Central

Mullen, Saul A.; Carvill, Gemma L.; Bellows, Susannah; Bayly, Marta A.; Berkovic, Samuel F.; Dibbens, Leanne M.

2013-01-01

Objective: We examined whether copy number variants (CNVs) were more common in those with a combination of intellectual disability (ID) and genetic generalized epilepsy (GGE) than in those with either phenotype alone via a case-control study. Methods: CNVs contribute to the genetics of multiple neurodevelopmental disorders with complex inheritance, including GGE and ID. Three hundred fifty-nine probands with GGE and 60 probands with ID-GGE were screened for GGE-associated recurrent microdeletions at 15q13.3, 15q11.2, and 16p13.11 via quantitative PCR or loss of heterozygosity. Deletions were confirmed by comparative genomic hybridization (CGH). ID-GGE probands also had genome-wide CGH. Results: ID-GGE probands showed a significantly higher rate of CNVs compared with probands with GGE alone, with 17 of 60 (28%) ID-GGE probands having one or more potentially causative CNVs. The patients with ID-GGE had a 3-fold-higher rate of the 3 GGE-associated recurrent microdeletions than probands with GGE alone (10% vs 3%, p = 0.02). They also showed a high rate (13/60, 22%) of rare CNVs identified using genome-wide CGH. Conclusions: This study shows that CNVs are common in those with ID-GGE with recurrent deletions at 15q13.3, 15q11.2, and 16p13.11, particularly enriched compared with individuals with GGE or ID alone. Recurrent CNVs are likely to act as risk factors for multiple phenotypes not just at the population level, but also in any given individual. Testing for CNVs in ID-GGE will have a high diagnostic yield in a clinical setting and will inform genetic counseling. PMID:24068782

Intellectual Disability and Epilepsy in Down Syndrome

PubMed Central

BARCA, Diana; TARTA-ARSENE, Oana; DICA, Alice; ILIESCU, Catrinel; BUDISTEANU, Magdalena; MOTOESCU, Cristina; BUTOIANU, Niculina; CRAIU, Dana

2014-01-01

Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability. Objectives: The purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort. Methods: A four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination. Results: 23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment. Conclusions: The most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics

Talking about epilepsy: Challenges parents face when communicating with their child about epilepsy and epilepsy-related issues.

PubMed

O'Toole, Stephanie; Lambert, Veronica; Gallagher, Pamela; Shahwan, Amre; Austin, Joan K

2016-04-01

The aim of this qualitative study was to explore the challenges that parents of children with epilepsy experienced when engaging in dialog with their child about epilepsy and epilepsy-related issues. Using a qualitative exploratory approach, interviews were conducted with 34 parents of children with epilepsy (aged 6-16 years), consisting of 27 mothers and 7 fathers. Data were transcribed verbatim and thematically analyzed. Findings revealed five main themes: normalizing epilepsy, the invisibility of epilepsy, information concealment, fear of misinforming the child, and difficulty in discussing particular epilepsy-related issues. Many of the communicative challenges experienced by parents impacted on their ability to engage openly in parent-child dialog about epilepsy in the home. Parents face specific challenges when choosing to communicate with their child about epilepsy, relating to creating a sense of normality, reducing fear of causing their child worry, and having a lack of epilepsy-related knowledge. Healthcare professionals who work closely with families living with epilepsy should remain mindful of the importance of discussing family communication surrounding epilepsy and the challenges parents of children with epilepsy face when talking about epilepsy within the home. Copyright © 2016 Elsevier Inc. All rights reserved.

Photosensitive epilepsy is associated with reduced inhibition of alpha rhythm generating networks

PubMed Central

Vaudano, Anna Elisabetta; Ruggieri, Andrea; Avanzini, Pietro; Gessaroli, Giuliana; Cantalupo, Gaetano; Coppola, Antonietta; Sisodiya, Sanjay M.

2017-01-01

Abstract See Hamandi (doi:10.1093/awx049) for a scientific commentary on this article. Photosensitivity is a condition in which lights induce epileptiform activities. This abnormal electroencephalographic response has been associated with hyperexcitability of the visuo-motor system. Here, we evaluate if intrinsic dysfunction of this network is present in brain activity at rest, independently of any stimulus and of any paroxysmal electroencephalographic activity. To address this issue, we investigated the haemodynamic correlates of the spontaneous alpha rhythm, which is considered the hallmark of the brain resting state, in photosensitive patients and in people without photosensitivity. Second, we evaluated the whole-brain functional connectivity of the visual thalamic nuclei in the various populations of subjects under investigation. Forty-four patients with epilepsy and 16 healthy control subjects underwent an electroencephalography-correlated functional magnetic resonance imaging study, during an eyes-closed condition. The following patient groups were included: (i) genetic generalized epilepsy with photosensitivity, 16 subjects (mean age 25 ± 10 years); (ii) genetic generalized epilepsy without photosensitivity, 13 patients (mean age 25 ± 11 years); (iii) focal epilepsy, 15 patients (mean age 25 ± 9 years). For each subject, the posterior alpha power variations were convolved with the standard haemodynamic response function and used as a regressor. Within- and between-groups second level analyses were performed. Whole brain functional connectivity was evaluated for two thalamic regions of interest, based on the haemodynamic findings, which included the posterior thalamus (pulvinar) and the medio-dorsal thalamic nuclei. Genetic generalized epilepsy with photosensitivity demonstrated significantly greater mean alpha-power with respect to controls and other epilepsy groups. In photosensitive epilepsy, alpha-related blood oxygen level-dependent signal changes

Epilepsy - resources

MedlinePlus

Resources - epilepsy ... The following organizations are good resources for information on epilepsy : Epilepsy Foundation -- www.epilepsy.com National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/ ...

A targeted resequencing gene panel for focal epilepsy.

PubMed

Hildebrand, Michael S; Myers, Candace T; Carvill, Gemma L; Regan, Brigid M; Damiano, John A; Mullen, Saul A; Newton, Mark R; Nair, Umesh; Gazina, Elena V; Milligan, Carol J; Reid, Christopher A; Petrou, Steven; Scheffer, Ingrid E; Berkovic, Samuel F; Mefford, Heather C

2016-04-26

We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases. We searched for both germline and somatic mutations in 251 patients with unsolved sporadic or familial focal epilepsy and identified 11 novel or very rare missense variants in 5 different genes: CHRNA4, GRIN2B, KCNT1, PCDH19, and SCN1A. Of these, 2 were predicted to be pathogenic or likely pathogenic, explaining ∼0.8% of the cohort, and 8 were of uncertain significance based on available data. We have developed and validated a targeted resequencing panel for focal epilepsies, the most important clinical class of epilepsies, accounting for about 60% of all cases. Our application of MIP technology is an innovative approach that will be advantageous in the clinical setting because it is highly sensitive, efficient, and cost-effective for screening large patient cohorts. Our findings indicate that mutations in known genes likely explain only a small proportion of focal epilepsy cases. This is not surprising given the established clinical and genetic heterogeneity of these disorders and underscores the importance of further gene discovery studies in this complex syndrome. © 2016 American Academy of Neurology.

Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies

PubMed Central

Pérez-Palma, Eduardo; Helbig, Ingo; Klein, Karl Martin; Anttila, Verneri; Horn, Heiko; Reinthaler, Eva Maria; Gormley, Padhraig; Ganna, Andrea; Byrnes, Andrea; Pernhorst, Katharina; Toliat, Mohammad R; Saarentaus, Elmo; Howrigan, Daniel P; Hoffman, Per; Miquel, Juan Francisco; De Ferrari, Giancarlo V; Nürnberg, Peter; Lerche, Holger; Zimprich, Fritz; Neubauer, Bern A; Becker, Albert J; Rosenow, Felix; Perucca, Emilio; Zara, Federico; Weber, Yvonne G; Lal, Dennis

2017-01-01

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE. PMID:28756411

Association of cytokine gene polymorphisms and risk factors with otitis media proneness in children.

PubMed

Miljanović, Olivera; Cikota-Aleksić, Bojana; Likić, Dragan; Vojvodić, Danilo; Jovićević, Ognjen; Magić, Zvonko

2016-06-01

In order to assess the association between gene polymorphisms and otitis media (OM) proneness, tumor necrosis factor alpha (TNFA) -308, interleukin (IL) 10-1082 and -3575, IL6 -597, IL2 -330, and CD14 -159 genotyping was performed in 58 OM-prone children and 85 controls who were exposed to similar number and frequency of environmental and host risk factors. The frequencies of genotypes (wild type vs. genotypes containing at least one polymorphic allele) were not significantly different between groups, except for IL10 -1082. Polymorphic genotypes IL10 -1082 GA and GG were more frequent in OM-prone children than in control group (RR 1.145, 95 % CI 1.011-1.298; p = 0.047). However, logistic regression did not confirm IL10 -1082 polymorphic genotypes as an independent risk factor for OM proneness. The present study indicates that high-producing IL10 -1082 GA/GG genotypes may increase the risk for OM proneness in its carriers when exposed to other environmental/host risk factors (day care attendance, passive smoking, male sex, respiratory infections, and atopic manifestations). This study revealed no significant independent genetic association, but the lack of breastfeeding in infancy was found to be the only independent risk factor for development of OM-prone phenotype, implying that breastfeeding had a protective role in development of susceptibility to OM. • The pathogenesis of OM is of multifactorial nature, dependent on infection, environmental factors, and immune response of the child. • Cytokines and CD14 play an important role in the presentation and clinical course of otitis media, but a clear link with otitis media proneness was not established. What is new: • This is the first clinical and genetic study on Montenegrin children with the otitis media-prone phenotype. • The study revealed that high-producing IL10 -1082 genotypes may influence otitis media proneness in children exposed to other environmental/host risk factors.

Migraine and epilepsy: a focus on overlapping clinical, pathophysiological, molecular, and therapeutic aspects.

PubMed

Bianchin, Marino Muxfeldt; Londero, Renata Gomes; Lima, José Eduardo; Bigal, Marcelo Eduardo

2010-08-01

The association of epilepsy and migraine has been long recognized. Migraine and epilepsy are both chronic disorders with episodic attacks. Furthermore, headache may be a premonitory or postdromic symptom of seizures, and migraine headaches may cause seizures per se (migralepsy). Migraine and epilepsy are comorbid, sharing pathophysiological mechanisms and common clinical features. Several recent studies identified common genetic and molecular substrates for migraine and epilepsy, including phenotypic-genotypic correlations with mutations in the CACNA1A, ATP1A2, and SCN1A genes, as well as in syndromes due to mutations in the SLC1A3, POLG, and C10orF2 genes. Herein, we review the relationship between migraine and epilepsy, focusing on clinical aspects and some recent pathophysiological and molecular studies.

Incidence and Classification of New-Onset Epilepsy and Epilepsy Syndromes in Children in Olmsted County, Minnesota from 1980–2004: A population-based study

PubMed Central

Wirrell, Elaine C.; Grossardt, Brandon R.; Wong-Kisiel, Lily C.-L.; Nickels, Katherine C.

2012-01-01

Purpose To determine the incidence and classification of new-onset epilepsy, as well as the distribution of epilepsy syndromes in a population-based group of children, using the newly proposed Report of the ILAE Commission on Classification and Terminology 2005–2009. Methods We identified all children residing in Olmsted County, MN, 1 month through 17 years with newly diagnosed epilepsy from 1980–2004. For each patient, epilepsy was classified into mode of onset, etiology, and syndrome or constellation (if present). Incidence rates were calculated overall and also separately for categories of mode of onset and etiology. Results The adjusted incidence rate of new-onset epilepsy in children was 44.5 cases per 100,000 persons per year. Incidence rates were highest in the first year of life and diminished with age. Mode of onset was focal in 68%, generalized/bilateral in 23%, spasms in 3% and unknown in 5%. Approximately half of children had an unknown etiology for their epilepsy, and of the remainder, 78 (22%) were genetic and 101 (28%) were structural/metabolic. A specific epilepsy syndrome could be defined at initial diagnosis in 99/359 (28%) children, but only 9/359 (3%) had a defined constellation. Conclusion Nearly half of childhood epilepsy is of “unknown” etiology. While a small proportion of this group met criteria for a known epilepsy syndrome, 41% of all childhood epilepsy is of “unknown” cause with no clear syndrome identified. Further work is needed to define more specific etiologies for this group. PMID:21482075

Familial epilepsy in Algeria: Clinical features and inheritance profiles.

PubMed

Chentouf, Amina; Dahdouh, Aïcha; Guipponi, Michel; Oubaiche, Mohand Laïd; Chaouch, Malika; Hamamy, Hanan; Antonarakis, Stylianos E

2015-09-01

To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5 ± 6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Urban population genetics of slum-dwelling rats (Rattus norvegicus) in Salvador, Brazil

PubMed Central

Kajdacsi, Brittney; Costa, Federico; Hyseni, Chaz; Porter, Fleur; Brown, Julia; Rodrigues, Gorete; Farias, Helena; Reis, Mitermeyer G.; Childs, James E.; Ko, Albert I.; Caccone, Adalgisa

2013-01-01

Throughout the developing world, urban centers with sprawling slum settlements are rapidly expanding and invading previously forested ecosystems. Slum communities are characterized by untended refuse, open sewers, and overgrown vegetation, which promote rodent infestation. Norway rats (Rattus norvegicus), are reservoirs for epidemic transmission of many zoonotic pathogens of public health importance. Understanding the population ecology of R. norvegicus is essential to formulate effective rodent control strategies, as this knowledge aids estimation of the temporal stability and spatial connectivity of populations. We screened for genetic variation, characterized the population genetic structure, and evaluated the extent and patterns of gene flow in the urban landscape using 17 microsatellite loci in 146 rats from 9 sites in the city of Salvador, Brazil. These sites were divided between three neighborhoods within the city spaced an average of 2.7 km apart. Surprisingly, we detected very little relatedness among animals trapped at the same site and found high levels of genetic diversity, as well as structuring across small geographic distances. Most FST comparisons among sites were statistically significant, including sites <400 m apart. Bayesian analyses grouped the samples in three genetic clusters, each associated with distinct sampling sites from different neighborhoods or valleys within neighborhoods. These data indicate the existence of complex genetic structure in R. norvegicus in Salvador, linked to the heterogeneous urban landscape. Future rodent control measures need to take into account the spatial and temporal linkage of rat populations in Salvador, as revealed by genetic data, to develop informed eradication strategies. PMID:24118116

Urban population genetics of slum-dwelling rats (Rattus norvegicus) in Salvador, Brazil.

PubMed

Kajdacsi, Brittney; Costa, Federico; Hyseni, Chaz; Porter, Fleur; Brown, Julia; Rodrigues, Gorete; Farias, Helena; Reis, Mitermayer G; Childs, James E; Ko, Albert I; Caccone, Adalgisa

2013-10-01

Throughout the developing world, urban centres with sprawling slum settlements are rapidly expanding and invading previously forested ecosystems. Slum communities are characterized by untended refuse, open sewers and overgrown vegetation, which promote rodent infestation. Norway rats (Rattus norvegicus) are reservoirs for epidemic transmission of many zoonotic pathogens of public health importance. Understanding the population ecology of R. norvegicus is essential to formulate effective rodent control strategies, as this knowledge aids estimation of the temporal stability and spatial connectivity of populations. We screened for genetic variation, characterized the population genetic structure and evaluated the extent and patterns of gene flow in the urban landscape using 17 microsatellite loci in 146 rats from nine sites in the city of Salvador, Brazil. These sites were divided between three neighbourhoods within the city spaced an average of 2.7 km apart. Surprisingly, we detected very little relatedness among animals trapped at the same site and found high levels of genetic diversity, as well as structuring across small geographical distances. Most F(ST) comparisons among sites were statistically significant, including sites <400 m apart. Bayesian analyses grouped the samples in three genetic clusters, each associated with distinct sampling sites from different neighbourhoods or valleys within neighbourhoods. These data indicate the existence of complex genetic structure in R. norvegicus in Salvador, linked to the heterogeneous urban landscape. Future rodent control measures need to take into account the spatial and temporal linkage of rat populations in Salvador, as revealed by genetic data, to develop informed eradication strategies. © 2013 John Wiley & Sons Ltd.

Kindling epileptogenesis and panic-like behavior: Their bidirectional connection and contribution to epilepsy-associated depression.

PubMed

Medel-Matus, Jesús-Servando; Shin, Don; Sankar, Raman; Mazarati, Andrey

2017-12-01

Anxiety is one of the most common comorbidities of epilepsy, which has major detrimental effects on the quality of life. Generalized anxiety disorder (GAD) associated with epilepsy has been receiving most attention. However, several other forms of anxiety reportedly present in patients with epilepsy, including panic disorder (PD). In this study, using an animal model of limbic epilepsy, we examined the interplay between epilepsy and panic-like behavior (PLB). Further, considering the high degree of comorbidity between depression on the one hand, and both epilepsy and PD on the other hand, we studied whether and how the presence of PLB in animals with epilepsy would affect their performance in depression-relevant tests. Fifty-day-old male Wistar rats were subjected to repeated alternating electrical stimulations of the basolateral amygdala (BLA) to induce kindling of limbic seizures, and the dorsal periaqueductal gray (DPAG) to induce panic-like episodes. Seizure susceptibility and panic reaction threshold were examined before the first and 24h after the last stimulation. At the end of the stimulations, the rats were examined in depression-relevant tests: saccharin preference test (SPT) for anhedonia and forced swimming test (FST) for despair/hopelessness. With regard to kindling, BLA+DPAG stimulation induced more profound increase of seizure susceptibility than BLA stimulation alone (evident as the reduction of the afterdischarge threshold and the increase of the afterdischarge duration). With regard to PLB, the BLA+DPAG stimulation exacerbated the severity of panic-like episodes, as compared with the DPAG stimulation alone. Basolateral amygdala stimulation alone had no effects on panic-like reactions, and DPAG stimulation alone did not modify kindling epileptogenesis. Combined stimulation of BLA and DPAG induced depressive-like behavioral impairments. This is the first experimental study showing bidirectional, mutually exacerbating effect of epilepsy and PLB, and

Lactobacillus johnsonii N6.2 diminishes caspase-1 maturation in the gastrointestinal system of diabetes prone rats.

PubMed

Teixeira, L D; Kling, D N; Lorca, G L; Gonzalez, C F

2018-04-25

The cells of the gastrointestinal (GI) epithelium are the first to contact the microbiota and food components. As a direct consequence of this, these cells are the first line of defence and key players in priming the immune response. One of the first responses against GI insults is the formation of the inflammasome, a multiprotein complex assembled in response to environmental threats. The formation of the inflammasome regulates caspase-1 by cleaving it into its active form. Once activated, caspase-1 can cleave interleukin-1β (IL-1β), which promotes adaptive and humoral immunity. Some strains, like Lactobacillus johnsonii N6.2, are able to modulate the biosynthesis of important host metabolites mediating inflammation. Of these metabolites are the pro-inflammatory kynurenines. L. johnsonii N6.2 is able to downregulate kynurenines biosynthesis via a redox active mechanism negatively affecting indoleamine 2,3-dioxygenase activity. In this study, we evaluated the effects of L. johnsonii N6.2 combined with the natural antioxidant and anti-inflammatory molecule rosmarinic acid (RA). Inflammasome assembly and the kynurenine pathway were evaluated in GI samples of BioBreeding diabetes-prone (BB-DP) rats. In this work, BB-DP rats were fed daily with RA, L. johnsonii N6.2; or both combined. The transcriptional rate and proteins levels of inflammasome and kynurenine pathway components in ileum tissue were evaluated. Elevated levels of pro-caspase-1 were observed in rats fed with L. johnsonii, while RA had no effect on pro-caspase-1 expression. Western blot assays demonstrated that L. johnsonii fed rats showed lower levels of mature caspase-1, when compared to the other treatments. Furthermore, IL-1β maturation followed a similar pattern across the treatments. Differences were also observed between treatments in expression levels of key enzymes in the kynurenine pathway. These findings support the role of L. johnsonii in modulating the assembly of the inflammasome as well

Consanguinity and epilepsy in Oran, Algeria: A case-control study.

PubMed

Chentouf, Amina; Talhi, Randa; Dahdouh, Aicha; Benbihi, Latifa; Benilha, Soumia; Oubaiche, Mohand Laid; Chaouch, Malika

2015-03-01

The goal of this case-control study was to identify the significance of consanguinity and other risk factors for epilepsy in Oran, Algeria. Unrelated epileptic patients upwards of 16 years, who attended the Neurology Department between October 2013 and March 2014 were included in the study. Controls, matched for age and sex, were selected among non-epileptic patients attending the same department during the same period. The risk factors evaluated were: consanguinity, family history of epilepsy, perinatal complications, infection of the central nervous system, mental retardation, neurological impairment, history of febrile seizures, severe head trauma, cerebrovascular diseases, and addiction. 101 cases and 202 controls participated in the study. Multivariate logistic regression identified five factors significantly associated with epilepsy: first-degree of consanguinity (odds ratio (OR)=2.15), history of epilepsy in first-degree relatives (OR=4.03), antecedent of febrile seizures (OR=5.38), severe head injury (OR=2.94) and mental retardation (OR=9.32). Consanguinity, family history of epilepsy, history of febrile seizures, severe head trauma and mental retardation are risk factors for epilepsy. The implementation of a strategy for prevention and awareness of the impact of consanguineous marriages as well as genetic counseling for couples with a family history of epilepsy are needed. Copyright © 2015 Elsevier B.V. All rights reserved.

Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y.

PubMed

Diané, Abdoulaye; Pierce, W David; Russell, James C; Heth, C Donald; Vine, Donna F; Richard, Denis; Proctor, Spencer D

2014-03-14

We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21-25 d old) and early adulthood (8-12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams' milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.

Methylphenidate and Atomoxetine-Responsive Prefrontal Cortical Genetic Overlaps in "Impulsive" SHR/NCrl and Wistar Rats.

PubMed

Dela Peña, Ike; Dela Peña, Irene Joy; de la Peña, June Bryan; Kim, Hee Jin; Shin, Chan Young; Han, Doug Hyun; Kim, Bung-Nyun; Ryu, Jong Hoon; Cheong, Jae Hoon

2017-09-01

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.

[Epilepsy and psychic seizures].

PubMed

Fukao, Kenjiro

2006-01-01

Various psychic symptoms as ictal manifestation have been found in epileptic patients. They are classified as psychic seizures within simple partial seizures, and subclassified into affective, cognitive, dysmnesic seizures and so on, although the subclassification is not yet satisfactory and almost nothing is known about their relationships with normal brain functions. In this presentation, the speaker picked ictal fear, déjà vu and out-of-body experience (OBE) from them and suggested that studies on these symptoms could uniquely contribute to the progress of cognitive neuroscience, presenting some results from the research and case study that he had been engaged in. Psychic seizures are prone to be missed or misdiagnosed unless psychiatrists with sufficient knowledge and experience on epilepsy care would not treat them, because they are subjective symptoms that are diverse and subtle, while they have some characteristics as ictal symptoms.

Classification of childhood epilepsies in a tertiary pediatric neurology clinic using a customized classification scheme from the international league against epilepsy 2010 report.

PubMed

Khoo, Teik-Beng

2013-01-01

In its 2010 report, the International League Against Epilepsy Commission on Classification and Terminology had made a number of changes to the organization, terminology, and classification of seizures and epilepsies. This study aims to test the usefulness of this revised classification scheme on children with epilepsies aged between 0 and 18 years old. Of 527 patients, 75.1% only had 1 type of seizure and the commonest was focal seizure (61.9%). A specific electroclinical syndrome diagnosis could be made in 27.5%. Only 2.1% had a distinctive constellation. In this cohort, 46.9% had an underlying structural, metabolic, or genetic etiology. Among the important causes were pre-/perinatal insults, malformation of cortical development, intracranial infections, and neurocutaneous syndromes. However, 23.5% of the patients in our cohort were classified as having "epilepsies of unknown cause." The revised classification scheme is generally useful for pediatric patients. To make it more inclusive and clinically meaningful, some local customizations are required.

Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy.

PubMed

Maia, Gisela H; Brazete, Cátia S; Soares, Joana I; Luz, Liliana L; Lukoyanov, Nikolai V

2017-09-01

Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Strong genetic influences on measures of behavioral-regulation among inbred rat strains

PubMed Central

Richards, Jerry B.; Lloyd, David R.; Kuehlewind, Brandon; Militello, Leah; Paredez, Marita; Solberg -Woods, Leah; Palmer, Abraham A.

2013-01-01

A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral regulation were tested in a panel of 8 inbred rat strains. These measures were; 1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, 2) attention and impulsivity, as measured by a choice reaction time task, and 3) impulsivity as measured by a delay discounting task. Deficient behavioral regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n=9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the 8 inbred rat strains on the choice reaction time task was compared to the performance of out bred Sprague Dawley (n=28) and Heterogeneous strain rats (n=48). The results indicate a strong genetic influence on complex tasks related to behavioral regulation and indicate that some of measures tap common genetically-driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders. PMID:23710681

Cannabis agonist injection effect on the coupling architecture in cortex of WAG/Rij rats during absence seizures

NASA Astrophysics Data System (ADS)

Sysoeva, Marina V.; Kuznetsova, Galina D.; van Rijn, Clementina M.; Sysoev, Ilya V.

2016-04-01

WAG/Rij rats are well known genetic model of absence epilepsy, which is traditionally considered as a nonconvulsive generalised epilepsy of unknown aetiology. In current study the effect of (R)-(+)-WIN 55,212-2 (cannabis agonist) injection on the coupling between different parts of cortex was studied on 27 male 8 month old rats using local field potentials. Recently developed non-linear adapted Granger causality approach was used as a primary method. It was shown that first 2 hours after the injection the coupling between most channel pairs rises in comparison with the spontaneous activity, whilst long after the injection (2-6 hours) it drops down. The coupling increase corresponds to the mentioned before treatment effect, when the number and the longitude of seizures significantly decreases. However the subsequent decrease of the coupling in the cortex is accompanied by the dramatic increase of the longitude and the number of seizures. This assumes the hypothesis that a relatively higher coupling in the cortical network can prevent the seizure propagation and generalisation.

Association of BDNF Polymorphisms with the Risk of Epilepsy: a Multicenter Study.

PubMed

Sha'ari, Hidayati Mohd; Haerian, Batoul Sadat; Baum, Larry; Tan, Hui Jan; Rafia, Mohd Hanip; Kwan, Patrick; Cherny, Stacey S; Sham, Pak Chung; Gui, Hongsheng; Raymond, Azman Ali; Lim, Kheng Seang; Mohamed, Zahurin

2016-07-01

Epilepsy is a common neurological disease characterized by recurrent unprovoked seizures. Evidence suggested that abnormal activity of brain-derived neurotrophic factor (BDNF) contributes to the pathogenesis of epilepsy. Some previous studies identified association between genetic variants of BDNF and risk of epilepsy. In this study, this association has been examined in the Hong Kong and Malaysian epilepsy cohorts. Genomic DNA of 6047 subjects (1640 patients with epilepsy and 4407 healthy individuals) was genotyped for rs6265, rs11030104, rs7103411, and rs7127507 polymorphisms by using Sequenom MassArray and Illumina HumanHap 610-Quad or 550-Duo BeadChip arrays techniques. Results showed significant association between rs6265 T, rs7103411 C, and rs7127507 T and cryptgenic epilepsy risk (p = 0.00003, p = 0.0002, and p = 0.002, respectively) or between rs6265 and rs7103411 and symptomatic epilepsy risk in Malaysian Indians (TT vs. CC, p = 0.004 and T vs. C, p = 0.0002, respectively) as well as between rs6265 T and risk of cryptogenic epilepsy in Malaysian Chinese (p = 0.005). The Trs6265-Crs7103411-Trs7127507 was significantly associated with cryptogenic epilepsy in Malaysian Indians (p = 0.00005). In conclusion, our results suggest that BDNF polymorphisms might contribute to the risk of epilepsy in Malaysian Indians and Chinese.

Parental Infertility, Fertility Treatment, and Childhood Epilepsy: A Population-Based Cohort Study.

PubMed

Kettner, Laura O; Ramlau-Hansen, Cecilia H; Kesmodel, Ulrik S; Bay, Bjørn; Matthiesen, Niels B; Henriksen, Tine B

2016-09-01

A few studies have indicated an increased risk of epilepsy in children conceived by fertility treatment possibly due to characteristics of the infertile couple rather than the treatment. We therefore aimed to investigate the association between parental infertility, fertility treatment, and epilepsy in the offspring, including the subtypes of epilepsy; idiopathic generalised epilepsy and focal epilepsy. This cohort included all pregnancies resulting in liveborn singletons from the Aarhus Birth Cohort, Denmark (1995-2013). Information on time to pregnancy and fertility treatment was obtained from pregnancy questionnaires in early pregnancy. Children developing epilepsy were identified from the Danish National Patient Register and the Danish National Prescription Registry until 2013. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. A total of 60 440 pregnancies were included, and 0.8% of the children developed epilepsy.The primary analyses showed no association between parental infertility or fertility treatment, and the overall risk of childhood epilepsy (hazard rate ratios (HRs); 95% confidence intervals (CIs): 1.08 (0.73, 1.60) and 1.04 (0.71, 1.52)). In secondary analyses, both parental infertility and fertility treatment were associated with an increased risk of idiopathic generalised epilepsy (HRs and 95% CIs: 2.25 (1.10, 4.58) and 2.45 (1.26, 4.75)). No association was seen for focal epilepsy. Parental infertility or fertility treatment was not associated with an overall risk of childhood epilepsy. Parental infertility may be associated with an increased risk of idiopathic generalised epilepsy; a subtype of epilepsy believed to be of genetic origin. © 2016 John Wiley & Sons Ltd.

Antiepileptic drug behavioral side effects and baseline hyperactivity in children and adolescents with new onset epilepsy.

PubMed

Guilfoyle, Shanna M; Follansbee-Junger, Katherine; Smith, Aimee W; Combs, Angela; Ollier, Shannon; Hater, Brooke; Modi, Avani C

2018-01-01

To examine baseline psychological functioning and antiepileptic drug (AED) behavioral side effects in new onset epilepsy and determine, by age, whether baseline psychological functioning predicts AED behavioral side effects 1 month following AED initiation. A retrospective chart review was conducted between July 2011 and December 2014 that included youths with new onset epilepsy. As part of routine interdisciplinary care, caregivers completed the Behavior Assessment System for Children, 2nd Edition: Parent Rating Scale to report on baseline psychological functioning at the diagnostic visit and the Pediatric Epilepsy Side Effects Questionnaire to identify AED behavioral side effects at the 1-month follow-up clinic visit following AED initiation. Children (age = 2-11 years) and adolescents (age = 12-18 years) were examined separately. A total of 380 youths with new onset epilepsy (M age  = 8.9 ± 4.3 years; 83.4% Caucasian; 34.8% focal epilepsy, 41.1% generalized epilepsy, 23.7% unclassified epilepsy) were included. Seventy percent of youths had at-risk or clinically elevated baseline psychological symptoms. Children had significantly greater AED behavioral side effects (M = 25.08 ± 26.36) compared to adolescents (M = 12.36 ± 17.73), regardless of AED. Valproic acid demonstrated significantly greater behavioral side effects compared to all other AEDs, with the exception of levetiracetam. Higher hyperactivity/impulsivity at baseline significantly predicted higher AED behavioral side effects 1 month after AED initiation in both age groups. Younger children seem to be more prone to experience behavioral side effects, and these are likely to be higher if youths with epilepsy have baseline hyperactivity/impulsivity. Baseline psychological screening, specifically hyperactivity, can be used as a precision medicine tool for AED selection. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Catastrophic childhood epilepsy: a recent convergence of basic and clinical neuroscience.

PubMed

Katsnelson, Alla; Buzsáki, Gyorgy; Swann, John W

2014-11-12

Advances in understanding the genetics and underlying pathology of the catastrophic childhood epilepsies are pointing toward treatments. Copyright © 2014, American Association for the Advancement of Science.

Plants used to treat epilepsy by Tanzanian traditional healers.

PubMed

Moshi, Mainen J; Kagashe, Godeliver A B; Mbwambo, Zakaria H

2005-02-28

A cross-sectional study performed in Temeke District (Dar es Salaam, Tanzania) showed that 5.5% of the traditional healers have knowledge for the treatment of epilepsy. Of the 100 healers interviewed, 30 (30%) believed that epilepsy was caused by witchcraft, while 19 (19%) thought epilepsy has a genetic origin which can be inherited. Other healers thought epilepsy can be caused by head injury or malaria (24%), and the remaining 27% did not know the cause. Most of the healers (92%) could present an accurate account on the symptoms of the disease, including dizziness, loss of consciousness, abrupt falling down, frothing from the mouth, loss of memory, biting of the tongue, confusion, and restlessness. They showed competence in the treatment of the disease, whereby 60 plants that are commonly used were mentioned. Abrus precatorius L. (Leguminosae), Clausena anisata (Willd.) Oliv. (Rutaceae) and Hoslundia opposita Vahl (Lamiaceae), which are among the plants mentioned, have proven anticonvulsant activity, while a few other species on their list have been reported to be useful in the treatment of epilepsy. Biological testing of these plants, using different models of convulsions is, suggested.

Genetics Home Reference: GM3 synthase deficiency

MedlinePlus

... GM3 synthase deficiency is characterized by recurrent seizures (epilepsy) and problems with brain development. Within the first ... Testing (1 link) Genetic Testing Registry: Amish infantile epilepsy syndrome Other Diagnosis and Management Resources (2 links) ...

Structural MRI biomarkers of shared pathogenesis in autism spectrum disorder and epilepsy.

PubMed

Blackmon, Karen

2015-06-01

Etiological factors that contribute to a high comorbidity between autism spectrum disorder (ASD) and epilepsy are the subject of much debate. Does epilepsy cause ASD or are there common underlying brain abnormalities that increase the risk of developing both disorders? This review summarizes evidence from quantitative MRI studies to suggest that abnormalities of brain structure are not necessarily the consequence of ASD and epilepsy but are antecedent to disease expression. Abnormal gray and white matter volumes are present prior to onset of ASD and evident at the time of onset in pediatric epilepsy. Aberrant brain growth trajectories are also common in both disorders, as evidenced by blunted gray matter maturation and white matter maturation. Although the etiological factors that explain these abnormalities are unclear, high heritability estimates for gray matter volume and white matter microstructure demonstrate that genetic factors assert a strong influence on brain structure. In addition, histopathological studies of ASD and epilepsy brain tissue reveal elevated rates of malformations of cortical development (MCDs), such as focal cortical dysplasia and heterotopias, which supports disruption of neuronal migration as a contributing factor. Although MCDs are not always visible on MRI with conventional radiological analysis, quantitative MRI detection methods show high sensitivity to subtle malformations in epilepsy and can be potentially applied to MCD detection in ASD. Such an approach is critical for establishing quantitative neuroanatomic endophenotypes that can be used in genetic research. In the context of emerging drug treatments for seizures and autism symptoms, such as rapamycin and rapalogs, in vivo neuroimaging markers of subtle structural brain abnormalities could improve sample stratification in human clinical trials and potentially extend the range of patients that might benefit from treatment. This article is part of a Special Issue entitled "Autism

Candidate genes for idiopathic epilepsy in four dog breeds.

PubMed

Ekenstedt, Kari J; Patterson, Edward E; Minor, Katie M; Mickelson, James R

2011-04-25

Idiopathic epilepsy (IE) is a naturally occurring and significant seizure disorder affecting all dog breeds. Because dog breeds are genetically isolated populations, it is possible that IE is attributable to common founders and is genetically homogenous within breeds. In humans, a number of mutations, the majority of which are genes encoding ion channels, neurotransmitters, or their regulatory subunits, have been discovered to cause rare, specific types of IE. It was hypothesized that there are simple genetic bases for IE in some purebred dog breeds, specifically in Vizslas, English Springer Spaniels (ESS), Greater Swiss Mountain Dogs (GSMD), and Beagles, and that the gene(s) responsible may, in some cases, be the same as those already discovered in humans. Candidate genes known to be involved in human epilepsy, along with selected additional genes in the same gene families that are involved in murine epilepsy or are expressed in neural tissue, were examined in populations of affected and unaffected dogs. Microsatellite markers in close proximity to each candidate gene were genotyped and subjected to two-point linkage in Vizslas, and association analysis in ESS, GSMD and Beagles. Most of these candidate genes were not significantly associated with IE in these four dog breeds, while a few genes remained inconclusive. Other genes not included in this study may still be causing monogenic IE in these breeds or, like many cases of human IE, the disease in dogs may be likewise polygenic.

Epilepsy in TSC: certain etiology does not mean certain prognosis.

PubMed

Vignoli, Aglaia; La Briola, Francesca; Turner, Katherine; Scornavacca, Giulia; Chiesa, Valentina; Zambrelli, Elena; Piazzini, Ada; Savini, Miriam Nella; Alfano, Rosa Maria; Canevini, Maria Paola

2013-12-01

Prevalence and long-term outcome of epilepsy in tuberous sclerosis complex (TSC) is reported to be variable, and the reasons for this variability are still controversial. We reviewed the clinical characteristics of patients with TSC who were regularly followed since 2000 at the San Paolo Multidisciplinary Tuberous Sclerosis Centre in Milan, Italy. From patient charts we collected data about age at epilepsy onset, seizure frequency and seizure type, history of infantile spasms (IS), epileptic syndrome, evolution to refractory epilepsy or to seizure freedom and/or medication freedom, electroencephalography (EEG) features, magnetic resonance imaging (MRI) findings, cognitive outcome, and genetic background. Among the 160 subjects (120 adults and 40 children), 116 (72.5%) had epilepsy: 57 (35.6%) were seizure-free, and 59 (36.9%) had drug-resistant epilepsy. Most seizure-free patients had a focal epilepsy (89.5%), with 54.4% of them drug resistant for a period of their lives. Epilepsy onset in the first year of life with IS and/or focal seizures was characteristic of the drug-resistant group of patients, as well as cognitive impairment and TSC2 mutation (p < 0.05). A small group of patients (7 patients, 4.4%) experienced a seizure only once; all of them had normal cognition. Although epilepsy management can be challenging in TSC, more than one third of patients had their seizures controlled: through monotherapy in 56% and by polytherapy in 32%. Moreover, 12% of the patients became seizure-free and were off medication. Identifying predictive features of epilepsy and cognitive outcome can ensure better management for patients with TSC and delineate genotype-phenotype correlations. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Genetic variation reveals influence of landscape connectivity on population dynamics and resiliency of western trout in disturbance-prone habitats

USGS Publications Warehouse

Helen M. Neville,; Gresswell, Robert E.; Dunham, Jason B.

2012-01-01

Salmonid fishes have evolved and persisted in dynamic ecosystems where disturbance events vary in frequency, magnitude, timing, and duration, as well as the specific nature of associated effects (e.g., changes in thermal or flow regimes, geomorphology, or water chemistry). In the western United States, one of the major drivers of disturbance in stream ecosystems is fire. Although there is a growing consensus that fish populations can ultimately benefit from the productive and heterogeneous habitats created by fire, to persist they obviously have to withstand the immediate and shorter-term effects of fire, which can reduce or even extirpate local populations. Movement among interconnected stream habitats is thought to be an important strategy enabling persistence during and following fire, and there is mounting concern that the extensive isolation of salmonid populations in fragmented habitats is reducing their resiliency to fire. In spite of this concern, there are few direct observations of salmonid responses to fire. In fact, guidance is based largely on a broader understanding of the influences of landscape structure and disturbance in general on salmonid fishes, and there is considerable uncertainty about how best to manage for salmonid resilience to wildfire. Studies are limited by the difficult logistics of following fish responses in the face of unpredictable events such as wildfires. Therefore, BACI (Before-After-Control-Impact) study designs are nearly impossible, and replication is similarly challenging because fires are often low-frequency events. Furthermore, conventional ecological study approaches (e.g., studies of fish distribution, abundance, life histories, and movement) are logistically difficult to implement. Overall, a major challenge to understanding resilience of salmonid populations in fire-prone environments is related to moving beyond localized case studies to those with broader applicability in wildfire management . Genetic data can be

Inhibition of mTOR Pathway by Rapamycin Decreases P-glycoprotein Expression and Spontaneous Seizures in Pharmacoresistant Epilepsy.

PubMed

Chi, Xiaosa; Huang, Cheng; Li, Rui; Wang, Wei; Wu, Mengqian; Li, Jinmei; Zhou, Dong

2017-04-01

The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin. Non-responders were treated for 4 weeks with vehicle only or with the mTOR pathway inhibitor rapamycin at doses of 1, 3, and 6 mg/kg. Western blotting and immunohistochemistry were used to detect the expression of phospho-S6 (P-S6) and P-gp at different time points (1 h, 8 h, 1 day, 3 days, 1 weeks, 2 weeks, and 4 weeks) after the onset of treatment. Overexpression of P-S6 and P-gp was detected in both refractory mTLE patients and non-responder rats. Rapamycin showed an inhibitory effect on P-S6 and P-gp expression 1 week after treatment in rats. In addition, the expression levels of P-S6 and P-gp in the 6 mg/kg group were significantly lower than those in the 1 mg/kg or the 3 mg/kg group at the same time points (all P < 0.05). Moreover, rapamycin decreased the duration and number of CL-induced seizures, as well as the stage of non-responders (all P < 0.05). The current study indicates that the mTOR signaling pathway plays a critical role in P-gp expression in drug-resistant epilepsy. Inhibition of the mTOR pathway by rapamycin may be a potential therapeutic approach for pharmacoresistant epilepsy.

Genetic diversity and sex ratio of naked mole rat, Heterocephalus glaber, zoo populations.

PubMed

Chau, Linh M; Groh, Amy M; Anderson, Emily C; Alcala, Micaela O; Mendelson, Joseph R; Slade, Stephanie B; Kerns, Kenton; Sarro, Steve; Lusardi, Clinton; Goodisman, Michael A D

2018-05-01

The naked mole rat, Heterocephalus glaber, is a highly unusual mammal that displays a complex social system similar to that found in eusocial insects. Colonies of H. glaber are commonly maintained in zoo collections because they represent fascinating educational exhibits for the public. However, little is known about the genetic structure or sex ratio of captive populations of H. glaber. In this study, we developed a set of microsatellite markers to examine genetic variation in three captive zoo populations of H. glaber. We also studied sex ratio of these captive populations. Our goal was to determine levels of genetic variation within, and genetic differences between, captive populations of H. glaber. Overall, we found modest levels of genetic variation in zoo populations. We also uncovered little evidence for inbreeding within the captive populations. However, zoo populations did differ genetically, which may reflect the isolation of captive naked mole rat colonies. Finally, we found no evidence of biased sex ratios within colonies. Overall, our study documents levels of genetic variation and sex ratios in a captive eusocial mammalian population. Our results may provide insight into how to manage captive populations of H. glaber. © 2018 Wiley Periodicals, Inc.

Managing Epilepsy Well: Emerging e-Tools for epilepsy self-management.

PubMed

Shegog, Ross; Bamps, Yvan A; Patel, Archna; Kakacek, Jody; Escoffery, Cam; Johnson, Erica K; Ilozumba, Ukwuoma O

2013-10-01

The Managing Epilepsy Well (MEW) Network was established in 2007 by the Centers for Disease Control and Prevention Epilepsy Program to expand epilepsy self-management research. The network has employed collaborative research strategies to develop, test, and disseminate evidence-based, community-based, and e-Health interventions (e-Tools) for epilepsy self-management for people with epilepsy, caregivers, and health-care providers. Since its inception, MEW Network collaborators have conducted formative studies (n=7) investigating the potential of e-Health to support epilepsy self-management and intervention studies evaluating e-Tools (n=5). The MEW e-Tools (the MEW website, WebEase, UPLIFT, MINDSET, and PEARLS online training) and affiliated e-Tools (Texting 4 Control) are designed to complement self-management practices in each phase of the epilepsy care continuum. These tools exemplify a concerted research agenda, shared methodological principles and models for epilepsy self-management, and a communal knowledge base for implementing e-Health to improve quality of life for people with epilepsy. © 2013.

Familial aggregation of focal seizure semiology in the Epilepsy Phenome/Genome Project.

PubMed

Tobochnik, Steven; Fahlstrom, Robyn; Shain, Catherine; Winawer, Melodie R

2017-07-04

To improve phenotype definition in genetic studies of epilepsy, we assessed the familial aggregation of focal seizure types and of specific seizure symptoms within the focal epilepsies in families from the Epilepsy Phenome/Genome Project. We studied 302 individuals with nonacquired focal epilepsy from 149 families. Familial aggregation was assessed by logistic regression analysis of relatives' traits (dependent variable) by probands' traits (independent variable), estimating the odds ratio for each symptom in a relative given presence vs absence of the symptom in the proband. In families containing multiple individuals with nonacquired focal epilepsy, we found significant evidence for familial aggregation of ictal motor, autonomic, psychic, and aphasic symptoms. Within these categories, ictal whole body posturing, diaphoresis, dyspnea, fear/anxiety, and déjà vu/jamais vu showed significant familial aggregation. Focal seizure type aggregated as well, including complex partial, simple partial, and secondarily generalized tonic-clonic seizures. Our results provide insight into genotype-phenotype correlation in the nonacquired focal epilepsies and a framework for identifying subgroups of patients likely to share susceptibility genes. © 2017 American Academy of Neurology.

Epilepsy, behavior, and art (Epilepsy, Brain, and Mind, part 1).

PubMed

Rektor, Ivan; Schachter, Steven C; Arzy, Shahar; Baloyannis, Stavros J; Bazil, Carl; Brázdil, Milan; Engel, Jerome; Helmstaedter, Gerhard; Hesdorffer, Dale C; Jones-Gotman, Marilyn; Kesner, Ladislav; Komárek, Vladimír; Krämer, Günter; Leppik, Ilo E; Mann, Michael W; Mula, Marco; Risse, Gail L; Stoker, Guy W; Kasteleijn-Nolst Trenité, Dorothée G A; Trimble, Michael; Tyrliková, Ivana; Korczyn, Amos D

2013-08-01

Epilepsy is both a disease of the brain and the mind. Brain diseases, structural and/or functional, underlie the appearance of epilepsy, but the notion of epilepsy is larger and cannot be reduced exclusively to the brain. We can therefore look at epilepsy from two angles. The first perspective is intrinsic: the etiology and pathophysiology, problems of therapy, impact on the brain networks, and the "mind" aspects of brain functions - cognitive, emotional, and affective. The second perspective is extrinsic: the social interactions of the person with epilepsy, the influence of the surrounding environment, and the influences of epilepsy on society. All these aspects reaching far beyond the pure biological nature of epilepsy have been the topics of two International Congresses of Epilepsy, Brain, and Mind that were held in Prague, Czech Republic, in 2010 and 2012 (the third Congress will be held in Brno, Czech Republic on April 3-5, 2014; www.epilepsy-brain-mind2014.eu). Here, we present the first of two papers with extended summaries of selected presentations of the 2012 Congress that focused on epilepsy, behavior, and art. Copyright © 2013. Published by Elsevier Inc.

Attention and executive functions in the early course of pediatric epilepsy.

PubMed

Reuner, Gitta; Kadish, Navah Esther; Doering, Jan Henje; Balke, Doreen; Schubert-Bast, Susanne

2016-07-01

Our prospective study aimed at exploring attention and executive functions in children with new-onset epilepsy prior to and during the early course of antiepileptic treatment. Sociodemographic and epilepsy-related factors were analyzed as potential predictors both of impaired cognitive functions as well as for changes in cognitive functioning in the early course of illness. From a total group of 115 children aged six to 17years without major disabilities, 76 children were assessed longitudinally with a screening tool for attention and executive functions (EpiTrack Junior®). Sociodemographic variables (gender, age at epilepsy onset, need of special education) and epilepsy-related variables (etiology of epilepsy, semiology of seizures, number of seizures) were considered as potential predictors for impaired functions prior to treatment and for deterioration/amelioration in cognitive functions in the early course. Attention and executive functions of children with new-onset epilepsy were significantly more often impaired when compared with a healthy population, but less often when compared with children with chronic epilepsy. The majority of children showed stable cognitive functioning in the early course of treatment. The risk of impaired cognitive functions was significantly heightened when etiology of epilepsy was unknown or not classifiable. The chance for improvement of functioning was lowered by having a genetic epilepsy, or an unknown semiology of seizures. Children with new-onset epilepsy are at high risk for impaired attention and executive functions even prior to antiepileptic treatment, especially when etiology of their epilepsy remains unclear. The high stability of cognitive functioning in the early course can be used in counseling of families who worry about negative side effects of drug treatment. Finally, a systematic assessment of cognitive functions in children with new-onset epilepsy is necessary to detect subtle deficits in the early course and

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes

PubMed Central

Moreno-Moral, Aida

2016-01-01

ABSTRACT Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. PMID:27736746

From integrative genomics to systems genetics in the rat to link genotypes to phenotypes.

PubMed

Moreno-Moral, Aida; Petretto, Enrico

2016-10-01

Complementary to traditional gene mapping approaches used to identify the hereditary components of complex diseases, integrative genomics and systems genetics have emerged as powerful strategies to decipher the key genetic drivers of molecular pathways that underlie disease. Broadly speaking, integrative genomics aims to link cellular-level traits (such as mRNA expression) to the genome to identify their genetic determinants. With the characterization of several cellular-level traits within the same system, the integrative genomics approach evolved into a more comprehensive study design, called systems genetics, which aims to unravel the complex biological networks and pathways involved in disease, and in turn map their genetic control points. The first fully integrated systems genetics study was carried out in rats, and the results, which revealed conserved trans-acting genetic regulation of a pro-inflammatory network relevant to type 1 diabetes, were translated to humans. Many studies using different organisms subsequently stemmed from this example. The aim of this Review is to describe the most recent advances in the fields of integrative genomics and systems genetics applied in the rat, with a focus on studies of complex diseases ranging from inflammatory to cardiometabolic disorders. We aim to provide the genetics community with a comprehensive insight into how the systems genetics approach came to life, starting from the first integrative genomics strategies [such as expression quantitative trait loci (eQTLs) mapping] and concluding with the most sophisticated gene network-based analyses in multiple systems and disease states. Although not limited to studies that have been directly translated to humans, we will focus particularly on the successful investigations in the rat that have led to primary discoveries of genes and pathways relevant to human disease. © 2016. Published by The Company of Biologists Ltd.

The antiepileptic effect of Centella asiatica on the activities of Na+/K+, Mg2+ and Ca2+-ATPases in rat brain during pentylenetetrazol–induced epilepsy

PubMed Central

G., Visweswari; K., Siva Prasad; V., Lokanatha; Rajendra, W.

2010-01-01

Background: To study the anticonvulsant effect of different extracts of Centella asiatica (CA) in male albino rats with reference to Na+/K+, Mg2+ and Ca2+-ATPase activities. Materials and Methods: Male Wistar rats (150±25 g b.w.) were divided into seven groups of six each i.e. (a) control rats treated with saline, (b) pentylenetetrazol (PTZ)-induced epileptic group (60 mg/kg, i.p.), (c) epileptic group pretreated with n-hexane extract (n-HE), (d) epileptic group pretreated with chloroform extract (CE), (e) epileptic group pretreated with ethyl acetate extract (EAE), (f) epileptic group pretreated with n-butanol extract (n-BE), and (g) epileptic group pretreated with aqueous extract (AE). Results: The activities of three ATPases were decreased in different regions of brain during PTZ-induced epilepsy and were increased in epileptic rats pretreated with different extracts of CA except AE. Conclusion: The extracts of C. asiatica, except AE, possess anticonvulsant and neuroprotective activity and thus can be used for effective management in treatment of epileptic seizures. PMID:20711371

Personalized translational epilepsy research - Novel approaches and future perspectives: Part II: Experimental and translational approaches.

PubMed

Bauer, Sebastian; van Alphen, Natascha; Becker, Albert; Chiocchetti, Andreas; Deichmann, Ralf; Deller, Thomas; Freiman, Thomas; Freitag, Christine M; Gehrig, Johannes; Hermsen, Anke M; Jedlicka, Peter; Kell, Christian; Klein, Karl Martin; Knake, Susanne; Kullmann, Dimitri M; Liebner, Stefan; Norwood, Braxton A; Omigie, Diana; Plate, Karlheinz; Reif, Andreas; Reif, Philipp S; Reiss, Yvonne; Roeper, Jochen; Ronellenfitsch, Michael W; Schorge, Stephanie; Schratt, Gerhard; Schwarzacher, Stephan W; Steinbach, Joachim P; Strzelczyk, Adam; Triesch, Jochen; Wagner, Marlies; Walker, Matthew C; von Wegner, Frederic; Rosenow, Felix

2017-11-01

Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics, and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. This Part II includes the experimental and translational approaches and a discussion of the future perspectives, while the diagnostic methods, EEG network analysis, biomarkers, and personalized treatment approaches were addressed in Part I [1]. Copyright © 2017

Basic knowledge of epilepsy among medical students.

PubMed

Tiamkao, Siriporn; Tiamkao, Somsak; Auevitchayapat, Narong; Arunpongpaisal, Suwanna; Chaiyakum, Aporanee; Jitpimolmard, Suthipun; Phuttharak, Warinthorn; Phunikhom, Kutcharin; Saengsuwan M, Jiamjit; Vannaprasaht, Suda

2007-11-01

The medical students' knowledge about basic medical neuroscience in the preclinical level may be fragmented and incomplete. Evaluate the knowledge of students prior to a lecture on epilepsy in clinical level. One hundred ten fourth-year medical students' knowledge was accessed by a self-administered questionnaire. The presented results revealed that 91.8% of respondents knew that epilepsy arose from a transient dysfunction in the brain. Generalized tonic-clonic seizures (GTCs) were the most common type (91.5%) they knew and absence seizures were the least common type (33.6%) they knew. All of them knew that eating pork and punishment of gods did not cause epilepsy. However 50% thought that genetics was a cause and 80.3% did not know that stroke and sleep deprivation (92.7%) cause epilepsy. About treatment and prognosis, only 28.2% of respondents thought epilepsy can be cured and patients should take antiepileptic drugs (AEDs) for seizure free 2-5 years (48.2%), life long (33.6%). They knew that the patients should be prohibited from driving (80%), working on machinery (74.5%), and (27.3%) avoid drinking. However, they knew that the patients could marry (100%), get pregnant (98.2%), and lactate (91.9%). Regarding the first aid management, 50.9% of them recommended that placing a piece of wood between the teeth during a seizure and perform chest compressions (20.0%). Means knowledge scores is about 60%, the highest score is the definition of epilepsy (90.2%) and the lowest is type of seizure (43%). The findings indicated that lecturers should review aspects ofpathophysiology and emphasize on type of seizure, cause, consequences, and prognosis including first-aid management.

Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference.

PubMed

Oinio, Ville; Sundström, Mikko; Bäckström, Pia; Uhari-Väänänen, Johanna; Kiianmaa, Kalervo; Raasmaja, Atso; Piepponen, Petteri

2018-05-01

Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior. In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options. The lever choices were guided by different-sized sucrose rewards (one or three pellets), and the probability of gaining the larger reward was slowly changed to a level where choosing the smaller reward would be the most profitable in the long run. After training, rats were injected (s.c.) with dopamine releaser D-amphetamine (0.3, 1.0 mg/kg) to study the impact of rapid dopamine release on this learned decision making behavior. Administration of D-amphetamine promoted unprofitable decision making of AA rats more robustly when compared to Wistar rats. At the same time, D-amphetamine reduced lever pressing responses. Interestingly, we found that this reduction in lever pressing was significantly greater in Wistar rats than in AA rats and it was not linked to motivation to consume sucrose. Our results indicate that conditioning to the lever pressing in uncertain environments is more pronounced in AA than in Wistar rats and indicate that the reinforcing effects of a gambling-like environment act as a stronger conditioning factor for rats that exhibit a genetic tendency for high alcohol drinking.

Cingulate Epilepsy

PubMed Central

Alkawadri, Rafeed; So, Norman K.; Van Ness, Paul C.; Alexopoulos, Andreas V.

2016-01-01

IMPORTANCE The literature on cingulate gyrus epilepsy in the magnetic resonance imaging era is limited to case reports and small case series. To our knowledge, this is the largest study of surgically confirmed epilepsy arising from the anterior or posterior cingulate region. OBJECTIVE To characterize the clinical and electrophysiological findings of epilepsies arising from the anterior and posterior cingulate gyrus. DESIGN, SETTING, AND PARTICIPANTS We studied consecutive cingulate gyrus epilepsy cases identified retrospectively from the Cleveland Clinic and University of Texas Southwestern Medical Center epilepsy databases from 1992 to 2009. Participants included 14 consecutive cases of cingulate gyrus epilepsies confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. MAIN OUTCOMES AND MEASURES The main outcome measure was improvement in seizure frequency following surgery. The clinical, video electroencephalography, neuroimaging, pathology, and surgical outcome data were reviewed. RESULTS All 14 patients had cingulate epilepsy confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. They were divided into 3 groups based on anatomical location of the lesion and corresponding seizure semiology. In the posterior cingulate group, all 4 patients had electroclinical findings suggestive of temporal origin of the epilepsy. The anterior cingulate cases were divided into a typical (Bancaud) group (6 cases with hypermotor seizures and infrequent generalization with the presence of fear, laughter, or severe interictal personality changes) and an atypical group (4 cases presenting with simple motor seizures and a tendency for more frequent generalization and less-favorable long-term surgical outcome). All atypical cases were associated with an underlying infiltrative astrocytoma. CONCLUSIONS AND RELEVANCE Posterior cingulate gyrus epilepsy may

Validation of reference genes for quantitative gene expression analysis in experimental epilepsy.

PubMed

Sadangi, Chinmaya; Rosenow, Felix; Norwood, Braxton A

2017-12-01

To grasp the molecular mechanisms and pathophysiology underlying epilepsy development (epileptogenesis) and epilepsy itself, it is important to understand the gene expression changes that occur during these phases. Quantitative real-time polymerase chain reaction (qPCR) is a technique that rapidly and accurately determines gene expression changes. It is crucial, however, that stable reference genes are selected for each experimental condition to ensure that accurate values are obtained for genes of interest. If reference genes are unstably expressed, this can lead to inaccurate data and erroneous conclusions. To date, epilepsy studies have used mostly single, nonvalidated reference genes. This is the first study to systematically evaluate reference genes in male Sprague-Dawley rat models of epilepsy. We assessed 15 potential reference genes in hippocampal tissue obtained from 2 different models during epileptogenesis, 1 model during chronic epilepsy, and a model of noninjurious seizures. Reference gene ranking varied between models and also differed between epileptogenesis and chronic epilepsy time points. There was also some variance between the four mathematical models used to rank reference genes. Notably, we found novel reference genes to be more stably expressed than those most often used in experimental epilepsy studies. The consequence of these findings is that reference genes suitable for one epilepsy model may not be appropriate for others and that reference genes can change over time. It is, therefore, critically important to validate potential reference genes before using them as normalizing factors in expression analysis in order to ensure accurate, valid results. © 2017 Wiley Periodicals, Inc.

Tangeretin alters neuronal apoptosis and ameliorates the severity of seizures in experimental epilepsy-induced rats by modulating apoptotic protein expressions, regulating matrix metalloproteinases, and activating the PI3K/Akt cell survival pathway.

PubMed

Guo, Xiao-Qian; Cao, Yu-Ling; Hao, Fang; Yan, Zhong-Rui; Wang, Mei-Ling; Liu, Xue-Wu

2017-09-01

Epilepsy is complex neural disarray categorized by recurring seizures. Despite recent advances in pharmacotherapies for epilepsy, its treatment remains a challenge due to the contrary effects of the drugs. As a result, the identification of novel anti-epileptic drugs (AEDs) with neuroprotective properties and few side effects is of great value. Thus, the present study assessed the treatment effects of tangeretin using a rat model of pilocarpine-induced epilepsy. Separate groups of male Wistar rats received oral administrations of tangeretin at 50, 100, or 200mg/kg for 10 days and then, on the 10th day, they received an intraperitoneal injection of pilocarpine (30mg/kg). Subsequently, neuronal degeneration and apoptosis were assessed using Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay procedures. Additionally, the expressions of phosphatidylinositol-3-kinase (PI3K/Akt) pathway proteins, cleaved caspase-3, Bad, Bcl-2, Bcl-xL, and Bax were determined using Western blot analyses. Tangeretin reduced the seizure scores and latency to first seizure of the rats and effectively activated the pilocarpine-induced suppression of PI3K/Akt signaling. Additionally, tangeretin effectively regulated the levels of apoptosis-inducing factor (AIF) in mitochondria as well as the expressions of apoptotic pathway proteins. Seizure-induced elevations in the activities and expressions of matrix metalloproteinases (MMPs)-2 and -9 were also modulated. The present results indicate that tangeretin exerted potent neuroprotective effects against pilocarpine-induced seizures via the activation of PI3K/Akt signaling and the regulation of MMPs. Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Review: Hippocampal sclerosis in epilepsy: a neuropathology review

PubMed Central

Thom, Maria

2014-01-01

Hippocampal sclerosis (HS) is a common pathology encountered in mesial temporal lobe epilepsy (MTLE) as well as other epilepsy syndromes and in both surgical and post-mortem practice. The 2013 International League Against Epilepsy (ILAE) classification segregates HS into typical (type 1) and atypical (type 2 and 3) groups, based on the histological patterns of subfield neuronal loss and gliosis. In addition, granule cell reorganization and alterations of interneuronal populations, neuropeptide fibre networks and mossy fibre sprouting are distinctive features of HS associated with epilepsies; they can be useful diagnostic aids to discriminate from other causes of HS, as well as highlighting potential mechanisms of hippocampal epileptogenesis. The cause of HS remains elusive and may be multifactorial; the contribution of febrile seizures, genetic susceptibility, inflammatory and neurodevelopmental factors are discussed. Post-mortem based research in HS, as an addition to studies on surgical samples, has the added advantage of enabling the study of the wider network changes associated with HS, the long-term effects of epilepsy on the pathology and associated comorbidities. It is likely that HS is heterogeneous in aspects of its cause, epileptogenetic mechanisms, network alterations and response to medical and surgical treatments. Future neuropathological studies will contribute to better recognition and understanding of these clinical and patho-aetiological subtypes of HS. PMID:24762203

Managing Epilepsy

MedlinePlus

... Epilepsy Well Network The Managing Epilepsy Well (MEW) Network is a group of academic Prevention Research Centers that conduct studies related to epilepsy self-management. Read about MEW Network projects and how they are improving health and ...

Decreased astroglial monocarboxylate transporter 4 expression in temporal lobe epilepsy.

PubMed

Liu, Bei; Niu, Le; Shen, Ming-Zhi; Gao, Lei; Wang, Chao; Li, Jie; Song, Li-Jia; Tao, Ye; Meng, Qiang; Yang, Qian-Li; Gao, Guo-Dong; Zhang, Hua

2014-10-01

Efflux of monocaroxylates like lactate, pyruvate, and ketone bodies from astrocytes through monocarboxylate transporter 4 (MCT4) supplies the local neuron population with metabolic intermediates to meet energy requirements under conditions of increased demand. Disruption of this astroglial-neuron metabolic coupling pathway may contribute to epileptogenesis. We measured MCT4 expression in temporal lobe epileptic foci excised from patients with intractable epilepsy and in rats injected with pilocarpine, an animal model of temporal lobe epilepsy (TLE). Cortical MCT4 expression levels were significantly lower in TLE patients compared with controls, due at least partially to MCT4 promoter methylation. Expression of MCT4 also decreased progressively in pilocarpine-treated rats from 12 h to 14 days post-administration. Underexpression of MCT4 in cultured astrocytes induced by a short hairpin RNA promoted apoptosis. Knockdown of astrocyte MCT4 also suppressed excitatory amino acid transporter 1 (EAAT1) expression. Reduced MCT4 and EAAT1 expression by astrocytes may lead to neuronal hyperexcitability and epileptogenesis in the temporal lobe by reducing the supply of metabolic intermediates and by allowing accumulation of extracellular glutamate.

Novel Frontiers in Epilepsy Treatments: Preventing Epileptogenesis by Targeting Inflammation

PubMed Central

D'Ambrosio, Raimondo; Eastman, Clifford L.; Fattore, Cinzia; Perucca, Emilio

2014-01-01

Currently available epilepsy drugs only affect the symptoms (seizures), and there is a need for innovative treatments that target the underlying disease. Increasing evidence points to inflammation as a potentially important mechanism in epileptogenesis. In the last decade, a new generation of etiologically realistic syndrome-specific experimental models have been developed which are expected to capture the epileptogenic mechanisms operating in the corresponding patient populations, and to exhibit similar treatment-responsiveness. Recently, an intervention known have broad-ranging anti-inflammatory effects (selective brain cooling) has been found to prevent the development of spontaneously occurring seizures in an etiologically realistic rat model of post-traumatic epilepsy. Several drugs used clinically for other indications also have the potential for inhibiting inflammation, and should be investigated for anti-epileptogenic activity in these models. If results of such studies are positive, these compounds could enter rapidly Phase III trials in patients at high risk of developing epilepsy. PMID:23738999

Partial monosomy Xq(Xq23 --> qter) and trisomy 4p(4p15.33 --> pter) in a woman with intractable focal epilepsy, borderline intellectual functioning, and dysmorphic features.

PubMed

Bartocci, Arnaldo; Striano, Pasquale; Mancardi, Maria Margherita; Fichera, Marco; Castiglia, Lucia; Galesi, Ornella; Michelucci, Roberto; Elia, Maurizio

2008-06-01

Studies of epilepsy associated with chromosomal abnormalities may provide information about clinical and EEG phenotypes and possibly to identify new epilepsy genes. We describe a female patient with intractable focal epilepsy, borderline intellectual functioning, and facial dysmorphisms, in whom genetic study (i.e., karyotype and array-CGH analysis) revealed a distal trisomy 4p and distal monosomy Xq. Although any genetic hypothesis remains speculative, several genes are located in the 4p chromosome segment involved in the rearrangement, some of which may be related to epilepsy.

DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy.

PubMed

Striano, Pasquale; Serioli, Elena; Santulli, Lia; Manna, Ida; Labate, Angelo; Dazzo, Emanuela; Pasini, Elena; Gambardella, Antonio; Michelucci, Roberto; Striano, Salvatore; Nobile, Carlo

2015-10-01

Mutations in the DEPDC5 (DEP domain-containing protein 5) gene are a major cause of familial focal epilepsy with variable foci (FFEVF) and are predicted to account for 12-37% of families with inherited focal epilepsies. To assess the clinical impact of DEPDC5 mutations in familial temporal lobe epilepsy, we screened a collection of Italian families with either autosomal dominant lateral temporal epilepsy (ADLTE) or familial mesial temporal lobe epilepsy (FMTLE). The probands of 28 families classified as ADLTE and 17 families as FMTLE were screened for DEPDC5 mutations by whole exome or targeted massive parallel sequencing. Putative mutations were validated by Sanger sequencing. We identified a DEPDC5 nonsense mutation (c.918C>G; p.Tyr306*) in a family with two affected members, clinically classified as FMTLE. The proband had temporal lobe seizures with prominent psychic symptoms (déjà vu, derealization, and forced thoughts); her mother had temporal lobe seizures, mainly featuring visceral epigastric auras and anxiety. In total, we found a single DEPDC5 mutation in one of (2.2%) 45 families with genetic temporal lobe epilepsy, a proportion much lower than that reported in other inherited focal epilepsies. © 2015 The Authors. Epilepsia published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy.

Interleukin-1β causes fluoxetine resistance in an animal model of epilepsy-associated depression.

PubMed

Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman; Shin, Don; Burke, Teresa F; Mazarati, Andréy M

2012-04-01

Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.

Prioritization of Epilepsy Associated Candidate Genes by Convergent Analysis

PubMed Central

Jia, Peilin; Ewers, Jeffrey M.; Zhao, Zhongming

2011-01-01

Background Epilepsy is a severe neurological disorder affecting a large number of individuals, yet the underlying genetic risk factors for epilepsy remain unclear. Recent studies have revealed several recurrent copy number variations (CNVs) that are more likely to be associated with epilepsy. The responsible gene(s) within these regions have yet to be definitively linked to the disorder, and the implications of their interactions are not fully understood. Identification of these genes may contribute to a better pathological understanding of epilepsy, and serve to implicate novel therapeutic targets for further research. Methodology/Principal Findings In this study, we examined genes within heterozygous deletion regions identified in a recent large-scale study, encompassing a diverse spectrum of epileptic syndromes. By integrating additional protein-protein interaction data, we constructed subnetworks for these CNV-region genes and also those previously studied for epilepsy. We observed 20 genes common to both networks, primarily concentrated within a small molecular network populated by GABA receptor, BDNF/MAPK signaling, and estrogen receptor genes. From among the hundreds of genes in the initial networks, these were designated by convergent evidence for their likely association with epilepsy. Importantly, the identified molecular network was found to contain complex interrelationships, providing further insight into epilepsy's underlying pathology. We further performed pathway enrichment and crosstalk analysis and revealed a functional map which indicates the significant enrichment of closely related neurological, immune, and kinase regulatory pathways. Conclusions/Significance The convergent framework we proposed here provides a unique and powerful approach to screening and identifying promising disease genes out of typically hundreds to thousands of genes in disease-related CNV-regions. Our network and pathway analysis provides important implications for the

Prioritization of epilepsy associated candidate genes by convergent analysis.

PubMed

Jia, Peilin; Ewers, Jeffrey M; Zhao, Zhongming

2011-02-24

Epilepsy is a severe neurological disorder affecting a large number of individuals, yet the underlying genetic risk factors for epilepsy remain unclear. Recent studies have revealed several recurrent copy number variations (CNVs) that are more likely to be associated with epilepsy. The responsible gene(s) within these regions have yet to be definitively linked to the disorder, and the implications of their interactions are not fully understood. Identification of these genes may contribute to a better pathological understanding of epilepsy, and serve to implicate novel therapeutic targets for further research. In this study, we examined genes within heterozygous deletion regions identified in a recent large-scale study, encompassing a diverse spectrum of epileptic syndromes. By integrating additional protein-protein interaction data, we constructed subnetworks for these CNV-region genes and also those previously studied for epilepsy. We observed 20 genes common to both networks, primarily concentrated within a small molecular network populated by GABA receptor, BDNF/MAPK signaling, and estrogen receptor genes. From among the hundreds of genes in the initial networks, these were designated by convergent evidence for their likely association with epilepsy. Importantly, the identified molecular network was found to contain complex interrelationships, providing further insight into epilepsy's underlying pathology. We further performed pathway enrichment and crosstalk analysis and revealed a functional map which indicates the significant enrichment of closely related neurological, immune, and kinase regulatory pathways. The convergent framework we proposed here provides a unique and powerful approach to screening and identifying promising disease genes out of typically hundreds to thousands of genes in disease-related CNV-regions. Our network and pathway analysis provides important implications for the underlying molecular mechanisms for epilepsy. The strategy can be

Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy.

PubMed

Kaur, Harpreet; Patro, Ishan; Tikoo, Kulbhushan; Sandhir, Rajat

2015-10-01

Evidence suggests that glial cells play a critical role in inflammation in chronic epilepsy, contributing to perpetuation of seizures and cognitive dysfunctions. The present study was designed to evaluate the beneficial effect of curcumin, a polyphenol with pleiotropic properties, on cognitive deficits and inflammation in chronic epilepsy. Kindled model of epilepsy was induced by administering sub-convulsive dose of pentylenetetrazole (PTZ) at 40 mg/kg, i.p. every alternative day for 30 days to Wistar rats. The animals were assessed for cognitive deficits by Morris water maze and inflammatory response in terms of microglial and astrocyte activation. PTZ treated animals had increased escape latency suggesting impaired cognitive functions. Further, an increased expression of astrocyte (GFAP) and microglial (Iba-1) activation markers were observed in terms of mRNA and protein levels in the PTZ treated animals. Concomitantly, mRNA and protein levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokine (MCP-1) were increased in hippocampus and cortex. Immunoreactivity to anti-GFAP and anti-Iba-1 antibodies was also enhanced in hippocampus and cortex suggesting gliosis in PTZ treated animals. However, curcumin administration at a dose of 100 mg/kg to PTZ animals prevented cognitive deficits. A significant decrease in pro-inflammatory cytokines and chemokine expression was observed in hippocampus and cortex of PTZ treated rats supplemented with curcumin. In addition, curcumin also attenuated increased expression of GFAP and Iba-1 in animals with PTZ induced chronic epilepsy. Moreover, immunohistochemical analysis also showed significant reduction in number of activated glial cells on curcumin administration to PTZ treated animals. Taken together, these findings suggest that curcumin is effective in attenuating glial activation and ameliorates cognitive deficits in chronic epilepsy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epilepsy phenotypes in siblings with Norrie disease.

PubMed

Okumura, Akihisa; Arai, Eisuke; Kitamura, Yuri; Abe, Shinpei; Ikeno, Mitsuru; Fujimaki, Takuro; Yamamoto, Toshiyuki; Shimizu, Toshiaki

2015-11-01

Norrie disease is an X-linked recessive disorder that is characterized by congenital blindness. Although epileptic seizures are observed in some patients with Norrie disease, little is known about this phenomenon. Here, we report the manifestation of epilepsy in siblings with Norrie disease to increase our knowledge of epilepsy in this condition. Three brothers with congenital blindness were diagnosed with Norrie disease after genetic analyses indicated the deletion of exon 2 of the NDP gene. The eldest brother had suffered from epileptic seizures since the age of 11years, and his seizures were resistant to antiepileptic drugs. Although the second brother had no epileptic seizures, the youngest sibling had experiences epileptic seizures since the age of 8years. His seizures were controlled using lamotrigine and levetiracetam. An electroencephalography (EEG) revealed epileptiform discharges in the occipital areas in all three brothers. A study of these patients will increase our knowledge of epilepsy in patients with Norrie disease. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Personalized translational epilepsy research - Novel approaches and future perspectives: Part I: Clinical and network analysis approaches.

PubMed

Rosenow, Felix; van Alphen, Natascha; Becker, Albert; Chiocchetti, Andreas; Deichmann, Ralf; Deller, Thomas; Freiman, Thomas; Freitag, Christine M; Gehrig, Johannes; Hermsen, Anke M; Jedlicka, Peter; Kell, Christian; Klein, Karl Martin; Knake, Susanne; Kullmann, Dimitri M; Liebner, Stefan; Norwood, Braxton A; Omigie, Diana; Plate, Karlheinz; Reif, Andreas; Reif, Philipp S; Reiss, Yvonne; Roeper, Jochen; Ronellenfitsch, Michael W; Schorge, Stephanie; Schratt, Gerhard; Schwarzacher, Stephan W; Steinbach, Joachim P; Strzelczyk, Adam; Triesch, Jochen; Wagner, Marlies; Walker, Matthew C; von Wegner, Frederic; Bauer, Sebastian

2017-11-01

Despite the availability of more than 15 new "antiepileptic drugs", the proportion of patients with pharmacoresistant epilepsy has remained constant at about 20-30%. Furthermore, no disease-modifying treatments shown to prevent the development of epilepsy following an initial precipitating brain injury or to reverse established epilepsy have been identified to date. This is likely in part due to the polyetiologic nature of epilepsy, which in turn requires personalized medicine approaches. Recent advances in imaging, pathology, genetics and epigenetics have led to new pathophysiological concepts and the identification of monogenic causes of epilepsy. In the context of these advances, the First International Symposium on Personalized Translational Epilepsy Research (1st ISymPTER) was held in Frankfurt on September 8, 2016, to discuss novel approaches and future perspectives for personalized translational research. These included new developments and ideas in a range of experimental and clinical areas such as deep phenotyping, quantitative brain imaging, EEG/MEG-based analysis of network dysfunction, tissue-based translational studies, innate immunity mechanisms, microRNA as treatment targets, functional characterization of genetic variants in human cell models and rodent organotypic slice cultures, personalized treatment approaches for monogenic epilepsies, blood-brain barrier dysfunction, therapeutic focal tissue modification, computational modeling for target and biomarker identification, and cost analysis in (monogenic) disease and its treatment. This report on the meeting proceedings is aimed at stimulating much needed investments of time and resources in personalized translational epilepsy research. Part I includes the clinical phenotyping and diagnostic methods, EEG network-analysis, biomarkers, and personalized treatment approaches. In Part II, experimental and translational approaches will be discussed (Bauer et al., 2017) [1]. Copyright © 2017 Elsevier Inc

[Linkage analysis in an extended multigenerational family segregating for idiopathic epilepsy].

PubMed