Glucose transporter-1 deficiency syndrome with extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant.

BACKGROUND AND PURPOSE: Glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1-DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1-DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant. METHODS: We present clinical and genetic features of a five-generation family with GLUT1-DS. RESULTS: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8-year-old proband, who also had drug-responsive absences associated with attention-deficit/hyperactivity disorder. His 52-year-old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core. CONCLUSIONS: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1-DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1-DS.

Predicting the therapeutic response to valproic acid in childhood absence epilepsy through electroencephalogram analysis using machine learning.

Childhood absence epilepsy (CAE) is a common type of idiopathic generalized epilepsy, manifesting as daily multiple absence seizures. Although seizures in most patients can be adequately controlled with first-line antiseizure medication (ASM), approximately 25 % of patients respond poorly to first-line ASM. In addition, an accurate method for predicting first-line medication responsiveness is lacking. We used the quantitative electroencephalogram (QEEG) features of patients with CAE along with machine learning to predict the therapeutic effects of valproic acid in this population. We enrolled 25 patients with CAE from multiple medical centers. Twelve patients who required additional medication for seizure control or who were shifted to another ASM and 13 patients who achieved seizure freedom with valproic acid within 6 months served as the nonresponder and responder groups. Using machine learning, we analyzed the interictal background EEG data without epileptiform discharge before ASM. The following features were analyzed: EEG frequency bands, Hjorth parameters, detrended fluctuation analysis, Higuchi fractal dimension, Lempel-Ziv complexity (LZC), Petrosian fractal dimension, and sample entropy (SE). We applied leave-one-out cross-validation with support vector machine, K-nearest neighbor (KNN), random forest, decision tree, Ada boost, and extreme gradient boosting, and we tested the performance of these models. The responders had significantly higher alpha band power and lower delta band power than the nonresponders. The Hjorth mobility, LZC, and SE values in the temporal, parietal, and occipital lobes were higher in the responders than in the nonresponders. Hjorth complexity was higher in the nonresponders than in the responders in almost all the brain regions, except for the leads FP1 and FP2. Using KNN classification with theta band power in the temporal lobe yielded optimal performance, with sensitivity of 92.31 %, specificity of 76.92 %, accuracy of 84.62 %, and area under the curve of 88.46 %.We used various EEG features along with machine learning to accurately predict whether patients with CAE would respond to valproic acid. Our method could provide valuable assistance for pediatric neurologists in selecting suitable ASM.

Efficacy of highly purified cannabidiol (CBD) in typical absence seizures: A pilot study.

OBJECTIVES: Clinical trials for typical absence seizures are notoriously difficult, because those seizures are clinically subtle and brief, so that seizure counts by caregivers are inaccurate. As a result, treatment options are limited. Currently, there are no published studies on the use of CBD in typical absence seizures. This pilot study aims to evaluate the efficacy of pharmaceutical grade CBD in typical absence seizures. METHODS: We prospectively enrolled 14 patients aged 6 years and older, diagnosed with typical absence seizures. A baseline 24-hour ambulatory EEG was conducted, followed by a second 24-hour EEG after 90 days of treatment. The outcome was an objective measure of spike-wave complexes (SWC) burden change from pre- to post- treatment. RESULTS: After taking CBD for 90 days, 9 (64.3%) patients had an increase in SWC (ranging from 8% to 2876.5%) and 5 (35.7%) had a decrease in SWC (ranging from 62.3% to 98.9%). Of the 5 patients who had a decrease, 3 (60%) were on concomitant ethosuximide (with or without other ASMs). All 3 patients on CBD and ethosuximide improved. CONCLUSIONS: Although based on a small subset of patients, our results suggest that CBD may not be effective for typical absence seizures. However, patients on concomitant ethosuximide or on CBD monotherapy were more likely to improve.

Differences in generation and maintenance between ictal and interictal generalized spike-and-wave discharges in childhood absence epilepsy: A magnetoencephalography study.

PURPOSE: Childhood absence epilepsy (CAE) is characterized by impaired consciousness and distinct electroencephalogram (EEG) patterns. However, interictal epileptiform discharges (IEDs) do not lead to noticeable symptoms. This study examines the disparity between ictal and interictal generalized spike-and-wave discharges (GSWDs) to determine the mechanisms behind CAE and consciousness. METHODS: We enrolled 24 patients with ictal and interictal GSWDs in the study. The magnetoencephalography (MEG) data were recorded before and during GSWDs at a sampling rate of 6000 Hz and analyzed across six frequency bands. The absolute and relative spectral power were estimated with the Minimum Norm Estimate (MNE) combined with the Welch technique. All the statistical analyses were performed using paired-sample tests. RESULTS: During GSWDs, the right lateral occipital cortex indicated a significant difference in the theta band (5-7 Hz) with stronger power (P = 0.027). The interictal group possessed stronger spectral power in the delta band (P < 0.01) and weaker power in the alpha band (P < 0.01) as early as 10 s before GSWDs in absolute and relative spectral power. Additionally, the ictal group revealed enhanced spectral power inside the occipital cortex in the alpha band and stronger spectral power in the right frontal regions within beta (15-29 Hz), gamma 1 (30-59 Hz), and gamma 2 (60-90 Hz) bands. CONCLUSIONS: GSWDs seem to change gradually, with local neural activity changing even 10 s before discharge. During GSWDs, visual afferent stimulus insensitivity could be related to the impaired response state in CAE. The inhibitory signal in the low-frequency band can shorten GSWD duration, thereby achieving seizure control through inhibitory effect strengthening.

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.

ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

Absence seizures and their relationship to depression and anxiety: Evidence for bidirectionality.

Absence seizures (AS), presenting as short losses of consciousness with staring spells, are a common manifestation of childhood epilepsy that is associated with behavioral, emotional, and social impairments. It has also been suggested that patients with AS are more likely to suffer from mood disorders such as depression and anxiety. This systematic review and meta-analysis synthesizes human and animal models that investigated mood disorders and AS. Of the 1019 scientific publications identified, 35 articles met the inclusion criteria for this review. We found that patients with AS had greater odds of developing depression and anxiety when compared to controls (odds ratio = 4.93, 95% confidence interval = 2.91-8.35, p < .01). The included studies further suggest a strong correlation between AS and depression and anxiety in the form of a bidirectional relationship. The current literature emphasizes that these conditions likely share underlying mechanisms, such as genetic predisposition, neurophysiology, and anatomical pathways. Further research will clarify this relationship and ensure more effective treatment for AS and mood disorders.

Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.

OBJECTIVE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. METHODS: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. RESULTS: Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. SIGNIFICANCE: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.

Adult loss of Cacna1a in mice recapitulates childhood absence epilepsy by distinct thalamic bursting mechanisms.

Inborn errors of CACNA1A-encoded P/Q-type calcium channels impair synaptic transmission, producing early and lifelong neurological deficits, including childhood absence epilepsy, ataxia and dystonia. Whether these impairments owe their pathologies to defective channel function during the critical period for thalamic network stabilization in immature brain remains unclear. Here we show that mice with tamoxifen-induced adult-onset ablation of P/Q channel alpha subunit (iKOp/q) display identical patterns of dysfunction, replicating the inborn loss-of-function phenotypes and, therefore demonstrate that these neurological defects do not rely upon developmental abnormality. Unexpectedly, unlike the inborn model, the adult-onset pattern of excitability changes believed to be pathogenic within the thalamic network is non-canonical. Specifically, adult ablation of P/Q channels does not promote Cacna1g-mediated burst firing or T-type calcium current (IT) in the thalamocortical relay neurons; however, burst firing in thalamocortical relay neurons remains essential as iKOp/q mice generated on a Cacna1g deleted background show substantially diminished seizure generation. Moreover, in thalamic reticular nucleus neurons, burst firing is impaired accompanied by attenuated IT. Interestingly, inborn deletion of thalamic reticular nucleus-enriched, human childhood absence epilepsy-linked gene Cacna1h in iKOp/q mice reduces thalamic reticular nucleus burst firing and promotes rather than reduces seizure, indicating an epileptogenic role for loss-of-function Cacna1h gene variants reported in human childhood absence epilepsy cases. Together, our results demonstrate that P/Q channels remain critical for maintaining normal thalamocortical oscillations and motor control in the adult brain, and suggest that the developmental plasticity of membrane currents regulating pathological rhythmicity is both degenerate and age-dependent.

Functional reorganization of brain regions into a network in childhood absence epilepsy: A magnetoencephalography study.

OBJECTIVE: Epilepsy is considered as a network disorder. However, it is unknown how normal brain activity develops into the highly synchronized discharging activity seen in disordered networks. This study aimed to explore the epilepsy brain network and the significant re-combined brain areas in childhood absence epilepsy (CAE). METHODS: Twenty-two children with CAE were recruited to study the neural source activity during ictal-onset and interictal periods at frequency bands of 1-30 Hz and 30-80 Hz with magnetoencephalography (MEG) scanning. Accumulated source imaging (ASI) was used to analyze the locations of neural source activity and peak source strength. RESULTS: Most of the participants had more active source activity locations in the ictal-onset period rather than in the interictal period, both at 1-30 Hz and 30-80 Hz. The frontal lobe (FL), the temporo-parietal junction (T-P), and the parietal lobe (PL) became the main active areas of source activity during the ictal period, while the precuneus (PC), cuneus, and thalamus were relatively inactive. CONCLUSIONS: Some brain areas become more excited and have increased source activity during seizures. These significant brain regions might be re-combined to form an epilepsy network that regulates the process of absence seizures. SIGNIFICANCE: The study confirmed that important brain regions are reorganized in an epilepsy network, which provides a basis for exploring the network mechanism of CAE development. Imaging findings may provide a reference for clinical characteristics.

Alterations in white matter integrity and asymmetry in patients with benign childhood epilepsy with centrotemporal spikes and childhood absence epilepsy: An automated fiber quantification tractography study.

PURPOSE: To investigate whether patients with benign childhood epilepsy with centrotemporal spikes (BECTS) and childhood absence epilepsy (CAE) show distinct patterns of white matter (WM) alterations and structural asymmetry compared with healthy controls and the relationship between WM alterations and epilepsy-related clinical variables. METHODS: We used automated fiber quantification to create tract profiles of fractional anisotropy (FA) and mean diffusivity (MD) in twenty-six patients with BECTS, twenty-nine patients with CAE, and twenty-four healthy controls. Group differences in FA and MD were quantified at 100 equidistant nodes along the fiber tract and these alterations and epilepsy-related clinical variables were correlated. A lateralization index (LI) representing the structural asymmetry of the fiber tract was computed and compared between both patient groups and controls. RESULTS: Compared with healthy controls, the BECTS group showed widespread FA reduction in 43.75% (7/16) and MD elevation in 50% (8/16) of identified fiber tracts, and the CAE group showed regional FA reduction in 31.25% (5/16) and MD elevation in 25% (4/16) of identified fiber tracts. In the BECTS group, FA and MD in the right anterior thalamic radiation positively and negatively correlated with the number of antiepileptic drugs, respectively, and MD in the right arcuate fasciculus (AF) positively correlated with seizure frequency. In the CAE group, the LI values were significantly lower in the inferior fronto-occipital fasciculus and the AF. CONCLUSION: The two childhood epilepsy syndromes display different patterns of WM alterations and structural asymmetry, suggesting that neuroanatomical differences may underlie the different profiles of BECTS and CAE.

Identifying epilepsy psychiatric comorbidities with machine learning.

OBJECTIVE: People with epilepsy are at increased risk for mental health comorbidities. Machine-learning methods based on spoken language can detect suicidality in adults. This study's purpose was to use spoken words to create machine-learning classifiers that identify current or lifetime history of comorbid psychiatric conditions in teenagers and young adults with epilepsy. MATERIALS AND METHODS: Eligible participants were >12 years old with epilepsy. All participants were interviewed using the Mini International Neuropsychiatric Interview (MINI) or the MINI Kid Tracking and asked five open-ended conversational questions. N-grams and Linguistic Inquiry and Word Count (LIWC) word categories were used to construct machine learning classification models from language harvested from interviews. Data were analyzed for four individual MINI identified disorders and for three mutually exclusive groups: participants with no psychiatric disorders, participants with non-suicidal psychiatric disorders, and participants with any degree of suicidality. Performance was measured using areas under the receiver operating characteristic curve (AROCs). RESULTS: Classifiers were constructed from 227 interviews with 122 participants (7.5 ± 3.1 minutes and 454 ± 299 words). AROCs for models differentiating the non-overlapping groups and individual disorders ranged 57%-78% (many with P < .02). DISCUSSION AND CONCLUSION: Machine-learning classifiers of spoken language can reliably identify current or lifetime history of suicidality and depression in people with epilepsy. Data suggest identification of anxiety and bipolar disorders may be achieved with larger data sets. Machine-learning analysis of spoken language can be promising as a useful screening alternative when traditional approaches are unwieldy (eg, telephone calls, primary care offices, school health clinics).

Outgrowing seizures in Childhood Absence Epilepsy: time delays and bistability.

We formulate a conductance-based model for a 3-neuron motif associated with Childhood Absence Epilepsy (CAE). The motif consists of neurons from the thalamic relay (TC) and reticular nuclei (RT) and the cortex (CT). We focus on a genetic defect common to the mouse homolog of CAE which is associated with loss of GABAA receptors on the TC neuron, and the fact that myelination of axons as children age can increase the conduction velocity between neurons. We show the combination of low GABAA mediated inhibition of TC neurons and the long corticothalamic loop delay gives rise to a variety of complex dynamics in the motif, including bistability. This bistability disappears as the corticothalamic conduction delay shortens even though GABAA activity remains impaired. Thus the combination of deficient GABAA activity and changing axonal myelination in the corticothalamic loop may be sufficient to account for the clinical course of CAE.

The epileptic network and cognition: What functional connectivity is teaching us about the childhood epilepsies.

Our objective was to summarize and evaluate the rapidly expanding body of literature studying functional connectivity in childhood epilepsy. In the self-limited childhood epilepsies, awareness of cognitive comorbidities has been steadily increasing, and recent advances in our understanding of the network effects of these disorders promise insights into the underlying neurobiology. We reviewed publications addressing functional connectivity in children with epilepsy with an emphasis on studies of children with self-limited childhood epilepsies. The majority of studies have been published in the past 10 years and predominantly examine childhood epilepsy with centrotemporal spikes and childhood absence epilepsy. Cognitive network alterations are commonly observed across the childhood epilepsies. Some of these effects appear to be nonspecific to epilepsy syndrome or even to category of neurological disorder. Other patterns, such as changes in the connectivity of cortical language areas in childhood epilepsy with centrotemporal spikes, provide clues to the underlying cognitive deficits seen in affected children. The literature to date is dominated by general observations of connectivity patterns without a priori hypotheses. These data-driven studies build an important foundation for hypothesis generation and are already providing useful insights into the neuropathology of the childhood epilepsies. Future work should emphasize hypothesis-driven approaches and rigorous clinical correlations to better understand how the knowledge of network alterations can be applied to guidance and treatment for the children in our clinics.

Ictal Source Locations and Cortico-Thalamic Connectivity in Childhood Absence Epilepsy: Associations with Treatment Response.

Childhood absence epilepsy (CAE), the most common pediatric epilepsy syndrome, is usually treated with valproic acid (VPA) and lamotrigine (LTG) in China. This study aimed to investigate the ictal source locations and functional connectivity (FC) networks between the cortices and thalamus that are related to treatment response. Magnetoencephalography (MEG) data from 25 patients with CAE were recorded at 300 Hz and analyzed in 1-30 Hz frequency bands. Neuromagnetic sources were volumetrically scanned with accumulated source imaging. The FC networks between the cortices and thalamus were evaluated at the source level through a connectivity analysis. Treatment outcome was assessed after 36-66 months following MEG recording. The children with CAE were divided into LTG responder, LTG non-responder, VPA responder and VPA non-responder groups. The ictal source locations and cortico-thalamic FC networks were compared to the treatment response. The ictal source locations in the post-dorsal medial frontal cortex (post-DMFC, including the medial primary motor cortex and the supplementary sensorimotor area) were observed in all LTG non-responders but in all LTG responders. At 1-7 Hz, patients with fronto-thalamo-parietal/occipital (F-T-P/O) networks were older than those with fronto-thalamic (F-T) networks or other cortico-thalamic networks (p = 0.000). The duration of seizures in patients with F-T-P/O networks at 1-7 Hz was longer than that in patients with F-T networks or other cortico-thalamic networks (p = 0.001). The ictal post-DMFC source localizations suggest that children with CAE might experience initial LTG monotherapy failure. Moreover, the cortico-thalamo-cortical network is associated with age. Finally, the cortico-thalamo-cortical network consists of anterior and posterior cortices and might contribute to the maintenance of discharges.

Time perception in childhood absence epilepsy: Findings from a pilot study.

OBJECTIVES: With this explorative study, we aimed to examine time perception in children with childhood absence epilepsy (CAE) and to compare those children with a matched control group. The study also investigated the association between the neuropsychological performance of the group with CAE and time judgment. We hypothesize that children with CAE could fail in time perception and that this may be because of a common underlying substrate with executive impairments. METHODS: Thirteen children with CAE, aged 6-13 years, and 17 healthy children were recruited. All children performed the time bisection task; the children with CAE also performed a cognitive and neuropsychological assessment. We performed a univariate analysis using each parameter of the bisection task (bisection point [BP]) and Weber ratio (WR) as dependent variables, the group (patients vs. controls) as fixed factors and age at evaluation and vocabulary scores as covariates. In the subgroup of patients, we correlated bisection task parameters with neuropsychological tests using a nonparametric partial correlation; the analysis has corrected for age at evaluation. RESULTS: The BP and WR measures differed between controls and patients with CAE. In the subgroup of patients also performing a neuropsychological assessment, we found a correlation between the WR measure and performance on the inhibition test (r = -0.641, p = .025), coding test (r = -0.815, p = .014), and Trail Making Test B (TMT B) (r = 0.72, p = .042). CONCLUSIONS: We found an altered time perception in a pilot study of a small group of children with CAE. A neurophysiological mechanism underlying CAE seems to influence cognitive and behavioral deficits and time sensibility.

The glucose transporter type 1 (Glut1) syndromes.

The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype-phenotype correlations. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Source localization of epileptiform discharges in childhood absence epilepsy using a distributed source model: a standardized, low-resolution, brain electromagnetic tomography (sLORETA) study.

Localizing the source of epileptiform discharges in generalized epilepsy has been controversial for the past few decades. Recent neuroimaging studies have shown that epileptiform discharges in generalized epilepsy can be localized to a particular region. Childhood absence epilepsy (CAE) is the most common generalized epilepsy in childhood and is considered the prototype of idiopathic generalized epilepsy (IGE). To better understand electrophysiological changes and their development in CAE, we investigated the origin of epileptiform discharges. We performed distributed source localization with standardized, low-resolution, brain electromagnetic tomography (sLORETA). In 16 children with CAE, sLORETA images corresponding to the midpoint of the ascending phase and the negative peak of the spike were obtained from a total of 242 EEG epochs (121 epochs at each timepoint). Maximal current source density (CSD) was mostly located in the frontal lobe (69.4%). At the gyral level, maximal CSD was most commonly in the superior frontal gyrus (39.3%) followed by the middle frontal gyrus (14.0%) and medial frontal gyrus (8.7%). At the hemisphere level, maximal CSD was dominant in the right cerebral hemisphere (63.6%). These results were consistent at the midpoint of the ascending phase and the negative peak of the spike. Our results demonstrated that the major source of epileptiform discharges in CAE was the frontal lobe. These results suggest that the frontal lobe is involved in generating CAE. This finding is consistent with recent studies that have suggested selective cortical involvement, especially in the frontal regions, in IGE.

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

BACKGROUND AND PURPOSE: 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. METHODS: A total of 76 adults with GGE were assessed with the Woodcock Johnson III Tests of Cognitive Abilities. RESULTS: 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. CONCLUSIONS: 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.

Altered Effective Connectivity Network in Childhood Absence Epilepsy: A Multi-frequency MEG Study.

Using multi-frequency magnetoencephalography (MEG) data, we investigated whether the effective connectivity (EC) network of patients with childhood absence epilepsy (CAE) is altered during the inter-ictal period in comparison with healthy controls. MEG data from 13 untreated CAE patients and 10 healthy controls were recorded. Correlation analysis and Granger causality analysis were used to construct an EC network at the source level in eight frequency bands. Alterations in the spatial pattern and topology of the network in CAE were investigated by comparing the patients with the controls. The network pattern was altered mainly in 1-4 Hz, showing strong connections within the frontal cortex and weak connections in the anterior-posterior pathways. The EC involving the precuneus/posterior cingulate cortex (PC/PCC) significantly decreased in low-frequency bands. In addition, the parameters of graph theory were significantly altered in several low- and high-frequency bands. CAE patients display frequency-specific abnormalities in the network pattern even during the inter-ictal period, and the frontal cortex and PC/PCC might play crucial roles in the pathophysiology of CAE. The EC network of CAE patients was over-connective and random during the inter-ictal period. This study is the first to reveal the frequency-specific alteration in the EC network during the inter-ictal period in CAE patients. Multiple-frequency MEG data are useful in investigating the pathophysiology of CAE, which can serve as new biomarkers of this disorder.