Childhood Absence Epilepsy Patients Research Articles

Neurocognitive Profiles in Childhood Absence Epilepsy.

Although neuropsychological studies have demonstrated specific cognitive impairments in children with childhood absence epilepsy (CAE), the potential role of the frontal lobe in these cognitive deficits remains unclear. We therefore evaluated cognitive functions related to and unrelated to the functionality of the frontal lobe in childhood absence epilepsy patients and control subjects. Thirty-seven childhood absence epilepsy patients and 37 age- and gender-matched healthy control subjects were recruited and assessed using a computerized neuropsychological test battery. Childhood absence epilepsy patients, especially a drug-naïve subgroup, showed cognitive deficits in reasoning, visual attention, and executive function, which are typical cognitive functions of the frontal lobe. In contrast, treated childhood absence epilepsy patients only exhibited cognitive deficits in visual attention. There were no significant between-group differences for other cognitive tests. Our findings suggest that frontal lobe-related cognitive deficits represent the characteristic neuropsychological profile associated with childhood absence epilepsy.

Structural Abnormalities in Childhood Absence Epilepsy: Voxel-Based Analysis Using Diffusion Tensor Imaging.

Purpose: Childhood absence epilepsy (CAE) is a common syndrome of idiopathic generalized epilepsy. However, little is known about the brain structural changes in this type of epilepsy, especially in the default mode network (DMN) regions. This study aims at using the diffusion tensor imaging (DTI) technique to quantify structural abnormalities of DMN nodes in CAE patients.Method: DTI data were acquired in 14 CAE patients (aged 8.64 ± 2.59 years, seven females and seven males) and 16 age- and sex-matched healthy controls. The data were analyzed using voxel-based analysis (VBA) and statistically compared between patients and controls. Pearson correlation was explored between altered DTI metrics and clinical parameters. The difference of brain volumes between patients and controls were also tested using unpaired t-test.Results: Patients showed significant increase of mean diffusivity (MD) and radial diffusivity (RD) in left medial prefrontal cortex (MPFC), and decrease of fractional anisotropy (FA) in left precuneus and axial diffusivity (AD) in both left MPFC and precuneus. In correlation analysis, MD value from left MPFC was positively associated with duration of epilepsy. Neither the disease duration nor the seizure frequency showed significant correlation with FA values. Between-group comparison of brain volumes got no significant difference.Conclusion: The findings indicate that structural impairments exist in DMN regions in children suffering from absence epilepsy and MD values positively correlate with epilepsy duration. This may contribute to understanding the pathological mechanisms of chronic neurological deficits and promote the development of new therapies for this disorder.

Altered EEG resting-state effective connectivity in drug-naïve childhood absence epilepsy

ObjectiveWe investigated interictal EEG activity in patients with childhood absence seizures with the aim of detecting markers of network defects generating “idiopathic” hyperexcitability in this form of epilepsy. MethodsWe included 11 drug-naïve patients with childhood absence epilepsy (CAE), and 11 age matched controls (CTRL). We analyzed interictal EEG using partial directed coherence (PDC), a connectivity estimator in frequency domain based on autoregressive multivariate (MVAR) modeling giving the advantage of indicating the direction and strength of the interactions between multiple variables. ResultsOur results revealed the presence of an abnormal cortico-cortical network occurring in the interictal condition in CAE and involving a large span of frequencies, with prominence in the alpha band; the most evident finding was a highly significant increase of out-going connectivity involving frontal and central cortical areas in CAE patients compared to CTRL subjects. ConclusionsOur observation indicates that, in interictal conditions, a distorted network characterizes CAE, and a hyperconnected network is already detectable under resting conditions in the delta, theta and alpha bands. SignificanceThe increased interictal EEG connectivity demonstrated here provides support for a persistent abnormal relationship between the thalamus and a hyperexcitable cortex outside the ictal phase.

Temporal current-source of spikes suggests initial treatment failure in childhood absence epilepsy

PurposeIn addition to the frontal lobe, the temporal lobe may also be involved in typical absence seizures. However, few studies have addressed the relationship between this involvement and drug responsiveness in childhood absence epilepsy (CAE). In this study, we observed the current-source distribution (CSD) of generalized spike-and-wave discharges (GSWDs) and investigated the relationship between temporal lobe involvement in the CSD and responsiveness to initial antiepileptic drug (AED) in CAE. MethodSeventeen consecutive patients with CAE were retrospectively enrolled in the study. Patients were divided into an initial-response group and an initial-failure group, according to their responsiveness to the initial AED treatment. For each patient, the spike peak CSD of an averaged GSWD was obtained from the initial electroencephalogram. We compared the incidence of temporal involvement in the CSD between the two groups. We also compared clinical variables, including age of onset, gender, type and dose of first AED, time to cessation of clinical seizures, and seizure-free status. ResultsThe initial-response and initial-failure groups contained 12 and five patients, respectively. Temporal lobe involvement was more frequent (80% vs. 17%, p=0.03), and time to cessation of clinical seizures was more prolonged (median 2.5 months vs. 8 months, p<0.01) in the initial-failure than in the initial-response group. None of the other variables studied differed between groups. ConclusionInitial AED failure was associated with temporal involvement in the CSD of CAE patients. This electrophysiological information may be helpful in clinical practice by estimating the efficacy of initial AED treatment in AED-naïve CAE patients in advance.

CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy.

CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.

Default mode network in childhood absence epilepsy by 3.0T magnetic resonance imaging

To explore the default mode network (DMN) in childhood absence epilepsy (CAE) patients and examine their correlations between functional connectivity (FC) and clinical characteristics. Fourteen CAE patients and 14 healthy volunteers were prospectively recruited from Henan Provincial People's Hospital from September 2012 to June 2014. FC in DMN of each group, between-group comparison of DMN FC and their relationships with clinical characteristics were respectively analyzed with 3.0T resting-state functional magnetic resonance imaging (fMRI) FC analysis seeding at bilateral precuneus/posterior cingulate cortex (PCC). Seeding at bilateral precuneus/posterior cingulate cortex (PCC), positive connection was found in bilateral angular gyrus, bilateral superior parietal gyrus, bilateral superior and middle frontal gyrus, bilateral superior medial frontal gyrus, bilateral middle temporal gyrus and bilateral superior and middle occipital gyrus in controls. However, positive connection in CAE patients was observed in bilateral superior parietal gyrus and bilateral superior occipital gyrus. Between-group analysis of DMN connectivity revealed a reduction of DMN FC in bilateral medial orbitofrontal cortex, bilateral anterior cingulate cortex, bilateral superior frontal gyrus, bilateral middle frontal gyrus and left caudate in CAE patients. Moreover, increased DMN FC was present in right paracentral lobule and right middle cingulate gyrus. FC between PCC and bilateral medial orbitofrontal cortex or bilateral superior/middle frontal gyrus correlated negatively with disease duration, but there was no correlation with seizure frequency or initial age. Brain's default mode network in childhood absence epilepsy is impaired, presumably, as a result of unconsciousness and cognitive impairment during absence seizure. Abnormal DMN activities may be a biomaker of disease progress in absence epilepsy.

Study on EEG of childhood absence epilepsy

Objective To investigate the characteristics of electroencephalograms （ EEGs ） of patients with childhood absence epilepsy （ CAE ） .Methods EEG of 46 patients with CAE were analyzed .Results Of 46 patients,there were 44 cases （95.6%） with guided bilateral symmetry 3Hz spike-and-wave.16 cases were character-ized by multiple spike-and-wave on the 3Hz spike and slow wave;and the centrotemporal spikes was found in 1 case. Additionally,the 3Hzδactivity in occipital region has been traced in 34 cases of these 46 patients.Conclusion In general,the EEGs of CAE patients have typical characteristics ,and few of them showed atypical manifestation ,which must be verified by clinical attention . Key words: Childhood absence epilepsy ; 3 Hz spike-and-wave ; Electroencephalogram

Transition issues for benign epilepsy with centrotemporal spikes, nonlesional focal epilepsy in otherwise normal children, childhood absence epilepsy, and juvenile myoclonic epilepsy.

This chapter covers the syndromes of benign epilepsy with centrotemporal spikes (BECTS), nonlesional focal epilepsy in otherwise normal children (NLFN), and the genetic generalized epilepsies. BECTS is an epilepsy syndrome that always enters terminal remission before the general age of a planned transition of adolescents. This is also the case for the majority (65%) of those with childhood absence epilepsy (CAE). Approximately 15% of patients with CAE who initially remit during their childhood years later develop juvenile myoclonic epilepsy (JME) as teenagers. They will have many issues for continuing medical care and transition, because their seizure disorder generally persists into adulthood. A significant minority of NLFN (~35%) and most patients with JME continue to have active epilepsy into adulthood. In addition, CAE, JME, and NLFN patients are at risk of a number of significant adverse social outcomes that require ongoing advice and counseling.

Altered spontaneous activity in treatment-naive childhood absence epilepsy revealed by Regional Homogeneity

PurposeTo explore the differences in regional spontaneous activities throughout the whole brain by the Regional Homogeneity (ReHo) method in untreated childhood absence epilepsy (CAE), in order to understand the neuro-pathophysiological mechanism of function impairments in CAE. MethodsThe rest-functional MRI was used to measure the ReHo in 16 patients with untreated CAE and 16 age- and sex-matched healthy controls. The correlations between the ReHo at each voxel of the whole brain and duration of epilepsy were analyzed.Results: Compared with healthy controls, we found that ReHo was decreased in bilateral thalamus, caudate, posterior lobe of cerebellum and areas mainly in the default mode network (DMN) (including precuneus and posterior cingulate cortex-PCC, bilateral inferior lateral parietal lobule). The increase of ReHo was found in bilateral insula, left occipital cortex. Moreover, a correlation analysis of the ReHo measurement versus the epilepsy duration was performed, and highly positive correlation was observed in precuneus/PCC and supplementary motor area (SMA). SignificanceThe current findings demonstrated alterations of ReHo in the striato-thalamo-cortical network in drug naïve CAE subjects during interictal resting state. Some regions with decreased ReHo followed the pattern of ‘default’ state of brain function. In addition, positive correlations between the ReHo values in the precuneus/PCC and SMA and the disease duration were identified. These results indicate that the involvement of these regions may be related to the pathomechanisms of seizure generation and the neurological deficits observed in CAE patients. ReHo has demonstrated the capability to characterize spontaneous brain dysfunction in epilepsy.

Absence epilepsy subnetworks revealed by event‐related independent components analysis of functional magnetic resonance imaging

The aim of this study was to provide better spatiotemporal description of the brain activity observed during generalized spike-and-wave (GSW) discharges. Simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) studies of these epileptiform events have shown regional differences in the timing of fMRI signal changes, which suggests activities within multiple interacting networks rather than a single unified network. EEG-fMRI recordings from eight patients with childhood absence epilepsy (CAE) were studied using event-related independent components analysis (eICA). This technique separates the fMRI signal changes observed during GSW discharges into different spatial components, each showing different event-related timing. Unlike standard independent components analysis (ICA), which is applied to the entire fMRI time series, the eICA method is applied only to the event-related time courses at each voxel, which means that only a small number of components are generated that are all explicitly related to the event of interest. Six eICA components were identified, representing distinct GSW-related subnetworks. Activations were detected in a number of brain regions, including the striatum, which have not previously been reported in association with GSW in CAE patients. The eICA results support previous findings that the earliest activity associated with GSW may be in posterior cortical regions and provide new evidence that the thalamostriate network may play a more important role in the generation of GSW than suggested by previous studies.

Attention impairment in childhood absence epilepsy: An impulsivity problem?

Although attention problems have often been described in children with childhood absence epilepsy (CAE), the use of different methodological approaches, neuropsychological tests, and heterogeneous experimental groups has prevented identification of the selective areas of attention deficit in this population. In this study, we investigated several components of attention in children with CAE using a unique computerized test battery for attention performance. Participants included 24 patients with CAE and 24 controls matched for age and sex. They were tested with a computerized test battery, which included the following tasks: selective attention, impulsivity, focused attention, divided attention, alertness, and vigilance. Compared with healthy controls, patients with CAE made more commission errors in the Go/No-Go task and more omission errors in the divided attention task. Childhood absence epilepsy patients also showed decreased reaction times in measures of selective attention and a great variability of reaction times in alertness and Go/No-Go tasks.Our findings suggest that patients with CAE were impaired in tonic and phasic alertness, divided attention, selective attention, and impulsivity.

Altered resting‐state connectivity during interictal generalized spike‐wave discharges in drug‐naïve childhood absence epilepsy

To investigate the intrinsic brain connections at the time of interictal generalized spike-wave discharges (GSWDs) to understand their mechanism of effect on brain function in untreated childhood absence epilepsy (CAE). The EEG-functional MRI (fMRI) was used to measure the resting state functional connectivity during interictal GSWDs in drug-naïve CAE, and three different brain networks-the default mode network (DMN), cognitive control network (CCN), and affective network (AN)-were investigated. Cross-correlation functional connectivity analysis with priori seed revealed decreased functional connectivity within each of these three networks in the CAE patients during interictal GSWDS. It included precuneus-dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), and inferior parietal lobule in the DMN; DLPFC-inferior frontal junction (IFJ), and pre-supplementary motor area (pre-SMA) subregions connectivity disruption in CCN; ACC-ventrolateral prefrontal cortex (VLPFC) and DMPFC in AN; There were also some regions, primarily the parahippcampus, paracentral in AN, and the left frontal mid orb in the CCN, which showed increased connectivity. The current findings demonstrate significant alterations of resting-state networks in drug naïve CAE subjects during interictal GSWDs and interictal GSWDs can cause dysfunction in specific networks important for psychosocial function. Impairment of these networks may cause deficits both during and between seizures. Our study may contribute to the understanding of neuro-pathophysiological mechanism of psychosocial function impairments in patients with CAE.

Cortical and thalamic resting-state functional connectivity is altered in childhood absence epilepsy

Functional imaging studies have identified a common network of brain regions that activate and deactivate during the generalised spike wave (GSW) discharges of childhood absence epilepsy (CAE). Functional connectivity within this network is also altered during the resting state. In this study our aim was to assess functional connectivity throughout the whole brain of patients with CAE. We studied a group of eleven patients with untreated CAE and eleven matched controls using resting-state fMRI. We measured functional connectivity between every pair of voxels and generated images of "whole-brain" functional connectivity by counting the number of functional connections of each voxel. There were marked differences between CAE patients and controls in whole brain functional connectivity. The patients had decreased connectivity in the thalamus and basal ganglia and increased connectivity in the medial occipital cortex. These findings suggest enduring changes in function of the thalamus and the cortex in CAE patients even when there is no GSW activity. These human functional connectivity data support the findings in animal models of involvement of cortex as well as thalamus in absence epilepsy.

White matter impairment in the basal ganglia-thalamocortical circuit of drug-naïve childhood absence epilepsy

It is unknown whether white matter abnormalities exist in childhood absence epilepsy (CAE), a syndrome of idiopathic epilepsy (IGE). Diffusion tensor imaging (DTI) can noninvasively quantify white matter integrity. This study used DTI to investigate abnormal changes in white matter of untreated CAE patients. Subjects included nine patients with untreated CAE and nine age-and sex-matched healthy controls. Diffusion tensor imaging parameters were voxel based and statistically compared between patients and controls. The correlations between DTI parameters in regions of interest (ROIs) and age of seizure onset or duration of epilepsy were analyzed. Untreated CAE patients had a significantly higher fractional anisotropy (FA) value in the bilateral thalamus, anterior corpus callosum and upper brainstem, while also displaying a lower FA value in prefrontal white matter, anterior cingulate, and bilateral posterior limbs of the internal capsule compared to control subjects. An increase in mean diffusivity (MD) value was observed in parietal lobe white matter, prefrontal white matter, and posterior cerebellar hemispheres, in addition to subcortical structures including bilateral putamen and posterior limb of internal capsule. MD significant correlations between ROI diffusion parameters and the duration of the disease or the age of onset. The results showed white matter integrity impairment in the basal ganglia-thalamocortical circuit of drug-naïve CAE patients. These abnormalities in white matter may be related to increased cortical excitability and cause cognitive, linguistic, and behavioral/emotional deficits both during and between seizures.

Mutation Screening of the γ-Aminobutyric Acid Type-A Receptor Subunit γ2 Gene in Korean Patients with Childhood Absence Epilepsy

Background and PurposeSince the γ-aminobutyric acid type-A receptor subunit γ2 gene (GABRG2) mutation was discovered in an Australian family with childhood absence epilepsy (CAE) and febrile convulsions, a few screening studies for the GABRG2 mutation have been conducted in sporadic individuals with CAE from other ethnic groups. The aim of this study was to determine whether or not the previously reported genetic mutations and single-nucleotide polymorphisms (SNPs) of GABRG2 can be reproduced in sporadic Korean individuals with CAE, compared to healthy Korean individuals.MethodsThirty-five children with CAE in Chonnam National University Hospital and healthy controls (n=207) were enrolled, and the medical records of patients with CAE were reviewed. CAE was diagnosed according to the Classification and Terminology of the International League Against Epilepsy. All nine exons of GABRG2 were directly sequenced. In addition, the two SNPs found in our CAE patients were analyzed: C315T in exon 3 (E3) and C588T in exon 5 (E5). The frequencies of the two SNPs in the CAE patients were compared with data from healthy controls (for E3 and E5) and from previously reported Korean population data (only for E3).ResultsNo mutation of GABRG2 was found in our CAE patients. In addition, the allele and genotype frequencies of the two polymorphisms did not differ significantly between CAE patients, healthy controls, and the Korean general population (p>0.05).ConclusionsOur study of sporadic Korean individuals with CAE found no evidence that GABRG2 contributes to the genetic basis of CAE.

Localization of epileptic foci in Children with childhood absence epilepsy by magnetoencephalography combined with synthetic aperture magnetometry

This present study was aimed to investigate the localizable diagnostic value of magnetoencephalography (MEG) combined with synthetic aperture magnetometry (SAM) in childhood absence epilepsy (CAE). Thirteen CAE patients underwent MEG detection at resting state and after hyperventilation, and then the epileptic foci were located by SAM. In the thirteen CAE patients, epileptic foci were found in five cases (38.5%), and they were all located in the bilateral frontal lobe, suggesting that the frontal lobe in some CAE patients may serve as the epileptic foci. Our findings indicate that MEG combined with SAM could be of diagnostic value in localizing the epileptic foci in certain CAE patients.

A pilot study of topiramate in childhood absence epilepsy

Evaluate the antiepileptic effect of topiramate monotherapy in childhood absence epilepsy (CAE). Childhood absence epilepsy patients aged 4-9 years were initiated with topiramate 15 or 25 mg/day, which was titrated upwards until patients were free of absence seizures. The primary efficacy outcome was seizure-free rates after a 12-week maintenance period. The study was terminated early due to lack of efficacy after enrollment of 12 patients. Four patients completed the study; two became clinically seizure-free, but without a significant reduction in the number of electrographic seizures. Six patients discontinued for lack of efficacy, none due to adverse events (AEs). Mean reduction in seizure count was seen on Days 22 (P = 0.0391) and 36 (P = 0.0156) and percentage of days with seizures decreased from baseline. Most AEs were mild. Although well-tolerated, this pilot study did not demonstrate an antiepileptic effect of topiramate monotherapy for treatment of CAE.

Distinguishing childhood absence epilepsy patients from controls by the analysis of their background brain electrical activity (II): A combinatorial optimization approach for electrode selection

In this sequel to our previous work [Rosso OA, Mendes A, Rostas JA, Hunter M, Moscato P. Distinguishing childhood absence epilepsy patients from controls by the analysis of their background brain electrical activity. J. Neurosci. Methods 2009;177:461–68], we extend the analysis of background electroencephalography (EEG), recorded with scalp electrodes in a clinical setting, in children with childhood absence epilepsy (CAE) and control individuals. The same set of individuals was considered—five CAE patients, all right-handed females and aged 6–8 years. The EEG was obtained using bipolar connections from a standard 10–20 electrode placement. The functional activity between electrodes was evaluated using a wavelet decomposition in conjunction with the Wootters distance. In the previous study, a Kruskal–Wallis statistical test was used to select the pairs of electrodes with differentiated behavior between CAE and control samples (classes). In this contribution, we present the results for a combinatorial optimization approach to select the pairs of electrodes. The new method produces a better separation between the classes, and at the same time uses a smaller number of features (pairs of electrodes). It managed to almost halve the number of features and also improves the separation between the CAE and control samples. The new results strengthen the hypothesis that mostly fronto-central electrodes carry useful information and patterns that can help to discriminate CAE cases from controls. Finally, we provide a comprehensive set of tests and in-depth explanation of the method and results.

Distinguishing childhood absence epilepsy patients from controls by the analysis of their background brain electrical activity

Background electroencephalography (EEG), recorded with scalp electrodes, in children with childhood absence epilepsy (CAE) and control individuals has been analyzed. We considered 5 CAE patients, all right-handed females and aged 6–8 years. The 15 control individuals had the same characteristics of the CAE ones, but presented a normal EEG. The EEG was obtained using bipolar connections from a standard 10–20 electrode placement (Fp1, Fp2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1 and O2). Recordings were undertaken in the resting state with eyes closed. EEG hallmarks of absence seizure activity are widely accepted, but there is a recognition that the bulk of interictal EEG in CAE appears normal to visual inspection. The functional activity between electrodes was evaluated using a wavelet decomposition in conjunction with the Wootters distance. Then, pairs of electrodes with differentiated behavior between CAE and controls were identified using a test statistic-based feature selection technique. This approach identified clear differences between CAE and healthy control background EEG in the frontocentral electrodes, as measured by Principal Component Analysis. The findings of this pilot study can have strong implications in future clinical practice.

Linkage and association analysis of CACNG3 in childhood absence epilepsy

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.