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Objective Previous studies have shown moderate agreement between physicians when diagnosing epilepsy, but have included small numbers. The EpiNet study group was established to undertake multicentre clinical trials in epilepsy. Before commencing trials, we wanted to determine levels of agreement between physicians from different countries and different health systems when diagnosing epilepsy, specific seizure types and etiologies. Methods 30 Case scenarios describing six children and 24 adults with paroxysmal events (21 epileptic seizures, nine non-epileptic attacks) were presented to physicians with an interest in epilepsy. Physicians were asked how likely was a diagnosis of epilepsy; if seizures were generalised or focal; and the likely etiology. For 23 cases, clinical information was presented in Step 1, and investigations in Step 2. Results 189 Participants from 36 countries completed the 30 cases. Levels of agreement were determined for 154 participants who provided details regarding their clinical experience. There was substantial agreement for diagnosis of epilepsy (kappa = 0.61); agreement was fair to moderate for seizure type(s) (kappa = 0.40) and etiology (kappa = 0.41). For 23 cases with two steps, agreement increased from step 1 to step 2 for diagnosis of epilepsy (kappa 0.56–0.70), seizure type(s) (kappa 0.38–0.52), and etiology (kappa 0.38–0.47). Agreement was better for 53 epileptologists (diagnosis of epilepsy, kappa = 0.66) than 56 neurologists with a special interest in epilepsy (kappa = 0.58). Levels of agreement differed slightly between physicians practicing in different parts of the world, between child and adult neurologists, and according to one's experience with epilepsy. Conclusion Although there is substantial agreement when epileptologists diagnose epilepsy, there is less agreement for diagnoses of seizure types and etiology. Further education of physicians regarding semiology of different seizure types is required. Differences in approac

Purpose: To evaluate EEG differences among syndromes in genetic generalized epilepsy based on quantified data. Method(s): Twenty-four-hour ambulatory EEGs were recorded in consecutive patients diagnosed with genetic generalized epilepsy. All epileptiform EEG abnormalities were quantified into density scores (total duration of epileptiform discharges per hour). One-way analysis of variance was conducted to find out differences in EEG density scores among the syndromes. Generalized linear mixed models were also fitted to explore the association between the proportion of "pure" generalized spike-wave paroxysms and fragments (without intervening polyspikes/polyspike-waves) and the syndromes. Result(s): In total, 6,923 epileptiform discharges were analyzed from 105 abnormal EEGs. In the analysis of variance, six EEG variables were significantly different among syndromes: total spike density (P = 0.001), total polyspike and polyspike-wave density (P = 0.049), generalized spike-wave-only density (P , 0.001), generalized paroxysm density (P , 0.001), generalized paroxysm duration mean (P = 0.018), and generalized paroxysm duration maximum (P = 0.009). The density of epileptiform discharges and the paroxysm durations were the highest in juvenile absence epilepsy followed by juvenile myoclonic epilepsy, childhood absence epilepsy, and generalized epilepsy with tonic-clonic seizures only. Generalized linear mixed models revealed that "pure" generalized spike-wave discharges (without intervening polyspikes/polyspike waves) tended to be more frequent in absence epilepsies, although the difference was not statistically significant (P = 0.21). Conclusion(s): The findings of this study suggest that the density and duration of epileptiform discharges can help differentiate among genetic generalized epilepsy syndromes.Copyright © 2016 by the American Clinical Neurophysiology Society.

Background: We investigated the association between epileptiform EEG abnormalities and the preceding duration of seizure freedom in genetic generalized epilepsies (GGE). Method(s): We analyzed 24-hour ambulatory EEG recordings of patients with GGE diagnosed and classified according to the International League Against Epilepsy criteria. We quantified epileptiform EEG abnormalities into density scores (total duration of epileptiform discharges per hour) and estimated the preceding seizure-free duration at the time of EEG recording based on the last self-reported seizure. We then employed regression analysis to quantitate the relationship between the duration of seizure freedom and EEG variables. Result(s): We analyzed 6,923 epileptiform discharges from 105 patients with abnormal 24-hour EEGs. In the regression analysis exploring the crude associations, we found significant correlations between 6 EEG variables and the duration of seizure freedom indicating that shorter duration of seizure freedom was associated with higher spike densities and longer paroxysms. These associations were not affected by confounders such as syndrome, age at EEG, age at epilepsy onset, sex, duration of epilepsy, or number of antiepileptic drugs. Conclusion(s): Higher densities and longer durations of epileptiform discharges may be retrospectively associated with a shorter duration of self-reported seizure freedom. Hence, EEG can potentially be used as a biomarker of prognosis in GGE. These findings need to be validated in a prospective study in order to define EEG markers of future seizure freedom.Copyright © 2016 American Academy of Neurology.

According to the International League Against Epilepsy (ILAE) definition, no structural abnormalities are present on a standard brain magnetic resonance image in genetic generalized epilepsy (GGE) patients. However, recent studies raise contradictory evidence with increasing use of quantitative magnetic resonance imaging techniques. Following PRISMA guidelines, a systematic, quantitative review was conducted using 28 peer-reviewed, case-control studies published after 1989. Furthermore, a meta-analysis with a random-effect model revealed differences in structural brain abnormalities between GGE patients and controls. Significant structural differences between GGE and healthy controls were observed with volume reductions in whole brain, thalamus, putamen, caudate, pallidum, and supplementary motor area. Furthermore, gray matter volume reduction in the right and left hemispheres, thalamus, and insula, and surface area reduction in the caudal anterior cingulate cortex were revealed, along with gray matter increase in the medial frontal gyrus. Due to methodological differences, findings should be interpreted with caution. Nevertheless, contrary to the ILAE definition, it would appear that structural brain abnormalities may be present in GGE patients. Findings are consistent with a hypothesis regarding the underlying involvement of the thalamocortical networks in the generation of generalized spike-wave discharges, but structural abnormalities appear to extend outside these regions to potentially involve attention and other cognitive domains.

OBJECTIVE: It is now well appreciated that benign epilepsy with centrotemporal spikes (BECTS, or more recently, ECTS) is associated with a range of cognitive and behavioral disturbances. Despite our improved understanding of cognitive functioning in ECTS, there have been to date no efforts to quantitatively synthesize the available literature within a comprehensive cognitive framework. METHODS: The present systematic review and meta-analysis was conducted according to PRISMA guidelines. Forty-two case-control samples met eligibility criteria comprising a total of 1,237 children with ECTS and 1,137 healthy control children. Univariate, random-effects meta-analyses were conducted on eight cognitive factors in accordance with the Cattell-Horn-Carroll model of intelligence. RESULTS: Overall, children with ECTS demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls. Observed effects ranged from 0.42 to 0.81 pooled standard deviation units, with the largest effect for long-term storage and retrieval and the smallest effect for visual processing. SIGNIFICANCE: The results of the present meta-analysis provide the first clear evidence that children with ECTS display a profile of pervasive cognitive difficulties and thus challenge current conceptions of ECTS as a benign disease or of limited specific or localized cognitive effect.

Purpose: We created an epilepsy patient database that can be accessed via the Internet by neurologists from anywhere in the world. The database was designed to enroll and follow large cohorts of patients with specific epilepsy syndromes, and to facilitate recruitment of patients for investigator-initiated clinical trials. Methods: The EpiNet database records physician-derived information regarding seizure type and frequency, epilepsy syndrome, etiology, drug history, and investigations. It can be accessed from any country by approved investigators via a secure, password-protected Website. All data are encrypted. The database is for both research and clinical purposes. Investigators were invited to register any patient with epilepsy, but were particularly encouraged to register patients when uncertain of the optimal management. Participation required approval from investigators' ethics committees and institutional review boards, and all patients or their caregiver provided written informed consent. Patients were not enrolled in clinical trials in this pilot study. Key Findings: The international pilot study recruited patients from September 2010 to November 2011. Sixty-four investigators or research assistants from 25 centers in 13 countries registered 1,050 patients. Patients with a wide range of epilepsy syndromes and etiologies were registered. Patients' ages ranged from 2 weeks to 90 years. Significance: The Website was successfully used by doctors working in different health systems. The pilot study confirmed that this low-cost, collaborative approach to research has great potential. Large, multicenter cohort studies will commence in 2012, and randomized clinical trials are being planned. All epileptologists are invited to join this project.

Objective: Bilateral, symmetric and synchronous generalized epileptiform activity is considered to be the typical electroencephalographic (EEG) abnormality in genetic generalized epilepsy (GGE). We sought to study atypical EEG abnormalities in a systematic way based on 24-h ambulatory EEG recordings. Method(s): The diagnosis of GGE was validated and classified into syndromes according to the International League against Epilepsy criteria. All participants underwent 24-h ambulatory EEG recording. Epileptiform discharges were counted and detailed information was entered into an electronic database. Amplitude asymmetry, focal onset/offset of paroxysms, focal discharges, atypical morphology and generalized paroxysmal fast rhythm were defined as atypical abnormalities. Result(s): Of the total of 120 patients, 107 had abnormal EEGs, of which 66.4% had at least one atypical epileptiform abnormality on EEG. Atypical morphology was the most frequent abnormality in 93.4% of patients, followed by amplitude asymmetry (28.0%), focal discharges (21.5%), focal onset of paroxysms (13.1%), focal offset of paroxysms (8.2%) and generalized paroxysmal fast rhythm (1.9%). The analysis of individual discharges revealed that 76% of paroxysms were of atypical morphology. Significant associations were found between (a) amplitude asymmetry and state of arousal (p < 0.001) as well as seizure-free duration (p 0.013); (b) atypical morphology and state of arousal (p < 0.001). Conclusion(s): In GGE, there are both common and rare atypical epileptiform EEG abnormalities that may vary according to the state of arousal and seizure-free duration. Significance: Awareness of these variations is important to avoid misdiagnosis.Copyright © 2015.

Purpose: To study the frequency of epileptiform K-complexes and sleep spindles as well as clinical variables influencing those abnormalities. Method(s): We prospectively performed 24-hour ambulatory EEGs in a cohort of patients with genetic generalized epilepsy diagnosed and classified according to the International League against Epilepsy criteria. Overlapping of epileptiform discharges with K-complexes and sleep spindles was defined as epileptiform K-complexes and epileptiform sleep spindles. The presence of epileptiform K-complexes and sleep spindles was tabulated for each patient, and frequencies were calculated. We performed multiple regression analysis to study the influence of clinical predictors on the occurrence of epileptiform K-complexes and sleep spindles. The predictor variables tested in the model were seizure-free duration, epilepsy duration, genetic generalized epilepsy syndrome, number of antiepileptic drugs, use of sodium valproate, and use of lamotrigine. Result(s): A total of 107 patients (37 males and 70 females) were studied. The mean age was 28.5 +/- 10.7 years (range, 13-58). Juvenile absence epilepsy was the most common epilepsy syndrome in the cohort (31.8%), followed by generalized epilepsy with tonic-clonic seizures only (26.2%), juvenile myoclonic epilepsy (26.2%), and childhood absence epilepsy (14%). Epileptiform K-complexes and sleep spindles were seen in 65.4% and 10.3% of patients, respectively. None of the clinical variables had any significant impact on the occurrence of epileptiform K-complexes and sleep spindles in our multivariable analysis. Conclusion(s): Epileptiform K-complexes are common in the sleep EEGs of patients diagnosed with genetic generalized epilepsy. This underreported phenomenon highlights the important association of arousals and epileptiform discharges in genetic generalized epilepsy.Copyright © 2015 by the American Clinical Neurophysiology Society.

Purpose: We sought to study the circadian patterns and sleep-specific epileptiform abnormalities in genetic generalised epilepsy (GGE). Method(s): The diagnosis of GGE was established according to International League against Epilepsy criteria. All patients had 24-hour ambulatory electroencephalograms recorded according to a standard protocol. The duration of all epileptiform discharges were measured manually using a software tool and details of all discharges were entered into an electronic database. The details included time of discharge, state of arousal and duration. Generalised epileptiform discharges lasting >=2 second were classified as paroxysms and <2 seconds as fragments. Spikes overlapping with K-complexes (epileptiform K-complexes) and sleep spindles (epileptiform spindles) were identified as sleep-specific epileptiform abnormalities. We plotted a histogram of the frequency of epileptiform discharges against 24-hour time scale followed by cluster analysis to study circadian patterns. Result(s): Out of 120 patients who participated, 107 had abnormal EEGs which were analysed. The cohort consisted of 37 (34.6%) males and 70 (65.4%) females with mean age of 28.5 +/- 10.7 years (range, 13-58). Epileptiform K-complexes were more frequent (66.7%) than epileptiform spindles (10.5%). Amongst syndromes, epileptiform K-complexes and spindles were more commonly seen in juvenile myoclonic epilepsy (71.4%) and juvenile absence epilepsy (70.6%). Generalised fragments and focal discharges were more frequently seen during non-REM sleep whilst paroxysms were more in wakefulness. Overall, 67% of epileptiform discharges occurred in non-REM sleep, whilst 33% occurred in wakefulness. The cluster analysis showed four clusters of epileptiform discharges around 2 am, 7 am, 2.30 pm and 10 pm confirming the impression from the histogram. Conclusion(s): Our study demonstrates epileptiform K-complexes occur in the majority of GGE indicating the importance of arousal in the generatio

Objective We sought to investigate the temporal patterns and sleep-wake cycle-related epileptiform discharges (EDs) in genetic generalized epilepsies (GGEs). Methods We studied 24-hour ambulatory electroencephalography (EEG) recordings of patients with GGE, diagnosed and classified according to the International League against Epilepsy criteria. We manually coded the type of discharge, time of occurrence, duration, and arousal state of each ED. We employed mixed effects Poisson regression modeling to study the temporal distribution of epileptiform discharges. Additionally, we used multinomial regression analysis to explore the significance of the relationship between different states of arousal and types of epileptiform discharges. Results We analyzed 6923 EDs from 105 abnormal 24-hour EEGs. Mixed effects Poisson regression analysis demonstrated significant changes in ED counts across time blocks. This distribution was largely influenced by the state of arousal. Generalized fragments (duration < 2 s) and focal discharges were more frequent during non-REM sleep while paroxysms (duration >= 2 s) were more frequent in wakefulness. Overall, 67% of epileptiform discharges occurred in non-REM sleep and only 33% occurred in wakefulness. Twenty-four patients (23%) had ED exclusively in sleep. Epileptiform discharges peaked from 23:00 through 07:00 h. Significance There is a time-of-day dependency of ED with a significant influence exerted by the state of arousal. Our observations suggest that the generation of epileptiform discharges is not a random process but is the result of complex interactions among biological rhythms such as the sleep-wake cycle and the intrinsic circadian pacemaker. High density of ED in sleep suggests that 24-hour EEG recording with the capture of natural sleep may be more useful than routine EEG to diagnose GGE.Copyright © 2016 Elsevier Inc.

Objective: To provide a quantitative evaluation of typical electroencephalographic (EEG) abnormalities in genetic generalized epilepsy (GGE). Method(s): We prospectively performed 24-ambulatory EEG recordings in a cohort of patients with GGE. The diagnosis was established according to the International League Against Epilepsy criteria. Details of all epileptiform discharges across the 24-time scale were entered into an electronic database. We carried out descriptive statistics to provide a quantitative breakdown of typical EEG abnormalities. Result(s): A total of 6923 epileptiform discharges from 105 abnormal 24-ambulatory EEGs were analyzed. 96% of discharges were symmetric in amplitude with fronto-central maximum topographically. Only 24% of the paroxysms had typical morphology while 43% were regular. Photoparoxysmal response, eye-closure sensitivity and hyperventilation-induced generalized paroxysms were less common in around 10%, whereas occipital intermittent rhythmic delta activity was very rare (2%). Conclusion(s): Our results indicate that generalized discharges with symmetric amplitude and fronto-central maxima are the most consistent findings in GGE, and other features are observed less frequently. Significance: Epileptiform discharges displaying highly consistent amplitude symmetry coupled with fronto-central topography should provoke consideration of GGE. Recognition of variations from typical abnormalities is important to avoid the risk of misdiagnosis and delayed diagnosis.Copyright © 2015 Published by Elsevier Ireland Ltd.

Objective: We sought to study the frequency and prognostic value of focal seizure symptoms (FSS) in idiopathic generalized epilepsies (IGE) using a validated tool: Epilepsy Diagnostic Interview Questionnaire and Partial Seizure Symptom Definitions. Method(s): Participants with IGE were recruited from epilepsy clinics at 2 tertiary hospitals. The diagnosis was validated and classified into syndromes according to the International League Against Epilepsy criteria by 2 epileptologists independently with discordance resolved by consensus. The Epilepsy Diagnostic Interview Questionnaire utilizes both open- and closed-ended questions to elicit FSS in association with generalized tonic-clonic seizures, myoclonus, and absences. The elicited FSS were classified according to the Partial Seizure Symptom Definitions. Regression analysis was conducted to examine the relationship between the duration of seizure freedom and FSS. Result(s): A total of 135 patients were studied, of whom 70 (51.9%) reported FSS. Those symptoms occurred in association with generalized tonic-clonic seizures (53.1%) as well as myoclonus and absences (58%). FSS were reported with similar frequency in juvenile absence epilepsy (62.5%) and juvenile myoclonic epilepsy (60%), and with a lesser frequency in generalized epilepsy with tonic-clonic seizures only (39.5%) and childhood absence epilepsy (33.3%). A strong relationship between FSS and duration of seizure freedom was found (regression coefficient -0.665, p 0.037). Conclusion(s): FSS are frequently reported by patients with IGE. A shorter duration of seizure freedom is associated with FSS. Recognition of the presence of FSS in IGE is important to avoid misdiagnosis and delayed diagnosis as well as to choose appropriate antiepileptic drug therapy.Copyright © 2015 American Academy of Neurology.

Rationale: Genetic generalized epilepsies (GGE) constitute a rubric of several electroclinical syndromes. Although the use of electroencephalography (EEG) in the diagnosis and classification of GGE is well established, its value as a predictor of seizure freedom is less well defined with studies reporting variable and conflicting results. To our knowledge, this is the first study to evaluate quantified EEG data with seizure freedom. Method(s): We performed a study of 83 patients (mean age 26.8+/-9.9, range 11-58 y) with GGE on treatment, diagnosed and classified according to the International League against Epilepsy criteria and subsequently validated by a panel of epileptologists. All had 24-hour ambulatory EEG recordings. All EEGs were visually analyzed and manually scored by the same investigator. A custom-made electronic database was used for data entry. Epileptiform discharges were classified as generalized paroxysms (GP) (duration >=2 sec) and fragments (duration <2 sec). Furthermore, the morphology of each discharge (spike-wave, polyspike, polyspike-wave or combination) and the state (awake, sleep) were recorded. The total duration of epileptiform discharges over 24 hours was defined as total spike density (TSD). The average duration of epileptiform discharges over an hour during wakefulness and sleep were defined as awake (ASD) and sleep spike density (SSD) respectively. The time lag from morning arousal to the first GP was also measured in each case. Clinical and demographic data including the length of seizure freedom (LSF) was collated by interviewing the patient using a validated seizure questionnaire on the day of ambulatory EEG and prospectively at six month intervals. We applied Spearman's correlation to determine the strength of association between the LSF and various EEG parameters. Result(s): The LSF demonstrated strong inverse correlation (correlation coefficient rho>=0.5) with TSD, ASD and SSD in childhood absence epilepsy (CAE), and with ASD in

Summary Conventionally, epilepsy is dichotomized into distinct "focal" and "generalized" categories. However, many studies have reported so-called focal features among patients with idiopathic generalized epilepsy (IGE) in the domains of semiology, electroencephalography, neuropsychology, neuropathology, and neuroimaging. We sought to review such features and clinical implications. A Web of Science database search was conducted to identify relevant publications. Our search yielded 145 papers describing focal features involving different domains in IGE, with 117 papers analyzed after excluding abstracts and case reports. Focal semiologic features are commonly seen in IGE. There are conflicting data from studies in the domains of electroencephalography, neuroimaging, and neuropathology. Studies on neuropsychology are suggestive of frontal lobe functional deficits in juvenile myoclonic epilepsy. Most advanced neuroimaging studies demonstrate the involvement of both the thalamus and the cortex during generalized spike-wave discharges (GSWDs). A few electroencephalographic and neuroimaging studies indicate that the cortex precedes the thalamus at the onset of GSWD. Focal features may contribute to misdiagnosis of IGE as focal epilepsy. However there are methodologic limitations in the studies that affect the results. © 2014 International League Against Epilepsy.

Cognitive function in idiopathic generalised epilepsies (IGE) is of increasing research attention. Current research seeks to understand phenotypic traits associated with this most common group of inherited epilepsies and evaluate educational and occupational trajectories. A specific deficit in executive function in a subgroup of IGE, juvenile myoclonic epilepsy (JME) has been a particular focus of recent research. This systematic review provides a quantitative synthesis of cognitive function outcomes in 26 peer-reviewed, case-control studies published since 1989. Univariate random-effects meta-analyses were conducted on seven cognitive factor-domains and separately on executive function. Patients with IGE demonstrated significantly lower scores on tests across all cognitive factor-domains except visual-spatial abilities. Effect sizes ranged from 0.42 to 0.88 pooled standard deviation units. The average reduction of scores on tests of executive function in IGE compared to controls was 0.72 standard deviation units. Contrary to current thinking, there was no specific deficit in executive function in JME samples, nor in other IGE syndromes. Of more concern, people with IGE are at risk of pervasive cognitive impairment.