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Purpose: While hyperventilation (HV) increases the diagnostic yield of EEG in children, there is conflicting evidence to support its application in adults. For the first time in history, a large cohort of patients has undergone EEGs without HV during the COVID-19 pandemic. Utilizing this opportunity, we sought to investigate whether HV increases the diagnostic yield of EEG in children compared with adults., Methods: Patients aged six years and above who had routine EEGs at Monash Health between January 2019 and December 2020 were studied. The cohort was divided into two, pediatric (younger than 18 years) and adult (18 years or older). Epileptiform abnormalities (ictal and interictal) were the outcomes investigated. The effect of HV was examined with logistic regression to determine odds ratios with 95% confidence intervals., Results: In total, we studied 3,273 patients (pediatric = 830, adult = 2,443). In the pediatric cohort, HV significantly increased the diagnostic yield of absence seizures ( p = 0.01, odds ratios 2.44, 95% confidence intervals 1.21-4.93). In adults, HV did not increase the yield of absence seizures ( p = 0.34, odds ratios 0.36, 95% confidence intervals 0.05-2.88). Interictal epileptiform discharges during HV were significantly more frequent in children compared with adults ( p < 0.001, odds ratios 3.81, 95% confidence intervals 2.51-5.77)., Conclusions: Hyperventilation is useful to increase the yield of interictal epileptiform discharges and absence seizures in pediatric patients but not in adults. Hence, routine EEG may be recorded in adults without HV when it is unsafe to perform., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Objectives: Absence seizures impair psychosocial function, yet their detailed neuronal basis remains unknown. Recent work in a rat model suggests that cortical arousal state changes prior to seizures and that single neurons show diverse firing patterns during seizures. Our aim was to extend these investigations to a mouse model with studies of neuronal activity and arousal state to facilitate future fundamental investigations of absence epilepsy., Methods: We performed in vivo extracellular single unit recordings on awake head-fixed C3H/HeJ mice. Mice were implanted with tripolar electrodes for cortical electroencephalography (EEG). Extracellular single unit recordings were obtained with glass micropipettes in the somatosensory barrel cortex, while animals ambulated freely on a running wheel. Signals were digitized and analyzed during seizures and at baseline., Results: Neuronal activity was recorded from 36 cortical neurons in 19 mice while EEG showed characteristic 7-8 Hz spike-wave discharges. Different single neurons showed distinct firing patterns during seizures, but the overall mean population neuronal firing rate during seizures was no different from pre-seizure baseline. However, the rhythmicity of neuronal firing during seizures was significantly increased (p < 0.001). In addition, beginning 10s prior to seizure initiation, we observed a progressive decrease in cortical high frequency (>40 Hz) EEG and an increase in lower frequency (1-39 Hz) activity suggesting decreased arousal state., Significance: We found that the awake head-fixed C3H/HeJ mouse model demonstrated rhythmic neuronal firing during seizures, and a decreased cortical arousal state prior to seizure onset. Unlike the rat model we did not observe an overall decrease in neuronal firing during seizures. Similarities and differences across species strengthen the ability to investigate fundamental key mechanisms. Future work in the mouse model will identify the molecular basis of neurons with different firing patterns, their role in seizure initiation and behavioral deficits, with ultimate translation to human absence epilepsy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: We hypothesized that the frequency (in Hertz) of generalized spike-waves (GSWs) in patients with idiopathic generalized epilepsy (IGE) has associations with the syndromic diagnosis as well as with the prognosis of patients (their response to medical treatment)., Methods: This was a retrospective study of a prospectively developed database. All patients with a diagnosis of IGE were studied at the epilepsy center at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2022. Patients were classified into four IGE syndromes: childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and generalized tonic-clonic seizures alone., Results: Five hundred and eighty-three patients were studied. GSWs were commonly observed in all four syndromes of IGE. Frequency of GSW (in Hertz) did not have a significant association with the syndromic diagnosis of the patients (p = .179). The presence of GSW did not have a significant association with the seizure outcome (becoming seizure free or not) of the patients (p = .416). Frequency of GSW did not have a significant association with the seizure outcome of the patients either (p = .574)., Conclusion: GSWs are the hallmark electroencephalographic footprints of idiopathic generalized epilepsies; however, neither their presence nor their frequency has practical associations with the syndromic diagnosis of IGEs or their outcome (response to treatment)., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Childhood absence epilepsy is one of the most prevalent pediatric epilepsy syndromes, but diagnostic delay is common and consequential. Childhood absence epilepsy is diagnosed by history and physical examination including hyperventilation with electroencephalography (EEG) used to confirm the diagnosis. Hyperventilation produces generalized spike-wave discharges on EEG in >90% of patients with childhood absence epilepsy and provokes clinical absence seizures consisting of brief loss of consciousness typically within 90 seconds. Child neurologists report a high volume of referrals for children with "staring spells" that strain already limited health care resources. Resources are further strained by the use of EEG for monitoring antiseizure medication effectiveness with unclear benefit. In this review, we examine the safety and efficacy of hyperventilation activation as a tool for the diagnosis and management of childhood absence seizures., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Spike-and-wave discharges (SWDs) and sleep spindles are characteristic electroencephalographic (EEG) hallmarks of absence seizures and nonrapid eye movement sleep, respectively. They are commonly generated by the cortico-thalamo-cortical network including the thalamic reticular nucleus (TRN). It has been reported that SWD development is accompanied by a decrease in sleep spindle density in absence seizure patients and animal models. However, whether the decrease in sleep spindle density precedes, coincides with, or follows, the SWD development remains unknown. To clarify this, we exploited Pvalb -tetracycline transactivator (tTA)::tetO-ArchT (PV-ArchT) double-transgenic mouse, which can induce an absence seizure phenotype in a time-controllable manner by expressing ArchT in PV neurons of the TRN. In these mice, EEG recordings demonstrated that a decrease in sleep spindle density occurred 1 week before the onset of typical SWDs, with the expression of ArchT. To confirm such temporal relationship observed in these genetic model mice, we used a gamma-butyrolactone (GBL) pharmacological model of SWDs. Prior to GBL administration, we administered caffeine to wild-type mice for 3 consecutive days to induce a decrease in sleep spindle density. We then administered low-dose GBL, which cannot induce SWDs in normally conditioned mice but led to the occurrence of SWDs in caffeine-conditioned mice. These findings indicate a temporal relationship in which the decrease in sleep spindle density consistently precedes SWD development. Furthermore, the decrease in sleep spindle activity may have a role in facilitating the development of SWDs. Our findings suggest that sleep spindle reductions could serve as early indicators of seizure susceptibility., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Abdelaal et al.)

The accuracy of headband electroencephalogram (EEG) was compared to traditional EEG in pediatric patients with absence epilepsy. This study enrolled 10 patients with previously diagnosed absence epilepsy and examined the concordance of headband EEG and traditional EEG in the follow-up EEG of treated absence epilepsy. The study found a concordant result in 80% of cases providing a signal that absence epilepsy is an effective target for headband EEG. The study showcases a need for further research in headband EEG technology and continued improvements in technology., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Long-term ambulatory EEG recordings can improve the monitoring of absence epilepsy in children, but signal quality and increased review workload are a concern. We evaluated the feasibility of around-the-ears EEG arrays (cEEGrids) to capture 3-Hz short-lasting and ictal spike-and-wave discharges and assessed the performance of automated detection software in cEEGrids data. We compared patterns of bilateral synchronisation between short-lasting and ictal spike-and-wave discharges., Methods: We recruited children with suspected generalised epilepsy undergoing routine video-EEG monitoring and performed simultaneous cEEGrids recordings. We used ASSYST software to detect short-lasting 3-Hz spike-and-wave discharges (1-3 s) and ictal spike-and-wave discharges in the cEEGrids data. We assessed data quality and sensitivity of cEEGrids for spike-and-wave discharges in routine EEG. We determined the sensitivity and false detection rate for automated spike-and-wave discharge detection in cEEGrids data. We compared bihemispheric synchrony across the onset of short-lasting and ictal spike-and-wave discharges using the mean phase coherence in the 2-4 Hz frequency band., Results: We included nine children with absence epilepsy (median age = 11 y, range 8-15 y, nine females) and recorded 4 h and 27 min of cEEGrids data. The recordings from seven participants were suitable for quantitative analysis, containing 82 spike-and-wave discharges. The cEEGrids captured 58 % of all spike-and-wave discharges (median individual sensitivity: 100 %, range: 47-100 %). ASSYST detected 82 % of all spike-and-wave discharges (median: 100 %, range: 41-100 %) with a false detection rate of 48/h (median: 6/h, range: 0-154/h). The mean phase coherence significantly increased during short-lasting and ictal spike-and-wave discharges in the 500-ms pre-onset to 1-s post-onset interval., Conclusions: cEEGrids are of variable quality for monitoring spike-and-wave discharges in children with absence epilepsy. ASSYST could facilitate the detection of short-lasting and ictal spike-and-wave discharges with clear periodic structures but with low specificity. A similar course of bihemispheric synchrony between short-lasting and ictal spike-and-wave discharges indicates that cortico-thalamic driving may be relevant for both types of spike-and-wave discharges., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Advancing the mechanistic understanding of absence epilepsy is crucial for developing new therapeutics, especially for patients unresponsive to current treatments. Utilizing a recently developed mouse model of absence epilepsy carrying the BK gain-of-function channelopathy D434G, here we report that attenuating the burst firing of midline thalamus (MLT) neurons effectively prevents absence seizures. We found that enhanced BK channel activity in the BK-D434G MLT neurons promotes synchronized bursting during the ictal phase of absence seizures. Modulating MLT neurons through pharmacological reagents, optogenetic stimulation, or deep brain stimulation effectively attenuates burst firing, leading to reduced absence seizure frequency and increased vigilance. Additionally, enhancing vigilance by amphetamine, a stimulant medication, or physical perturbation also effectively suppresses MLT bursting and prevents absence seizures. These findings suggest that the MLT is a promising target for clinical interventions. Our diverse approaches offer valuable insights for developing next generation therapeutics to treat absence epilepsy., Competing Interests: Competing interests statement:The authors declare no competing interest.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process., Competing Interests: PS, IG, FT, OM, NC, VS, AD, VC, OD, EB No competing interests declared, (© 2023, Stenroos et al.)

Objective: This study aims to detect the seizure onset, in childhood absence epilepsy, as early as possible. Indeed, interfering with absence seizures with sensory simulation has been shown to be possible on the condition that the stimulation occurs soon enough after the seizure onset., Methods: We present four variations (two supervised, two unsupervised) of an algorithm designed to detect the onset of absence seizures from 4 scalp electrodes, and compare their performance with that of a state-of-the-art algorithm. We exploit the characteristic shape of spike-wave discharges to detect the seizure onset. Their performance is assessed on clinical electroencephalograms from 63 patients with confirmed childhood absence epilepsy., Results: The proposed approaches succeed in early detection of the seizure onset, contrary to the classical detection algorithm. Indeed, the results clearly show the superiority of the proposed methods for small delays of detection, under 750 ms from the onset., Conclusion: The performance of the proposed unsupervised methods is equivalent to that of the supervised ones. The use of only four electrodes makes the pipeline suitable to be embedded in a wearable device., Significance: The proposed pipelines perform early detection of absence seizures, which constitutes a prerequisite for a closed-loop system., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Childhood absence epilepsy (CAE) has a typical electroencephalography (EEG) pattern of generalized 3 Hz spike and wave discharges (SWD). Focal interictal discharges were also documented in a small number of documents. The aim was to investigate the amplitudes of interictal 3 Hz SWD within the 1 st second in drug-naïve CAE patients. In this way, areas with maximal electronegativity at the beginning of clinically generalized discharges will be documented., Methods: The EEG records of children with drug-naïve CAE were evaluated retrospectively by two child neurologists first for 3 Hz SWD. Then, a machine-learning model evaluated the amplitudes of 3 Hz in the 1 st second of SWD. Maximum electronegativity areas were documented and classified as focal, bilateral, and generalized., Results: One hundred and twelve 3 Hz SWD were evaluated in 11 patients. Among discharges within the 1 st second, maximum electronegativity areas were documented as focal for 44 (39.2%), bilateral for 8 (7.1%), generalized for 60 (53.5%). Among focal electronegativity areas, mostly right central, left occipital and midline parietal areas were documented in 12 (10.7%), 7 (6.2%), and 6 (5.3%), respectively. Eight (7.1%) of the maximum electronegativity areas were detected bilaterally, of which 7 (6.2%) originated from the frontopolar areas., Conclusions: Focal maximal electronegativity areas were frequently observed in drug-naïve CAE patients, comprising approximately half of non-generalized discharges. Focal discharges might be misleading in diagnosis. Focal areas within the brain may be responsible for and contribute to absence seizures that appear bilaterally symmetrical and generalized clinically. Although its clinical implication is unknown, this warrants further study.

Background: GABA, a key inhibitory neurotransmitter, has synaptic and extrasynaptic receptors on the postsynaptic neuron. Background GABA, which spills over from the synaptic cleft, acts on extrasynaptic delta subunit containing GABAA receptors. The role of extrasynaptic GABAergic input in migraine is unknown. We investigated the susceptibility to valid migraine-provoking substances with clinically relevant behavioral readouts in Genetic Absence Epilepsy of Rats Strasbourg (GAERS), in which the GABAergic tonus was altered. Subsequently, we screened relevant GABAergic mechanisms in Wistar rats by pharmacological means to identify the mechanisms., Methods: Wistar and GAERS rats were administered nitroglycerin (10 mg/kg) or levcromakalim (1 mg/kg). Mechanical allodynia and photophobia were assessed using von Frey monofilaments and a dark-light box. Effects of GAT-1 blocker tiagabine (5 mg/kg), GABAB receptor agonist baclofen (2 mg/kg), synaptic GABAA receptor agonist diazepam (1 mg/kg), extrasynaptic GABAA receptor agonists gaboxadol (4 mg/kg), and muscimol (0.75 mg/kg), T-type calcium channel blocker ethosuximide (100 mg/kg) or synaptic GABAA receptor antagonist flumazenil (15 mg/kg) on levcromakalim-induced migraine phenotype were screened., Results: Unlike Wistar rats, GAERS exhibited no reduction in mechanical pain thresholds or light aversion following nitroglycerin or levcromakalim injection. Ethosuximide did not reverse the resistant phenotype in GAERS, excluding the role of T-type calcium channel dysfunction in this phenomenon. Tiagabine prevented levcromakalim-induced mechanical allodynia in Wistar rats, suggesting a key role in enhanced GABA spillover. Baclofen did not alleviate mechanical allodynia. Diazepam failed to mitigate levcromakalim-induced migraine phenotype. Additionally, the resistant phenotype in GAERS was not affected by flumazenil. Extrasynaptic GABAA receptor agonists gaboxadol and muscimol inhibited periorbital allodynia in Wistar rats., Conclusion: Our study introduced a rat strain resistant to migraine-provoking agents and signified a critical involvement of extrasynaptic δGABAergic receptors. Extrasynaptic δ GABAA receptors, by mediating constant background inhibition on the excitability of neurons, stand as a novel drug target with a therapeutic potential in migraine., (© 2024. The Author(s).)

Purpose: The aim of our work is to describe the characteristics of Early Onset Absence Epilepsy (EOAE) and to observe whether specific anamnestic, clinical or electroencephalographic characteristics can influence the drug sensitivity of this pathology., Methods: We carried out a retrospective study of patients affected by absence epilepsy with onset under four years of age, born between January 1st 2000 and December 31st 2018, who were reffered to the Regional Epilepsy Center of Spedali Civili of Brescia. We then divided the sample into three groups based on the age of onset., Results: Our sample is composed of 56 patients. Among the children with epilepsy onset under two years of age (11), all were still on therapy after three and six years of follow-up, and 64 % of them required polytherapy. Among patients with epilepsy onset between two and three years of age (24), 87 % were still on therapy after three years of follow-up and 68 % after six years of follow-up; 46 % of these subjects required polytherapy. Among patients with epilepsy onset between three and four years of age (21), 89 % were still on therapy after three years of follow-up and 38 % after six years of follow-up; 38 % of them required polytherapy., Conclusions: We observe that patients with an earlier epilepsy onset have a worse outcome and a lower drug sensitivity. This may allow to predict in which cases it would be appropriate to maintain antiseizure therapy for a prolonged period., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The persistence of typical absence seizures (AS) in adolescence and adulthood may reduce the quality of life of patients with genetic generalized epilepsies (GGEs). The prevalence of drug resistant AS is probably underestimated in this patient population, and treatment options are relatively scarce. Similarly, atypical absence seizures in developmental and epileptic encephalopathies (DEEs) may be unrecognized, and often persist into adulthood despite improvement of more severe seizures. These two seemingly distant conditions, represented by typical AS in GGE and atypical AS in DEE, share at least partially overlapping pathophysiological and genetic mechanisms, which may be the target of drug and neurostimulation therapies. In addition, some patients with drug-resistant typical AS may present electroclinical features that lie in between the two extremes represented by these generalized forms of epilepsy., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction : typical absences (TAs), are brief, generalized epileptic seizures of abrupt onset and termination clinically manifesting with impairment of awareness and associated with 3 Hz spike-wave discharges on EEG. TAs may occur in different idiopathic generalized epilepsies (IGE). Despite treatment with adequate anti-seizure medications (ASMs), TAs may persist in ~25% of subjects. This narrative review focuses on the therapeutic approach to difficult-to-treat TAs occurring in the setting of IGE. Areas covered : a literature search was conducted on the topic of treatment of TAs. Expert opinion : ethosuximide (ESX), valproic acid (VPA) and lamotrigine (LTG), alone or in combination, are considered the first-choice drugs. In women of childbearing potential, VPA should be avoided. Alternative therapies (benzodiazepines, levetiracetam, topiramate, or zonisamide) should be considered in subjects unresponsive to monotherapy after the exclusion of pseudo-drug resistance. Newer ASMs such as brivaracetam and perampanel seem to be promising options. Well-conducted clinical trials aimed to evaluate the efficacy of alternative monotherapy (beyond ESX, VPA or LTG) or combination of ASMs on difficult-to-treat TAs, are warranted.

Absence epilepsy is frequently associated with cognitive dysfunction, although the underlying mechanisms are not well understood. Here we report that some forms of hippocampal synaptic plasticity are abnormal in symptomatic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Metabotropic Glu 1/5 receptor-mediated long term depression (LTD) at Schaffer collateral CA1 synapses is significantly reduced in symptomatic, 5-6 months old WAG/Rij rats compared to age-matched non epileptic control rats. There were no significant changes in mGlu1/5-dependent LTD in pre-symptomatic, 4-6 weeks old WAG/Rij rats compared to age matched controls. The changes in LTD found in symptomatic WAG/Rij forms are not indicative of general deficits in all forms of synaptic plasticity as long term potentiation (LTP) was unchanged. Immunoblot analysis of hippocampal tissue showed a significant reduction in mGlu5 receptor expression, a trend to an increase in pan Homer protein levels and a decrease in GluA1 receptor expression in the hippocampus of symptomatic WAG/Rij rats vs non-epileptic control rats. There were no changes in mGlu1α receptor or GluA2 protein levels. These findings suggest that abnormalities in hippocampal mGlu5 receptor-dependent synaptic plasticity are associated with the pathological phenotype of WAG/Rij rats. This lays the groundwork for the study of mGlu5 receptors as a candidate drug target for the treatment of cognitive dysfunction linked to absence epilepsy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The new aggregate data analyses revealed the earlier missing role of cerebellum long-term electrical stimulation in the absence epilepsy. Neurophysiologic data gained by authors favor that cerebellar serial deep brain stimulation (DBS) (100 Hz) causes the transformation of penicillin-induced cortical focal discharges into prolonged 3,5-3,75 sec oscillations resembling spike-wave discharges (SWD) in cats. Such SWDs were not organized in the form of bursts and persisted continuously after stimulation. Therefore, the appearance of prolonged periods of SWD is regarded as a tonic cerebellar influence upon pacemaker of SWD and might be caused by the long-lasting DBS-induced increase of GABA-ergic extrasynaptic inhibition in the forebrain networks. The absence seizure facilitation caused by cerebellar DBS was discussed with the reviewed data on optogenetic stimulation, neuronal activity of cerebellar structures, and imaging data., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Childhood absence epilepsy (CAE) is a disease with distinct seizure semiology and electroencephalographic (EEG) features. Differentiating ictal and subclinical generalized spikes and waves discharges (GSWDs) in the EEG is challenging, since they appear to be identical upon visual inspection. Here, spectral and functional connectivity (FC) analyses were applied to routine EEG data of CAE patients, to differentiate ictal and subclinical GSWDs., Methods: Twelve CAE patients with both ictal and subclinical GSWDs were retrospectively selected for this study. The selected EEG epochs were subjected to frequency analysis in the range of 1-30 Hz. Further, FC analysis based on the imaginary part of coherency was used to determine sensor level networks., Results: Delta, alpha and beta band frequencies during ictal GSWDs showed significantly higher power compared to subclinical GSWDs. FC showed significant network differences for all frequency bands, demonstrating weaker connectivity between channels during ictal GSWDs., Conclusion: Using spectral and FC analyses significant differences between ictal and subclinical GSWDs in CAE patients were detected, suggesting that these features could be used for machine learning classification purposes to improve EEG monitoring., Significance: Identifying differences between ictal and subclinical GSWDs using routine EEG, may improve understanding of this syndrome and the management of patients with CAE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

(1) Background: Absence seizures (ASs) are sudden, transient lapses of consciousness associated with lack of voluntary movements and generalized 2.5-4 Hz spike-wave discharges (SWDs) in the EEG. In addition to the thalamocortical system, where these pathological oscillations are generated, multiple neuronal circuits have been involved in their modulation and associated comorbidities including the serotonergic system. Neuronal activity in one of the major synaptic input structures to the brainstem dorsal raphé nucleus (DRN), the lateral hypothalamus (LH), has not been characterized. (2) Methods: We used viral tract tracing and optogenetics combined with in vitro and in vivo electrophysiology to assess the involvement of the LH in absence epilepsy in a genetic rodent model. (3) Results: We found that a substantial fraction of LH neurons project to the DRN of which a minority is GABAergic. The LH to DRN projection can lead to monosynaptic iGluR mediated excitation in DRN 5-HT neurons. Neuronal activity in the LH is coupled to SWDs. (4) Conclusions: Our results indicate that a brain area involved in the regulation of autonomic functions and heavily innervating the RN is involved in ASs. The decreased activity of LH neurons during SWDs could lead to both a decreased excitation and disinhibition in the DRN. These results support a long-range subcortical regulation of serotonergic neuromodulation during ASs and further our understanding of the state-dependence of these seizures and some of their associated comorbidities.

Purpose: The purpose of the current study is to detect changes of topological organization of whole-brain functional networks and their relationship with the clinical treatment effects of antiepileptic drugs (AEDs) for patients with childhood absence epilepsy (CAE) using resting-state functional MRI (RS-fMRI). Patients and Methods . RS-fMRI data from 30 CAE patients were collected and compared with findings from 30 age- and gender-matched healthy controls (HCs). The patients were treated with first-line AEDs for 46.03 months before undergoing a second RS-fMRI scan., Results: CAE children at baseline showed a reduced clustering coefficient (Cp) and local efficiency (El) than the HC group, implying the reduction of functional segregation. CAE children at baseline also showed smaller characteristic path length (Lp) and higher global efficiency (Eg) compared with the HC group, implying the impairment of functional segregation. However, those metrics showed no significant differences between CAE children at follow-up and the HC group which indicated a clear renormalization of topological organization after AED treatments. CAE at follow-up also showed significantly decreased connectivity between several network regions, with which the thalamus is mainly involved. Furthermore, the reduced connectivity change between the left superior parietal gyrus and the left thalamus is positively correlated with the symptom improvements after AED treatment., Conclusion: We highlighted the convergence and divergence of brain functional network dysfunctions in CAE patients and provided crucial insights into pathophysiological mechanisms and the AED effects., Competing Interests: There are no conflicts of interest., (Copyright © 2021 Xueyu Wang et al.)

Childhood Absence Epilepsy (CAE) accounts for approximately 10% of all pediatric epilepsies. Current treatments for CAE are ineffective in approximately 1/3 of patients and can be associated with severe side effects such as hepatotoxicity. Certain cannabinoids, such as cannabidiol (CBD), have shown promise in the treatment of pediatric epilepsies. However, CBD remains limited or prohibited in many jurisdictions, and has not been shown to have efficacy in CAE. Modulation of the type 1 cannabinoid receptor (CB1R) may provide more desirable pharmacological treatments. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model many aspects of CAE, including cortical spike and wave discharges (SWDs). We have recently demonstrated that Δ 9 -tetrahydrocannabinol (THC) increases SWDs in GAERS whereas CBD decreases these events. Here, we characterized aspects of the endocannabinoid system in brain areas relevant to seizures in GAERS and tested whether positive allosteric modulators (PAMs) of CB1R reduced SWDs. Both female and male GAERS had reduced (>50%) expression of CB1R and elevated levels of the endocannabinoid 2-AG in cortex compared to non-epileptic controls (NEC). We then administered the CB1R PAMs GAT211 and GAT229 to GAERS implanted with cortical electrodes. Systemic administration of GAT211 to male GAERS reduced SWDs by 40%. Systemic GAT229 administration reduced SWDs in female and male GAERS. Intracerebral infusion of GAT229 into the cortex of male GAERS reduced SWDs by >60% in a CB1R-dependent manner that was blocked by SR141716A. Together, these experiments identify altered endocannabinoid tone in GAERS and suggest that CB1R PAMs should be explored for treatment of absence seizures., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Hyperventilation (HV) is one of the main and basic activation methods during ambulatory electroencephalogram (EEG), unless medical reasons contraindicate it. During the COVID-19 pandemic, with the high risk of human-to-human infection, local guidelines and recommendations have been developed that suggest not to perform the HV maneuver routinely. Our objective was to characterize patients who present positive HV in an epilepsy center., Methods: We analyzed retrospectively all the ambulatory EEGs performed during one year in our specialized ambulatory child and adolescent epilepsy center, and describe patients with positive maneuver., Results: A total of 305 EEGs were performed. Patients under 3 years and 11 months were excluded as well as all patients that did not fill up the criteria for epilepsy diagnosis. From the 252 EEGs that were included in the study, 194 EEGs (77%) were classified as abnormal and 58 (23%) as normal. From these same 252 EEGs, 150 EEG finished correctly the HV maneuver. Physiological slowing response was found in 54 EEGs (36%), no changes (negative) in 83 (55%), and abnormal response (positive) in 13 EEGs (9%). The 13 HV-positive EEGs showed 4 patients with an increase of epileptiform activity, 3 patients experienced an increase of basal preregistered abnormal slowing, and 6 EEGs showed trigger of bilaterally synchronous and symmetric 2-4 Hz spike-and-slow wave discharges and absences. None of these last 6 patients needed more than 3 minutes to elicit the paroxysmal discharge., Significance: Based on these findings and according with other studies, the low positivity and high specificity of the HV maneuver support the idea that HV could be excluded during the COVID-19 pandemic situation, and also reevaluate whether it could be changed to a complementary maneuver, restricted only for cases where absence epilepsy is suspected. Larger studies will be needed to reaffirm this proposal., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABA A and GABA B receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABA A and GABA B antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABA A Rα1, GABA A Rβ3, and GABA B R2 subunits in the LDN as well as GABA A Rα1, GABA A Rβ3, GABA A Rγ2, and GABA B R2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARβ3 in the LDN as well as reduction of GABAARα1, GABAARβ3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABA A antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABA B antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study aimed to evaluate the effects of leptin, ghrelin and neuropeptide-Y on the development of nonconvulsive seizure activity and their role on combating oxidative stress and cytokines produced by the systemic immune response in the WAG/Rij rat model for genetic absence epilepsy. Current study showed that all three peptides aggravated spike wave discharges activity and affected the oxidative stress in WAG/Rij rats without any significant changes in the levels of IL-1β, IL-6 and TNF-α except leptin that only induced an increment in the concentration of IL-1β. Our results support the modulatory role of these endogenous peptides on absence epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epileptic myoclonus (EM) is reported in many paediatric epilepsies from neonatal period to adolescence. Myoclonus can be the only seizure type or may occur among others, independently or in combination as a single ictal event. We report two children presenting with absences associated with myoclonus, predominating on one side, in a setting of two different types of absence seizures and two different electro-clinical syndromes. Patients were explored with long-duration video-EEG coupled to surface EMG polygraphy. EEG was visually analysed and complemented by jerk-locked back-averaging. Two types of seizure, encompassing myoclonus and absence, were identified: myoclonic absences in the context of epilepsy with myoclonic absences and atypical absences with atonic component (negative myoclonus) in the context of encephalopathy related to status epilepticus during slow sleep (ESES). In the latter case, rhythmic upper limb jerking, mimicking positive myoclonus, corresponded to recovery of muscular tone after each negative myoclonus. Due to the rhythmic recovery of muscle tone, subsequent rhythmic negative myoclonus may exhibit a similar clinical picture to that of rhythmic positive myoclonus. Video-EEG recording coupled to EMG polygraphy is essential in order to precisely characterize motor manifestations during seizures with myoclonus [Published with video sequences].

Objective: A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT)., Methods: Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4 weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed., Results: Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures., Significance: Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management., (© 2021 International League Against Epilepsy.)

Aim: To investigate neurogenesis in both adult and 3-week-old genetic absence epilepsy rats from Strasbourg (GAERS) to determine if newly formed neurons within the dentate gyrus (DG) form synaptic contacts with GABAergic (gamma aminobutyric acid) and glutamatergic nerve terminals and compared to the control (non-GAERS) Wistar rats., Material and Methods: Brain tissue was processed for electron microscopic assessment. Thin sections from the hippocampal DG were double-labelled for anti-GABA or anti-VGLUT1 (vesicular glutamate transporter 1) and anti-doublecortin (DCX) antibodies using immunogold methodology and examined with the transmission electron microscope for morphological changes and to quantify the density of gold labeling., Results: DCX immunoreactivity was demonstrated within axon terminals, dendrites and somata in all groups. DCX and GABA or VGLUT1 were found to be co-localized in the axon terminals in all groups. We observed that DCX-immunoreactive (-ir) profiles formed synaptic contacts with GABAergic and glutamatergic terminals. The percentage of DCX labeling in dendrites, compared to axons, and the percentage of DCX-ir terminal profiles forming asymmetrical synapses, compared to those forming symmetrical synapses, were increased in all groups compared to the control group. DCX immunoreactivity in the 21-day-old GAERS group was found to be increased compared to the Wistar group., Conclusion: We conclude that newly born neurons are incorporated into the local hippocampal network in both the GAERS and the control Wistar rats. The results suggest that the neurogenesis taking place in the hippocampus may also be involved in the mechanism underlying absence seizures in GAERS.

Neurological disorders are often accompanied by impairment of memory, attention deficit that cause learning difficulties. Better understanding of learning problems in neurological patients might help to improve the quality of their life. Here we studied the character of fear-based associative learning using the standard active avoidance test in WAG/Rij rats with genetic predisposition to absence epilepsy. Electroencephalographic properties of spike-wave seizures (i.e., hallmarks of absence epilepsy) were examined at the age of 5 and 7 m. Around 24 % of rats did not express epileptic activity despite genetic predisposition. In the active avoidance test, 6 m old rats with the epileptic phenotype needed more trails to obtain the first avoidance than non-epileptic rats, but showed the same number of avoidances to reach the learning criterion. The total time of spike-wave activity positively correlated with the outcomes of avoidance performance only in subjects with severe epilepsy, but not in subjects with mild epilepsy. In order to evaluate early sensory (epigenetic) factors governing cognitive comorbidities in adult WAG/Rij rats, we performed bilateral whisker trimming during PN1-8 and PN9-16. This led to a quicker development of SWD, but did not influence cognitive abilities at the age of 6 m. In summary, epileptic WAG/Rij rats had difficulties with executive functions before the first avoidance of adverse stimulus, rather than impairment of memory after the first avoidance. Our data assume that cognitive comorbidities in epileptic WAG/Rij rats primarily may relate to executive deficit during the initial stage of avoidance test and secondary - to impairment of short-term memory. This fits well to outcomes of clinical studies in patients with generalized epilepsy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The role of α 2A adrenergic receptors (α 2A ARs) in absence epilepsy is not well characterized. Therefore, we investigated the outcomes of the specific antagonism of α 2A ARs on the spike-and-wave discharges (SWDs) in genetic absence epilepsy rats from Strasbourg (GAERSs), together with its influence on the behavior and second messenger systems, which may point to the mechanisms to which a possible SWD modulation can be related., Methods: Atipamezole, an α 2A AR antagonist, was administered intracerebroventricularly to the adult GAERSs, and electroencephalography (EEG) was conducted. The cumulative duration and number of SWDs, and the mean duration of each SWD complex were counted. The relative power of the EEG frequency bands and behavioral activity after the acute application of two doses (12 and 31 μg/5 μL) of atipamezole were evaluated. The levels of cyclic adenosine monophosphate and calcium/calmodulin-dependent kinase II (CaMKII) were measured in the cortex, thalamus, and hippocampus of naive Wistar rats and GAERSs, administered with artificial cerebrospinal fluid (aCSF) as a vehicle, or either acute or chronic atipamezole (12 μg), the latter being administered for 5 consecutive days., Results: Atipamezole significantly suppressed SWDs dose-dependently, without affecting the relative power values of EEG frequency spectrum. The stereotypic activity was significantly lower in both naive Wistar rats and GAERSs receiving the highest dose (31 μg) of atipamezole compared to GAERSs receiving aCSF. In GAERSs, CaMKII levels were found to be higher in the thalamus after the acute and chronic application of SWD-suppressing doses of atipamezole (12 and 31 μg) compared to aCSF., Significance: This study emphasizes the α 2 AR-related modulation of absence epilepsy and particularly the significance of α 2 AR antagonism in suppressing SWDs. Atipamezole's SWD-suppressive actions may be through CaMKII-mediated second messenger systems in the thalamus., (© 2020 International League Against Epilepsy.)

Objective: Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and Childhood Absence Epilepsy (CAE) are the most common childhood epilepsy syndromes and they share a similar age-dependence. However, the two syndromes clearly differ in seizures and EEG patterns. The aim of this study is to investigate whether children of the same age with BECTS, CAE and typically-developing children have significant differences in grey matter volume that may underlie the different profiles of these syndromes., Methods: Twenty one patients with newly-diagnosed BECTS and 18 newly diagnosed and drug naïve CAE were included and compared to 31 typically-developing children. Voxel-based morphometry was utilized to investigate grey matter volume differences among BECTS, CAE, and controls. We also examined the effect of age on grey matter volume in all three groups. In addition to the whole brain analysis, we chose regions of interest analysis based on previous literature suggesting the involvement of these regions in BECTS or CAE. The group differences of grey matter volume was tested with 2-sample t-test for between two groups' comparisons and ANOVA for three group comparisons., Results: In the whole brain group comparisons, the grey matter volume in CAE was significantly decreased in the areas of right inferior frontal and anterior temporal compared to BECTS and controls (F 2,67  = 27.53, p < 0.001). In the control group, grey matter volume in bifrontal lobes showed a negative correlation with age (r=-0.54, p < 0.05), whereas no correlation was found in either CAE or BECTS. With ROI analyses, the grey matter volume of posterior thalami was increased in CAE compared to other 2 groups (p < 0.05)., Significance: This study shows that there are grey matter volume differences between CAE and BECTS. Our findings of grey matter volume differences may suggest that there may be localized, specific differences in brain structure between these two types of epilepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The human brain is increasingly seen as a dynamic neural system, the function of which relies on a diverse set of connections between brain regions. To assess these complex dynamical interactions, formalism of complex networks was suggested as one of the most promising tools to offer new insight into the brain's structural and functional organization, with a potential also for clinical implications. Irrespective of the brain mapping technique, modern network approaches have revealed fundamental aspects of normal brain-network organization, such as small-world and scale-free patterns, hierarchical modularity, and the presence of hubs. Moreover, the utility of these approaches, to gain a better understanding of neurological diseases, is of great interest. In the present contribution, we first describe the basic network measures and how the brain networks are constructed on the basis of brain activity data in order to introduce clinical neurologists to this new theoretical paradigm. We then demonstrate how network formalism can be used to detect changes in EEG-based functional connectivity patterns in six paediatric patients with childhood absence epilepsy. Notably, our results do not only indicate enhanced synchronicity during epileptic episodes but also reveal specific spatial changes in the electrical activity of the brain. We argue that the network-based evaluation of functional brain networks can provide clinicians with more detailed insight into the activity of a pathological brain and can also be regarded as a support for objective diagnosis and treatment for various neurological diseases.

A mesoscale network model is proposed for the development of spike and wave discharges (SWDs) in the cortico-thalamo-cortical (C-T-C) circuit. It is based on experimental findings in two genetic models of childhood absence epilepsy-rats of WAG/Rij and GAERS strains. The model is organized hierarchically into two levels (brain structures and individual neurons) and composed of compartments for representation of somatosensory cortex, reticular and ventroposteriomedial thalamic nuclei. The cortex and the two thalamic compartments contain excitatory and inhibitory connections between four populations of neurons. Two connected subnetworks both including relevant parts of a C-T-C network responsible for SWD generation are modelled: a smaller subnetwork for the focal area in which the SWD generation can take place, and a larger subnetwork for surrounding areas which can be only passively involved into SWDs, but which is mostly responsible for normal brain activity. This assumption allows modeling of both normal and SWD activity as a dynamical system (no noise is necessary), providing reproducibility of results and allowing future analysis by means of theory of dynamical system theories. The model is able to reproduce most time-frequency changes in EEG activity accompanying the transition from normal to epileptiform activity and back. Three different mechanisms of SWD initiation reported previously in experimental studies were successfully reproduced in the model. The model incorporates also a separate mechanism for the maintenance of SWDs based on coupling analysis from experimental data. Finally, the model reproduces the possibility to stop ongoing SWDs with high frequency electrical stimulation, as described in the literature., Competing Interests: The authors have declared that no competing interests exist.

Insulin-mediated signalling in the brain is critical for neuronal functioning. Insulin resistance is implicated in the development of some neurological diseases, although changes associated with absence epilepsy have not been established yet. Therefore, we examined the major components of PI3K/Akt-mediated insulin signalling in cortical, thalamic, and hippocampal tissues collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and Non-Epileptic Control (NEC) rats. Insulin levels were also measured in plasma and cerebrospinal fluid (CSF). For the brain samples, the nuclear fraction (NF) and total homogenate (TH) were isolated and investigated for insulin signalling markers including insulin receptor beta (IRβ), IR substrate-1 and 2 (IRS1 & 2), phosphatase and tensin homologue (PTEN), phosphoinositide 3-kinase phospho-85 alpha (PI3K p85α), phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol (3,4,5)-trisphosphate, protein kinase B (PKB/Akt1/2/3), glucose transporter-1 and 4 (GLUT1 & 4) and glycogen synthase kinase-3β (GSK3β) using western blotting. A significant increase in PTEN and GSK3β levels and decreased PI3K p85α and pAkt1/2/3 levels were observed in NF of GAERS cortical and hippocampal tissues. IRβ, IRS1, GLUT1, and GLUT4 levels were significantly decreased in hippocampal TH of GAERS compared to NEC. A non-significant increase in insulin levels was observed in plasma and CSF of GAERS rats. An insulin sensitivity assay showed decreased p-Akt level in cortical and hippocampal tissues. Together, altered hippocampal insulin signalling was more prominent in NF and TH compared to cortical and thalamic regions in GAERS. Restoring insulin signalling may improve the pathophysiology displayed by GAERS, including the spike-and-wave discharges that relate to absence seizures in patients., (© 2020 John Wiley & Sons Australia, Ltd.)

Our goal was to assess the interrater agreement (IRA) of photoparoxysmal response (PPR) using the classification proposed by a task force of the International League Against Epilepsy (ILAE), and a simplified classification system proposed by our group. In addition, we evaluated IRA of epileptiform discharges (EDs) and the diagnostic significance of the electroencephalographic (EEG) abnormalities. We used EEG recordings from the European Reference Network (EpiCARE) and Standardized Computer-based Organized Reporting of EEG (SCORE). Six raters independently scored EEG recordings from 30 patients. We calculated the agreement coefficient (AC) for each feature. IRA of PPR using the classification proposed by the ILAE task force was only fair (AC = 0.38). This improved to a moderate agreement by using the simplified classification (AC = 0.56; P = .004). IRA of EDs was almost perfect (AC = 0.98), and IRA of scoring the diagnostic significance was moderate (AC = 0.51). Our results suggest that the simplified classification of the PPR is suitable for implementation in clinical practice., (© 2020 International League Against Epilepsy.)

Idiopathic or genetic generalized epilepsies (IGE) constitute an electroclinically well-defined group that accounts for almost one third of all people with epilepsy. They consist of four well-established syndromes and some other rarer phenotypes. The main four IGEs are juvenile myoclonic epilepsy, childhood absence epilepsy, juvenile absence epilepsy and IGE with generalized tonic-clonic seizures alone. There are three main seizure types in IGE, namely generalized tonic-clonic seizures, typical absences and myoclonic seizures, occurring either alone or in any combination. Diagnosing IGEs requires a multidimensional approach. The diagnostic process begins with a thorough medical history with a specific focus on seizure types, age at onset, timing and triggers. Comorbidities and family history should be questioned comprehensively. The EEG can provide valuable information for the diagnosis, including specific IGE syndromes, and therefore contribute to their optimal pharmacological treatment and management.

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures. The anti-absence seizure drug ethosuximide blocks SWDs and rescues behavioral arrests and social memory impairment in the knockout mice. Restoring GABAergic transmission either by optogenetic activation of the thalamic reticular nucleus (nRT) presynaptic terminals or postsynaptic NLG2 expression in the thalamic neurons reduces the SWDs and behavioral arrests in the knockout mice. These results indicate that NLG2-mediated GABAergic transmission at the nRT-thalamic circuit represents a common mechanism underlying both epileptic seizures and ASD.

Objective: Absence status epilepticus (ASE) is a form of non-convulsive status epilepticus characterized by ongoing or intermittent epileptic activity accompanied by behavioral and cognitive changes. Herein, we assessed high-frequency oscillations in the ripple band in patients with ASE and typical absence seizures., Methods: We enrolled five patients with ASE, 26 patients with childhood absence epilepsy (CAE), and 15 patients with juvenile absence epilepsy (JAE). We performed time-frequency analysis of electroencephalogram data for ictal absence seizures at each electrode to assess the high frequency activity (HFA) rate, peak frequency, and peak power., Results: The average HFA rates were 60.7%, 20.8%, and 12.9% in ASE, CAE, and JAE patients, respectively. The average peak frequencies were 126.4 Hz, 120.9 Hz, and 126.1 Hz in ASE, CAE, and JAE patients, respectively. The average peak power values were 2,388.8 μV 2 , 120.9 μV 2 , and 126.1 μV 2 in ASE, CAE, and JAE patients, respectively, and all epilepsy groups exhibited frontal-dominant ripple distribution., Conclusion: ASE patients presented higher power and frontal dominant ripples of absence seizure, compared to CAE and JAE patients., Significance: Future studies should utilize scalp-recorded ripples as a biomarker of absence epilepsy. This may aid in the development of novel treatment strategies for ASE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Epilepsy with eyelid myoclonia or Jeavons Syndrome is a unique idiopathic generalized epilepsy with onset in childhood. It is characterized by eyelid myoclonia which may be associated with absence seizures, eyelid closure-induced epileptiform discharges and/or seizures and photosensitivity. It is frequently underrecognized and misdiagnosed because it may be mistaken for some other type of generalized epilepsy or facial tic disorder. The intent of this narrative review is to focus on existing literature and highlight the distinct electroencephalographic features including characteristic eye movements, associated waveforms, interictal and ictal findings that are suggestive and characteristic of Jeavons Syndrome to aid in timely recognition of this syndrome.

Jeavons syndrome (JS) is mainly characterized by eyelid myoclonia with or without absences. It is thought to be underdiagnosed rather than have a rare prevalence. We aimed to investigate the electroclinical features of JS to determine possible factors influencing the diagnosis. We retrospectively identified the medical records of 32 cases (0.55%) from 5,796 patients with epilepsy. The inclusion criteria were: (1) eyelid myoclonia with or without absences; (2) generalized paroxysmal activity on EEG; and (3) discharges triggered by eyelid closure and/or intermittent photic stimulation. Eighteen (56.2%) of the patients were female. The mean age at seizure onset was 8.7±5.3 years and the mean age at admission to hospital was 17.8±10.7 years. A family history of epilepsy was present in 15 (46.8%) patients. Eyelid myoclonias were noticed in six (18.7%) patients by themselves. Based on the analysis of video-EEG recordings, 26 (81.2%) patients were sensitive to eye closure, 22 (68.7%) had photoparoxysmal responses, and 16 (50%) presented with absence seizures. Ten (31.2%) patients had focal epileptic discharges. Eight (25%) patients were on monotherapy. Seven (21.8%) patients achieved seizure freedom. Three patients underwent ketogenic diet therapy, which was effective in two patients. A vagus nerve stimulator was implanted into three patients, one of whom reported seizure reduction. Eyelid myoclonias are the main seizure type of JS but are usually overlooked. The time interval between seizure onset and clinical diagnosis suggests that this syndrome continues to be under-recognized. The genetic heterogeneity and phenotypic variability are likely to be more extensive than currently recognized, making the diagnosis more phalangine. [Published with video sequence].

The study aims to detect resting-state functional MRI (RS-fMRI) changes and their relationships with the clinical treatment effects of anti-epileptic drugs (AEDs) for patients with childhood absence epilepsy (CAE) using the fractional amplitude of low-frequency fluctuation (fALFF). RS-fMRI data from 30 CAE patients were collected and compared with findings from 30 healthy controls (HCs) with matched sex and age. Patients were treated with first-line AEDs for 46.2 months before undergoing a second RS-fMRI scan. fALFF data were processed using DPABI and SPM12 software. Compared with the HCs, CAE patients at baseline showed increased fALFF in anterior cingulate cortex, inferior parietal lobule, inferior frontal lobule, supplementary motor area and reduced fALFF in putamen and thalamus. At follow-up, the fALFF showed a clear rebound which indicated a normalization of spontaneous brain activities in these regions. In addition, the fALFF changes within thalamus showed significant positive correlation with the seizure frequency improvements. Our results suggest that specific cortical and subcortical regions are involved in seizure generation and the neurological impairments found in CAE children and might shed new light about the AEDs effects on CAE patients.

Mutations in SLC6A1, encoding γ-aminobutyric acid (GABA) transporter 1 (GAT-1), have been recently associated with a spectrum of epilepsy syndromes, intellectual disability and autism in clinic. However, the pathophysiology of the gene mutations is far from clear. Here we report a novel SLC6A1 missense mutation in a patient with epilepsy and autism spectrum disorder and characterized the molecular defects of the mutant GAT-1, from transporter protein trafficking to GABA uptake function in heterologous cells and neurons. The heterozygous missense mutation (c1081C to A (P361T)) in SLC6A1 was identified by exome sequencing. We have thoroughly characterized the molecular pathophysiology underlying the clinical phenotypes. We performed EEG recordings and autism diagnostic interview. The patient had neurodevelopmental delay, absence epilepsy, generalized epilepsy, and 2.5-3 Hz generalized spike and slow waves on EEG recordings. The impact of the mutation on GAT-1 function and trafficking was evaluated by 3 H GABA uptake, structural simulation with machine learning tools, live cell confocal microscopy and protein expression in mouse neurons and nonneuronal cells. We demonstrated that the GAT-1(P361T) mutation destabilizes the global protein conformation and reduces total protein expression. The mutant transporter protein was localized intracellularly inside the endoplasmic reticulum (ER) with a pattern of expression very similar to the cells treated with tunicamycin, an ER stress inducer. Radioactive 3 H-labeled GABA uptake assay indicated the mutation reduced the function of the mutant GAT-1(P361T), to a level that is similar to the cells treated with GAT-1 inhibitors. In summary, this mutation destabilizes the mutant transporter protein, which results in retention of the mutant protein inside cells and reduction of total transporter expression, likely via excessive endoplasmic reticulum associated degradation. This thus likely causes reduced functional transporter number on the cell surface, which then could cause the observed reduced GABA uptake function. Consequently, malfunctioning GABA signaling may cause altered neurodevelopment and neurotransmission, such as enhanced tonic inhibition and altered cell proliferation in vivo. The pathophysiology due to severely impaired GAT-1 function may give rise to a wide spectrum of neurodevelopmental phenotypes including autism and epilepsy.

Objective: The neuronal underpinnings of impaired consciousness during absence seizures remain largely unknown. Spike-and-wave (SW) activity associated with absences imposes two extremely different states in cortical neurons, which transition from suprathreshold synaptic depolarizations during spike phases to membrane hyperpolarization and electrical silence during wave phases. To investigate whether this rhythmic alternation of neuronal states affects the processing of sensory information during seizures, we examined cortical and thalamic responsiveness to brief sensory stimuli in the different phases of the epileptic cycle., Methods: Electrocorticographic (ECoG) monitoring from the primary somatosensory cortex combined with intracellular recordings of subjacent pyramidal neurons, or extracellular recordings of somatosensory thalamic neurons, were performed in the Genetic Absence Epilepsy Rat From Strasbourg. Sensory stimuli consisted of pulses of compressed air applied to the contralateral whiskers., Results: Whisker stimuli delivered during spike phases evoked smaller depolarizing synaptic potentials and fewer action potentials in cortical neurons compared to stimuli occurring during wave phases. This spike-related attenuation of cortical responsiveness was accompanied by a reduced neuronal membrane resistance, likely due to the large increase in synaptic conductance. Sensory-evoked firing in thalamocortical neurons was also decreased during ECoG spikes as compared to wave phases, indicating that time-to-time changes in the thalamocortical volley may also contribute to the variability of cortical responses during seizures., Significance: These findings demonstrate that thalamocortical sensory processing during absence seizures is nonstationary and strongly suggest that the cortical impact of a given environmental stimulus is conditioned by its exact timing relative to the SW cycle. The lack of stability of thalamic and cortical responses along seizures may contribute to impaired conscious sensory perception during absences., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

Aim: Psychiatric disorders, especially depression and anxiety, are among the most disabling comorbidities in patients with epilepsy, and they are difficult to treat because many antidepressants cause proconvulsive effects. Thus, it is important to identify the seizure risks associated with antidepressants. Trazodone is one of the most frequently prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs for the treatment of depression and anxiety. The aim of the present study was to evaluate the effects of trazodone on epileptiform activity in a penicillin-evoked focal seizure model in Wistar rats and in a genetic absence epilepsy model in Wistar Albino Glaxo/Rijswijk strain (WAG/Rij) rats., Methods: Trazodone at 5-, 10-, and 30-mg/kg doses was injected intraperitoneally in Wistar rats 30 min after penicillin injection, and spike frequency and amplitude of penicillin-induced epileptiform activity were evaluated. In a separate experimental model, the same trazodone doses were injected in WAG/Rij rats to elucidate their effects on number, duration, and amplitude of spike-and-wave discharges (SWDs) and on depression-anxiety like behavior. In both experimental groups, after trazodone injections recordings were made for 3 h. Depression-anxiety like behaviors in WAG/Rij rats were examined using forced swim test and open-field test., Results: Trazodone at 10- and 30-mg/kg doses significantly reduced the frequency of penicillin-induced epileptiform activity without changing the amplitude. Trazodone at a 5-mg/kg dose had no effect on either frequency or amplitude of epileptiform activity. Trazodone at all doses significantly increased number and duration of SWDs without changing the amplitude. In addition, all doses of trazodone decreased the number of squares crossed and duration of grooming in open-field test, and reduced swimming time activity and increased immobility time in forced swim test., Conclusion: Our results suggest that depending on the dose used, trazodone had an anticonvulsant effect or no effect on penicillin-evoked focal seizure model, but all trazodone doses resulted in proconvulsant and depression-anxiety like behavior in WAG/Rij rats, which represent a genetic absence model of epilepsy., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The quality of fMRI data impacts functional connectivity measures and consequently, the decisions that clinicians and researchers make regarding functional connectivity interpretation. The present study used resting state fMRI to investigate resting state network connectivity in a sample of patients with Juvenile Absence Epilepsy. Single-subject manual independent component analysis was used in two levels, whereby all noise components were removed, and cerebrospinal fluid pulsation components only were isolated and removed. Improved temporal signal to noise ratios and functional connectivity metrics were observed in each of the cleaning levels for both epilepsy and control cohorts. Results showed full, single-subject manual independent component analysis reduced the number of functional connectivity correlations and increased the strength of these correlations. Similar effects were also observed for the cerebrospinal fluid pulsation only cleaned data relative to the uncleaned, and fully cleaned data. Single-subject manual independent component analysis coupled with short TR multiband acquisition can significantly improve the validity of findings derived from fMRI data sets., (Copyright © 2019 Elsevier Inc. All rights reserved.)