Genetic Generalized Epilepsy Syndromes Research Articles

Generalized Fast Discharges Along the Genetic Generalized Epilepsy Spectrum: Clinical and Prognostic Significance.

ObjectiveTo investigate the electroclinical characteristics and the prognostic impact of generalized fast discharges in a large cohort of genetic generalized epilepsy (GGE) patients studied with 24-h prolonged ambulatory electroencephalography (paEEG).MethodsThis retrospective multicenter cohort study included 202 GGE patients. The occurrence of generalized paroxysmal fast activity (GPFA) and generalized polyspike train (GPT) was reviewed. GGE patients were classified as having idiopathic generalized epilepsy (IGE) or another GGE syndrome (namely perioral myoclonia with absences, eyelid myoclonia with absences, epilepsy with myoclonic absences, generalized epilepsy with febrile seizures plus, or GGE without a specific epilepsy syndrome) according to recent classification proposals.ResultsGPFA/GPT was found in overall 25 (12.4%) patients, though it was significantly less frequent in IGE compared with other GGE syndromes (9.3 vs. 25%, p = 0.007). GPFA/GPT was found independently of seizure type experienced during history, the presence of mild intellectual disability/borderline intellectual functioning, or EEG features. At multivariable analysis, GPFA/GPT was significantly associated with drug resistance (p = 0.04) and with a higher number of antiseizure medications (ASMs) at the time of paEEG (p < 0.001) and at the last medical observation (p < 0.001). Similarly, GPFA/GPT, frequent/abundant generalized spike-wave discharges during sleep, and a higher number of seizure types during history were the only factors independently associated with a lower chance of achieving 2-year seizure remission at the last medical observation. Additionally, a greater number of GPFA/GPT discharges significantly discriminated between patients who achieved 2-year seizure remission at the last medical observation and those who did not (area under the curve = 0.77, 95% confidence interval 0.57–0.97, p = 0.02)ConclusionWe found that generalized fast discharges were more common than expected in GGE patients when considering the entire GGE spectrum. In addition, our study highlighted that GPFA/GPT could be found along the entire GGE continuum, though their occurrence was more common in less benign GGE syndromes. Finally, we confirmed that GPFA/GPT was associated with difficult-to-treat GGE, as evidenced by the multivariable analysis and the higher ASM load during history.

Effect of Sleep on Epileptic Discharges in Patients with Idiopathic Generalized Epilepsy.

Background. It is known that sleep and sleep deprivation affect the EEG findings, onset, frequency and semiology of the seizures. Generalized spike and wave discharges were found more common in drowsiness and sleep states, especially in childhood and juvenile absence epilepsy syndromes. Aim. In this study we aimed to show the effects of short sleep on the interictal and ictal discharges of the patients with genetic generalized epileptic seizures and to show the effects of treatment on the discharges during awake and sleep states. Method. 37 patients (29 females and 8 males) with a diagnosis of genetic generalized epilepsy syndrome were included. All the patients were investigated with video-EEG recording during awake, sleep and post sleep states. Epileptic discharges were counted manually. Discharge numbers and their relation with triggers were analyzed to see the difference between different vigilance states. Results. Number of ictal discharges is found to be increased after sleep. There was no difference in the control EEGs, which were taken under treatment. Conclusion. Sleep is a trigger of epileptic discharges in ictal nature, but an effective antiepileptic treatment prevents this effect.

Genetic generalized epilepsies in adults - challenging assumptions and dogmas.

Genetic generalized epilepsy (GGE) syndromes start during childhood or adolescence, and four commonly persist into adulthood, making up 15-20% of all cases of epilepsy in adults. These four GGE syndromes are childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy and epilepsy with generalized tonic-clonic seizures alone. However, in ~20% of patients with GGE, characteristics of more than one syndrome are present. Novel insights into the genetic aetiology, comorbidities and prognosis of the GGE syndromes have emerged and challenge traditional concepts about these conditions. Evidence has shown that the mode of inheritance in GGE is mostly polygenic. Neuropsychological and imaging studies indicate similar abnormalities in unaffected relatives of patients with GGE, supporting the concept that underlying alterations in bilateral frontothalamocortical networks are genetically determined. Contrary to popular belief, first-line anti-seizure medication often fails to provide seizure freedom in combination with good tolerability. Nevertheless, long-term follow-up studies have shown that with advancing age, many patients can discontinue their anti-seizure medication without seizure relapses. Several outcome predictors have been identified, but prognosis across the syndromes is more homogeneous than previously assumed. Overall, overlap in pathophysiology, seizure types, treatment responses and outcomes support the idea that GGEs are not separate nosological entities but represent a neurobiological continuum.

Abnormal cortical and subcortical structure in juvenile myoclonic epilepsy demonstrated with advanced MRI analysis

Juvenile myoclonic epilepsy (JME) is the most frequent genetic generalized epilepsy syndrome. It typically occurs during adolescence with predominant myoclonic seizures, variably intermixed with generalized tonic-clonic and absences. Neurophysiological, neuropsychological and imaging studies in JME have shown focal abnormalities in the medial and dorsolateral prefrontal lobe. Our study's aim was to explore for additional evidence of focal cortical abnormalities in JME using advanced neuroimaging techniques.

Transition from pediatric to adult care in a Japanese cohort of childhood-onset epilepsy: prevalence of epileptic syndromes and complexity in the transition

AimWe retrospectively examined patients with childhood-onset epilepsy who transitioned from pediatric to adult care to reveal the clinical characteristics and evaluate the complexity of transitioning. MethodsThe subjects were 220 patients (89 males, 131 females) who had been treated at our pediatric epilepsy clinic and had transferred to adult care between 2014 and 2018 without attending a transition clinic or program. The demographic data of the patients were retrospectively analyzed. ResultsThe ages at transition ranged from 15 to 54 years (median: 27 years old). There were 91 patients with focal epilepsies (FEs) and 129 patients with generalized epilepsies [genetic generalized epilepsy (GGE) n = 30, generalized epilepsy of various etiologies (GEv) n = 99]. A most frequent epileptic syndrome was temporal lobe epilepsy followed by frontal lobe epilepsy in FEs, GTCS only followed by juvenile myoclonic epilepsy in GGE and Lennox-Gastaut syndrome followed by Dravet syndrome in GEv. At the age of transition, a total of 77 of the 96 patients with developmental and epileptic encephalopathies (DEE) had pharmacoresistant seizures, which was positively correlated with a late transition age (P≤0.05). More than monthly seizures and greater than moderate disabilities were noted in 45% and 55% of the patients, respectively. ConclusionThe patients with childhood-onset epilepsy transitioned to adult care from the hospital-based pediatric epilepsy clinic were characterized by generalized>focal epilepsy, a frequent complication of DEE, more than monthly seizures, and worse than moderate intellectual disabilities. The complication of DEE made a smooth transition difficult and delayed the transition age.

Network characteristics of genetic generalized epilepsy: Are the syndromes distinct?

ObjectivesThis study evaluated the structural and functional connectivity of patients with genetic generalized epilepsy (GGE) compared to healthy subjects. We also investigated whether there are differences in structural and functional connectivity among different GGE syndromes. MethodsWe enrolled 100 patients with a clinical diagnosis of GGE. The patients were classified into different syndrome groups(12 cases of childhood absence epilepsy, 13 cases of juvenile absence epilepsy, 56 cases of juvenile myoclonic epilepsy, and 19 cases of epilepsy with GTC alone). We applied graph theoretical analysis to structural brain volumes and EEG to evaluate structural and functional connectivity in the GGE patients. ResultsThe global network measures showed significant differences in the structural and functional connectivity between the patients with GGE and the healthy controls, and the local network measures revealed hub reorganization in the GGE patients. The global efficiency, local efficiency, and clustering coefficients of the structural connectivity were significantly decreased, whereas the characteristic path length and small-worldness index were increased in the GGE patients. The global efficiency and local efficiency were increased and the small-worldness index decreased in the functional connectivity. The patients with juvenile myoclonic epilepsy had the most extensive changes in structural and functional connectivity compared to the healthy subjects. SignificanceThis study’s main finding is that structural and functional connectivity in patients with GGE is significantly different from that in healthy controls. We find that the different GGE syndromes show distinct structural and functional connectivity, which can lead further understanding of the pathogenesis of GGE syndromes.

Motor hyperactivation during cognitive tasks: An endophenotype of juvenile myoclonic epilepsy.

ObjectiveJuvenile myoclonic epilepsy (JME) is the most common genetic generalized epilepsy syndrome. Myoclonus may relate to motor system hyperexcitability and can be provoked by cognitive activities. To aid genetic mapping in complex neuropsychiatric disorders, recent research has utilized imaging intermediate phenotypes (endophenotypes). Here, we aimed to (a) characterize activation profiles of the motor system during different cognitive tasks in patients with JME and their unaffected siblings, and (b) validate those as endophenotypes of JME.MethodsThis prospective cross‐sectional investigation included 32 patients with JME, 12 unaffected siblings, and 26 controls, comparable for age, sex, handedness, language laterality, neuropsychological performance, and anxiety and depression scores. We investigated patterns of motor system activation during episodic memory encoding and verb generation functional magnetic resonance imaging (fMRI) tasks.ResultsDuring both tasks, patients and unaffected siblings showed increased activation of motor system areas compared to controls. Effects were more prominent during memory encoding, which entailed hand motion via joystick responses. Subgroup analyses identified stronger activation of the motor cortex in JME patients with ongoing seizures compared to seizure‐free patients. Receiver‐operating characteristic curves, based on measures of motor activation, accurately discriminated both patients with JME and their siblings from healthy controls (area under the curve: 0.75 and 0.77, for JME and a combined patient‐sibling group against controls, respectively; P < .005).SignificanceMotor system hyperactivation represents a cognitive, domain‐independent endophenotype of JME. We propose measures of motor system activation as quantitative traits for future genetic imaging studies in this syndrome.

Clinico-electrographic characteristics and classification of genetic generalized epilepsy in Oman

PurposeThere is a lack of information on the annual incidence of genetic generalized epilepsy (GGE) in the Arab countries, especially Oman. Ascertaining the true burden of illness has crucial implications for health policies and priorities. We aim to study the clinico-electrographic characteristics, classification, and annual incidence of GGE in Oman. MethodUsing the cross-sectional data of EEGs obtained from all patients with GGE who presented to Sultan Qaboos University hospital (major referral center for epilepsy in Oman) from January 2007 to June 2014. Analyses were performed using univariate statistics. ResultsApproximately 10,423 patients had EEG studies during the study period of which 376 patients (3.6 %) had EEG abnormalities suggestive of GGE. Forty two percent of the 376 GGE patients were male with ages ranging from 3 to 58 years. We were able to classify 273 patients to one of the GGE syndromes. Forty-three percent of 130 patients had a positive family history of epilepsy in their first or second-degree relatives. The generalized tonic-clonic seizure was the most common seizure type observed in 242 patients (64 %; 95 %CI: 59.2 %–68.9 %). Juvenile myoclonic epilepsy was the most common epilepsy syndrome (41 % of the total GGE patients) encountered in our region. A significant female predominance (9.7 % vs 2.5 %; p = 0.016) was observed in juvenile absence epilepsy. Certain interictal focal EEG abnormalities did not exclude a diagnosis of GGE. An average annual GGE incidence of 2.9 % (95 % CI: 2.6 %–3.2 %) was observed during the study period. ConclusionThis hospital-based study is the first of its kind in the Arabian Gulf region, classifying the different subcategories of GGE. Our results indicate that GGE is a common epilepsy subtype in Oman. A prospective population-based epidemiological study is required to estimate the precise frequency of GGE in Oman.

Circadian Rhythms and Epilepsy: A Suitable Case for Absence Epilepsy.

Many physiological processes such as sleep, hormonal secretion, or thermoregulation, are expressed as daily rhythms orchestrated by the circadian timing system. A powerful internal clock mechanism ensures proper synchronization of vital functions within an organism on the one hand, and between the organism and the external environment on the other. Some of the pathological processes developing in the brain and body are subjected to circadian modulation as well. Epilepsy is one of the conditions which symptoms often worsen at a very specific time of a day. Variation in peak occurrence depends on the syndrome and localization of the epileptic focus. Moreover, the timing of some types of seizures is closely related to the sleep-wake cycle, one of the most prominent circadian rhythms. This review focuses on childhood absence epilepsy (CAE), a genetic generalized epilepsy syndrome, in which both, the circadian and sleep influences play a significant role in manifestation of symptoms. Human and animal studies report rhythmical occurrence of spike-wave discharges (SWDs), an EEG hallmark of CAE. The endogenous nature of the SWDs rhythm has been confirmed experimentally in a genetic animal model of the disease, rats of the WAG/Rij strain. Well-known detrimental effects of circadian misalignment were demonstrated to impact the severity of ongoing epileptic activity. SWDs are vigilance-dependent in both humans and animal models, occurring most frequently during passive behavioral states and light slow-wave sleep. The relationship with the sleep-wake cycle seems to be bidirectional, while sleep shapes the rhythm of seizures, epileptic phenotype changes sleep architecture. Circadian factors and the sleep-wake states dependency have a potential as add-ons in seizures' forecasting. Stability of the rhythm of recurrent seizures in individual patients has been already used as a variable which refines existing algorithms for seizures' prediction. On the other hand, apart from successful pharmacological approach, circadian hygiene including sufficient sleep and avoidance of internal desynchronization or sleep loss, may be beneficial for patients with epilepsy in everyday management of seizures.

Cognitive functioning in new-onset juvenile myoclonic epilepsy

PurposeJuvenile myoclonic epilepsy (JME) is a common genetic generalized epilepsy syndrome. Adult patients with JME have shown a neuropsychological profile suggestive of subtle frontal dysfunction, but studies of cognitive functioning in the early phases of JME are rare. We analyzed the cognitive performance data of 18 patients who had undergone a neuropsychological assessment either at the time of JME diagnosis and before the initiation of an antiepileptic drug (AED) treatment (11 patients) or during the first 6 years after JME diagnosis (seven patients). MethodsThe cognitive performance of the18 patients with JME (mean age: 18.1, range: 15–33 years) and 18 healthy controls (mean age: 18.7, range: 15–25 years) was compared in a retrospective study. The assessed cognitive domains were visuomotor speed, attention, executive function, and verbal memory. ResultsThe patients with JME and the healthy controls did not differ in any of the assessed cognitive domains. The clinical variables did not correlate to cognitive performance. Furthermore, cognitive performance did not differ between the patients evaluated at the time of diagnosis and before the initiation of AEDs and the patients evaluated during the first 6 years after diagnosis and with an AED treatment. ConclusionsThe cognitive performance of patients with new-onset JME was similar to healthy controls. We could not detect the frontal dysfunction that has been suggested to be associated with JME. Patients were in adolescence or early adulthood with a short duration of epilepsy, which may have contributed to the discovery of no cognitive impairments.

Gender characteristics of therapy for genetic generalized epilepsy in adults

Valproate is generally the drug of choice in genetic generalized epilepsy (GGE). But its therapy was changed after the appearance of the 2015 International League against Epilepsy (ILAE) recommendations to limit the dose of valproates in women. Objective: to assess the spectrum of antiepileptic drugs (AEDs) and to evaluate the efficiency of therapy in adults with GGE, in terms of the gender characteristics of the latter and the ILAE recommendations. Patients and methods. A retrospective open-label observational study was conducted. A cohort of patients was formed according to their visits to physicians in 2013 to 2017. Two patient groups were identified. Group 1 included 80 patients (35 males, 45 females); their mean age was 27.1±3.6 years; they were followed in 2013–2014. Group 2 consisted of 137 patients (53 males, 84 females); their mean age was 29.4±4.6 years; they visited their physicians in 2015–2017. The spectrum of AEDs that were used in monotherapy or polytherapy was assessed. The efficiency of therapy was determined by the onset of remission. Results and discussion. The patients of the two groups were matched for the spectrum of GGE syndromes. Most patients received valproates; more than 35% took levetiracetam; lamotrigine was used slightly less often. In Group 2, females used polytherapy more frequently than males (p=0.03). The percentage of achievement of clinical and encephalographic remission (CER) was higher in Group 2 (p=0.05); there was no significant difference in this indicator between men and women in the two groups. In Group 2, among those achieving CER, the percentage of patients receiving monotherapy decreased and that of those having polytherapy increased (p=0.02). The spectrum of AEDs used to achieve CEP remained unchanged in both groups; however, there was a significant difference in the drug dosing regimens. Conclusion. Current therapy for GGE is successful and leads to remission in most patients. After 2015, dual therapy for GGE is used significantly more often in women than in men (p<0.05). The combination of valproate with levetiracetam or lamotrigine predominates.

Seizures in Epilepsy With Eyelid Myoclonia May Be Provoked by Eye Closure, Not Fixation Removal

Epilepsy with eyelid myoclonia ([EEM] also known as Jeavons syndrome) is a genetic generalized epilepsy syndrome with onset in childhood or adolescence. 1 Hirsch E. Panayiotopoulos C.P. Childhood absence epilepsy and related syndromes. in: Roger J. Bureau M. Dravet C. Genton P. Tassinari C.A. Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John LibbeyEurotext: Montrouge, France, 2005: 315-336 Google Scholar ,2 International League Against EpilepsyEpilepsyDiagnosis.org. epilepsydiagnosis.orgDate: 2014 Google Scholar Affected individuals experience brief episodes of eyelid myoclonia, typically involving 4 to 6 Hz low-amplitude rhythmic myoclonic jerks of the eyelids. 1 Hirsch E. Panayiotopoulos C.P. Childhood absence epilepsy and related syndromes. in: Roger J. Bureau M. Dravet C. Genton P. Tassinari C.A. Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John LibbeyEurotext: Montrouge, France, 2005: 315-336 Google Scholar ,2 International League Against EpilepsyEpilepsyDiagnosis.org. epilepsydiagnosis.orgDate: 2014 Google Scholar These seizures occur spontaneously but can also be provoked by voluntary eye closure. Typically, patients have hundreds of seizures per day before treatment. 1 Hirsch E. Panayiotopoulos C.P. Childhood absence epilepsy and related syndromes. in: Roger J. Bureau M. Dravet C. Genton P. Tassinari C.A. Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John LibbeyEurotext: Montrouge, France, 2005: 315-336 Google Scholar The events may or may not be associated with impaired awareness, in which case, they are classified as absence seizures with eyelid myoclonia. 1 Hirsch E. Panayiotopoulos C.P. Childhood absence epilepsy and related syndromes. in: Roger J. Bureau M. Dravet C. Genton P. Tassinari C.A. Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John LibbeyEurotext: Montrouge, France, 2005: 315-336 Google Scholar ,2 International League Against EpilepsyEpilepsyDiagnosis.org. epilepsydiagnosis.orgDate: 2014 Google Scholar Other seizure types may also occur, including febrile and afebrile generalized tonic-clonic seizures. 1 Hirsch E. Panayiotopoulos C.P. Childhood absence epilepsy and related syndromes. in: Roger J. Bureau M. Dravet C. Genton P. Tassinari C.A. Wolf P. Epileptic Syndromes in Infancy, Childhood and Adolescence. 4th ed. John LibbeyEurotext: Montrouge, France, 2005: 315-336 Google Scholar ,2 International League Against EpilepsyEpilepsyDiagnosis.org. epilepsydiagnosis.orgDate: 2014 Google Scholar

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70–80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical (frontal and parietal) and subcortical structures (thalamus, putamen, and hippocampus). Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants (GABRA1, GABRD, EFHC1, BRD2, CASR, and ICK) with Mendelian and complex inheritance and covering a limited proportion of the world population, are considered as major susceptibility alleles for JME. Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells (including interneuron cortical progenitors) sculpture subtle alterations in brain networks and microcircuits during development. These alterations may explain “microdysgenesis” neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.

Abnormal hippocampal structure and function in juvenile myoclonic epilepsy and unaffected siblings.

Juvenile myoclonic epilepsy is the most common genetic generalized epilepsy syndrome, characterized by a complex polygenetic aetiology. Structural and functional MRI studies demonstrated mesial or lateral frontal cortical derangements and impaired fronto-cortico-subcortical connectivity in patients and their unaffected siblings. The presence of hippocampal abnormalities and associated memory deficits is controversial, and functional MRI studies in juvenile myoclonic epilepsy have not tested hippocampal activation. In this observational study, we implemented multi-modal MRI and neuropsychological data to investigate hippocampal structure and function in 37 patients with juvenile myoclonic epilepsy, 16 unaffected siblings and 20 healthy controls, comparable for age, gender, handedness and hemispheric dominance as assessed with language laterality indices. Automated hippocampal volumetry was complemented by validated qualitative and quantitative morphological criteria to detect hippocampal malrotation, assumed to represent a neurodevelopmental marker. Neuropsychological measures of verbal and visuo-spatial learning and an event-related verbal and visual memory functional MRI paradigm addressed mesiotemporal function. We detected a reduction of mean left hippocampal volume in patients and their siblings compared with controls (P < 0.01). Unilateral or bilateral hippocampal malrotation was identified in 51% of patients and 50% of siblings, against 15% of controls (P < 0.05). For bilateral hippocampi, quantitative markers of verticalization had significantly larger values in patients and siblings compared with controls (P < 0.05). In the patient subgroup, there was no relationship between structural measures and age at disease onset or degree of seizure control. No overt impairment of verbal and visual memory was identified with neuropsychological tests. Functional mapping highlighted atypical patterns of hippocampal activation, pointing to abnormal recruitment during verbal encoding in patients and their siblings [P < 0.05, familywise error (FWE)-corrected]. Subgroup analyses indicated distinct profiles of hypoactivation along the hippocampal long axis in juvenile myoclonic epilepsy patients with and without malrotation; patients with malrotation also exhibited reduced frontal recruitment for verbal memory, and more pronounced left posterior hippocampal involvement for visual memory. Linear models across the entire study cohort indicated significant associations between morphological markers of hippocampal positioning and hippocampal activation for verbal items (all P < 0.05, FWE-corrected). We demonstrate abnormalities of hippocampal volume, shape and positioning in patients with juvenile myoclonic epilepsy and their siblings, which are associated with reorganization of function and imply an underlying neurodevelopmental mechanism with expression during the prenatal stage. Co-segregation of abnormal hippocampal morphology in patients and their siblings is suggestive of a genetic imaging phenotype, independent of disease activity, and can be construed as a novel endophenotype of juvenile myoclonic epilepsy.

Implementation of the new ILAE classification of epilepsies into clinical practice — A cohort study

PurposeAppropriate management of patients with epilepsy requires precise classification of their disease. Implementation of the recent International League Against Epilepsy (ILAE) classification of seizures and epilepsies may affect data on the relative proportions of specific types of seizures or epilepsies and should be tested in everyday practice. The aim of the study was to determine the prevalence of specific epilepsy types, syndromes, and etiologies, as defined by the new ILAE classification, in a large cohort of adult patients with epilepsy. Material and methodsThe single-center cohort study involved consecutive adult patients with epilepsy seen at the university epilepsy clinic. Information about medical history, neurological examination, neuroimaging, electroencephalography (EEG), genetic tests, epilepsy treatment, and other investigations was collected from medical records and prospectively updated if necessary. Epilepsy types and etiology, as well as epileptic syndromes, were classified according to the new ILAE classifications. ResultsWe studied 653 patients (mean age: 37.2 years, 59.9% were women). Epilepsy was classified as focal in 458 cases (70.2%), generalized in 155 subjects (23.7%), or as combined focal and generalized in 11 patients (1.7%). The epilepsy type was labeled as unknown in 29 (4.4%) patients. A definite cause of epilepsy was identified in 59.4% of the cases, with a structural etiology (n = 179, 27.4%) and genetic or presumed genetic etiology (n = 169, 25.9%) being the most common. In 167 (25.5%) patients, specific epilepsy syndromes, mostly genetic generalized epilepsy syndromes, were diagnosed. ConclusionThe use of the recent ILAE classification of seizures and epilepsies in the cohort of patients with epilepsy seen in single epilepsy center enabled unequivocal characterization of epilepsy type in >95% of patients. A definite etiology of epilepsy could be established in about 60% of patients.

Brain Morphology in Patients with Genetic Generalized Epilepsy: Its Heterogeneity among Subsyndromes

Background: We aimed to evaluate the brain morphology of patients with genetic generalized epilepsy (GGE) compared to healthy subjects. In addition, we investigated whether there are differences in brain morphology among different GGE syndromes. Methods: We enrolled 100 patients with a clinical diagnosis of GGE. The patients were classified into different syndrome groups according to their predominant seizure type, age of seizure onset, and electroencephalography characteristics (12 childhood absence epilepsy [AE], 13 juvenile AE, 56 juvenile myoclonic epilepsy, and 19 epilepsy with generalized tonic-clonic alone). We used surface-based morphometry of brain magnetic resonance imaging to evaluate brain morphology. Results: We found significantly widespread alterations of brain morphology, including cortical thickness and volumes in several regions in the patients with GGE compared to healthy controls. In addition, we observed significant differences in alterations of cortical thickness and volumes among the different GGE syndromes. However, there were no differences in cortical surface areas between the patients with GGE and healthy controls. There was a significantly negative correlation between the duration of epilepsy and most of the each measures of abnormal brain morphology. Conclusions: The main finding of this study is that brain morphology in patients with GGE is significantly different from that in healthy controls. In addition, we found that the different GGE syndromes show distinct structural brain morphology, especially cortical thickness, which can help us understand the pathogenesis of GGE syndromes.

Rare gene deletions in genetic generalized and Rolandic epilepsies.

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

Multi-gene panel testing in Korean patients with common genetic generalized epilepsy syndromes.

Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca2+ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca2+ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Experimental Treatment Options in Absence Epilepsy.

The benign character of absence epilepsy compared to other genetic generalized epilepsy syndromes has often hampered the search for new treatment options. Absence epilepsy is most often treated with ethosuximide or valproic acid. However, both drugs are not always well tolerated or fail, and seizure freedom for a larger proportion of patients remains to be achieved. The availability of genuine animal models of epilepsy does allow to search for new treatment options not only for absence epilepsy per se but also for other genetic - previously called idiopathic - forms of epilepsy. The recent discovery of a highly excitable cortical zone in these models is considered as a new therapeutic target area. Here, we provide an overview regarding the search for new therapeutical options as has been investigated in the genetic rodent models (mainly WAG/Rij and GAERS) including drugs and whether antiepileptogenesis can be achieved, various types of electrical and optogenetical invasive stimulations, different types of noninvasive stimulation and finally whether absence seizures can be predicted and prevented. Many factors determine either the cortical and or thalamic excitability or the interaction between cortex and thalamus and offer new possibilities for new anti-absence drugs, among others metabotropic glutamatergic positive and negative allosteric modulators. The inhibition of epileptogenesis by various drugs with its widespread consequences seems feasible, although its mechanisms remain obscure and seems different from the antiabsence action. Surgical intervention on the cortical zone initiating seizures, either with radiosurgery using synchrotron- generated microbeams, or ablation techniques might reduce spike-and-wave discharges in the rodent models. High frequency electrical subcortical or cortical stimulation might be a good way to abort ongoing spikeand- wave discharges. In addition, possibilities for prevention with real-time EEG analyses in combination with electrical stimulation could also be a way to fully control these seizures. Although it is obvious that some of these treatment possibilities will not be used for absence epilepsy and/or need to be further developed, all can be considered as proof of principle and provide clear directives for further developments.

Modeling pathogenesis and treatment response in childhood absence epilepsy.

Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.