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People with focal epilepsies are known to under-document their seizures, but there is no data on self-documentation in adults with genetic (idiopathic) generalized epilepsy (GGE/IGE). We assessed the accuracy of self-evaluation of typical absences (TA) or myoclonic seizures (MS) in adults with IGE based on home video-EEG telemetry (HVET). Patients' own estimates were compared to the objective count of definite TA and MS, performed visually. We considered definite TA as generalized spike-wave discharges (GSWD) that met any of the following criteria: 1) coinciding with clear behavioural arrest on video, 2) followed after a few seconds by positive indication that an absence occurred, or 3) in the absence of video, consistently coinciding with clear motor arrest, as evidenced by interruption of continuous muscle activity. For each patient, we also classified probable TA as GSWDs that were longer than those corresponding to the shortest definite TA on HVET or based on the most recent sleep-deprived EEG (SDEEG). From the first 300 consecutive adults who had HVET, 24 had IGE with TA and / or MS; 23 were women. Only one patient had newly diagnosed IGE. Erroneous self-assessment of TA and MS was noted in 16/24 patients (66.7%). Seizures were overestimated in nine (37.5%) and underestimated in seven (29.2%). Only one patient (4.2%) documented all her TA and MS without false-positive estimates. Overestimation (but not underestimation) of TA on HVET could be predicted when patients reported daily or multiple weekly TA and a recent SDEEG was either normal or contained only subclinical GSWD (p=0.0095). Under- and over-self-documentation of TA and MS occurred in two thirds of adults with GGE/IGE, with substantial impact on their outpatient management and treatment. Diagnostic HVET is a useful tool for the detection of erroneous self-evaluation in these patients.

Generalized-onset seizures originate at a point within the brain and rapidly engage bilaterally distributed networks, whilst focal-onset seizures originate within networks limited to one hemisphere which may be discretely localized or more widely distributed. Challenges in data capturing have resulted in a lack of consistency across incidence and prevalence studies for estimates of generalized versus focal epilepsies in population groups, with a preponderance of unclassified cases. Infants and young children can further challenge delineation due to variable expression at different stages of brain maturation and impaired ability to express sensory seizure semiology. Focal seizures are divided into those in which the affected person is aware and those with impaired awareness; these events can be motor or non-motor. Generalized seizures are also categorized as motor and non-motor, but loss of awareness occurs with most events. Delineation between generalized and focal epilepsies is important for ongoing management. EEG, neuroimaging and other investigations (genetics, immune markers, etc.) can support the outcome but distinction between focal and generalized epilepsy in isolation is rarely achieved using such techniques. Certain clinical settings such as age, underlying aetiologies, and co-morbidities may be more predisposed to specific types of epilepsy. The differentiation between generalized and focal seizures remains a clinical process based on meticulous clinical history and examination, and is of relevance for the selection of antiseizure medications and identification of patients who may be viable for epilepsy surgery.

Perioral myoclonia with absences (POMA) is not recognized as a unique electro-clinical syndrome and studies suggest its inclusion under the genetic generalized epilepsy (GGE) spectrum. The aim of this study was to explore the prevalence and electro-clinical homogeneity of this disorder in an epilepsy monitoring unit. Between 2013 and 2019, among drug-resistant epilepsy patients who were referred for video-telemetry, those diagnosed with POMA based on the presence of documented absences with prominently observed peri-oral muscular contractions accompanied by generalized EEG features were included. Among 62 patients who were diagnosed with absence epilepsy, five finally met the criteria for POMA (8.1%) with late childhood or adolescent onset of epilepsy. Four (80%) had a referral diagnosis of focal epilepsy based on historical focal features with exacerbation of seizures on oxcarbazepine. All five patients demonstrated brief absences with orbicularis oris muscle contractions accompanied by subtle focal phenomenology. One patient had concurrent axial-appendicular myoclonic jerks precipitated by hyperventilation. While four patients had strikingly identical interictal and ictal characteristics of typical absence epilepsy, one patient demonstrated additional atypical generalized polyspike discharges without a "dart-dome" morphology. Therapeutic response to introduction of sodium valproate was noted in all five patients. Features that were not consistent with the diagnosis were apparent in one patient who was re-classified with combined focal and generalized epilepsy. Differentiating aspects in this patient included multifocal discharges, background slowing, fast-recruiting ictal rhythms and valproate resistance. This is one of the largest case series of POMA. This entity, which falls under the spectrum of GGE, remains under-diagnosed and its distinctive electro-clinical features need to be recorded in order to prevent misclassification as focal epilepsy of probable opercular origin. Background-slowing, atypical ictal rhythms and valproate unresponsiveness are not consistent with the diagnosis of this unique absence epilepsy. [Published with video sequences].

Epilepsy treatment is challenging because of multiple impediments like lack of efficacy of monotherapy, adverse drug reactions, and different comorbidities. Add-on therapy to first-line antiepileptics may be the option to overcome therapeutic hurdles. The present randomized, double-blind, add-on placebo-controlled clinical trial was conducted to evaluate the effect of add-on melatonin in the treatment of generalized epilepsy with generalized onset motor seizure in adults. The control group (n = 52) received add-on placebo, and the test group (n = 52) received add-on melatonin (3 mg/day) with valproate (20 mg/kg in two divided doses). Clinical evaluation of seizure frequency, Chalfont-National Hospital seizure severity scale (NHS3), Pittsburgh sleep quality index (PSQI), quality of life in epilepsy inventory, Epworth sleepiness scale (ESS), and biochemical estimation of serum neuron-specific enolase (NSE) and glutathione reductase were done at baseline and compared with follow-up at 8 weeks. Among 104 patients randomized [mean (SD) age of 27.6 (11.5); 84 (80.8%) male], 88 (84.6%) completed the trial. The responder rate and seizure-free rate in the test group were significantly (p = 0.006 and 0.034) higher than the control group. There was a significantly higher reduction in the frequency of seizures (p = 0.016) and NHS3 (-2.39; 95%CI: -4.56 to -0.21; p = 0.032) in the test group compared to the control group. Similarly, improvement in PSQI (-1.40; 95%CI: -2.64 to -0.15; p = 0.029) was significantly better in the test group. There was no significant difference in the change in ESS (p = 0.621) and quality of life scoring (p = 0.456) between the study groups. The decrease in serum NSE was significantly higher with the test group compared to the control group (-2.01; 95% CI: -3.74 to -0.27; p = 0.024). Add-on melatonin increased serum glutathione reductase significantly (p = 0.038), but there was no significant difference between the groups (p = 0.685). Add-on melatonin with valproate for generalized epilepsy with generalized onset motor seizures in adults can achieve a significantly better clinical outcome by reducing the seizure frequency, severity and attaining a better seizure-free rate in comparison to the control group.

We present a rare patient clinically suspected to have mixed idiopathic generalized and focal epilepsy, which was supported by BOLD pattern based on EEG-fMRI. A 37-year-old female with three types of refractory seizures starting at age six - tonic with breathing difficulties and confusion, generalized tonic-clonic, and focal with brief impairment of awareness and versive head movement, initially thought to represent atypical absences - was evaluated by EEG-fMRI. She was also shown to have three types of interictal epileptic discharges: generalized spike or polyspikes and slow waves, and left fronto-temporal and right fronto-temporal discharges. We assessed BOLD activation and deactivation for each type. For generalized patterns, the BOLD activation and deactivation were typical of that seen in primary generalized epilepsy. Whereas maximum activation for left fronto-temporal EEG patterns was observed in the left superior frontal gyrus and posterior superior temporal gyrus, maximum activation for right fronto-temporal patterns was bilateral in the right posterior middle temporal gyrus and left posterior middle temporal gyrus. The EEG-fMRI results suggested that the patient had both refractory idiopathic generalized and focal epilepsy, and not a generalized epilepsy originating from a focus.

Epilepsy is a common brain network disorder associated with disrupted large‐scale excitatory and inhibitory neural interactions. Recent resting‐state fMRI evidence indicates that global signal (GS) fluctuations that have commonly been ignored are linked to neural activity. However, the mechanisms underlying the altered global pattern of fMRI spontaneous fluctuations in epilepsy remain unclear. Here, we quantified GS topography using beta weights obtained from a multiple regression model in a large group of epilepsy with different subtypes (98 focal temporal epilepsy; 116 generalized epilepsy) and healthy population (n = 151). We revealed that the nonuniformly distributed GS topography across association and sensory areas in healthy controls was significantly shifted in patients. Particularly, such shifts of GS topography disturbances were more widespread and bilaterally distributed in the midbrain, cerebellum, visual cortex, and medial and orbital cortex in generalized epilepsy, whereas in focal temporal epilepsy, these networks spread beyond the temporal areas but mainly remain lateralized. Moreover, we found that these abnormal GS topography patterns were likely to evolve over the course of a longer epilepsy disease. Our study demonstrates that epileptic processes can potentially affect global excitation/inhibition balance and shift the normal GS topological distribution. These progressive topographical GS disturbances in subcortical–cortical networks may underlie pathophysiological mechanisms of global fluctuations in human epilepsy., This study demonstrated spatial shifts of non‐uniform GS topography across higher‐order prefrontal cortex and sensory areas in generalized and focal epilepsy. We found that these abnormal GS topography patterns were likely to evolve over the course of a longer disease. Our findings have potential implications for understanding the neuronal mechanisms of disrupted global excitation/inhibition balance in epilepsy.

The photoparoxysmal response (PPR) is defined as the occurrence of generalized spike, spike-wave or polyspike-wave discharges consistently elicited by intermittent photic stimulation (IPS). PPR is not well studied in Sub-Saharan African people. We prospectively studied the epidemiological, clinical, and EEG characteristics of PPR among consecutive patients recorded at the clinical neurophysiology unit of Fann University Hospital (Dakar, Senegal). Among 6,808 EEG recordings including 3,065 pathological EEGs, we collected 56 EEGs with PPR (0.8% of all recorded EEGs and 1.8% of anormal EEGs), from 31 women and 25 men (sex ratio: 0.8). The mean age was 13.3 years (range: 8 months to 59 years). The peak of photosensitivity was found in the range of 6 to 10 years. Of the PPR cases, 12 had clinical manifestations during IPS. Generalized epilepsy was diagnosed in 23 (41%) patients and 18 (32%) had focal epilepsies. The most epileptogenic stimulation frequencies were between 12 and 24 Hz (range: 1-28 Hz). PPR were mainly triggered during eye closure (64%), and 41 patients (73% of PPR cases) were classified as Type 4 (Waltz classification). Our results confirm lower rates of photosensitivity in African Sub-Saharan people compared with others. Although the current data do not support a role of short-term ambient light levels, subject to consistent data from larger cohorts, it may be interesting to study the probable epigenetic-mediated protective role of sunshine against photosensitivity.

To evaluate cortical excitability with transcranial magnetic stimulation (TMS) in children with new-onset epilepsy before and after antiepileptic drugs (AEDs).Fifty-five drug-naïve patients (29 females, 26 males; 3-18y), with new-onset epilepsy were recruited from 1st May 2014 to 31st October 2017 at the Child Neurology Department, Queen Silvia's Children's Hospital, Gothenburg, Sweden. We performed TMS in 48 children (23 females, 25 males; mean [SD] age 10y [3y], range 4-15y) with epilepsy (27 generalized and 21 focal) before and after the introduction of AEDs. We used single- and paired-pulse TMS. We used single-pulse TMS to record resting motor thresholds (RMTs), stimulus-response curves, and cortical silent periods (CSPs). We used paired-pulse TMS to record intracortical inhibition and facilitation at short, long, and intermediate intervals.There were no differences in cortical excitability between children with generalized and focal epilepsy at baseline. After AED treatment, RMTs increased (p=0.001), especially in children receiving sodium valproate (p=0.005). CSPs decreased after sodium valproate was administered (p=0.050). As in previous studies, we noted a negative correlation between RMT and age in our study cohort. Paired-pulse TMS could not be performed in most children because high RMTs made suprathreshold stimulation impossible.Cortical excitability as measured with RMT decreased after the introduction of AEDs. This was seen in children with both generalized and focal epilepsy who were treated with sodium valproate, although it was most prominent in children with generalized epilepsy. We suggest that TMS might be used as a prognostic tool to predict AED efficacy.Resting motor threshold (RMT) correlated negatively with age in children with epilepsy. No differences in cortical excitability were noted between patients with generalized and focal epilepsy. Treatment with antiepileptic drugs decreased cortical excitability as measured with transcranial magnetic stimulation (TMS). Decreased cortical excitability with increased RMT was recorded, especially after sodium valproate treatment. Paired-pulse TMS was difficult to perform because of high RMTs in children.Medición de la excitabilidad cortical con estimulación magnética transcraneal en niños con epilepsia antes y después de los fármacos antiepilépticos OBJETIVO: Evaluar la excitabilidad cortical con estimulación magnética transcraneal (EMT) en niños con epilepsia de nueva aparición antes y después del uso de un fármaco antiepiléptico (FAE). MÉTODO: Cincuenta y cinco pacientes sin tratamiento previo (29 mujeres, 26 varones; de 3-18 años), con epilepsia de nueva aparición fueron reclutados del 1 de mayo de 2014 al 31 de octubre de 2017 en el Departamento de Neurología Infantil del Hospital de Niños Queen Silvia, en Gotemburgo, Suecia. Se realizó EMT en 48 niños (23 mujeres, 25 varones; media [DE] de 10 años [3 años], rango 4-15 años) con epilepsia (27 generalizada y 21 focal) antes y después de la introducción de los FAE. Usamos EMT de pulso único y de pulso emparejado. Utilizamos EMT de pulso único para registrar umbrales motores en reposo (UMR), curvas de estímulo-respuesta y períodos silenciosos corticales (PSC). Usamos EMT de pulso emparejado para registrar la inhibición y la facilitación intracorticales a intervalos cortos, largos e intermedios. RESULTADOS: No hubo diferencias en la excitabilidad cortical entre niños con epilepsia generalizada y focal al inicio. Después del tratamiento con FAE, los UMR aumentaron (p.0,001), especialmente en niños que recibieron valproato de sodio (p.0,005). Los PSC disminuyeron después de la administración del valproato sódico (p.0,050). Como en estudios anteriores, observamos una correlación negativa entre UMR y edad en nuestra cohorte de estudio. La EMT de pulso emparejado no se pudo realizar en la mayoría de los niños porque los UMR altos hacían imposible la estimulación supraumbral. INTERPRETACIÓN: La excitabilidad cortical medida con UMR disminuyó después de la introducción de los FAE. Esto se vio en niños con epilepsia generalizada y focal que fueron tratados con valproato de sodio, fue más prominente en niños con epilepsia generalizada. Sugerimos que EMT podría utilizarse como una herramienta de pronóstico para predecir la eficacia de la FAE.Excitabilidade cortical medida com estimulação magnética transcraniana em crianças com epilepsia antes e após drogas antiepilépticas OBJETIVO: Avaliar a excitabilidade cortical com estimulação magnética transcraniana (TMS) em crianças com epilepsia de início recente antes e após drogas antiepilépticas (DAEs). MÉTODO: Cinquenta e cinco pacientes não expostos a drogas (29 do sexo feminino, 26 do sexo masculino; 3-18a), com epilepsia de início recente foram recrutadas de 1 de maio de 2014a a 31 de outubro de 2017 no Departamento de Neurologia Infantil, Hospital Rainha Silvia, Gothenburg, Suécia. Aplicamos TMS em 48 crianças (23 do sexo feminino, 25 do sexo masculino; média [DP] de idade 10a [3a], variação 4-15a) com epilepsia (27 generalizada e 21 focal) antes e após a introdução de DAEs. Usamos TMS de pulso único e pareado. O TMS de pulso único foi usado para registrar os limiares motores de repouso (LMR), curvas de estímulo-resposta, e períodos de silêncio cortical (PSC). Usamos TMS de pulsos pareados para registrar inibição e facilitação intracortical nos intervalos curto, longo e intermediário. RESULTADOS: Não houve diferenças na excitabiildade cortical entre crianças com epilepsia generalizada e focal na linha de base. Após o tratamento com DAE, o LMR aumentou (p=0,001), especialmente em crianças recebendo valproato de sódio (p=0,005). Os PSCs diminuíram após o valproato de sódio ser (p=0,050). Como em estudos prévios, notamos correlação negativa entre LMR e idade em nossa coorte. TMS de pulso pareado não pôde ser realizado na maioria das crianças porque os altos LMRs tornaram a estimulação supra-limiar impossível. INTERPRETAÇÃO: A excitabilidade cortical mensurada por LMR diminuiu após a introdução de DAEs. Isso foi visto em crianças com epilepsia generalizada e focal tratadas com valproato de sódio, embora tenha sido mais proeminente naquelas com epilepsia generalizada. Sugerimos que o TMS pode ser usada como ferramenta prognóstica para predizer a eficácia da DAE.

OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.

Responsive neurostimulation (RNS) has emerged as an adjunctive treatment modality for patients with intractable focal epilepsy who are not surgical candidates or have more than one ictal onset focus. We report a 34‐year‐old patient with intractable, childhood‐onset, genetic generalized epilepsy (GGE) with tonic, atonic, myoclonic and absence seizures treated with RNS. Strip electrodes over the right posterior frontal cortex and depth electrodes placed in the right anterior nucleus were used for event detection and responsive stimulation. Two‐year follow‐up revealed 90–95% clinical seizure reduction. This case suggests that refractory GGE may be effectively treated with RNS targeting thalamocortical networks.

Variants in GABRA1 have been associated with different epilepsies ranging from mild generalized forms to epileptic encephalopathies. Despite the broad clinical spectrum, phenotypes were found to be largely concordant within families. Contrary to this observation, we report monozygotic twin sisters with generalized epilepsy due to the c.541C>T; p.(Pro181Ser) de novo variant in GABRA1. One experienced juvenile absence seizures promptly responding to first‐line medication, whereas the second developed severe treatment‐refractory epilepsy with febrile, absence, atonic, and tonic‐clonic seizures indicating marked intrafamilial variability in GABRA1‐related epilepsy. Moreover, we provide a molecular characterization of the novel variant based on recently published structural data.

Objective Patients with generalized epilepsy exhibit different epileptiform events including asymptomatic interictal spikes (IS), absence seizures with spike-wave discharges (SWDs), and myoclonic seizures (MS). Our objective was to determine the spatiotemporal patterns of cortical activation in SWDs, IS, and MS in the Gabra1+/A322D juvenile myoclonic epilepsy mouse. Methods We fabricated affordable, flexible high-density electroencephalography (HdEEG) arrays and recorded spontaneous SWD, IS, and MS with video/HdEEG. We determined differences among the events in amplitude spectral density (ASD) in the δ/θ/α/β/γ frequency bands at baseline (3.5-4.0 seconds before the first spike time, t0 ) and the prespike period (0.1-0.5 seconds before t0 ), and we elucidated the spatiotemporal activation during the t0 spike. Results All three events had an increase in ASD between baseline and prespike in at least one frequency band. During prespike, MS had the largest δ-band ASD, but SWD had the greatest α/β/γ band ASD. For all three events, the ASD was largest in the anterior regions. The t0 spike voltage was also greatest in the anterior regions for all three events and IS and MS had larger voltages than SWD. From 7.5 to 17.5 msec after t0 , MS had greater voltage than IS and SWD, and maximal voltage was in the posterior parietal region. Significance Changes in spectral density from baseline to prespike indicate that none of these generalized events are instantaneous or entirely unpredictable. Prominent engagement of anterior cortical regions during prespike and at t0 suggest that common anterior neural circuits participate in each event. Differences in prespike ASD signify that although the events may engage similar brain regions, they may arise from distinct proictal states with different neuronal activity or connectivity. Prolonged activation of the posterior parietal area in MS suggests that posterior circuits contribute to the myoclonic jerk. Together, these findings identify brain regions and processes that could be specifically targeted for further recording and modulation.

Levetiracetam (LEV) is a pyrrolidine derivative antiepileptic medication used for the treatment of seizures in pediatric and adult patients. We report a case of probable LEV-induced aseptic meningitis in a 13-year-old girl. The patient received LEV for a generalized seizure disorder and presented with symptoms 5 days after medication initiation. Ten days after LEV initiation, the patient presented to the hospital for further management. During her hospital course, infectious etiologies were ruled out with clinical and diagnostic testing. Upon discontinuation of LEV, the patient's symptoms resolved. Although select antiepileptic medications have been associated with drug-induced aseptic meningitis (DIAM), to date, no reports have been published about DIAM following the administration of LEV. We describe and categorize the probability of DIAM in association with LEV, as observed in a patient case.

Objective Deletions of CACNA1A, encoding the α1 subunit of CaV 2.1 channels, cause epilepsy with ataxia in humans. Whereas the deletion of Cacna1a in γ-aminobutyric acidergic (GABAergic) interneurons (INs) derived from the medial ganglionic eminence (MGE) impairs cortical inhibition and causes generalized seizures in Nkx2.1Cre ;Cacna1ac/c mice, the targeted deletion of Cacna1a in somatostatin-expressing INs (SOM-INs), a subset of MGE-derived INs, does not result in seizures, indicating a crucial role of parvalbumin-expressing (PV) INs. Here we identify the cellular and network consequences of Cacna1a deletion specifically in PV-INs. Methods We generated PVCre ;Cacna1ac/c mutant mice carrying a conditional Cacna1a deletion in PV neurons and evaluated the cortical cellular and network outcomes of this mutation by combining immunohistochemical assays, in vitro electrophysiology, 2-photon imaging, and in vivo video-electroencephalographic recordings. Results PVCre ;Cacna1ac/c mice display reduced cortical perisomatic inhibition and frequent absences but only rare motor seizures. Compared to Nkx2.1Cre ;Cacna1ac/c mice, PVCre ;Cacna1ac/c mice have a net increase in cortical inhibition, with a gain of dendritic inhibition through sprouting of SOM-IN axons, largely preventing motor seizures. This beneficial compensatory remodeling of cortical GABAergic innervation is mTORC1-dependent and its inhibition with rapamycin leads to a striking increase in motor seizures. Furthermore, we show that a direct chemogenic activation of cortical SOM-INs prevents motor seizures in a model of kainate-induced seizures. Interpretation Our findings provide novel evidence suggesting that the remodeling of cortical inhibition, with an mTOR-dependent gain of dendritic inhibition, determines the seizure phenotype in generalized epilepsy and that mTOR inhibition can be detrimental in epilepsies not primarily due to mTOR hyperactivation. Ann Neurol 2018;84:436-451.

Brivaracetam is currently indicated as adjunctive therapy for patients with focal-onset seizures with or without secondary generalization. However, it has been suggested that it could provide broad-spectrum efficacy given its similarity to levetiracetam and based on the results from preclinical studies and others of patients with generalized epilepsy. We present the case of a woman with refractory idiopathic generalized epilepsy and absence seizures with dramatic response to brivaracetam. Our report supports a consideration of treatment with this new antiepileptic drug on a case-by-case basis in patients with refractory generalized epilepsy, while we await further studies on this topic.

SummaryObjective To examine baseline psychological functioning and antiepileptic drug (AED) behavioral side effects in new onset epilepsy and determine, by age, whether baseline psychological functioning predicts AED behavioral side effects 1 month following AED initiation. Methods A retrospective chart review was conducted between July 2011 and December 2014 that included youths with new onset epilepsy. As part of routine interdisciplinary care, caregivers completed the Behavior Assessment System for Children, 2nd Edition: Parent Rating Scale to report on baseline psychological functioning at the diagnostic visit and the Pediatric Epilepsy Side Effects Questionnaire to identify AED behavioral side effects at the 1-month follow-up clinic visit following AED initiation. Children (age = 2-11 years) and adolescents (age = 12-18 years) were examined separately. Results A total of 380 youths with new onset epilepsy (Mage = 8.9 ± 4.3 years; 83.4% Caucasian; 34.8% focal epilepsy, 41.1% generalized epilepsy, 23.7% unclassified epilepsy) were included. Seventy percent of youths had at-risk or clinically elevated baseline psychological symptoms. Children had significantly greater AED behavioral side effects (M = 25.08 ± 26.36) compared to adolescents (M = 12.36 ± 17.73), regardless of AED. Valproic acid demonstrated significantly greater behavioral side effects compared to all other AEDs, with the exception of levetiracetam. Higher hyperactivity/impulsivity at baseline significantly predicted higher AED behavioral side effects 1 month after AED initiation in both age groups. Significance Younger children seem to be more prone to experience behavioral side effects, and these are likely to be higher if youths with epilepsy have baseline hyperactivity/impulsivity. Baseline psychological screening, specifically hyperactivity, can be used as a precision medicine tool for AED selection.

SummaryObjective The International League Against Epilepsy (ILAE) has proposed to expand the definition of remission to 10 years seizure-free with the last 5 years off antiepileptic drugs (AEDs). We examined if a 10-year remission is needed to predict the lowest recurrence risk. Methods The population-based study cohort consisted of 148 patients with new-onset childhood epilepsy living in the catchment area of Turku University Hospital. They were prospectively followed for 44 years (median). Patients in first remission were prospectively followed for the duration of remission or possible relapse at 2 years in remission with the last year without antiepileptic drugs (AEDs), at 5 years in remission with the last 2 years without AEDs, and at 10 years with the last 5 years without AEDs. For comparison of the proportions of relapsed patients within each remission category exact Clopper Pearson 95% confidence intervals were used. Results The magnitude of the relapse rate estimates off AEDs did not significantly improve when remission increased from 2 years (2YR) to 5 years (5YR) and further to 10 years (10YR). However, 10YR was a more sensitive measure of no relapse than 2YR. Among patients with remission on or off AEDs, the ability to predict lower relapse rate increased markedly from 2 to 5 years, and again from 5 to 10 years. The risk of relapse was virtually the same estimated after 2YR off AEDs as after 10YR on or off AEDs, except for patients with generalized epilepsy whose 2YR off AEDs was a weaker predictor than 10YR on or off AEDs. Significance Given the modest differences in relapse rates between the 5 years seizure-free with last 2 years off medications definition and the 10 years seizure-free with last 5 years off medications, and the adverse impact of not being considered in remission, we propose that a return to the 5-year definition may be warranted.

Objective To evaluate the long-term pharmacological outcomes in teenagers with different epilepsies. Method This study included teenagers aged 13-19 years at treatment initiation who were newly treated with antiepileptic drugs (AEDs) at the epilepsy unit of the Western Infirmary in Glasgow, Scotland, between 1 September 1982 and 30 September 2012. Patients were prospectively followed until 30 April 2016, or death, with at least a 2-year follow-up. Results A total of 332 adolescent patients (53% female; median age 16 years; 54% with generalized epilepsy) were included. At the end of the study, 221 patients (67%) were seizure-free. A higher seizure-free rate was observed in those with generalized compared to focal epilepsy (72% versus 60%, P = 0.01). During the study, 108 patients had relapses after periods of being seizure-free, most commonly due to poor adherence to AEDs (49%, n = 53/108). AED withdrawal was associated with a high risk of seizure recurrence (70%, n = 26/37), but 56% (n = 61/108) of relapsed patients became seizure-free again by the end of the study, with only 9% (n = 31/332) meeting the International League Against Epilepsy (ILAE) definition of pharmacoresistance during follow-up. Of the 221 seizure-free patients, 83% achieved this on monotherapy. There was no significant difference in efficacy rate between new and standard AED monotherapy (74% versus 77%, P = 0.66). The overall poor tolerability rate of AEDs was 21% (n = 69/332). Among the different new and standard AEDs used as initial monotherapy, lamotrigine was associated with the lowest rate of adverse effects (12%, n = 15/124), while topiramate was associated with the highest rate (56%, n = 5/9). Significance Teenagers with epilepsy showed good seizure control, particularly those with generalized epilepsy. However, relapse was common and there was high risk of seizure recurrence after treatment withdrawal. Most patients were controlled on monotherapy. As the efficacy of AEDs was comparable, tolerability can be a primary consideration for AED selection in this population.

SummaryObjective To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. Methods Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. Results Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00–14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88–5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53–9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69–81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. Significance Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period.

Summary Objectives An intravenous (IV) formulation of brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, has been developed. We investigated the safety, tolerability, and pharmacokinetics of adjunctive IV BRV administered as a bolus or infusion to adults with epilepsy. Methods A phase III, multicenter, randomized, four-arm, parallel-group study (NCT01405508) of patients aged 16–70 years with focal or generalized epilepsy uncontrolled by 1–2 antiepileptic drugs was undertaken. The study comprised a 7-day baseline period, a 7-day double-blind run-in period (oral BRV 200 mg/day or placebo [PBO] twice daily [BID]), and 4.5-day open-label evaluation period (IV BRV 200 mg/day BID; 2-min bolus or 15-min infusion, total nine doses). Patients were randomized 1:1:1:1 PBO/BRV bolus; PBO/BRV infusion; BRV/BRV bolus; BRV/BRV infusion. Safety and tolerability were assessed using adverse events, electrocardiography, vital signs, and laboratory assessments. BRV plasma concentrations were measured before and 15 min after the first and last IV doses. Results Of the 105 patients randomized (53.3% women; 77.1% white; mean [standard deviation; SD] age 41.6 [12.2] years), 103 (98.1%) completed the study. Treatment-emergent adverse event (TEAE) incidence during IV BRV was similar whether IV BRV was initiated first (70.6%) or followed oral BRV (66.0%), and whether it was administered as a bolus (71.2%) or infusion (65.4%). Injection-related TEAEs were reported by 9.6% of patients following bolus and 11.5% following infusion. No serious TEAEs were reported. IV BRV plasma concentrations were higher after the first dose in the conversion groups than initiation groups, and slightly higher in the bolus arm than the infusion arm; concentrations were similar in all patients after the last IV dose. Significance IV BRV was generally well tolerated, with similar tolerability as a bolus or infusion and independent of de novo administration or as conversion from oral BRV tablets. IV BRV may be an option for patients who are unable to receive oral BRV.

SummaryObjective GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations. Methods In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively. Results We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously. Significance Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.

Objective The leading cause of epilepsy-related premature mortality is sudden unexpected death in epilepsy (SUDEP). The cause of SUDEP remains unknown. To search for genetic risk factors in SUDEP cases, we performed an exome-based analysis of rare variants. Methods Demographic and clinical information of 61 SUDEP cases were collected. Exome sequencing and rare variant collapsing analysis with 2,936 control exomes were performed to test for genes enriched with damaging variants. Additionally, cardiac arrhythmia, respiratory control, and epilepsy genes were screened for variants with frequency of

Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.

Objective Childhood absence epilepsy (CAE) is a childhood-onset generalized epilepsy. Recent fMRI studies have suggested that frontal cortex activity occurs before thalamic involvement in epileptic discharges suggesting that frontal cortex may play an important role in childhood absence seizures. Neurocognitive deficits can persist after resolution of the epilepsy. We investigate whether structural connectivity changes are present in the brains of CAE patients in young adulthood. Methods Cortical thickness measurements were obtained for 30 subjects with CAE (mean age 21 ± 2 years) and 56 healthy controls (mean age 24 ± 4) and regressed for age, sex, and total intracranial volume (TIV). Structural connectivity was evaluated by measuring the correlation between average cortical thicknesses in 915 regions over the brain. Maps of connectivity strength were then obtained for both groups. Results When compared to controls, the CAE group shows overall increased “connectivity” with focal increased connection strength in anterior regions including; the anterior cingulate and the insula and superior temporal gyrus bilaterally; the right orbito-frontal and supramarginal regions; and the left entorhinal cortex. Decreased connection strength in the CAE group was found in the left occipital lobe, with a similar trend in right occipital lobe. Interpretation Brains in young adults whose CAE was resolved had abnormal structural connectivity. Our findings suggest that frontal regions correlate most with cortical thickness throughout the brain in CAE patients, whereas occipital regions correlate most in well matched normal controls. We interpret this as evidence of a developmental difference in CAE that emphasizes these frontal lobe regions, perhaps driven by frontal lobe epileptiform activity.

Summary Aims We have recently reported that amiloride, a potent and nonselective blocker of acid-sensing ion channels, prevents the development of pilocarpine-induced seizures and status epilepticus. Amiloride is also known to suppress the activity of Na+/Ca2+ and Na+/H+ exchangers that have been implicated in the pathophysiology of seizures. Here, we evaluated the effects of amiloride, SN-6 (a potent blocker of Na+/Ca2+ exchangers) and zoniporide (a potent blocker of Na+/H+ exchangers) on acoustically evoked seizures (audiogenic seizures, AGS) in genetically epilepsy-prone rats (GEPR-3s), a model of inherited generalized epilepsy. Methods Male, six-week-old GEPR-3s were used. The GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of amiloride, SN-6, and zoniporide (1, 3, 10, and 30 mg/kg; per os). Results We found that pretreatment with amiloride and SN-6 markedly reduced the incidence and severity of AGS in the GEPR-3s. In contrast, administration of zoniporide only minimally reduced the incidence and severity of AGS in the GEPR-3s. A combination of noneffective doses of SN-6 and zoniporide also suppressed AGS susceptibility in the GEPR-3s. Conclusions These findings suggest acid-sensing ion channels and the Na+/Ca2+ exchanger may play an important role in the pathophysiology of inherited AGS susceptibility in the GEPR-3s.

Objectives Idiopathic-generalized epilepsy (IGE) is currently considered to be a genetic disease without structural alterations on conventional MRI. However, voxel-based morphometry has shown abnormalities in IGE. Another method to analyze the microstructure of the brain is diffusion-tensor imaging (DTI). We sought to clarify which structural alterations are present in IGE and the most frequent subsyndrome juvenile myoclonic epilepsy (JME). Experimental design We studied 25 patients (13 IGE and 12 JME) and 44 healthy controls with DTI. Fractional anisotropy (FA), mean diffusivity (MD), axial and radial diffusivity (AD/RD) were calculated and group differences were analyzed using tract-based spatial statistics (TBSS). Additionally we performed a target-based classification of TBSS results based on the Freesurfer cortical regions. Principle observations TBSS showed widespread FA reductions as well as MD and RD increases in patients compared to controls. Affected areas were corpus callosum, corticospinal tract, superior and inferior longitudinal fasciculus and supplementary motor regions. No significant differences were found between JME and IGE subgroups. The target-based classification confirmed a particular involvement of the superior frontal gyrus (mesiofrontal area) in IGE/ME. Conclusions IGE and JME patients showed clear microstructural alterations in several large white matter tracts. Similar findings have been reported in rodent models of IGE. Previous, region-of-interest-based DTI studies may have under-estimated the spatial extent of structural loss associated with generalized epilepsy. The comparison of clinically defined JME and IGE groups revealed no significant DTI differences in our cohort. Hum Brain Mapp 35:3332–3342, 2014. © 2013 Wiley Periodicals, Inc.

PurposeTo evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. MethodsThis was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) in adults (16-70years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20mg/day and increased, as needed, to 150mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16weeks). Key FindingsA total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV- and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV- and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n=323) over PBO (n=108) was 7.3% (p=0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/week was 26.9% BRV versus 18.9% PBO (p=0.070), and the 50% responder rate was 30.3% BRV versus 16.7% PBO (p=0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n=36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n=13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the 50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. SignificanceAdjunctive BRV given at individualized tailored doses (20-150mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.

Summary Purpose Deep brain stimulation (DBS) of the thalamus is an emerging surgical option for people with medically refractory epilepsy that is not suitable for resective surgery, or in whom surgery has failed. Our main aim was to evaluate the efficacy of bilateral centromedian thalamic nucleus (CMN) DBS for seizure control in generalized epilepsy and frontal lobe epilepsy with a two-center, single-blind, controlled trial. Methods Participants were adults with refractory generalized or frontal lobe epilepsy. Seizure diaries were kept by patients/carers prospectively from enrollment. The baseline preimplantation period was followed by a control period consisting of a blind stimulation-OFF phase of at least 3 months, a 3-month blind stimulation-ON phase, and a 6-month unblinded stimulation-ON phase. The control period was followed by an unblinded long-term extension phase with stimulation-ON in those patients in whom stimulation was thought to be effective. Key Findings Eleven patients were recruited at King's College Hospital (London, United Kingdom United Kingdom) and at University Hospital La Princesa (Madrid, Spain). Among the five patients with frontal lobe epilepsy, only one patient had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, two patients with frontal lobe epilepsy had >50% improvement in seizure frequency. All six patients with generalized epilepsy had >50% improvement in seizure frequency during the blind period. In the long-term extension phase, five of the six patients showed >50% improvement in the frequency of major seizures (one became seizure free, one had >99% improvement, and three had 60–95% reduction in seizure frequency). Among patients with generalized epilepsy, the DBS implantation itself appears to be effective, as two patients remained seizure free during 12 and 50 months with DBS OFF, and the remaining four had 50–91% improvement in the initial 3 months with DBS OFF. Significance DBS implantation and stimulation of the CMN appears to be a safe and efficacious treatment, particularly in patients with refractory generalized epilepsy. CMN stimulation was not as effective in frontal lobe epilepsy, which requires further studies. DBS of the CMN should be considered as a treatment option, particularly in patients with refractory generalized epilepsy syndromes.

Rare copy number variants (CNVs) have been established as an important cause of various neurodevelopmental disorders, including intellectual disability (ID) and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation. Here we present two siblings and their mother who have mild ID, short stature, obesity and seizures. Array CGH studies show that each affected individual has two large, rare CNVs. The first is a deletion of chromosome 16p11.2, which has been previously associated with ID and autism. The second is a 0.9 Mb deletion of 19p13.2, which results in the deletion of a cluster of zinc finger genes. We suggest that, while the 16p11.2 deletion is likely the primary cause of the obesity and ID in this family, the 19p13.2 deletion may act as a modifier of the epilepsy phenotype, which is not a core feature of the 16p11.2 deletion syndrome. We investigate the potential role of ZNF44, a gene within the deleted region, in a cohort of patients with generalized epilepsy.

Summary Purpose To investigate whether using transcranial magnetic stimulation (TMS) to derive if measures of cortical excitability changes can distinguish between various adolescent/adult-onset generalized epilepsy syndromes at different phases of the disorder. Methods One hundred thirty-seven patients with adolescent/adult-onset generalized epilepsy divided into juvenile myoclonic epilepsy, juvenile absence epilepsy, and generalized epilepsy with tonic–clonic seizures only were studied. The cohorts were further divided into drug naive-new onset, refractory, and seizure-free groups. Motor threshold (MT) and paired pulse TMS at short (2, 5, 10, 15 msec) and long (100–300 msec) interstimulus intervals (ISIs) were measured. Results were compared to those of 20 controls. Key Findings In the drug-naive cohorts MT was reduced (p

Purpose - To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence-assessment methods. Methods - A total of 100 children with epilepsy (≤17 years old) were recruited. Medication adherence was determined via parental and child self-reporting (≥9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self- or parental-led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children. Key Findings - The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.37–15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16–11.41). Significance - This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self-reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence.

Summary Purpose To test the applicability of the new International League Against Epilepsy (ILAE) 2010 classification for epilepsies and to compare it with the ILAE 1989 classification and the ILAE 2001 diagnostic scheme in developing countries with limited resources such as India. Methods Prospective data of 500 consecutive patients with epilepsy, presenting in neurology department of All India Institute of Medical Sciences, was collected from January 2011 to June 2012 and analyzed according to the three systems proposed by ILAE in 1989, 2001, and 2010. Key Findings All 500 patients could be classified in the ILAE 1989 classification system, but only 413 in the ILAE 2001 diagnostic scheme (in axes 3 and 4) and 420 in the ILAE 2010 classification system. Leading categories were localization-related epilepsies, symptomatic focal epilepsies, perinatal insult, and epilepsies attributed to structural and metabolic cause in ILAE 1989, 2001 axis 3, 2001 axis 4, and 2010 systems, respectively. The ILAE 1989 classification system could categorize significantly greater numbers of patients compared to the 2001 and 2010 systems, whereas the latter two remained similar. Significance A large group of patients remained unclassified in the new classification system despite our tremendous gain in knowledge through improved imaging, genomics, and molecular biology, and so on, which could be attributed to lack of availability of facilities in developing countries. Dichotomy of localization-related and generalized epilepsy still makes for a fundamental and pragmatic working diagnosis and guides the physician about the extent of investigations and treatment especially in “epilepsies of unknown cause.”

Summary Purpose Although epilepsy and migraine are known to co-occur within individuals, the contribution of a shared genetic susceptibility to this comorbidity remains unclear. We investigated the hypothesis of shared genetic effects on migraine and epilepsy in the Epilepsy Phenome/Genome Project (EPGP) cohort. Methods We studied prevalence of a history of migraine in 730 EPGP participants aged ≥12 years with nonacquired focal epilepsy (NAFE) or generalized epilepsy (GE) from 501 families containing two or more individuals with epilepsy of unknown cause. Information on migraine without aura (MO) and migraine with aura (MA) was collected using an instrument validated for individuals ≥12 years. Because many individuals have both MO and MA, we considered two nonoverlapping groups of individuals with migraine: those who met criteria for MA in any of their headaches (MA), and those who did not (“MO-only”). EPGP participants were interviewed about the history of seizure disorders in additional nonenrolled family members. We evaluated associations of migraine prevalence in enrolled subjects with a family history of seizure disorders in additional nonenrolled relatives, using generalized estimating equations to control for the nonindependence of observations within families. Key Findings Prevalence of a history of MA (but not MO-only) was significantly increased in enrolled participants with two or more additional affected first-degree relatives. Significance These findings support the hypothesis of a shared genetic susceptibility to epilepsy and MA.

Summary Febrile seizures are a common emergency faced by general pediatricians. They are mostly self-limiting, isolated events with no sequelae in later life. A minority are more complex. In the acute stage, there are a small number of underlying etiologies that are important to recognize in order to determine the prognosis accurately and to optimize management. There has been a long-standing debate about the relationship of early febrile seizures to the later development of epilepsy. It is now clear that this risk differs for simple and complex febrile seizures: complex febrile seizures may herald the presentation of a number of epilepsy syndromes of which febrile and illness-related seizures are part of the phenotype. This review examines the existing knowledge on febrile seizures and the various clinical phenotypes to which they are linked.

The longstanding dichotomy between the concepts of "focal" and "primary generalized" epilepsy has become increasingly blurred, raising fundamental questions about the nature of ictal onset in localized brain regions versus large-scale brain networks. We hypothesize that whether an EEG discharge appears focal or generalized is driven by the pattern of connections in brain networks, irrespective of the presence of focal brain abnormality. Using a computational model of a simple "brain" consisting of four regions and the connections between them, we explored the effects of altering connectivity structure versus the effects of introducing an "abnormal" brain region, and the interactions between these factors. Computer simulations demonstrated that electroencephalography (EEG) discharges representing either generalized or focal seizures arose purely as a consequence of subtle changes in network structure, without the requirement for any localized pathologic brain region. Furthermore we found that introducing a pathologic region gave rise to focal, secondary generalized, or primary generalized seizures depending on the network structure. Counterintuitively, we found that decreasing connectivity between regions of the brain increased the frequency of seizure-like activity. Our findings may enlighten current controversies surrounding the concepts of focal and generalized epilepsy, and help to explain recent observations in genetic animal models and human epilepsies, where loss of white matter pathways was associated with the occurrence of seizures.

This prospective study evaluated 19 individuals with refractory focal or generalized epilepsy utilizing an implantable cardiac loop recorder. Recording averaged 15 months (range 12-19 months) in 18 patients and 1.5 months in one patient. A median of 37 seizures per patient (range 3-657) occurred, with 1,477 seizures total. Cardiac arrhythmias and repolarization abnormalities occurred frequently (in 42% of patients) in refractory epilepsy, particularly during generalized tonic-clonic and tonic seizures. Patients with Lennox-Gastaut syndrome may be at high risk for cardiac abnormalities.

SUMMARY Purpose: Photosensitivity or photoparoxysmal response (PPR) is an electroencephalography trait that is highly associated with idiopathic generalized epilepsies (IGEs) and characterized by changes in cortical excitability in response to photic stimulation. Studying functional and structural changes of PPR might provide important insights into the pathogenesis of IGE. Recent studies revealed a functional network consisting of occipital, parietal, and precentral areas that might be implicated in PPR. Herein, we investigate the microstructural changes associated with PPR. Methods: Twelve healthy subjects with PPR, nine patients with IGE and PPR (IGE-PPR group), and 18 healthy controls were studied with diffusion magnetic resonance imaging. Tract-based spatial statistics were used to test for regional differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity between groups. Key Findings: Subjects with PPR exhibited higher FA in the right precentral juxtacortical white matter and higher MD in lateral occipital areas relative to controls. Patients with IGE-patients showed additional increases in regional FA in the thalamus and juxtacortical precentral and parietal areas. Both subjects with PPR and patients with IGE-PPR presented axial and radial diffusivity changes in the occipital regions. Significance: Our results show that PPR is associated with subcortical microstructural changes in precentral, parietal, and occipital regions. The coexistence of PPR and IGE is associated with white matter abnormalities in the thalamus and precuneus. PPR and epilepsy share similar functional and structural networks in widespread cortical and subcortical areas.

Summary Purpose: Neuropeptide Y (NPY) is an inhibitory neurotransmitter that suppresses focal and generalized seizures in animal models. In this study, we investigated the sites within the thalamocortical circuit that NPY acts to suppress seizures in genetic absence epilepsy rats from Strasbourg (GAERS). Methods: In conscious freely moving GAERS, NPY was administered via intracerebral microcannulae implanted bilaterally into one of the following regions: primary somatosensory cortex (S1), secondary somatosensory cortex (S2), the primary motor cortex (M1), caudal nucleus reticular thalamus (nRT), or ventrobasal thalamus (VB). Animals received vehicle and up to three doses of NPY, in a randomized order. Electroencephalography (EEG) recordings were carried out for 30 min prior to injection and 90 min after the injection of NPY or vehicle. Key Findings: Focal microinjections of NPY into the S2 cortex suppressed seizures in a dose-dependent manner, with the response being significantly different at the highest dose (1.5 mm) compared to vehicle for total time in seizures postinjection (7.2 ± 3.0% of saline, p

Purpose: Epilepsy may have far-reaching consequences for patients, other than having seizures and medication. At 15 years after diagnosis, this study investigates health perception, restrictions due to epilepsy, living arrangements (including marital status and offspring), and the educational and occupational attainment of patients with childhood-onset epilepsy.Methods: Atotal of 453 patients with epilepsy had a 5-year follow-up since diagnosis with regular visits and data collection. Ten years later, a questionnaire addressing epilepsy was completed by 413 patients, resulting in a mean followup of 15 years. Subjects were compared with age peers of the Dutch population for each etiologic group separately, and also for subjects with/without a 5-year terminal remission regardless of treatment. Age-adjusted standardized incidence rates were calculated for each variable.Key Findings: Subjects with normal intelligence had a health perception comparable with that of the general population, but significantly more subjects without remission had a worse health perception, especially those still using medication. Restrictions and symptoms due to epilepsy were reported by 14% of the subjects, mainly by those without remission or with ongoing medication. The living arrangement of subjects with idiopathic or cryptogenic etiology was similar to that of Dutch persons of the same age (age peers). Subjects with remote symptomatic etiology less often lived independently or with a partner, and more frequently resided in an institution or living group for the disabled. Those with and without remission were more often part of another household, mainly due (in both groups) to having a remote symptomatic etiology. Rates of having a partner and offspring were significantly reduced only for subjects with remote symptomatic etiology. Fewer students with idiopathic/remote symptomatic etiology and students in remission followed higher vocational or scientific education. In these latter groups, the highest attained education of employees was lower than expected. The employment status of subjects with idiopathic or cryptogenic etiology was comparable with that of their Dutch age peers, but fewer subjects with remote symptomatic etiology were employed and more of them were part of the dependent population. However, for those in the labor force (employed/unemployed) all employment rates were 90%, even for those with remote symptomatic etiology. Nevertheless, fewer employees than expected had a higher vocational or scientific level of occupation, even those with idiopathic etiology and those in remission.Significance: Health perception, living arrangement, and socioeconomic status were influenced by epilepsy, comorbidities, or treatment, particularly for subjects with remote symptomatic etiology or no remission. The group in remission fared less well than expected, mainly due to the numbers of subjects with remote symptomatic etiology in this group. In line with others, we conclude that childhood-onset epilepsy is associated with lower educational attainment, even for subjects with idiopathic etiology and subjects in remission; probably related to this, their occupational level was also lower than expected.

Summary Epilepsy with myoclonic absences (EMA) is a rare form of generalized epilepsy occurring in childhood and is often difficult to treat. The underlying etiology of EMA is unknown in the majority of patients. Herein, we describe a patient with EMA and intellectual disability who carries a de novo balanced translocation: t(6;22)(p21.32;q11.21). We mapped the translocation breakpoints by fluorescence in situ hybridization (FISH), and the breakpoint at 6p21.32 was found to truncate the N-methyl-d-aspartate (NMDA)–receptor associated gene SYNGAP1. The breakpoint at 22q11.21 was within a highly variable region without known protein-coding genes. Mutations of SYNGAP1 are associated with nonsyndromal intellectual disability (NSID). Two-thirds of the patients described so far also have generalized epilepsy. This finding, together with our report, suggests that dysfunction of SYNGAP1 contributes to the development of generalized epilepsy, including EMA.

Purpose: Epilepsy may have far-reaching consequences for patients, other than having seizures and medication. At 15 years after diagnosis, this study investigates health perception, restrictions due to epilepsy, living arrangements (including marital status and offspring), and the educational and occupational attainment of patients with childhood-onset epilepsy. Methods: Atotal of 453 patients with epilepsy had a 5-year follow-up since diagnosis with regular visits and data collection. Ten years later, a questionnaire addressing epilepsy was completed by 413 patients, resulting in a mean followup of 15 years. Subjects were compared with age peers of the Dutch population for each etiologic group separately, and also for subjects with/without a 5-year terminal remission regardless of treatment. Age-adjusted standardized incidence rates were calculated for each variable. Key Findings: Subjects with normal intelligence had a health perception comparable with that of the general population, but significantly more subjects without remission had a worse health perception, especially those still using medication. Restrictions and symptoms due to epilepsy were reported by 14% of the subjects, mainly by those without remission or with ongoing medication. The living arrangement of subjects with idiopathic or cryptogenic etiology was similar to that of Dutch persons of the same age (age peers). Subjects with remote symptomatic etiology less often lived independently or with a partner, and more frequently resided in an institution or living group for the disabled. Those with and without remission were more often part of another household, mainly due (in both groups) to having a remote symptomatic etiology. Rates of having a partner and offspring were significantly reduced only for subjects with remote symptomatic etiology. Fewer students with idiopathic/remote symptomatic etiology and students in remission followed higher vocational or scientific education. In these latter groups, the highest attained education of employees was lower than expected. The employment status of subjects with idiopathic or cryptogenic etiology was comparable with that of their Dutch age peers, but fewer subjects with remote symptomatic etiology were employed and more of them were part of the dependent population. However, for those in the labor force (employed/unemployed) all employment rates were 90%, even for those with remote symptomatic etiology. Nevertheless, fewer employees than expected had a higher vocational or scientific level of occupation, even those with idiopathic etiology and those in remission. Significance: Health perception, living arrangement, and socioeconomic status were influenced by epilepsy, comorbidities, or treatment, particularly for subjects with remote symptomatic etiology or no remission. The group in remission fared less well than expected, mainly due to the numbers of subjects with remote symptomatic etiology in this group. In line with others, we conclude that childhood-onset epilepsy is associated with lower educational attainment, even for subjects with idiopathic etiology and subjects in remission; probably related to this, their occupational level was also lower than expected.

Summary Purpose: Studies on seizures only with an alteration of consciousness were limited mainly to generalized epilepsy. This seizure type has been described rarely in focal epilepsy. We aimed to analyze the semiologic features of this seizure type in focal and generalized epilepsies in a blinded design. Methods: A total of 338 seizure videos in 100 patients were included exclusively by semiologic criteria. Two investigators evaluated the seizure semiology (aura, seizure duration, blinking, mild motor phenomena including automatisms, and so on) from the videos. Primarily the ictal electroencephalography (EEGs) studies and all laboratory findings were evaluated for the localization of the epileptogenic zone and delineating the syndromes, in the second step. Key Findings: Of the focal epilepsy patients (n = 57), the epileptogenic zone could be localized to the temporal (n = 20), frontal (n = 9), and parietooccipital (n = 3) regions. The most common etiology of the generalized epilepsy patients (n = 43) was presumably genetic (n = 33). The presence of aura (none in generalized epilepsy vs. 35% in focal epilepsy; p = 0.0008), lack of blinking (19.3% in focal vs 65.1% in generalized epilepsy; p = 0.01), and longer seizure duration (generalized 14.3 ± 17.7 s vs focal 54.9 ± 40.1 s; p

PURPOSE: To estimate the lifetime prevalence of epilepsy in Prey Veng province (Cambodia). METHODS: Door-to-door screening was performed using a random cluster survey whereby all people >1 year of age were screened for epilepsy by using a validated and standardized questionnaire for epilepsy in tropical countries. Suspected epilepsy patients identified by the questionnaire were revisited and examined by epileptologists. The confirmation of epilepsy was based on an in-depth clinical examination. Electroencephalograms were recorded at the community dispensary. Key FINDINGS: Five hundred three potential epilepsy cases were identified from 16,510 screened subjects, and 96 were diagnosed to have epilepsy. An overall prevalence of 5.8 per 1,000 [95% confidence interval (CI) 4.6-7.0 per 1,000] was obtained. Generalized epilepsy (76%) was more common than partial epilepsy (12.5%). Three cases were of generalized myoclonic epilepsy (3.1%) and one case each (1.0%) were of absence and olfactory partial epilepsy. Six cases (5.2%) had more than one seizure type [one case with absence + generalized tonic-clonic (GTC), one case each with GTC + partial seizures with secondary generalization and absence + generalized myoclonic seizures and absence + simple partial seizures, and two cases with GTC + complex partial seizures]. Electroencephalography (EEG) studies revealed spike and wave discharges in 43.8%, focal spikes in 21.0%, generalized slow waves in 19.2%, and generalized slowing of background in 15.7%. SIGNIFICANCE: This is the first population-based study in Cambodia that had epilepsy as a primary objective, and compared to Western and neighboring countries it shows a lower prevalence.

Summary Purpose: Epilepsy and electroencephalographic abnormalities are frequent in idiopathic autism, but there is little information regarding treatment-resistant epilepsy (TRE) in this group. We sought to define the clinical and electrophysiologic characteristics and treatment outcomes in these patients. Methods: We retrospectively reviewed clinical and laboratory data of patients with idiopathic autism evaluated at NYU Epilepsy Center during a 20-year period. Key Findings: One hundred twenty-seven patients had idiopathic autism and at least one epileptic seizure; 33.9% had TRE and 27.5% were seizure free. The remaining 38.6% of patients had infrequent seizures or insufficient data to categorize. Patients with TRE had a significantly earlier onset of seizures than seizure-free patients, and a trend for more developmental regression and motor and language delays. Three patients had surgical resection (two had limited improvement and one had no improvement) and one had an anterior callosotomy (no improvement). Vagus nerve stimulator (VNS) implantation provided limited improvement (2 patients) and no improvement (7). Significance: This study found that TRE is common in idiopathic autism and more common with early age of seizure onset. Relatively few patients underwent surgical resection due to multifocal partial epilepsy, comorbid generalized epilepsy, or limited impact of ongoing partial seizures given other problems related to autism. Our small sample suggests that surgical and VNS outcomes in this group are less favorable than in other TRE populations.

Summary Purpose: Generalized epilepsies are clinically and genetically heterogeneous syndromes. Idiopathic generalized epilepsy (IGE), which has a strong genetic background, is not associated with any additional clinical features, such as mental retardation (MR). Herein we report results of linkage analysis in a large family with autosomal dominant (AD) generalized epilepsy associated with MR. Methods: We identified a four-generation kindred with several affected members with generalized epilepsy without any evidence for secondary causes. Electroencephalography (EEG) studies and magnetic resonance imaging (MRI) results were reviewed when available. We performed a genome-wide linkage analysis. Key Findings: Fourteen individuals were classified as affected and an additional three were considered as nonpenetrant obligatory carriers. Thirteen affected individual had a history of generalized tonic–clonic seizures, and absence seizures were reported in nine affected individuals. There was no history of preceding febrile seizures. MR was present in nine affected individuals with epilepsy but the other affected individuals had normal intelligence. Neuroimaging did not reveal any structural abnormalities and EEG studies were consistent with IGE rather than symptomatic generalized epilepsy. Genetic analysis detected a group of markers with logarithmic (base 10) of odds (LOD) score >3 on chromosome 3p spanning a 5.5 Mbp region. Sequencing of several candidate genes, including dynein light chain-A, golgin subfamily a4, leucine rich repeat (in FLII) interacting gene, serine/threonine-protein kinase DCAMKL3 (doublecortin- like and CAM kinase-like 3), laforin (EPM2A) interacting protein 1 (EPM2AIP1, programmed cell death 6 interacting protein, and CLIP-associating protein 2 (cytoplasmic linker-associated protein 2) (hOrbit2) genes did not identify the disease-causing mutations. Significance: We report the identification of a genetic locus for generalized epilepsy associated with MR on chromosome 3p. Affected individuals have a form of genetic epilepsy with generalized seizures variably associated with MR. Despite the presence of MR in several affected patients, epilepsy phenotype was not fully consistent with symptomatic epilepsy and suggests a biologic continuum between symptomatic epilepsies and IGE.

The etiology of epilepsy is a major determinant of clinical course and prognosis, yet the current classifications of epilepsy do not list etiology in any detail. In this article, a classification (database) of the etiologies of epilepsy is proposed. In this scheme, the etiology of epilepsy is divided into four categories: idiopathic, symptomatic, provoked, and cryptogenic. These are defined and subcategories are proposed. A commentary addressing the following points is included: problems associated with assigning causation, symptomatic versus idiopathic epilepsy, focal versus generalized epilepsy, acquired epilepsy, acute symptomatic epilepsy, risk factor analysis, provoked epilepsy genetic and developmental epilepsy, and epilepsy as a disease not a symptom.