Common Epilepsy Research Articles

PP07.12 – 3021: Examination of speech processing in children with benign childhood epilepsy with centrotemporal spike

Objective Benign childhood epilepsy with centro-temporal spike (BCECTS) is the most common childhood epilepsy. Its prognosis is usually good, but involvement of cognitive function could be seen. The involvement of language processing was examined by several authors with mismatch negativity (MMN), but their results are controversial. The mismatch negativity is a negative component of the auditory event related potential, which is automatically elicited by detectable changes in any repetitive aspect of the auditory events. Based on Bedoin's results, the processing of phonemes differing of place of articulation is disturbed in left sided epilepsy, while processing of phonemes differing in voicing was the same as in typically developing child. Processing of place of articulation is linked in left hemisphere, while voicing are processed bilaterally. Based on our presumption the controversial results of MMN studies come from using stimuli differing in different features. Aims: Investigate the speech processing in BCECTS whit stimuli, processed by different hemispheres. Methods MMN was recorded in a passive oddball paradigm using phoneme deviants, differing in voicing or place of articulation or both. We compared an epileptic group (13 children with BCECTS) with an age matched typical developing group. Results MMN was elicited during all three conditions in control group. The processing of phonemes differing in both features was similar in two groups. In case of phonemes differing only voicing, the amplitude of MMN was smaller in BCECTS group (-1.12μV/-3.06 μV, p=0.059). In case of phonemes differing only place of articulation, the amplitude of MMN was higher in epileptic group (- 2.73μV/-1.11 μV) but this difference was not statistically significant. Conclusion Based of our results the speech processing of BCETCS children is differing from typical developing children. Furthermore the quantity and nature of this difference depend on hemispheric localisation of processing of the examined features.

CHD2 variants are a risk factor for photosensitivity in epilepsy.

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Galanin pathogenic mutations in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.

Common pediatric epilepsy syndromes.

Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as "fifth-day fits," are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as "benign" idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term "benign" may not be appropriate.

The genetic research progress in benign childhood epilepsy with centro-temporal spikes

Benign epilepsy with centro-temporal spikes(BECT)is the most common epilepsy syndrome in childhood.The seizures are manifested with facial jerking and twitching to guttural noises, salivating with inability to speak and twitched limbs.The episode is proved to be closely associated with sleep, especially the non-rapid eye movement period.Centrotemporal spikes are the hallmark of the syndrome of BECT.Although the pathogenesis of BECT is still unknown, it is generally acknowledged that hereditary features play a critical role in the occurrence of BECT.In this article we are going to summarize the progresses of BECT in the fields of clinical genetics, cytogenetics and molecular genetics. Key words: Benign partial epilepsy of childhood with centro-temporal spikes; Genetics; Epilepsy

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.

Status epilepticus results in region-specific alterations in seizure susceptibility along the hippocampal longitudinal axis

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. In particular, the hippocampus is highly susceptible to abnormal synchronization. Recent advances in the surgical treatment of patients with refractory TLE have shown that multiple hippocampal transections can effectively control seizures. It has been suggested that in TLE the synchrony in the longitudinal connections is required for seizure generation; however the physiological background for the increase in hippocampal synchronization along the longitudinal axis is not fully understood. The hippocampus varies in seizure susceptibility along its longitudinal axis with the ventral hippocampus (VH) region being more seizure-prone and susceptible to neuronal damage than the dorsal hippocampus (DH). In the present study we studied seizure susceptibility along the longitudinal axis of the hippocampus following pilocarpine-induced status epilepticus (SE). In control conditions the VH generates epileptiform activity (EA) more frequently than the DH when exposed to a low Mg(2+)/1Ca(2+)/5K(+) solution. Following SE the probability of inducing epileptiform activity (EA) is similar in the VH and DH slices. This SE-induced change is due to an increase in the proportion of DH slices responding to the low Mg(2+)/1Ca(2+)/5K(+) solution with EA. Moreover, both the VH and DH show similar responses to a low Mg(2+)/1Ca(2+)/5K(+) solution. These findings indicate that the hippocampus undergoes significant functional changes following SE, which may provide the necessary increase of synchrony along the longitudinal axis to generate seizures in TLE.

Functional network alterations and their structural substrate in drug-resistant epilepsy.

The advent of MRI has revolutionized the evaluation and management of drug-resistant epilepsy by allowing the detection of the lesion associated with the region that gives rise to seizures. Recent evidence indicates marked chronic alterations in the functional organization of lesional tissue and large-scale cortico-subcortical networks. In this review, we focus on recent methodological developments in functional MRI (fMRI) analysis techniques and their application to the two most common drug-resistant focal epilepsies, i.e., temporal lobe epilepsy related to mesial temporal sclerosis and extra-temporal lobe epilepsy related to focal cortical dysplasia. We put particular emphasis on methodological developments in the analysis of task-free or “resting-state” fMRI to probe the integrity of intrinsic networks on a regional, inter-regional, and connectome-wide level. In temporal lobe epilepsy, these techniques have revealed disrupted connectivity of the ipsilateral mesiotemporal lobe, together with contralateral compensatory reorganization and striking reconfigurations of large-scale networks. In cortical dysplasia, initial observations indicate functional alterations in lesional, peri-lesional, and remote neocortical regions. While future research is needed to critically evaluate the reliability, sensitivity, and specificity, fMRI mapping promises to lend distinct biomarkers for diagnosis, presurgical planning, and outcome prediction.

Electrical stimulation of hippocampus for the treatment of refractory temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome and is often associated with pharmacoresistance. Patients with pharmacoresistant TLE may be candidates for epilepsy surgery, and anterior temporal lobectomy if indicated is the most effective known treatment and has the best chance of a seizure-free outcome. For many patients with TLE, epilepsy surgery is not an option, for example when the seizure onset zone co-localizes with eloquent brain function and cannot be resected, or the seizure onset zone is not well localized, or when seizures independently originate from both temporal lobes. For many of these patients, electrical stimulation is a viable treatment option, such as electrical stimulation of the hippocampus, or temporal neocortex, or thalamus. Animal and clinical studies in humans have demonstrated electrical stimulation is an effective and safe treatment. Moreover, successful application of responsive neurostimulation system in the treatment of temporal lobe epilepsy has been reported recently. This review is intended to provide a comprehensive review of the modern history of electrical stimulation of the hippocampus for the treatment of refractory medial temporal lobe epilepsy and discuss the anatomical basis, validity, side effects, stimulation paradigm and mechanism of hippocampus stimulation and the responsive electrical stimulation trials.

Disrupted topological properties of brain white matter networks in left temporal lobe epilepsy: A diffusion tensor imaging study

Mesial temporal lobe epilepsy (mTLE) is the most common drug-refractory focal epilepsy in adults. Although previous functional and morphological studies have revealed abnormalities in the brain networks of mTLE, the topological organization of the brain white matter (WM) networks in mTLE patients is still ambiguous. In this study, we constructed brain WM networks for 14 left mTLE patients and 22 age- and gender-matched normal controls using diffusion tensor tractography and estimated the alterations of network properties in the mTLE brain networks using graph theoretical analysis. We found that networks for both the mTLE patients and the controls exhibited prominent small-world properties, suggesting a balanced topology of integration and segregation. However, the brain WM networks of mTLE patients showed a significant increased characteristic path length but significant decreased global efficiency, which indicate a disruption in the organization of the brain WM networks in mTLE patients. Moreover, we found significant between-group differences in the nodal properties in several brain regions, such as the left superior temporal gyrus, left hippocampus, the right occipital and right temporal cortices. The robustness analysis showed that the results were likely to be consistent for the networks constructed with different definitions of node and edge weight. Taken together, our findings may suggest an adverse effect of epileptic seizures on the organization of large-scale brain WM networks in mTLE patients.

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

Idiopathic epilepsies are thought to be almost entirely the result of genetic determinants, most of which remain undiscovered. It was once widely accepted that mutations that change the amino acid sequence of ion channel proteins were the major cause of these epilepsies, making epilepsy in general a “channelopathy.” Since then, more comprehensive analysis of ion channel-encoding genes has largely rejected this hypothesis for common forms of epilepsy. Here, we discuss some of the assumptions that led to the channelopathy hypothesis and propose ways to avoid similar mistakes going forward. We also offer insight into promising genetic candidates that we believe play a major role in susceptibility to common forms of idiopathic epilepsy.

The reliability of an epilepsy treatment clinical decision support system.

We developed a content validated computerized epilepsy treatment clinical decision support system to assist clinicians with selecting the best antiepilepsy treatments. Before disseminating our computerized epilepsy treatment clinical decision support system, further rigorous validation testing was necessary. As reliability is a precondition of validity, we verified proof of reliability first. We evaluated the consistency of the epilepsy treatment clinical decision support system in three areas including the preferred antiepilepsy drug choice, the top three recommended choices, and the rank order of the three choices. We demonstrated 100% reliability on 15,000 executions involving a three-step process on five different common pediatric epilepsy syndromes. Evidence for the reliability of the epilepsy treatment clinical decision support system was essential for the long-term viability of the system, and served as a crucial component for the next phase of system validation.

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

SummaryBackgroundThe epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy).MethodsWe combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8.FindingsWe included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy.InterpretationThis meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).FundingInternational League Against Epilepsy and multiple governmental and philanthropic agencies.

The genetics of common epilepsies: common or distinct?

The genetics of common epilepsies: common or distinct?

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy.

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Can ACTH therapy improve the long-term outcome of drug-resistant frontal lobe epilepsy?

Frontal lobe epilepsy is a common focal epilepsy in children and is often difficult to treat. Adrenocorticotropic hormone (ACTH) or steroids have been used for patients with several forms of medically intractable epilepsy. We evaluated the short, medium, and long-term evolution of patients with frontal lobe epilepsy and secondary bilateral synchrony on the EEG, who received ACTH treatment. Patients were recruited for an add-on trial during clinical practice, and data was retrospectively analysed. The study group comprised 6 patients treated with ACTH. The effects of ACTH were assessed in the short term (at the end of a 6-week period of ACTH treatment), medium term (at 6 months after the end of treatment), and long term (at 12 months after the end of treatment). At short-term follow-up, ACTH treatment was effective for all types of seizures in 5 of 6 patients and ineffective in 1 patient. All patients who were seizure-free at the end of ACTH treatment maintained an excellent outcome, remaining seizure-free at the end of follow-up. Our study demonstrates that ACTH may represent an effective treatment for frontal lobe epilepsy with secondary bilateral synchrony. Further double-blind prospective studies are required to confirm our initial findings.

Prognostic significance of failure of the initial antiepileptic drug in children with benign childhood epilepsy with centrotemporal spikes

Benign epilepsy with centrotemporal spikes is the most common partial epilepsy syndrome in children. The long-term prognosis for children with BECTS is believed to be generally excellent with seizures usually responding well to AEDs. The goal of the present study was to determine the risk factors associated with a poor prognosis. Eighty-four children with BECTS were retrospectively analyzed. Fifty-four (64.3%) were boys and 30 (35.7%) were girls with the mean age at seizure onset 7.1 ± 2.01 years (range: 3-12 years). Of the 84 patients, 72 (85.7%) were treated successfully with the first AED (Group A), and 12 (14.3%) failed to responded to the initial AED treatment (Group B [poor prognosis]). Univariate analyses suggested that younger age of seizure onset, presence of generalized seizures, and frequent seizures (>3 prior to the initial treatment) were associated with failure to control seizures with the initial AED. Multivariate analysis suggested that younger age of seizure onset was the independent risk factor predicting a poor response to initial AED treatment. About 14% of our cohort of children with BECTS continued to have seizures following the initial AED treatment. Further prospective studies are warranted to determine how well prognosis can be predicted by age of seizure onset, type of seizures, and frequency of pre-existing seizures in children with BECTS.

Chapter 11 - Remind me again what disease we are studying? A population genetics, genetic analysis, and real data perspective on why progress on identifying genetic influences on common epilepsies has been so slow

In this chapter, we will use the concepts and perspective of population genetics and genetic analysis to discuss the trends that are currently popular in the epilepsy genetics literature. We will also show that some of the recent approaches to understanding epilepsy genetics are unlikely to lead to insight into the causes of the most common epilepsies. Much effort has been directed toward very rare influences on epilepsy expression and away from approaches that could shed light on the most heritable epilepsies. The latest genetic technology, e.g., exome sequencing and copy number variants (CNV) analysis, has been applied without proper consideration of the important principles of population genetics, inheritance, or phenotype definition that are critical in common disease studies. We will show that ignoring these issues has led to unlikely suppositions about etiology and about which genes should be pursued. We also suggest that, taken together, the existing evidence supports a neurodevelopmental origin for common epilepsies. We recommend a return to thorough phenotype definition and family studies and a more careful and thoughtful application of the new technology.

Memory functioning in children with epilepsy: frontal lobe epilepsy, childhood absence epilepsy, and benign epilepsy with centrotemporal spikes.

Specific cognitive deficits have been identified in children with epilepsy irrespective of results on intelligence tests. Memory deficits are traditionally attributed to temporal lobe epilepsy, whereas the impact of frontal lobe epilepsy on memory functions has remained controversial. The aim of this study was the examination of memory abilities in other childhood common epilepsy syndromes (frontal lobe epilepsy (FLE), childhood absence epilepsy (CAE), and benign epilepsy with centrotemporal spikes (BECTS)) and the influence of epilepsy-related variables. Memory was examined in 90 children with epilepsy (each epilepsy group consisted of 30 children), aged 6–15, and compared with 30 control children. Children with FLE showed significant deficits in verbal and visual memory. In addition, type of epilepsy, earlier age at epilepsy onset, and longer active duration of epilepsy were associated with memory problems. Seizure frequency and treatment, however, did not influence memory performance. This study indicates that children with FLE show greater risk of developing memory deficits than children with CAE or BECTS, thus highlighting the importance of assessing also memory functions in frontal lobe epilepsy.

Neuropsychological abnormalities in children with the Panayiotopoulos syndrome point to parietal lobe dysfunction

Panayiotopoulos syndrome (PS) is a common epilepsy syndrome associated with rare clinical seizures and unknown localization of the epileptogenic area. Despite findings of normal development in patients with PS, recent neuropsychological studies point to subtle and diverse cognitive impairments. No well-outlined hypothesis about the localization of the brain dysfunction responsible for these impairments has been proposed. We further explored the cognitive dysfunctions in PS and made inferences on the most likely anatomical localization of brain impairment. A group of 19 patients (aged 6–12) with PS was rated according to spike activity and lateralization. The patients were submitted to a neuropsychological evaluation to assess general intelligence, memory, language, visual–perceptual abilities, attention, and executive functions. Using 35-channel scalp EEG recordings, the N170 face-evoked event-related potential (ERP) was obtained to assess the functional integrity of the ventral pathway. All patients with PS showed normal IQ but subtle and consistent neurocognitive impairments. Namely, we found abnormalities in the copy task of the Rey–Osterrieth Complex Figure and in the Narrative Memory Test. There was no correlation between neuropsychological impairments with spike activity and hemispheric spike lateralization. The N170 ERP was normal in all patients except for one. Our neuropsychological findings demonstrate impairments in visual–perceptual abilities and in semantic processing. These findings, paired with the absence of occipital lobe dysfunction in all neuropsychological studies of PS performed to this date, support the existence of parietal lobe dysfunction.