Childhood Absence Epilepsy Research Articles

HCN channels and absence seizures

Hyperpolarization-activation cyclic nucleotide-gated (HCN) channels were for the first time implicated in absence seizures (ASs) when an abnormal Ih (the current generated by these channels) was reported in neocortical layer 5 neurons of a mouse model. Genetic studies of large cohorts of children with Childhood Absence Epilepsy (where ASs are the only clinical symptom) have identified only 3 variants in HCN1 (one of the genes that code for the 4 HCN channel isoforms, HCN1–4), with one (R590Q) mutation leading to loss-of-function. Due to the multi-faceted effects that HCN channels exert on cellular excitability and neuronal network dynamics as well as their modulation by environmental factors, it has been difficult to identify the detailed mechanism by which different HCN isoforms modulate ASs. In this review, we systematically and critically analyze evidence from established AS models and normal non-epileptic animals with area- and time-selective ablation of HCN1, HCN2 and HCN4. Notably, whereas knockout of rat HCN1 and mouse HCN2 leads to the expression of ASs, the pharmacological block of all HCN channel isoforms abolishes genetically determined ASs. These seemingly contradictory results could be reconciled by taking into account the well-known opposite effects of Ih on cellular excitability and network function. Whereas existing evidence from mouse and rat AS models indicates that pan-HCN blockers may provide a novel approach for the treatment of human ASs, the development of HCN isoform-selective drugs would greatly contribute to current research on the role for these channels in ASs generation and maintenance as well as offer new potential clinical applications.

New Epilepsy Syndrome Classification of International League Against Epilepsy: Idiopathic Generalized Epilepsy Syndromes

The idiopathic generalized epilepsies (IGEs) have historically included the syndromes of childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The goal of this paper is to provide updated diagnostic criteria for the four syndromes of IGEs determined by the expert consensus opinion of the International League Against Epilepsy’s Task Force on Nosology and Definitions (2017–2021). The IGEs have polygenic inheritance, with or without environmental factors. Development is typically normal. Seizure types include one or a combination of the following: absence, myoclonic, tonic-clonic, and myoclonic-tonic-clonic seizures. Electroencephalography shows generalized 2.5 to 5.5-Hz spike-waves, which may be activated by hyperventilation or photic stimulation. Key words: Seizures; Childhood absence epilepsy; Juvenile absence epilepsy; Juvenile myoclonic epilepsy; generalized tonic-clonic seizures alone.

Altered neuromagnetic activity in default mode network in childhood absence epilepsy.

The electrophysiological characterization of resting state oscillatory functional connectivity within the default mode network (DMN) during interictal periods in childhood absence epilepsy (CAE) remains unclear. Using magnetoencephalographic (MEG) recordings, this study investigated how the connectivity within the DMN was altered in CAE. Using a cross-sectional design, we analyzed MEG data from 33 children newly diagnosed with CAE and 26 controls matched for age and sex. The spectral power and functional connectivity of the DMN were estimated using minimum norm estimation combined with the Welch technique and corrected amplitude envelope correlation. Default mode network showed stronger activation in the delta band during the ictal period, however, the relative spectral power in other bands was significantly lower than that in the interictal period (p corrected < 0.05 for DMN regions, except bilateral medial frontal cortex, left medial temporal lobe, left posterior cingulate cortex in the theta band, and the bilateral precuneus in the alpha band). It should be noted that the significant power peak in the alpha band was lost compared with the interictal data. Compared with controls, the interictal relative spectral power of DMN regions (except bilateral precuneus) in CAE patients was significantly increased in the delta band (p corrected < 0.01), whereas the values of all DMN regions in the beta-gamma 2 band were significantly decreased (p corrected < 0.01). In the higher frequency band (alpha-gamma1), especially in the beta and gamma1 band, the ictal node strength of DMN regions except the left precuneus was significantly higher than that in the interictal periods (p corrected < 0.01), and the node strength of the right inferior parietal lobe increased most significantly in the beta band (Ictal: 3.8712 vs. Interictal: 0.7503, p corrected < 0.01). Compared with the controls, the interictal node strength of DMN increased in all frequency bands, especially the right medial frontal cortex in the beta band (Controls: 0.1510 vs. Interictal: 3.527, p corrected < 0.01). Comparing relative node strength between groups, the right precuneus in CAE children decreased significantly (β: Controls: 0.1009 vs. Interictal: 0.0475; γ 1: Controls:0.1149 vs. Interictal:0.0587, p corrected < 0.01) such that it was no longer the central hub. These findings indicated DMN abnormalities in CAE patients, even in interictal periods without interictal epileptic discharges. Abnormal functional connectivity in CAE may reflect abnormal anatomo-functional architectural integration in DMN, as a result of cognitive mental impairment and unconsciousness during absence seizure. Future studies are needed to examine if the altered functional connectivity can be used as a biomarker for treatment responses, cognitive dysfunction, and prognosis in CAE patients.

Idiopathic generalized epilepsies: Analysis of 101 patients

Idiopathic generalized epilepsies (IGI) are an electroclinical syndrome that includes four subsyndromes according to the ILAE 2017 classification. The long-term prognosis of these syndromes is uncertain due to the scarcity and heterogeneity of the studies. The objective of this study is to analyze the long-term prognosis of these syndromes, pharmacological treatment and the seizure recurrence. Observational and retrospective study of a serie of patients diagnosed with EGI. Epidemiological variables, pharmacological treatment, freedom of seizures and recurrence after withdrawal of treatment were collected. We included 101 patients, the majority women (56.4%), with a median evolution of epilepsy of 17 years (interquartile range: 7-31). The most frequent syndrome was juvenile myoclonic epilepsy (46.5%), followed by epilepsy with generalized tonic-clonic seizures alone (25.7%), juvenile absence epilepsy (13.9%) and childhood absence epilepsy (13.9%). The 71.29% were on monotherapy and 20.79% on polytherapy, with significant differences between the different syndromes (P=.001). The most widely used drug was valproic acid. 39.6% presented seizure remission at 5 years, but we did not observe significant differences between the different syndromes (P=.982). The recurrence rate was 71.4% after withdrawal of treatment. Juvenile myoclonic epilepsy was the most frequent subtype of IGE. We observed significant differences in terms of polytherapy in the different syndromes, although not in the rates of remission of seizures at one year and at five years. The majority of patients with treatment withdrawal relapsed.

Epilepsy with myoclonic absences: A case series

Epilepsy with myoclonic absences (EMA) is a very rare childhood generalized epilepsy syndrome (<1% of all generalized epilepsies) associated with frequent myoclonic absence seizures that was described in 1969 by Tassinari et al. [ [1] Tassinari C.A. Lyagoubi S. Santos V. et al. Study on spike and wave discharges in man. II. Clinical and electroencephalographic aspects of myoclonic absences. Rev Neurol. 1969; 121: 379-383 PubMed Google Scholar ]. Seizures are characterized by bilateral rhythmic jerks of the upper limbs, superimposed on tonic abduction of the arms [ [2] Bureau M. Tassinari C.A. Epilepsy with myoclonic absences. Brain Dev. 2005; 27: 178-184 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ]. Ictal EEG consists of 3-Hz generalized spike-and-wave complexes that are time-locked with the upper limb myoclonus, while the EMG generally shows myoclonic jerks followed by tonic contraction of both deltoids. These seizures differ from typical absences of childhood absence epilepsy, since myoclonic jerks are generally not seen in typical absences and, if present, are subtle and spare the arms. The lack of an atonic component also distinguishes these seizures from myoclonic-atonic seizures [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. A recent position paper by the International League Against Epilepsy for the classification of epilepsy syndromes with onset in childhood retained EMA as an independent epilepsy syndrome and defined its diagnostic criteria [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. The mandatory requirements are myoclonic absences as the predominant type of seizures, and regular 3 Hz generalized spike-and-wave complexes synchronous with myoclonus.

Idiopathic generalized epilepsies: Analysis of 101 patients

PurposeIdiopathic generalized epilepsies (IGI) are an electroclinical syndrome that include four subsyndromes according to the ILAE 2017 classification. The long-term prognosis of these syndromes is uncertain due to the scarcity and heterogeneity of the studies. The objective of this study is to analyze the long-term prognosis of these syndromes, pharmacological treatment and the seizure recurrence. MethodObservational and retrospective study of a serie of patients diagnosed with EGI. Epidemiological variables, pharmacological treatment, freedom of seizures and recurrence after withdrawal of treatment were collected. ResultsWe included 101 patients, the majority women (56.4%), with a median evolution of epilepsy of 17 years (interquartile range: 7–31). The most frequent syndrome was juvenile myoclonic epilepsy (46.5%), followed by epilepsy with generalized tonic-clonic seizures alone (25.7%), juvenile absence epilepsy (13.9%) and childhood absence epilepsy (13.9%). 71.29% were on monotherapy and 20.79% on polytherapy, with significant differences between the different syndromes (p=0.001). The most widely used drug was valproic acid. 39.6% presented seizure remission at 5 years, but we did not observe significant differences between the different syndromes (p=0.982). The recurrence rate was 71.4% after withdrawal of treatment. ConclusionJuvenile myoclonic epilepsy was the most frequent subtype of IGE. We observed significant differences in terms of polytherapy in the different syndromes, although not in the rates of remission of seizures at one year and at five years. The majority of patients with treatment withdrawal relapsed.

Antiseizure medication withdrawal risk estimation and recommendations: A survey of American Academy of Neurology and EpiCARE members.

Choosing candidates for antiseizure medication (ASM) withdrawal in well-controlled epilepsy is challenging. We evaluated (a) the correlation between neurologists' seizure risk estimation ("clinician predictions") vs calculated predictions, (b) how viewing calculated predictions influenced recommendations, and (c) barriers to using risk calculation. We asked US and European neurologists to predict 2-year seizure risk after ASM withdrawal for hypothetical vignettes. We compared ASM withdrawal recommendations before vs after viewing calculated predictions, using generalized linear models. Three-hundred and forty-six neurologists responded. There was moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42). Clinician predictions varied widely, for example, predictions ranged 5%-100% for a 2-year seizure-free adult without epileptiform abnormalities. Mean clinician predictions exceeded calculated predictions for vignettes with epileptiform abnormalities (eg, childhood absence epilepsy: clinician 65%, 95% confidence interval [CI] 57%-74%; calculated 46%) and surgical vignettes (eg, focal cortical dysplasia 6-month seizure-free mean clinician 56%, 95% CI 52%-60%; calculated 28%). Clinicians overestimated the influence of epileptiform EEG findings on withdrawal risk (26%, 95% CI 24%-28%) compared with calculators (14%, 95% 13%-14%). Viewing calculated predictions slightly reduced willingness to withdraw (-0.8/10 change, 95% CI -1.0 to -0.7), particularly for vignettes without epileptiform abnormalities. The greatest barrier to calculator use was doubting its accuracy (44%). Clinicians overestimated the influence of abnormal EEGs particularly for low-risk patients and overestimated risk and the influence of seizure-free duration for surgical patients, compared with calculators. These data may question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients. Viewing calculated predictions reduced willingness to withdraw particularly without epileptiform abnormalities.

Clinical and electroencephalographic findings prior to the onset of juvenile myoclonic epilepsy: A case series.

The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike-wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike-waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.

Childhood absence epilepsy patients with cognitive impairment have decreased sleep spindle density

ObjectiveTo explore the differences in sleep spindle (SS) characteristics during stage N2 sleep between children with childhood absence epilepsy and healthy controls, and between children with childhood absence epilepsy with or without cognitive impairment. MethodsWe recruited 29 children (14 females, 15 males, mean age: 8 (2.5) years) with childhood absence epilepsy who did not undergone antiseizure treatments previously and 30 age-matched controls (14 females, 16 males, mean age: 9 (3.0) years). For all patients, data on medical history were collected. Each child was monitored overnight by long-term video electroencephalography and was evaluated by the Wechsler Intelligence Scale for Children-Fourth Edition. Next, we compared anterior SS characteristics, including density, frequency, cycle length, duration, amplitude, and percentage of sleep stages. ResultsThe childhood absence epilepsy group exhibited lower spindle density and duration in the first 37.5 min of stage N2 sleep than the control group (P < 0.01). A decrease in spindle density could be observed in the childhood absence epilepsy group with aggravated cognition impairment. The spindle density was substantially lower in the cognitively impaired group than in the cognitively unimpaired group (P < 0.01). No significant differences were observed in SS amplitude, SS frequency, SS cycle length, and the distribution of sleep stages. ConclusionsReduction in spindle density and duration is associated with the mechanisms underlying childhood absence epilepsy. The deficit in SS density is related with impaired cognition. This deficiency in SSs may be a useful predictive indicator of cognitive impairment in children with absence epilepsy, indicating that SSs may become a useful biomarker and potential adjuvant anti-seizure target for cognitive impairment caused by childhood absence epilepsy.

Developmental Inhibitory Changes in the Primary Somatosensory Cortex of the Stargazer Mouse Model of Absence Epilepsy.

Childhood absence epilepsy seizures arise in the cortico-thalamocortical network due to multiple cellular and molecular mechanisms, which are still under investigation. Understanding the precise mechanisms is imperative given that treatment fails in ~30% of patients while adverse neurological sequelae remain common. Impaired GABAergic neurotransmission is commonly reported in research models investigating these mechanisms. Recently, we reported a region-specific reduction in the whole-tissue and synaptic GABAA receptor (GABAAR) α1 subunit and an increase in whole-tissue GAD65 in the primary somatosensory cortex (SoCx) of the adult epileptic stargazer mouse compared with its non-epileptic (NE) littermate. The current study investigated whether these changes occurred prior to the onset of seizures on postnatal days (PN) 17-18, suggesting a causative role. Synaptic and cytosolic fractions were biochemically isolated from primary SoCx lysates followed by semiquantitative Western blot analyses for GABAAR α1 and GAD65. We found no significant changes in synaptic GABAAR α1 and cytosolic GAD65 in the primary SoCx of the stargazer mice at the critical developmental stages of PN 7-9, 13-15, and 17-18. This indicates that altered levels of GABAAR α1 and GAD65 in adult mice do not directly contribute to the initial onset of absence seizures but are a later consequence of seizure activity.

Suppression of seizure in childhood absence epilepsy using robust control of deep brain stimulation: a simulation study

Deep brain stimulation (DBS) is a promising technique to relieve the symptoms in patients with intractable seizures. Although the DBS therapy for seizure suppression dates back more than 40 years, determining stimulation parameters is a significant challenge to the success of this technique. One solution to this challenge with application in a real DBS system is to design a closed-loop control system to regulate the stimulation intensity using computational models of epilepsy automatically. The main goal of the current study is to develop a robust control technique based on adaptive fuzzy terminal sliding mode control (AFTSMC) for eliminating the oscillatory spiking behavior in childhood absence epilepsy (CAE) dynamical model consisting of cortical, thalamic relay, and reticular nuclei neurons. To this end, the membrane voltage dynamics of the three coupled neurons are considered as a three-input three-output nonlinear state delay system. A fuzzy logic system is developed to estimate the unknown nonlinear dynamics of the current and delayed states of the model embedded in the control input. Chattering-free control input (continuous DBS pulses) without any singularity problem is the superiority of the proposed control method. To guarantee the bounded stability of the closed-loop system in a finite time, the upper bounds of the external disturbance and minimum estimation errors are updated online with adaptive laws without any offline tuning phase. Simulation results are provided to show the robustness of AFTSMC in the presence of uncertainty and external disturbances.

School performance and psychiatric comorbidity in childhood absence epilepsy: A Danish cohort study.

The aim was to determine school performance and psychiatric comorbidity in children with childhood absence epilepsy (CAE). We reviewed the medical records in children with ICD-10 codes for idiopathic generalized epilepsy before 18 years of age, and pediatric neurologists confirmed the International League Against Epilepsy criteria for CAE were met. Control groups were the general pediatric population or children with non-neurological chronic disease. Outcomes were from nationwide and population-based registers on school performance and psychiatric comorbidity. We compared the mean grade point average using linear regression and estimated hazard ratios (HR) using Cox regression for the other outcomes. Analyses were adjusted for the child's sex, and year of birth, and parental highest education, receipt of cash benefits or early disability pension. We included 114 children with CAE with a median age at onset of 5.9 years (interquartile range=4.5-7.3 years). Compared with both population controls and non-neurological chronically ill children, children with CAE had increased hazard of special needs education (HR=2.7, 95% confidence interval (CI)=1.8-4.1, p<0.0001), lower grade point average at 9th grade by 1.7 grade points (95% CI=-2.5 to -1.0, p<0.001), increased ADHD medicine use (HR=4.4, 95% CI=2.7-7.2, p<0.001), increased sleep medicine use (HR 2.7, 95% CI=1.7-4.3, p<0.001), and increased psychiatry visits (HR=2.1; 95% CI=1.1-4.0; p=0.03). In conclusion, children with CAE have increased psychiatric comorbidity and a considerable proportion of these children receive special needs education in primary/secondary school, albeit insufficient to normalize their considerably lower grade point average in the 9th grade.

Long-term Prognosis of Childhood Absence Epilepsy.

We aimed to investigate the long-term prognosis of childhood absence epilepsy (CAE), and identify factors associated with treatment outcomes. Patients with a definitive diagnosis of CAE according to the International League Against Epilepsy 2021 criteria and with a minimum of 3-year follow-up duration were included. The children were divided according to the time of seizure control. Early seizure remission was defined as seizure freedom within 6 months after the treatment onset. Twenty-four patients with a mean age of 13.7 (9.4-22.0) were included in this study. At the final follow-up, all patients were seizure-free except for one case. Seizure freedom was achieved after initial treatment in a mean of 0.78 years. The treatment was ceased in 19 children (79.2%) after a mean of 3.2 years. Patients having absence seizures without motor components had a higher rate of early seizure remission (p=0.026). In 81.3% of the patients; all of whose repetitive post-treatment EEGs were devoid of any generalized spike-wave discharges and absence seizures; remission was established within 6 months or less (p=0.026). CAE has a favorable prognosis with seizure control obtained in the majority of the cases and more than half of them were obtained within 6 months following the initiation of treatment. Moreover, having an absence seizure without motor components and repetitively normal post-treatment EEGs appear to be associated with a higher rate of early seizure remission.

Two cases of childhood absence epilepsy who showed seizure disappearance after ethosuximide drug eruption

BackgroundRecent studies suggest potential roles of immune response in the pathophysiology of epilepsy. Anti-seizure medications (ASMs) are known to have side effects of drug eruption caused by immune responses. A few reports in adults have demonstrated disappearance of seizures after an ASM drug eruption episode. In this paper, we described 2 cases of childhood absence epilepsy (CAE) who showed seizure disappearance after ethosuximide (ESM) drug eruption, suggesting the possibility that the epilepsy disappears due to immune responses to ASM.Case presentationCase 1 was an 8-year-old girl diagnosed with CAE. She was treated with valproate acid (VPA) initially, and then ESM was administered as an additional treatment. Her epileptic seizure disappeared 4 days after initiation of ESM. However, drug eruption appeared 1 week after the administration of ESM. Even after discontinuation of ESM administration, she maintains no seizure after the drug eruption. Case 2 was a 5-year-old boy diagnosed as CAE. He was treated with VPA initially, and ESM was administered additionally. Drug eruption appeared 1 month after the administration of ESM. Even after ESM was terminated, he maintained seizure freedom after the appearance of eruption.ConclusionsEpileptic seizures may have been suppressed due to the immune responses caused by ASM eruption. Further studies are needed to elucidate the pathophysiologic effects of drug eruption on epilepsy through immune responses.

Neuronal networks underlying ictal and subclinical discharges in childhood absence epilepsy

Childhood absence epilepsy (CAE), involves 3 Hz generalized spikes and waves discharges (GSWDs) on the electroencephalogram (EEG), associated with ictal discharges (seizures) with clinical symptoms and impairment of consciousness and subclinical discharges without any objective clinical symptoms or impairment of consciousness. This study aims to comparatively characterize neuronal networks underlying absence seizures and subclinical discharges, using source localization and functional connectivity (FC), to better understand the pathophysiological mechanism of these discharges. Routine EEG data from 12 CAE patients, consisting of 45 ictal and 42 subclinical discharges were selected. Source localization was performed using the exact low-resolution electromagnetic tomography (eLORETA) algorithm, followed by FC based on the imaginary part of coherency. FC based on the thalamus as the seed of interest showed significant differences between ictal and subclinical GSWDs (p < 0.05). For delta (1–3 Hz) and alpha bands (8–12 Hz), the thalamus displayed stronger connectivity towards other brain regions for ictal GSWDs as compared to subclinical GSWDs. For delta band, the thalamus was strongly connected to the posterior cingulate cortex (PCC), precuneus, angular gyrus, supramarginal gyrus, parietal superior, and occipital mid-region for ictal GSWDs. The strong connections of the thalamus with other brain regions that are important for consciousness, and with components of the default mode network (DMN) suggest the severe impairment of consciousness in ictal GSWDs. However, for subclinical discharges, weaker connectivity between the thalamus and these brain regions may suggest the prevention of impairment of consciousness. This may benefit future therapeutic targets and improve the management of CAE patients.

Genetically proxied gut microbiota, gut metabolites with risk of epilepsy and the subtypes: A bi-directional Mendelian randomization study.

An increasing number of observational studies have revealed an association among the gut microbiota, gut metabolites, and epilepsy. However, this association is easily influenced by confounders such as diet, and the causality of this association remains obscure. Aiming to explore the causal relationship and ascertain specific gut microbe taxa for epilepsy, we conducted a bi-directional Mendelian randomization (MR) study based on the genome-wide association study (GWAS) data of epilepsy from the International League Against Epilepsy, with the gut microbiota GWAS results from MiBioGen, and summary-level GWAS data of gut microbiota-dependent metabolites trimethylamine N-oxide and its predecessors. Nine phyla, 15 classes, 19 orders, 30 families, and 96 genera were analyzed. A suggestive association of host-genetic-driven increase in family Veillonellaceae with a higher risk of childhood absence epilepsy (odds ratio [OR]: 1.033, confidential interval [CI]: 1.015-1.051, P IVW = 0.0003), class Melainabacteria with a lower risk of generalized epilepsy with tonic-clonic seizures (OR = 0.986, CI = 0.979-0.994, P IVW = 0.0002), class Betaproteobacteria (OR = 0.958, CI = 0.937-0.979, P IVW = 0.0001), and order Burkholderiales (OR = 0.960, CI = 0.937-0.984, P IVW = 0.0010) with a lower risk of juvenile myoclonic epilepsy were identified after multiple-testing correction. Our sensitivity analysis revealed no evidence of pleiotropy, reverse causality, weak instrument bias, or heterogeneity. This is the first MR analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. Four gut microbiota features (two class levels, one order level, and one family level) were identified as potential interventional targets for patients with childhood absence epilepsy, generalized epilepsy with tonic-clonic seizures, and juvenile myoclonic epilepsy. Previous associations in numerous observational studies may had been interfered by confounders. More rigorous studies were needed to ascertain the relationship among the gut microbiota, metabolites, and epilepsy.

Causal relationship among obesity and body fat distribution and epilepsy subtypes.

The observational studies indicate an association between obesity and epilepsy, but it is unclear whether such an association responds to causality. The objective of this study was to determine the causal relationship between obesity and fat distribution and epilepsy subtypes based on waist circumference, hip circumference (HP), waist-hip ratio (WHR), and body mass index (BMI). A two-sample Mendelian randomization study was conducted separately for the four indicators of obesity and epilepsy and its seven subtypes, with reverse Mendelian randomization and multivariate Mendelian randomization for significant outcomes. A two-sample Mendelian randomized analysis informed us that waist circumference was a risk factor for juvenile myoclonic epilepsy (beta = 0.0299, P = 4.60 × 10-3). The increase in hip circumference increased the risk of juvenile myoclonic epilepsy and epilepsy, with effect values of 0.0283 (P = 2.01 × 10-3) and 0.0928 (P = 1.40 × 10-2), respectively. Furthermore, children with a higher BMI exhibit a higher risk of epilepsy (beta = 0.0148 P = 1.05 × 10-3). The reverse Mendelian randomization study revealed that childhood absence epilepsy increased its BMI (beta = 0.8980, P = 7.52 × 10-7), and juvenile myoclonic epilepsy increased its waist circumference (beta = 0.7322, P = 3.26 × 10-2). Multivariate Mendelian randomization revealed that an increase in hip circumference and waist-hip ratio increased the risk of juvenile myoclonic epilepsy, with an effect value of 0.1051 (P = 9.75 × 10-4) and 0.1430 (P = 3.99 × 10-3), respectively, while an increase in BMI and waist circumference instead decreased their risk, with effect values of -0.0951 (P = 3.14 × 10-2) and-0.0541 (P = 1.71 × 10-2). In contrast, multivariate Mendelian randomization for childhood absence epilepsy and epilepsy did not identify any independent risk factors. Our findings provide novel evidence in favor of obesity as a risk factor for epilepsy and waist circumference as a risk factor for juvenile myoclonic epilepsy. Increased hip circumference confers an elevated risk of juvenile myoclonic epilepsy and epilepsy (all documented cases), and a high BMI increases the risk of childhood absence epilepsy. With this, new insights are provided into the energy metabolism of epilepsy, which supports further nutritional interventions and the search for new therapeutic targets.

Childhood vs. juvenile absence epilepsy: How to make a diagnosis

PurposeWe tried to differentiate childhood absence epilepsy (CAE) from juvenile absence epilepsy (JAE) based on their clinical characteristics. We planned to identify a cutoff point for the age at onset of seizures between CAE and JAE that is able to reliably predict the presence of generalized tonic-clonic seizures (GTCS) (that has important implications for treatment strategy and outcome prediction). MethodsThis was a retrospective database study. All patients with an electro-clinical diagnosis of CAE or JAE were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2022. The receiver operating characteristic (ROC) curve was used for the statistical analysis to predict a cutoff point for the age at onset of seizures between the syndromes. ResultsOne hundred and ninety-six patients were studied. Generalized tonic-clonic seizure was reported by 134 patients (68.4%). The ROC curve of the age at seizure onset was an acceptable indicator to anticipate GTCS; the best cutoff point was at 9.65 years; 87 patients (44.4%) had CAE and 109 people (55.6%) had JAE. The odds ratio of the presence of GTCS in JAE compared with CAE was 3.6. ConclusionSyndrome diagnosis of CAE vs. JAE has important practical implications. The age at onset of seizures serves as a reliable and meaningful variable to differentiate CAE from JAE.

Clinical and Instrumental Follow-Up of Childhood Absence Epilepsy (CAE): Exploration of Prognostic Factors.

Background: Idiopathic generalized epilepsies (IGEs) represent 15–20% of all cases of epilepsy in children. This study explores predictors of long-term outcome in a sample of children with childhood absence epilepsy (CAE). Methods: The medical records of patients with CAE treated at a university paediatric hospital between 1995 and 2022 were systematically reviewed. Demographics and relevant clinical data, including electroencephalogram, brain imaging, and treatment outcome were extracted. Outcomes of interest included success in seizure control and seizure freedom after anti-seizure medication (ASM) discontinuation. An analysis of covariance using the diagnostic group as a confounder was performed on putative predictors. Results: We included 106 children (age 16.5 ± 6.63 years) with CAE with a mean follow-up of 5 years. Seizure control was achieved in 98.1% (in 56.6% with one ASM). Headache and generalized tonic-clonic seizures (GTCS) were more frequent in children requiring more than one ASM (p < 0.001 and p < 0.002, respectively). Of 65 who discontinued ASM, 54 (83%) remained seizure-free, while 11 (17%) relapsed (mean relapse time 9 months, range 0–18 months). Relapse was associated with GTCS (p < 0.001) and number of ASM (p < 0.002). Conclusions: A history of headache or of GTCS, along with the cumulative number of ASMs utilized, predicted seizure recurrence upon ASM discontinuation. Withdrawing ASM in patients with these characteristics requires special attention.

The Adhesion GPCR VLGR1/ADGRV1 Regulates the Ca2+ Homeostasis at Mitochondria-Associated ER Membranes.

The very large G protein-coupled receptor (VLGR1, ADGRV1) is the largest member of the adhesion GPCR family. Mutations in VLGR1 have been associated with the human Usher syndrome (USH), the most common form of inherited deaf-blindness as well as childhood absence epilepsy. VLGR1 was previously found as membrane–membrane adhesion complexes and focal adhesions. Affinity proteomics revealed that in the interactome of VLGR1, molecules are enriched that are associated with both the ER and mitochondria, as well as mitochondria-associated ER membranes (MAMs), a compartment at the contact sites of both organelles. We confirmed the interaction of VLGR1 with key proteins of MAMs by pull-down assays in vitro complemented by in situ proximity ligation assays in cells. Immunocytochemistry by light and electron microscopy demonstrated the localization of VLGR1 in MAMs. The absence of VLGR1 in tissues and cells derived from VLGR1-deficient mouse models resulted in alterations in the MAM architecture and in the dysregulation of the Ca2+ transient from ER to mitochondria. Our data demonstrate the molecular and functional interaction of VLGR1 with components in MAMs and point to an essential role of VLGR1 in the regulation of Ca2+ homeostasis, one of the key functions of MAMs.