Common Idiopathic Epilepsy Research Articles

Resting-State EEG Functional Connectivity in Children with Rolandic Spikes with or without Clinical Seizures.

Alterations in dynamic brain network function are increasingly recognized in epilepsy. Benign childhood epilepsy with centrotemporal spikes (BECTS), or benign rolandic seizures, is the most common idiopathic focal epilepsy in children. In this study, we analyzed EEG functional connectivity (FC) among children with rolandic spikes with or without clinical seizures as compared to controls, to investigate the relationship between FC and clinical parameters in children with rolandic spikes. The FC analysis based on graph theory and network-based statistics in different frequency bands evaluated global efficiency, clustering coefficient, betweenness centrality, and nodal strength in four frequency bands. Similar to BECTS patients with seizures, children with rolandic spikes without seizures had significantly increased global efficiency, mean clustering coefficient, mean nodal strength, and connectivity strength, specifically in the theta frequency band at almost all proportional thresholds, compared with age-matched controls. Decreased mean betweenness centrality was only present in BECTS patients with seizures. Age at seizure onset was significantly positively associated with the strength of EEG-FC. The decreased function of betweenness centrality was only presented in BECTS patients with clinical seizures, suggesting weaker local connectivity may lower the seizure threshold. These findings may affect treatment policy in children with rolandic spikes.

Focal Sleep Spindle Deficits Reveal Focal Thalamocortical Dysfunction and Predict Cognitive Deficits in Sleep Activated Developmental Epilepsy.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common focal epilepsy syndrome, yet the cause of this disease remains unknown. Now recognized as a mild epileptic encephalopathy, children exhibit sleep-activated focal epileptiform discharges and cognitive difficulties during the active phase of the disease. The association between the abnormal electrophysiology and sleep suggests disruption to thalamocortical circuits. Thalamocortical circuit dysfunction resulting in pathologic epileptiform activity could hinder the production of sleep spindles, a brain rhythm essential for memory processes. Despite this pathophysiologic connection, the relationship between spindles and cognitive symptoms in epileptic encephalopathies has not been previously evaluated. A significant challenge limiting such work has been the poor performance of available automated spindle detection methods in the setting of sharp activities, such as epileptic spikes. Here, we validate a robust new method to accurately measure sleep spindles in patients with epilepsy. We then apply this detector to a prospective cohort of male and female children with CECTS with combined high-density EEGs during sleep and cognitive testing at varying time points of disease. We show that: (1) children have a transient, focal deficit in spindles during the symptomatic phase of disease; (2) spindle rate anticorrelates with spike rate; and (3) spindle rate, but not spike rate, predicts performance on cognitive tasks. These findings demonstrate focal thalamocortical circuit dysfunction and provide a pathophysiological explanation for the shared seizures and cognitive symptoms in CECTS. Further, this work identifies sleep spindles as a potential treatment target of cognitive dysfunction in this common epileptic encephalopathy.SIGNIFICANCE STATEMENT Childhood epilepsy with centrotemporal spikes is the most common idiopathic focal epilepsy syndrome, characterized by self-limited focal seizures and cognitive symptoms. Here, we provide the first evidence that focal thalamocortical circuit dysfunction underlies the shared seizures and cognitive dysfunction observed. In doing so, we identify sleep spindles as a mechanistic biomarker, and potential treatment target, of cognitive dysfunction in this common developmental epilepsy and provide a novel method to reliably quantify spindles in brain recordings from patients with epilepsy.

Autism spectrum disorder and attention-deficit/hyperactivity disorder-related symptoms in benign childhood epilepsy with centrotemporal spikes: A prospective case–control study

BackgroundBenign childhood epilepsy with centrotemporal spikes (BECTS), one of the most common idiopathic epilepsy syndromes in children, has been associated with neuropsychological problems. PurposeThe objective of this study was to investigate the frequency of symptoms related to comorbid neurodevelopmental disorders, the autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children with typical BECTS, and to identify corresponding risk factors. MethodsChildren and adolescents with typical BECTS aged 6–16 years were included in the study period from January 1, 2017, to December 31, 2017. Children with atypical presentations of BECTS, other neurological disorders, and preexisting neuropsychiatric disorders were excluded. The ASD and ADHD were assessed by the Social Communication Questionnaire (SCQ) and the Turgay Diagnostic and Statistical Manual of Mental Disorders – 4th Edition – Disruptive Behavior Disorders Rating Scale (T-DSM-IV-S), respectively. Patients' scores were compared with those of healthy subjects. Correlation analyses were performed to evaluate the association between the age at seizure onset, the total number of seizures and the SCQ and T-DSM-IV-S scores. ResultsFifty-eight children with BECTS and 60 healthy children participated in the study. The total SCQ score, the SCQ reciprocal social interaction score, and the SCQ communication score significantly differed between children with BECTS and the control group (p = 0.001, p < 0.001, p = 0.001, respectively). The total ADHD score was significantly different between patients and controls (p < 0.001). A significant difference was observed between patients and controls in terms of the T-DSM-IV-S hyperactivity–impulsivity score and the T-DSM-IV-S inattention score (p = 0.012, p < 0.001, respectively). The age at seizure onset was significantly correlated with the total SCQ score (p = 0.03). The Spearman's correlation coefficient was 0.352 for the total SCQ score, indicating a positive association between the age at seizure onset and the total SCQ score. ConclusionChildren with typical BECTS may have an increased risk of suffering from symptoms of ASD and ADHD. Children with late onset of seizures may be more likely to develop neuropsychological disturbances regarding ASD and ADHD.

Clinical Presentations and Factors Responsible for Delays in Diagnosis of Juvenile Myoclonic Epilepsy among Sudanese Patients

Introduction: Juvenile Myoclonic Epilepsy (JME) is common idiopathic epilepsy manifested by myoclonic jerks that commonly noticed in early childhood without consciousness disturbance, then the generalised tonic – clonic overwhelms the scene, absence attacks are not uncommon. The prominent and cardinal EEG features of JME syndrome that supports the diagnosis is the generalized 3.5-6 Hz single, bifid and polyspikes slow-wave’s complexes on normal brain background activity. Aim: Aims were to evaluate the demographic features and to detect the most common clinical presentations among Sudanese patients with JME and explain the possible causes of diagnosis delaying. Methods and patients: The study included all patients attended to National Ribat University – Faculty of Medicine and El-Magzoub Neurosciences centres whom their EEGs showed the characteristics features of JME (retrospectively). All the patients had been recruited (prospectively) and their EEGs have been repeated and clinical history and examination through pre-formed interview forms had bee done. The obtained data have been analysed using the SPSS and results were illustrated in by tables. Results and discussion: The mean age of JME patients at diagnosis was 19.55 ± 8.98 years. Myoclonic jerks were confirmed in about 91% of the patients. Sleep deprivation was the triggering factor for MJs in 61.4% of the patients. Absence attacks were confirmed in 77.27% of JME patients, and generalised tonic-clonic seizures in 84.1% of patients with a mean age of onset 13.92 ± 5.65 years. The elapsed time between jerks and GTC was 4.35 ± 3.61 years. Conclusion: MJs is common among Sudanese patients with JME and the sleep deprivation is the most frequent aggravating factors with the early awakening. Generalised tonic-clonic is common among JME patients and this great event may obscure MJs and confused the doctors to ask about them.

EEG resting state analysis of cortical sources in patients with benign epilepsy with centrotemporal spikes.

Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic childhood epilepsy, which is often associated with developmental disorders in children. In the present study, we analyzed resting state EEG spectral changes in the sensor and source spaces in eight BECTS patients compared with nine age-matched controls. Using high-resolution scalp EEG data, we assessed statistical differences in spatial distributions of EEG power spectra and cortical sources of resting state EEG rhythms in five frequency bands: δ (0.5–3.5 Hz), θ (4–8 Hz), α (8.5–13 Hz), β1 (13.5–20 Hz) and β2 (20.5–30 Hz) under the eyes-closed resting state condition. To further investigate the impact of centrotemporal spikes on EEG spectra, we split the EEG data of the patient group into EEG portions with and without spikes. Source localization demonstrated the homogeneity of our population of BECTS patients with a common epileptic zone over the right centrotemporal region. Significant differences in terms of both spectral power and cortical source densities were observed between controls and patients. Patients were characterized by significantly increased relative power in θ, α, β1 and β2 bands in the right centrotemporal areas over the spike zone and in the right temporo-parieto-occipital junction. Furthermore, the relative power in all bands significantly decreased in the bilateral frontal and parieto-occipital areas of patients regardless of the presence or absence of spikes in EEG segments. However, the spectral differences between patients and controls were more pronounced in the presence of spikes. This observation emphasized the impact of benign epilepsy on cortical source power, especially in the right centrotemporal regions. Spectral changes in bilateral frontal and parieto-occipital areas may also suggest alterations in the default mode network in BECTS patients.

Frontal lobe function and structure in juvenile myoclonic epilepsy: A comprehensive review of neuropsychological and imaging data

Juvenile myoclonic epilepsy is the most common idiopathic epilepsy syndrome and is considered a benign seizure disorder that responds well to antiepileptic drug treatment, in particular sodium valproate. By definition, routine brain imaging shows no abnormalities, but advanced imaging studies have identified functional and structural abnormalities in the frontal cortex and thalamus. Neuropsychological studies revealed subtle cognitive deficits in patients with JME, mainly implicating the frontal lobes. These findings are in keeping with anecdotal reports of behavioral problems in JME. Cognitive dysfunction in otherwise healthy siblings of patients with JME and a high heritability support the concept of a genetically determined thalamo-frontocortical network dysfunction, accounting for the cognitive impairment and cognitively triggered "motor seizures."

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes

To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

The state of the art in the genetic analysis of the epilepsies

Genetic influences as causal factors in the epilepsies continue to be vigorously investigated, and we review several important studies of genes reported in 2006. To date, mutations in ion channel and neuroreceptor component genes have been reported in the small fraction of cases with clear Mendelian inheritance. These findings confirm that the so-called "channelopathies" are generally inherited as monogenic disorders. At the same time, the literature in common epilepsies abounds with reports of associations and reports of nonreplication of those association studies, primarily with channel genes. These contradictory reports can mostly be explained by confounding factors unique to genetic studies. The methodology of genetic studies and their common biases and confounding factors are also explained in this review. Amid the controversy, steady progress is being made on the epilepsies of complex inheritance, which represent the most common idiopathic epilepsy. Recent discoveries show that genes influencing the developmental assembly of neural circuits and neuronal metabolism may play a more prominent role in the common epilepsies than genes affecting membrane excitability and synaptic transmission.

Benign childhood epilepsy with centro‐temporal spikes (BCECTS): early onset of seizures is associated with poorer response to initial treatment

ABSTRACT Aim Benign childhood epilepsy with centro‐temporal spikes (BCECTS) is the most common idiopathic partial epilepsy in children. Treatment attitudes remain a controversial issue. We examine features that could suggest refractoriness at onset. Methods We retrospectively reviewed the medical records of 144 children with BCECTS diagnosed at the Division of Pediatric Neurology, Asan Medical Center, from March 1, 1995, to April 30, 2002 and treated with AEDs. The patients were subdivided into two groups according to the number of antiepileptic drugs used for effective seizure control. Results Of the 144 patients, 75 were male and 69 were female, with a mean age at seizure‐onset of 7.2 ± 2.3 years (range, 2.1‐14.3 years); 119 children were taking one antiepileptic drug (AED) (Group A), and 25 were taking more than one (Group B). There were no significant group differences in female‐to‐male ratio, prescribed AEDs, number of seizures before the start of treatment, interval between seizure‐onset and start of treatment, presence of secondarily generalized seizures, or presence of bilateral EEG abnormalities. The groups differed however, in mean age at seizure onset (7.6 ± 2.2 years versus 5.1 ± 1.9 years, p &lt; 0.05) and percentage of patients with seizure‐onset before 3 years (p &lt; 0.05). Conclusions When treated with AEDs, children with BCECTS usually respond well. However, an earlier onset of seizures is associated with more frequent seizures and initial refractoriness to medical treatment.

Benign childhood epilepsy with centro-temporal spikes (BCECTS): early onset of seizures is associated with poorer response to initial treatment.

Benign childhood epilepsy with centro-temporal spikes (BCECTS) is the most common idiopathic partial epilepsy in children. Treatment attitudes remain a controversial issue. We examine features that could suggest refractoriness at onset. We retrospectively reviewed the medical records of 144 children with BCECTS diagnosed at the Division of Pediatric Neurology, Asan Medical Center, from March 1, 1995, to April 30, 2002 and treated with AEDs. The patients were subdivided into two groups according to the number of antiepileptic drugs used for effective seizure control. Of the 144 patients, 75 were male and 69 were female, with a mean age at seizure-onset of 7.2 +/- 2.3 years (range, 2.1-14.3 years); 119 children were taking one antiepileptic drug (AED) (Group A), and 25 were taking more than one (Group B). There were no significant group differences in female-to-male ratio, prescribed AEDs, number of seizures before the start of treatment, interval between seizure-onset and start of treatment, presence of secondarily generalized seizures, or presence of bilateral EEG abnormalities. The groups differed however, in mean age at seizure onset (7.6 +/- 2.2 years versus 5.1 +/- 1.9 years, p < 0.05) and percentage of patients with seizure-onset before 3 years (p < 0.05). When treated with AEDs, children with BCECTS usually respond well. However, an earlier onset of seizures is associated with more frequent seizures and initial refractoriness to medical treatment.

Susceptibility genes for complex epilepsy

Common idiopathic epilepsies are, clinically and genetically, a heterogeneous group of complex seizure disorders. Seizures arise from periodic neuronal hyperexcitability of unknown cause. The genetic component is mostly polygenic, where each susceptibility gene in any given individual is likely to represent a small component of the total heritability. Two susceptibility genes have been so far identified, where genetic variation is associated with experimentally demonstrated changes in ion channel properties, consistent with seizure susceptibility. Rare variants and a polymorphic allele of the T-type calcium channel CACNA1H and a polymorphic allele and a rare variant of the GABA(A) receptor delta subunit gene have differential functional effects. We speculate that these and other as yet undiscovered susceptibility genes for complex epilepsy could act as 'modifier' loci, affecting penetrance and expressivity of the mutations of large effect in those 'monogenic' epilepsies with simple inheritance that segregate through large families. Discovery of epilepsy-associated ion channel defects in these rare families has opened the door to the discovery of the first two susceptibility genes in epilepsies with complex genetics. The susceptibility genes so far detected are not commonly involved in complex epilepsy suggesting the likelihood of considerable underlying polygenic heterogeneity.

Symposium II

Symposium II

Genetics of Idiopathic Epilepsies

To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. Mutations identified as the causes of inherited idiopathic epilepsies were reviewed. Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy. These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.

BRD2 (RING3) Is a Probable Major Susceptibility Gene for Common Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy that starts in adolescence. A major JME susceptibility locus (EJM1) was mapped to chromosomal region 6p21 in three independent linkage studies, and association was reported between JME and a microsatellite marker in the 6p21 region. The critical region for EJM1 is delimited by obligate recombinants at HLA-DQ and HLA-DP. In the present study, we found highly significant linkage disequilibrium (LD) between JME and a core haplotype of five single-nucleotide-polymorphism (SNP) and microsatellite markers in this critical region, with LD peaking in the BRD2 (RING3) gene (odds ratio 6.45; 95% confidence interval 2.36-17.58). DNA sequencing revealed two JME-associated SNP variants in the BRD2 (RING3) promoter region but no other potentially causative coding mutations in 20 probands from families with positive LOD scores. BRD2 (RING3) is a putative nuclear transcriptional regulator from a family of genes that are expressed during development. Our findings strongly suggest that BRD2 (RING3) is EJM1, the first gene identified for a common idiopathic epilepsy. These findings also suggest that abnormalities of neural development may be a cause of common idiopathic epilepsy, and the findings have implications for the generalizability of proposed pathogenetic mechanisms, derived from diseases that show Mendelian transmission, to their complex counterparts.

A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions.

Missense mutations in the GABRG2 gene, which encodes the gamma 2 subunit of central nervous gamma-aminobutyric acid (GABA)(A) receptors, have recently been described in 2 families with idiopathic epilepsy. In one of these families, the affected individuals predominantly exhibited childhood absence epilepsy and febrile convulsions. To assess the role of GABRG2 in the genetic predisposition to idiopathic absence epilepsies. The GABRG2 gene was screened by single-strand conformation analysis for mutations. Furthermore, a population-based association study assessing a common exon 5 polymorphism (C588T) was carried out. The sample was composed of 135 patients with idiopathic absence epilepsy and 154 unrelated and ethnically matched controls. A point mutation (IVS6 + 2T-->G) leading to a splice-donor site mutation in intron 6 was found. The mutation, which is predicted to lead to a nonfunctional protein, cosegregates with the disease status in a family with childhood absence epilepsy and febrile convulsions. The association study did not find any significant differences in the allele and genotype frequencies of the common exon 5 polymorphism (C588T) between patients with idiopathic absence epilepsy and controls (P>.35). Our study identified a splice-donor-site mutation that was probably causing a nonfunctional GABRG2 subunit. This mutation occurred in heterozygosity in the affected members of a single nuclear family, exhibiting a phenotypic spectrum of childhood absence epilepsy and febrile convulsions. The GABRG2 gene seems to confer a rare rather than a frequent major susceptibility effect to common idiopathic absence epilepsy syndromes.

Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability.

Benign familial neonatal convulsion (BFNC) is a common idiopathic epilepsy with autosomal dominant inheritance. Recently, two novel voltage-dependent potassium channel genes, KCNQ2 and KCNQ3, were identified by positional cloning as being responsible for BFNC. Heterotetramers of the products of these genes form M-channels and regulate the threshold of electrical excitability of neurons. We disrupted the mouse KCNQ2 gene via gene targeting to study the relationship between KCNQ2 and epilepsy. Homozygous pups (KCNQ2 -/-) died within a few hours after birth owing to pulmonary atelectasis that was not due to the status of epileptic seizures, although their development was morphologically normal. Heterozygous mice had decreased expression of KCNQ2 and showed hypersensitivity to pentylenetetrazole, an inducer of seizure. These data indicate that the decreased expression of KCNQ2 might cause a hyperexcitability of the CNS, which accounts for the mechanism of BFNC.

Genetics of childhood epilepsy

The epilepsies are a heterogeneous group of disorders with many causes. However, a genetic aetiology may be present in up to 40% of patients, and this proportion is even higher...

Lack of association between juvenile myoclonic epilepsy and GABRA5 and GABRB3 genes

Alpha 5 and beta 3 GABAA receptor genes are major candidates for epilepsy, as they code for subunits of the most important human inhibitory neurotransmitter. Moreover, they are located within a region of the human genome previously implicated in disorders including epilepsy. We carried out an association study between dinucleotide repeat polymorphisms in these two genes and juvenile myoclonic epilepsy (JME). JME is the most common idiopathic epilepsy and is characterized by a complex mode of inheritance. We did not find significant differences between controls and patients for allele or genotype frequencies.

A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.