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Objective For epilepsy patients with drug-resistant, unresectable epilepsy, vagus nerve stimulation (VNS) is an option for seizure control. Approximately 40-70% of patients will achieve ≥50% seizure reduction with VNS. New closed loop VNS models detect ictal tachycardia and responsively stimulate the vagus nerve. The effectiveness of closed loop VNS compared to traditional VNS for pediatric epilepsy is unknown. Methods An 11-year retrospective electronic medical record review at Children's Hospital of Pittsburgh was performed. Patients with drug-resistant epilepsy who underwent VNS implantation were included. Patients were divided into groups based on VNS model: traditional versus closed loop. Those who transitioned from traditional to closed loop VNS were excluded. Given potential for selection bias, propensity scores matching was utilized to compare traditional to closed loop VNS patients. Patients with focal versus generalized epilepsy were also separately analyzed. The primary outcome was “VNS response”, defined as at least 50% seizure frequency reduction from baseline. Results A total of 320 patients were included in this sample. The percentage of matched patients (total n=220: n=179 traditional VNS, n=41 closed loop VNS) who responded to VNS after one year of therapy was 43% for traditional VNS and 39% for closed loop VNS (p=0.64). After two years of therapy, a higher proportion of closed loop VNS patients than traditional VNS patients responded to VNS among all subgroups, though no differences were statistically significant (p>0.05). Notably, for those with generalized epilepsy, 73% of closed loop patients responded to VNS compared to only 46% of traditional patients (p=0.10). After two years of VNS therapy, patients were taking approximately the same quantity of antiseizure medications as baseline (0.074 ± 0.90) with no difference between VNS models (p=0.87). Significance Among pediatric patients with drug-resistant epilepsy, closed loop VNS trends towards a higher rate of VNS response after two years of treatment, especially among generalized epilepsy patients. Neither model of VNS allows patients to reduce antiseizure medication quantity after two years.

Introduction Levetiracetam (LEV) is a second-generation antiseizure medicine (ASM) with broad-spectrum efficacy and tolerability. Few studies have compared the efficacy of valproate (VPA) and LEV as monotherapy in the pediatric population. Herein, we compare the efficacy, tolerability and safety of LEV monotherapy with those of VPA monotherapy in ASM-naive pediatric patients with idiopathic generalized epilepsy with tonic-clonic (GTC) seizures. Methods We retrospectively analyzed the clinical and electroencephalographic (EEG) data of these ASM-naive pediatric patients who were treated with either oral VPA or oral LEV as monotherapy for over 2 years at our center. Results This study included 60 patients with a seizure onset age between 2 months and 12 years. The patients on VPA (29 patients) and LEV monotherapy (31 patients) showed similar favorable 6-month treatment outcomes (complete seizure control in 79.31% vs 80.64%, p = 0.468052). Age at epilepsy onset, epilepsy syndrome, EEG features and ASM dose were not significant predictors of the 6-month treatment outcomes in either group. Lower seizure frequency at presentation was a predictor of favorable 6-month treatment outcomes in the LEV group but not in the VPA group. VPA and LEV treatment showed similar favorable 6-month treatment outcomes in the febrile seizures plus and patients with unidentified epilepsy syndrome subgroups. None of the patients discontinued VPA or LEV due to treatment-associated adverse effects. Discussion Our study showed that compared to VPA monotherapy, LEV monotherapy in ASM-naive infants and children with idiopathic generalized epilepsy with GTC seizures has a similarly favorable efficacy and tolerability, independent of age, EEG features and epilepsy syndrome.

Background This article explores the role of initial treatment on control of spasms and other epilepsies at four years in children previously treated for West syndrome. Methods The Sri Lanka Infantile Spasm Study is a prospective clinical trial evaluating response to intra-muscular adrenocorticotropic hormone (ACTH) versus oral prednisolone. A previous report documented response through age 12 months. This article provides four-year follow-up data. Results At age four years, 65 of the original 97 were available for follow-up; another 13 had died, and 19 moved and could not be contacted. Of the 65 children, 37 (57%) continued to have seizures and 28 were seizure free. In the 37 children with ongoing epilepsy, 32.4% continued to have spasms, either alone or in combination with other seizure types. The epilepsy types seen in these children were focal epilepsy (59.4%), mixed focal and generalized epilepsy (24%), generalized epilepsy only (10.8%), and uncertain (5%). The majority of those still having epilepsy (66.7%) were controlled on medication. There was no significant difference in the rate of epilepsy or spasms or their control by medication between those treated with ACTH or oral prednisolone. Spasm control at day 14 did not influence the four-year spasm or epilepsy outcome. Conclusions A majority of children diagnosed with West syndrome continued to have seizures at age four years, although most were controlled on antiseizure medication. The long-term risk of developing epilepsy or its control was the same, regardless of whether ACTH or prednisolone was initially used as treatment.

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

Purpose Eating epilepsy was previously known as a kind of focal reflex epilepsy. However, the development of eating-induced multiple generalized seizures and the associated EEG changes were rarely reported. Herein, we present a 13-year-old generalized epilepsy patient with eating-induced generalized seizures since the age of 5. Case presentation The 13-year-old male patient had suffered from late-onset eating-induced epileptic spasms during the meal since the age of 5. Meanwhile, he also experienced spontaneous epileptic spasms during the period of sleep. The seizure frequency and type gradually increased from 7 years of age. In addition to epileptic spasms, he started experiencing atypical absence with myoclonic jerks during the meal. Ictal EEG presented as the appearance of an irregular slow-wave mixed with generalized polyspike wave with the intake of food, and gradually evolved to bursts of generalized polyspike wave complexes. At the end of the meal, the EEG returned to normal. Nevertheless, at the age of 13, his seizure frequency increased and appeared new seizure type, and besides epileptic spasm and atypical absence, he began to experience myoclonic seizure during sleep and awaking-generalized tonic-clonic seizure in the morning. In this period he started taking valproic acid, topiramate and clonazepam, and his seizure frequency was reduced. Conclusion In conclusion, this case demonstrated the variability of eating induced multiple generalized seizure types, and eight years follow-up also indicates that generalized epilepsy progressed with age. The EEG and clinical changes of our patient contribute to a better understanding of the electro-clinical features of eating-induced multiple generalized seizures and the course of generalized epilepsy with such seizures.

Objectives To determine the clinical features and anti-seizure medication (ASM) strategies associated with an unanticipated substantial improvement in seizure control in patients with drug-resistant epilepsy (DRE). Methods This retrospective analysis of patients attending a tertiary care epilepsy clinic between 2008 and 2017 identified all patients with active DRE (at least 1 seizure per month for 6 months, despite treatment with 2 different ASMs). All treatment interventions were recorded from when DRE was first identified to the end of the study. The primary end points were seizure freedom or meaningful reduction in seizure frequency (greater than 75 %) sustained for at least 12 months after a treatment intervention. Results Three hundred and twenty-two patients were included in the analysis. Overall, 10 % became seizure free following ASM adjustment and an additional 10 % had a greater than 75 % improvement in seizure control (median follow-up, 4 years). An ASM introduction was ten times more likely than an ASM dose increase to improve seizure control. Combined focal and generalized epilepsy, intellectual disability and prior treatment with more than 5 ASMs were more frequently observed in those with continued pharmacoresistance. ASM responders were more likely to have primary generalized epilepsy. Rational polytherapy (combining ASMs with different mechanisms of action) was almost ubiquitous amongst ASMs responders (95 % taking at least 2 drugs with different mechanistic targets). Of the ASM additions that heralded improved seizure control, 85 % were maintained at submaximal doses. Conclusions This retrospective analysis of a large number of ‘real-world’ patients provides evidence to persist with ASM trials in DRE. Early rotation of ASMs if a clinical response is not observed at a substantial dose and rational ASM polytherapy may yield better clinical outcomes in patients with DRE, although a prospective study would need to be conducted to validate these findings.

Neurological disorders are often accompanied by impairment of memory, attention deficit that cause learning difficulties. Better understanding of learning problems in neurological patients might help to improve the quality of their life. Here we studied the character of fear-based associative learning using the standard active avoidance test in WAG/Rij rats with genetic predisposition to absence epilepsy. Electroencephalographic properties of spike-wave seizures (i.e., hallmarks of absence epilepsy) were examined at the age of 5 and 7 m. Around 24 % of rats did not express epileptic activity despite genetic predisposition. In the active avoidance test, 6 m old rats with the epileptic phenotype needed more trails to obtain the first avoidance than non-epileptic rats, but showed the same number of avoidances to reach the learning criterion. The total time of spike-wave activity positively correlated with the outcomes of avoidance performance only in subjects with severe epilepsy, but not in subjects with mild epilepsy. In order to evaluate early sensory (epigenetic) factors governing cognitive comorbidities in adult WAG/Rij rats, we performed bilateral whisker trimming during PN1-8 and PN9-16. This led to a quicker development of SWD, but did not influence cognitive abilities at the age of 6 m. In summary, epileptic WAG/Rij rats had difficulties with executive functions before the first avoidance of adverse stimulus, rather than impairment of memory after the first avoidance. Our data assume that cognitive comorbidities in epileptic WAG/Rij rats primarily may relate to executive deficit during the initial stage of avoidance test and secondary - to impairment of short-term memory. This fits well to outcomes of clinical studies in patients with generalized epilepsy.

Background Stereotactic radiosurgery (SRS) offers a noninvasive technique for division of the corpus callosum, which can confer improved seizure control to patients suffering from frequent atonic seizures due to rapid interhemispheric generalization. This noninvasive approach is well-suited for use in a palliative intervention for improved seizure control in this patient population. To our knowledge, this is the first report of radiosurgical completion corpus callosotomy in an adult in the United States. Case Description A 20-year-old ambidextrous nonverbal man with a history of refractory generalized epilepsy status post open anterior corpus callosotomy at age 10 years, Lennox-Gastaut syndrome, and autism presented after 2 years of incremental, progressive deterioration in seizure control and behavior including 1 year. The family decided to pursue SRS corpus callosotomy. Under general anesthesia, a volume of interest encompassing a full midsagittal plane of the corpus callosum was defined to deliver 60 Gy to the 50% isodose line fully encompassing the target. Gamma Knife was used with 2 isocenters at 90° and 1 at 110° and isodose lines of 60, 20, and 12 Gy. Treatment was carried out without difficulty or complications while the patient remained under close monitoring. The patient was discharged the next day with a 2-week taper of dexamethasone. Conclusions Eight months postradiosurgical corpus callosotomy, the patient is free of atonic seizures and is ambulatory. In carefully selected cases and with protective radiosurgical planning, SRS for completion corpus callosotomy represents an effective option for refractory seizure control.

Background Generalized epilepsy and tremor phenotypes have been reported in some genetic disorders. Among them benign adult familial myoclonus epilepsy (BAFME) has been confirmed as a clearly defined clinical and genetic entity. On the other hand, non-progressive tremor and generalized epilepsy phenotypes have also been reported in patients with DHDDS variants. Case presentation. We report on a long term follow-up of patient with de novo missense variant of DHDDS, who revealed non progressive nature. This 18-year-old woman presented non-progressive tremor since her early infancy. She had rare seizures. Her tremor was considered as cortical myoclonic tremor with giant somatosensory evoked potentials. Conclusion In patients with early onset, non-progressive tremor and rare generalized epilepsy phenotypes, DHDDS variants may be considered in the genetic differential diagnosis.

We report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE).Twenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300μsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline.Median age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p 0.001), atypical absence seizures (p 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033).This prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.

Introduction Over the past 20 years, Vagus Nerve Stimulation (VNS) has become one of the tools for surgical treatment of patients with refractory cryptogenic epilepsy. The objective of this study was to determine the feasibility of implanting a Vagus Nerve Stimulation in ambulatory patients with chronic epilepsy. Patients and methods VNS procedure was consecutively performed in outpatient surgery between November 2016 and November 2018 in patients with refractory epilepsy. The main endpoints were complications, prolonged hospitalization and readmission during the first postoperative month. This information was collected by retrospective analysis of clinical files. Results Of the 22 patients included, the majority were autonomous (77%) with only 5 institutionalized patients. Retrospective analysis revealed a single complication of temporary dysphonia (4.5%) and an unplanned hospitalisation for immediate post-operative vomiting (4.5%). No readmissions were observed during the postoperative month but an emergency room visit for generalized seizure disorder was reported for one patient. Conclusion The outpatient implantation of VNS in patients with epilepsy is a valid strategy for 95% of patients.

Objective Numerous types of nonepileptic paroxysmal events, such as syncopes and psychogenic nonepileptic seizures, may imitate epileptic seizures and lead to diagnostic difficulty. Such misdiagnoses may lead to inappropriate treatment in patients that can considerably affect their lives. Electroencephalogram (EEG) is a commonly used tool in assisting diagnosis of epilepsy. Although the appearance of epileptiform discharges (EDs) in EEG recordings is specific for epilepsy diagnosis, only 25%–56% of patients with epilepsy show EDs in their first EEG examination. Methods In this study, we developed an autoregressive (AR) model prediction error–based EEG classification method to distinguish EEG signals between controls and patients with epilepsy without EDs. Twenty-three patients with generalized epilepsy without EDs in their EEG recordings and 23 age-matched controls were enrolled. Their EEG recordings were classified using AR model prediction error–based EEG features. Results Among different classification methods, XGBoost achieved the highest performance in terms of accuracy and true positive rate. The results showed that the accuracy, area under the curve, true positive rate, and true negative rate were 85.17%, 87.54%, 89.98%, and 81.81%, respectively. Conclusions Our proposed method can help neurologists in the early diagnosis of epilepsy in patients without EDs and might help in differentiating between nonepileptic paroxysmal events and epilepsy. Significance EEG AR model prediction errors could be used as an alternative diagnostic marker of epilepsy.

Epileptic seizure semiology adds important information to the formulation of the hypothesis of the epileptogenic zone. Seizure semiology in infants and children are simple and elementary, becoming more complex with maturation of brain. Also in this age group, seizure semiology may be generalized in a setting of a focal lesion or may show focal signs with misleading localization values. We review seizure semiology of patients aged one month to ten years with respect to lateralization and localization of the epileptogenic zone.

Background Vagal nerve stimulation (VNS) is an alternative palliative therapy for pharmacoresistant epilepsy. It has been reported to be effective for both focal and generalized epilepsy; however, most of the relevant studies have involved children or young patients. Some patients develop intractable epilepsy after stroke, despite taking antiepileptic drugs (AEDs). In this study, we investigated the efficacy of VNS for pharmacoresistant poststroke epilepsy (PPSE). Methods We retrospectively studied 10 patients who underwent vagal nerve stimulator implantation for poststroke epilepsy after the seizures had proved refractory to appropriate AEDs. The seizure outcome was evaluated using the McHugh classification 2 years after the implantation. Results In total, 4 patients (40%) remained seizure-free throughout the 2-year duration. In addition, seizures were reduced by >50% after 2 years in 6 patients (60%). McHugh classification was class I for 5 patients and class II for 5 patients. Neither intraoperative complications nor postoperative adverse effects were reported. The average intensity of VNS was 1.75 mA. Conclusions In this small study, VNS proved to be a safe and effective therapy for PPSE. Patients with poststroke epilepsy experience physical or mental decline; therefore, it is important to control seizures in them to avoid deterioration in their quality of daily life.

Highlights • Hamartoma of the hypothalamus may presents as central precocious puberty and gelastic epilepsy. • It may be asymptomatic for long period. • MRI is diagnostic in most of the cases., Background Hamartoma of the hypothalamus represents a well-known but rare cause of central precocious puberty and gelastic epilepsy. Due to the delicate site in which a tumor is located, surgery is often difficult and associated with considerable risks. Case presentation 10-Year old girl presented with early and regular menstruation at the age of 1 year each cycle lasted for 3 days. She had developed breast, axillary and pubic hair at the age of five, and seven years respectively, with history of difficulty in speech especially articulation and epilepsy since childhood for which she is on medications. She had attacks of an inappropriate laugh. The laboratory tests were consisted with central precocious puberty, MRI shows suprasellar mass. She received leuprolide and antiepileptic medicines until surgery planned. Surgery was done with complete resection, with histopathology showing hypothalamic hamartoma. After surgery, there was complete remission of seizure. She developed recurrence 4 years later and she is currently on anticonvulsant medications with few attacks of convulsions per week, and she has intellectual disabilities and low school performance. Conclusion The treatment of hypothalamic hamartoma associated with generalized epilepsy has been found to improve seizures and behavioral disturbances with an acceptable morbidity rate by using a variety of surgical approaches. Partial resection of a tumor may be sufficient to reduce seizure frequency and to improve behavior and quality of life with few side effects. Best outcomes are achieved when the patients are managed by an experienced multidisciplinary team and lifelong follow up is recommended.

Background: Pharmacotherapy of epilepsy including antiepileptic drugs (AEDs) is one of the main treatment approaches. As a biological target, sodium channels (Nav channels) and glutamate receptor genes are playing a major role in the etiology and treatment of epilepsy. Objective: This study aims to investigate the genetic associations of certain genetic polymorphisms with increased risk of epilepsy susceptibility and variability in response to AEDs treatment in a Jordanian Arab population. Method: A pharmacogenetics and case-control study on 296 unrelated epileptic Jordanian patients recruited from the pediatric neurology clinic at the Queen Rania Al-Abdullah Hospital (QRAH) in Amman, Jordan and 299 healthy individuals was conducted. Children up to 15 years old which receiving AEDs for at least three months were scanned for genetic association of 7 single nucleotide polymorphisms (SNPs) within three candidate genes (SCN2A, SCN3B and GRM4) with epilepsy susceptibility. Results: SCN2A rs2304016 (P = 0.04) and GRM4 rs2499697 (P = 0.031) were statistically significant with generalized epilepsy. Haplotype of CAACG GRM4 was genetically associated with epilepsy and partial epilepsy (P = 0.036; P = 0.024, respectively). This study also found that TGTAA genetic haplotype formed within GRM4 gene was associated with generalized epilepsy susceptibility (P = 0.006). While, no significant linkage of SCN3B rs3851100 to either disease susceptibility or drug responsiveness was found. Conclusion: This study identified no significant associations of allelic or genotypic SNPs with the susceptibility of epilepsy and medication response with an exception of rs2304016 and rs2499697 SNPs that were associated with the generalized type of epilepsy among Jordanian population. Further studies are required in different populations to confirm our results and identify genetic factors that involved in susceptibility and treatment response. Keywords: Epilepsy, Pharmacogenetics, Anticonvulsants, Sodium channels, Glutamate receptors, Jordan

The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the mu-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the mu-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2 mu conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.

Objective Adults with drug-resistant epilepsy (DRE) are among the most challenging to treat. This study assessed whether specific subpopulations of adult patients with refractory epilepsy responded differently to modified ketogenic diet (MKD) therapy. Methods Changes in seizure frequency, severity, and quality of life (QOL) were retrospectively analyzed based on pre-MKD surgical history, type of epilepsy, imaging findings, and vagal nerve stimulation (VNS) history among adults, ≥ 17 years of age, with DRE, receiving MKD therapy for three months. Additionally, particular attention was made to medication and VNS adjustments. Results Responder rates in seizure frequency, severity, and QOL reported among those with prior surgery were 56%, 75%, and 94%, respectively. Among those with focal epilepsy: 57%, 76%, and 76% had improvements in seizure frequency, seizure severity, and QOL, respectively whereas 83% improvement was seen for all three measures in those with generalized epilepsy. Among those with abnormal imaging: just over 50% reported improvements on all measures. For those with VNS, 53%, 63%, and 95% had improvements in seizure frequency, seizure severity, and QOL, respectively. No statistical differences in seizure frequency, severity, or QOL were noted between groups based on prediet surgical history, seizure type, imaging abnormalities, or VNS history. Compared with expected improvement from medication adjustment alone, significant improvement was seen for all groups; notably, the Z-test for proportions for the surgery group, when compared with placebo responder rates at 20%, was 3.6, p Conclusions Modified ketogenic diet therapies are effective in improving seizure frequency, severity, and QOL and may offer the best chance for improvement among those whose seizures have persisted despite surgical intervention and VNS therapy. All types of epilepsy respond to MKDs, and possibly those with generalized epilepsy may respond better.

Generalized spike-wave discharges (SWDs) are the hallmark of generalized epilepsy on the electroencephalogram (EEG). In clinically obvious cases, generalized SWDs produce myoclonic, atonic/tonic, or absence seizures with brief episodes of staring and behavioral unresponsiveness. However, some generalized SWDs have no obvious behavioral effects. A serious challenge arises when patients with no clinical seizures request driving privileges and licensure, yet their EEG shows generalized SWD. Specialized behavioral testing has demonstrated prolonged reaction times or missed responses during SWD, which may present a driving hazard even when patients or family members do not notice any deficits. On the other hand, some SWDs are truly asymptomatic in which case driving privileges should not be restricted. Clinicians often decide on driving privileges based on SWD duration or other EEG features. However, there are currently no empirically-validated guidelines for distinguishing generalized SWDs that are "safe" versus "unsafe" for driving. Here, we review the clinical presentation of generalized SWD and recent work investigating mechanisms of behavioral impairment during SWD with implications for driving safety. As a future approach, computational analysis of large sets of EEG data during simulated driving utilizing machine learning could lead to powerful methods to classify generalized SWD as safe vs. unsafe. This may ultimately provide more objective EEG criteria to guide decisions on driving safety in people with epilepsy.

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = − 2.12; T (50) = − 2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = − 2.12; T (50) = − 2.47, p = 0.04) and Fatigue (MD = − 3.42; T (50) = − 2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.

Objective: The aim of the study was to determine risk factors associated with pseudoresistance in a large, representative cohort of patients with Idiopathic/Genetic Generalized Epilepsy (IGE) and the impact of pseudoresistance on socioeconomic parameters. Methods: We performed a literature review on definitions of pseudoresistance in IGE. In an established cohort of patients with IGE from Funen, patients with current or previous pseudoresistant seizures were retrospectively identified based on a comprehensive evaluation of the patients’ medical records and direct patient contact, if required. In addition, clinical characteristics, socioeconomic, and demographic data were assessed. Personal interviews were used to determine the brief version of Barratts (BIS-8) impulsivity score. Results: The literature review provided the following definition of pseudoresistance: Seizures due to (I) lacking adherence to antiseizure medication (ASM), (II) incompliance to general rule of conduct, (III) psychogenic nonepileptic seizures (PNES), (IV) inadequate choice of ASM/dosage, and (V) incorrect classification of epilepsy. Applying criteria I-III to a cohort of patients with IGE (n = 499), 73 patients (14.6%) were currently pseudoresistant and 62 (12.4%) were previously pseudoresistant, but currently seizure free. Current pseudoresistance was associated with younger age, drug/alcohol abuse, lower rate of full-time employment, and higher BIS-8 scores. We found no associations of pseudoresistance with juvenile myoclonic epilepsy, psychiatric disease, specific seizure types, or number of seizure types. Patients with previously pseudoresistant seizures have tried more ASMs and were characterized by male preponderance, higher BIS-8, and higher rates of abuse. Surrogate markers for social outcome did not differ. Significance: In IGE, pseudoresistance may be defined as PNES or insufficient adherence to medication/conduct and is associated with younger age, drug/alcohol abuse, and higher scores for impulsivity. If transient, its impact on socioeconomic status remains limited but may be associated with a risk of overtreatment with ASM.

Background Jeavons syndrome is an underreported epileptic syndrome characterized by eyelid myoclonia, eyelid closure-induced seizures or electroencephalography paroxysms, and photosensitivity. Drug-resistant epilepsy is common, but the prognostic factors and clinical course leading to drug resistance have not been well characterized. Methods We identified 30 patients who met the diagnostic criteria of Jeavons syndrome at a single institution between January 1, 2000 and December 15, 2016. Criteria for Jeavons syndrome included all of the following: (1) eyelid myoclonia with or without absences, (2) eye–closure-induced seizures or electroencephalography paroxysms, and (3) seizure onset after 12 months of age. We reviewed and described the epilepsy history, antiepileptic drug trials, and response to treatments. Results Mean age at seizure onset was 7.3 years, and 80% were female. Absence seizures (63%) and generalized tonic-clonic seizures (23%) were most common at onset. Diagnosis was delayed by an average of 9.6 years. After a median follow-up of two years, 80% of patients had drug resistant epilepsy and 70% experienced generalized tonic-clonic seizures. Generalized tonic-clonic seizures and seizure types other than absence seizures increased the risk of drug-resistant epilepsy (P values 0.049 and 0.03, respectively). Valproic acid, lamotrigine, ethosuximide, and levetiracetam were the most effective in reducing seizures by more than 50%. Conclusions The diagnosis of Jeavons syndrome is often delayed. Generalized tonic-clonic seizures and seizure types other than absence seizures may be predictors of drug-resistant epilepsy among patients with Jeavons syndrome.

Perampanel (PER) is a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, licensed as adjunctive therapy in focal epilepsy and primary generalized tonic-clonic seizures (pGTCSs). We performed a retrospective study on highly refractory adult patients taking PER, with 1-year follow-up. Retention rate represented the primary outcome of our work; seizure frequency reduction (≥50%), “switch rate” and proportion of adverse events (AEs) were evaluated as secondary endpoints. Eighty-nine subjects (47 females, age range: 19–78 years) were included. Seventy-three had focal epilepsy (FE), 9 generalized epilepsy and 7 epileptic encephalopathy. All patients were highly drug-resistant (medication failures: 5–17). Retention rate was 87.6%, 63% and 51.7% at 3, 6 and 12 months. Responders were 27/89 (30.3%), with 8/27 seizure-free. The number of previous treatment failures and the concomitant use of enzyme inducers negatively influenced clinical response, whereas no correlation was documented between PER dose and outcome. Responder proportion was more satisfying in structural FE than in FE of unknown etiology (33% versus 20%), and in secondarily GTCSs than focal seizures (54% vs 28%), whereas pGTCSs showed a lower reponse rate (25%). Mild-to-moderate AEs (mainly dizziness, gait disturbances and psychiatric effects) were reported by 40% of patients; serious psychiatric AEs usually occurred in subjects with psychiatric comorbidities. Our study confirms the tolerability and effectiveness of PER in highly drug-resistant patients with different epilepsy syndromes and aetiologies.

Psychiatric disorders are more common in patients with epilepsy than in the general population. The aims of the study were to assess the frequency and type of psychotropic drug usage in patients with epilepsy, to assess the risk factors for their use, and to assess their proconvulsive potential and the risk of interactions with antiepileptic drugs. This 20-month prospective study included patients treated at the university hospital outpatient clinic. Psychotropic drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. Of the 621 patients (with a mean age of 35.4years), 60% were women, and 37.5% were in remission; 54.8% of the patients used antiepileptic drug monotherapy. The most commonly used antiepileptic drugs were valproate, levetiracetam, lamotrigine, and carbamazepine. Eighty-nine (14.3%) patients received psychiatric comedication. Sertraline, perazine, and hydroxyzine were the predominantly used psychotropic drugs. Independent variables associated with psychotropic drug usage in the logistic regression model included age, active epilepsy, combined focal and generalized epilepsy type, use of somatic comedication, and phenobarbital. Over one-third of the patients simultaneously received antiepileptic drugs and psychotropic drugs, between which clinically significant interactions may occur, 10% of patients used psychotropic drugs to lower the seizure threshold. The results of the study indicate the need for closer cooperation between doctors of various specialties when caring for patients with epilepsy.

Generalized epilepsy is accompanied by large-amplitude synchronized spike-wave discharges on electroencephalography. The condition rapidly and synchronously involves most regions of the brain, but the mechanism underlying this global involvement remains unclear. Here I attempt to clarify this phenomenon by hypothesizing a series resonance in an equivalent electric circuit for the white matter. This hypothesis is based on the ideas that the electric conduction along an axon is due to the displacement current, and the unit structure composed of a node of Ranvier and the next node can be regarded as a capacitor or an inductor, depending on the geometry and the substance around the nodes. The flash-visual evoked potentials at various flash repetition rates were measured in generalized epilepsy patients, and compared with those for healthy controls and focal epilepsy patients. The P100 amplitude plotted against the flash repetition rate had a maximum peak at a certain flash repetition rate only for each of the generalized epilepsy patients. The observation of a peak in the P100 amplitude was inferred to reflect the series resonance phenomenon in the white matter. I speculate that patients with generalized epilepsy have large regions of white matter with similar resonance frequencies. Keywords: Spike-wave seizure, Axon conduction, Displacement current, Equivalent circuit, Series resonance, Visual evoked potential

Epilepsy with myoclonic absences is a rare generalized epilepsy syndrome with distinctive seizures. Two unrelated children had mild developmental impairment and onset of myoclonic-absences at 3 and 8 years. Seizures were characterized by bilateral 3 Hz myoclonic jerks superimposed on tonic abduction of the upper limbs. Events lasted 10-60 s, and complex gestural automatisms were often observed; in one case, a boy undid his seatbelt and attempted to exit a moving vehicle. Post-ictally, both children immediately regained awareness without recollection of their actions. Ictal EEGs showed 3 Hz generalized spike-wave. Complex automatisms have not been described in myoclonic absence seizures. This generalized seizure type can be confused with focal seizures when these ictal behaviours occur.

Angelman syndrome (AS) is a neurogenetic imprinting disorder caused by loss of the maternally inherited Ube3a gene and is characterized by generalized epilepsy, limited expressive speech, sleep dysfunction, and movement disorders. Myoclonic seizures are often the first seizure type to appear, and myoclonic status, associated with developmental regression, may occur in the first few years of life. Additionally, there have been rare reports of prolonged episodes of myoclonus without electrographic correlate in adults with AS. The medical records of 200 individuals seen in the Angelman Syndrome Clinic at the Massachusetts General Hospital and the Lurie Center for Autism were retrospectively reviewed to identify and characterize myoclonic seizures and episodes of nonepileptic myoclonus. Myoclonic seizures were reported in 14% of individuals with age of onset occurring before 8years. These are brief events, unless the individual was experiencing myoclonic status, and electroencephalographs show interictal generalized spike and wave activity. Nonepileptic myoclonus occurred in 40% of individuals over 10years of age, and prevalence appears to increase with age. The episodes of nonepileptic myoclonus arise during puberty or later, with age of onset ranging from 10 to 26years. These events were captured on 5 video electroencephalographs and had no electrographic correlate. They can last from seconds to hours, always occurring in the hands and spreading to the face and all extremities in some individuals. Episodes of nonepileptic myoclonus have a discrete beginning and end, lacks a postictal period, and are not associated with significant alteration of consciousness or developmental regression. These episodes can be difficult to treat and are often refractory to medication; however, levetiracetam, clobazam, and clonazepam appear to be effective for some individuals. Myoclonic seizures are common in AS, typically occurring in young children and associated with epileptiform changes on electroencephalographs. Prolonged episodes are associated with developmental regression. In contrast, nonepileptic myoclonus typically begins in adolescence or early adulthood and has no electroencephalogram (EEG) correlate, alteration in consciousness, or regression but can significantly impact quality of life.

We report a novel variant of DHDDS mutation in a patient with progressive adult-onset myoclonus ataxia. The mutation in our patient was different from previous reports of denovo mutations in DHDDS in 6 patients who showed tremor-like myoclonus and generalized epilepsy.

Purpose To characterize epilepsy in an elderly population and describe the prevalence of drug resistant epilepsy (DRE) using recently validated International League Against Epilepsy (ILAE) criteria. Methods Using a case-control design, 72 patients aged 60 years and older (cases) and 223 patients under age 60 (controls) were identified from the Saskatchewan Epilepsy Program database. Patients’ charts were retrospectively reviewed. Bivariate and multiple logistic regression analyses were performed to identify variables that were associated with epilepsy in elderly patients. Results Forty-seven elderly patients (65%) had focal epilepsy, while 9 (13%) had generalized epilepsy. The most common etiology in elderly patients with epilepsy was unknown in 30 (48%) patients. Other identified etiologies included brain tumors in 14 (19.4%), genetic in 6 (8%), degenerative disease in 4 (5%), stroke in 6 (8%) and head injury in 3 (4%). Significantly fewer elderly patients met criteria for DRE compared to non-elderly patients (26% vs. 51%, p = 0.001). In the multiple logistic regression analysis, elderly patients with epilepsy were more likely to have the presence of stroke, psychiatric comorbidity and to be on monotherapy. Conclusion In our sample, elderly patients with epilepsy were more likely to have seizures resulting from brain tumors and stroke, and less likely to have DRE than non-elderly patients. These unique features of elderly patients strongly suggest that clinical practice guidelines are needed to facilitate the highest quality of care in elderly patients with epilepsy.

To examine factors contributing to failure to achieve full seizure control during pregnancy in women with anti-seizure medication (ASM) treated generalized epilepsy compared with focal epilepsy.Full seizure control was not attained in 51.4% of 1223 pregnancies of women with focal epilepsies in the Australian Pregnancy Register, and in 38.7% of 1026 pregnancies in women with generalized epilepsy (P 0.05). For convulsive seizures only, the corresponding figures of 20.8% and 22.9% were reasonably similar. Where seizures had occurred in the pre-pregnancy year, 82.5% of the focal epilepsy pregnancies were seizure affected, and 70.1% of the generalized epilepsy ones (P 0.05). Where the pre-pregnancy year was seizure free, the corresponding figures were 22.6% and 16.4% (P 0.05), a roughly four-fold lower rate. Maternal age, epilepsy onset age, and epilepsy duration also differed between the focal and generalized epilepsy pregnancies. Multivariate regression analysis showed that generalized epilepsy and younger maternal age were associated with statistically significant decreased risks of seizure-affected pregnancy, and having seizure-affected pre-pregnancy years with an increased risk. However, for convulsive seizures only, the risk of seizure-affected pregnancy appeared increased in generalized epilepsy.The risk of seizure-affected pregnancy appears lower in women with generalized epilepsy, independently of pre-pregnancy seizure control, itself a major determinant of the risk. The risk of having only convulsive seizures in pregnancy was not lower in generalized epilepsy than in focal epilepsy. ASM therapy seemed less effective in controlling focal than generalized epileptic seizures during pregnancy.

BACKGROUND Depression, being the most frequent psychiatric comorbidity, has always been closely linked with epilepsy. However, there is a lack of screening for depressive symptoms resulting in failure to detect depression among people with epilepsy (PWE). While many studies have described the risks associated with depression in epilepsy, very few have elaborated whether these risks are similar for undiagnosed depression, especially in a multiethnic community. METHODS We aim to investigate the prevalence and associated risk factors of undiagnosed depression in PWE through a cross-sectional study at a tertiary teaching hospital. Epilepsy patients aged between 18 and 65 years old were recruited after excluding those with background illnesses, which may contribute to depressive symptoms. A total of 129 participants were recruited. We collated their demographic and clinical details before interviewing them using two questionnaires; the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and Beck’s Depression Inventory-II (BDI-II). Subsequently, if a participant is screened positive for depression, the diagnosis is confirmed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) questionnaire and a psychiatric clinic referral is offered. RESULTS Among the 129 participants, 9.3% had undiagnosed major depressive disorder (MDD), which had a female preponderance (66.7%). Risk factors of undiagnosed depression among PWE include low socioeconomic backgrounds (p = 0.026), generalized epilepsy (p = 0.036) and temporal lobe epilepsy (p = 0.010). Otherwise, while some variables such as being underweight and unmarried may be seen in a higher proportion in those who were depressed; we did not find a statistically significant relationship among them. CONCLUSION The prevalence of undiagnosed depression among PWE is higher when compared to population-based studies carried out in Western countries. While questionnaires to screen for depression are widely available, their infrequent use would lead to failure in identifying patients who may benefit from psychosocial support and treatment, which would subsequently improve their disease outcomes and quality of life. This study recommends the use of screening questionnaires to identify undiagnosed depression in PWE.

INTRODUCTION Epilepsy affects almost 1% of people and is characterized by sudden seizures. To date, no reliable biomarker has been found to diagnose or predict the outcomes of epilepsy. Brain-derived neurotrophic factor (BDNF) levels have recently been shown to differ between patients with certain neurologic disorders and normal population, and it is unknown whether this is the case for epilepsy. In this study, we mainly aim to answer this question. METHODS We searched three databases for studies comparing BDNF levels between patients with epilepsy and controls. Quality assessment of included studies was performed using the Newcastle-Ottawa scale and statistical analyses were carried out in STATA software version 16. RESULTS Final analyses included 10 studies involving 403 patients with epilepsy. BDNF levels were statistically similar between patients and controls (standardized mean difference (SMD) = - 0.30, 95% CI = - 1.32 to 0.71, p = 0.56). When categorized by epilepsy subtype, patients with partial epilepsy showed lower BDNF measures than controls (95% CI = - 1.42 to - 0.32, p

Objective Inflammation and oxidative stress plays an important role in the etiology of epilepsy. Interleukin-33 (IL-33), a new member of the cytokine family associated with interleukin-1 (IL-1), has been found to play a role in pathogenesis of central nervous system diseases and cause the production of proinflammatory cytokines and oxidative stress molecules. Our aim was to investigate IL-33 and oxidative stress values (total antioxidant capacity (TAS), total oxidant capacity (TOS), and oxidative stress index (OSI)) in patients with epilepsy and to evaluate their relationship with each other. Methods The study included 60 patients with epilepsy and 35 healthy controls. The group of patients with epilepsy consisted of 21 patients with treatment-resistant epilepsy and 39 patients with well-controlled epilepsy. The patients with epilepsy were also classified as monotherapy and polytherapy group according to the number of antiepileptic drugs they used, and focal and generalized epilepsy group according to the seizure type. Serum IL-33, TAS, TOS and OSI levels were measured in the patients with epilepsy and the control group. Results The mean serum TAS level was significantly lower in the all patients with epilepsy group compared to the control group, and the mean serum IL-33, TOS, and OSI levels were significantly higher. The mean serum TOS and OSI levels were significantly lower and TAS levels were significantly higher in the patients with well-controlled epilepsy than the patients with treatment-resistant epilepsy. While there was a positive correlation between serum IL-33 and OSI levels in the all patients with epilepsy group, a negative correlation was shown between IL-33 and TAS levels. Conclusion The IL-33/ST2 pathway may represent a new promising therapeutic strategy both for the treatment and the prevention of the disease.

As awareness of pediatric epilepsy increases, accompanied by advancements in technology and research, it is important to identify certain types of patients that are overlooked for surgical management of epilepsy. Identifying these populations will allow us to study and elucidate the factors contributing to the underutilization and/or delayed application of surgical interventions. Demographically, African-American and Hispanic patients, as well as patients of certain Asian ethnicities, have relatively lower rates of undergoing epilepsy surgery than non-Hispanic and white patients. Among patients with epilepsy, those with higher odds of seizure-freedom following surgery are more likely to be referred for surgical evaluation by their neurologists, with the most common diagnosis being lesional focal epilepsy. However, patients with multifocal or generalized epilepsy, genetic etiologies, or normal (non-lesional) brain magnetic resonance imaging (MRI) are less likely be to referred for evaluation for resective surgery. With an increasing number of high-quality imaging modalities to help localize the epileptogenic zone as well as new techniques for both curative and palliative epilepsy surgery, there are very few populations of patients and/or types of epilepsy that should be precluded from evaluation to determine the suitability of epilepsy surgery. Ultimately, a clearer understanding of the populations who are underrepresented among those considered for epilepsy surgery, coupled with further study of the underlying reasons for this trend, will lead to less disparity in access to this critical treatment among patients with epilepsy.

Investigations such as EEG and brain imaging are often difficult to obtain in primary care settings of resource-limited regions impacting millions of epilepsy patients. We wanted to test the hypothesis that classification of chronic epilepsy into focal and generalized based on clinical history and examination alone would be comparable to making such a classification with additional inputs from EEG and brain imaging.Two investigators independently classified consecutive chronic epilepsy patients into focal, generalized and unclassified epilepsy. Investigator 1 made this determination using clinical history and examination alone whereas Investigator II additionally used EEG and brain imaging too. We calculated inter observer agreement between the two investigators and also looked at the predictors of focal and generalized epilepsy.Five hundred and twelve patients were recruited. Inter observer agreement between the two investigators in making the focal versus generalized classification was 96.8%, kappa 0.91 (p0.0001). When EEG and neuroimaging findings were added to clinical information, there was a change in classification in 3.2% patients. Several predictors of focal and generalized epilepsy were identified.Classification of chronic epilepsy into focal and generalized can be done reliably in most patients using clinical information alone. Investigating chronic epilepsy patients with EEG and brain imaging may not be necessary in every patient. The results of our study are especially significant for epilepsy patients living in resource-limited regions where such investigations may not always be available.

Apathy as a state of decreased motivation has not been highlighted in people with epilepsy (PWE). We investigated its clinical significance in PWE.We invited adult PWE who had been administered antiepileptic drugs (AEDs) for at least 1year and compared them with age- and gender-matched healthy controls. Eligible participants completed several questionnaires including the Apathy Evaluation Scale-Self (AES-S), the Korean version of the Neurological Disorders Depression Inventory for Epilepsy (K-NDDI-E), the Generalized Anxiety Disorder-7 (GAD-7), the Epworth Sleepiness Scale (ESS), and the Insomnia Severity Index (ISI), and the Quality of Life in Epilepsy-10 (QOLIE-10). We investigated the degree of interictal apathy in PWE compared with controls and identified its predictors. We also measured the impact of apathy on patients' QOL.The mean overall AES-S score in PWE was similar to that of controls. However, the score was significantly higher in patients with uncontrolled epilepsy than controls (p0.01). Among subscale scores of the AES-S, the mean behavioral score was significantly higher in PWE than controls (p0.01). Education level, employment, household income, disease duration, AED-related factors, seizure control, and scores of the K-NDDI-E, GAD-7, ESS, and ISI were associated with the overall AES-S score by univariate analyses. However, major predictors were the K-NDDI-E (β=0.476, p0.001) and duration of AED intake (β=0.151, p0.01). The degree of apathy was significantly higher in patients receiving AEDs for 20 years or more than those receiving AEDs for 1-9 years (p0.01). The overall AES-S score was inversely correlated with the overall QOLIE-10 score (p0.001).Duration of AED intake in PWE seems to be a critical factor for apathy regardless of comorbid depression.

Objectives To describe the characteristics of epilepsy in patients with Neurofibromatosis type 1 (NF1). Methods Analysis of a cohort of consecutive NF1 patients seen in our NF1 clinic during a three-year period. Results Of the 184 NF1 patients seen during that period, 26 had epilepsy and three had febrile seizures. Of the 26, 17 (65%) had localization-related epilepsy, seven of whom (41%) were drug resistant. Six (23%) had apparently primary generalized epilepsy (0/6 drug resistant), two (8%) Lennox-Gastaut syndrome, and one (4%) West syndrome (all three were drug-resistant). As compared to the patients with no epilepsy, those with epilepsy were more likely to have MRI findings of mesial temporal sclerosis (MTS) (23% vs. 5%, p = 0.0064), and cerebral hemisphere tumors (31% vs. 10%, p = 0.0079), but not of the other MRI findings including neurofibromatosis bright objects, or optic gliomas. Three of the six patients with MTS underwent temporal lobectomy with subsequent control of their seizures with confirmation of MTS on pathology in 3/3 and presence of coexisting focal cortical dysplasia (FCD) in 2/3. We also have observed three additional patients outside the above study with the association of NF1, MTS, and intractable epilepsy. Significance Epilepsy is relatively common in NF1, often occurs in patients with brain tumors or with MTS which can coexist with FCD, can be associated with multiple types of epilepsy syndromes, and when localization-related is often drug-resistant. Patients with NF1 and MTS can respond to medial temporal lobectomy and may have coexisting medial temporal lobe cortical dysplasia.

Brain glucose transport is dependent on glucose transporter 1 (GLUT1), encoded by the solute carrier family 2 member 1 (SLC2A1) gene. Mutations in SLC2A1 cause GLUT1 deficiency which is characterized by a broad spectrum of neurological phenotypes including generalized epilepsy, motor disorders, developmental delay and microcephaly. Recent case reports suggest SLC2A1 mutations can contribute to non-acquired focal epilepsy (NAFE) but interrogation of a large patient cohort has not been reported. We studied 200 patients with NAFE (126 with temporal lobe epilepsy) comprising 104 females and 96 males with a mean age of onset of 18 years. Polymerase chain reaction (PCR) and Sanger sequencing was performed to detect variants in all 10 coding exons and splice site regions of the SLC2A1 gene. We did not detect any pathogenic mutations in SLC2A1 in this cohort. Our data suggests that the frequency of GLUT1 mutations in NAFE is low. Limitations of this study include the mean age of onset and cohort size. Future research should focus on subpopulations of focal epilepsy with lower age of seizure onset particularly with co-existent movement disorders in which GLUT1 mutations may play a more important role.

Epilepsy is an increasingly recognized comorbidity in Alzheimer's disease (AD). First described as generalized in dementia patients, epileptic AD patients are nowadays fully described in earlier stages of the disease (with mild or subjective cognitive impairment). At such early stages, patients may present not only with generalized seizures, but also with focal seizures (commonly localized in the frontal or temporal lobe). Thus, partial or generalized epilepsy is part of the semiological spectrum of AD that should be borne in mind at all stages of disease to ensure early identification and prevent the risk of repeated seizures (such as accidents, injury, progression of cognitive impairment). This review of the available (and still growing) literature shows that there are already sufficient data to inform physicians on seizure semiology, and on the diagnostic value of electroencephalography and brain imaging. Taken together, these tools can help to rapidly identify epilepsy in AD patients. Nevertheless, epilepsy diagnosis can be challenging, and test medication is sometimes necessary. Some cerebrospinal fluid biomarkers (or their ratios) may also prove to be good predictors of seizures in AD, but further studies are needed. Epilepsy in AD patients is frequently pharmacosensitive, and a good response can be obtained with standard doses of antiepileptic drugs. For all these reasons and based on our review of the literature, it appears that, at present, the diagnosis of epilepsy in AD is not only possible at any stage of the disease, but also to be recommended to improve the patient's prognosis.

Levetiracetam (LEV) is commonly used as a mono- or adjunctive therapy for treating patients with partial and generalized epilepsy. This study aimed to develop a population pharmacokinetic (PK) model of LEV, based on sparse data, and to explore LEV efficacy relative to its PK properties in patients with epilepsy. We included 483 LEV concentrations from 425 patients with epilepsy that received multiple oral LEV doses. We performed a population PK analysis, implemented in NONMEM (version 7.2). In addition, we explored the relationships between seizure control and PK variables (i.e., LEV dose, trough concentration, and the number of concomitant anti-epileptic drugs). LEV concentration-time profiles were adequately described with a one-compartment, open linear model, with first-order absorption, and additive residual error. The typical population estimates of the apparent clearance (CL/F) and the volume of distribution (V/F) were 3.9L/h and 65.3L, respectively. Body weight was a significant covariate for CL/F and V/F; the estimated glomerular filtration rate only significantly affected CL/F; and concomitant intake of other anti-epileptic drugs did not significantly affect either parameter. A cumulative percentage analysis revealed that over 95% of patients that remained seizure-free received LEV doses of 2000mg/day or lower. LEV trough concentrations were not significantly different between seizure-free and seizure groups, for each LEV dose. In conclusion, we successfully developed a population PK model of LEV, which enabled investigation of LEV efficacy, relative to its PK properties. The findings in this study can be utilized to optimize LEV dosing regimens in clinical practice.

Background Focal epilepsies (FEs) arise from a lateralized network, while in generalized epilepsies (GEs) there is a bilateral involvement from the outset. Intuitively, the corpus callosum is the anatomical substrate for interhemispheric spread. Objective We used transcranial magnetic stimulation (TMS) to explore whether there are any physiological differences in the corpus callosum of drug-treated patients with FE and those with genetic GE (GGE), compared to healthy subjects (HS). Methods TMS was used to measure the interhemispheric inhibition (IHI) from right-to-left primary motor cortex (M1) and viceversa in 16 patients with FE, 17 patients with GGE and 17 HS. A conditioning stimulus (CS) was given to one M1 10 and 50 ms before a test stimulus delivered to the contralateral M1. Motor evoked potentials (MEPs) were analysed both as a function of the side of stimulation and of the epileptic focus (left-right). Results In HS, IHI was reproducible with suppression of MEPs at ISIs of 10 and 50 ms. Similar effects occurred in GGE patients. FE patients behaved differently, since IHI was significantly reduced bilaterally. When FE patients were stratified according to the side of their epileptic focus, the long-ISI IHI (=50 ms) appeared to be defective only when the CS was applied over the “focal” hemisphere. Conclusions FE patients had a defective inhibitory response of contralateral M1 to inputs travelling from the “focal” hemisphere that was residual to the drug action. Whilst IHI changes would not be crucial for the GGE pathophysiology, they may represent one key factor for the contralateral spread of focal discharges, and seizure generalization.

To compare the clinical, psychiatric, and cognitive characteristics of older with younger patients presenting to a video-EEG monitoring (VEM) unit.This was a retrospective case-control study involving patients admitted for VEM over a two-year period (from April 2018 to April 2020) at two comprehensive epilepsy units. Patients were categorized into an older (≥60 years) and a younger (60 years) group. Younger patients were individually matched to older adults to form a matched younger group. Diagnosis was determined by a consensus opinion of epileptologists, neurologists, and neuropsychiatrists. The main diagnostic categories were epilepsy, psychogenic nonepileptic seizures (PNES), and 'other' diagnosis (non-diagnostic and other nonepileptic diagnoses). Clinical psychiatric diagnoses were obtained from neuropsychiatric reports. Objective cognitive function was measured with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG). Subjective cognitive function was assessed using the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) cognitive subscales.Five-hundred and thirty three patients (71 older, 462 younger) aged 16-91 years were admitted to the VEM unit during the study period. There was a diagnosis of focal epilepsy in 55% of the older group and 48% of the younger group, generalized epilepsy in 3% of the older group and 10% of the younger group, and 'other' in 32% of the older group and 19% of the younger group. Ten percent (2 males and 5 females) of the older group were diagnosed with PNES compared to 22% of the younger group (p = 0.016). A depressive disorder was diagnosed in 34% of the older group and 24% of the younger group (p = 0.20). An anxiety disorder was diagnosed in 15% of the older group and 25% of the younger group (p = 0.15). Mild neurocognitive disorder was more common in the older group (34%) compared to the matched younger group (34% vs 3%, p 0.001). The older group had lower mean NUCOG scores compared to the matched younger group (79.49 vs 87.73, p = 0.001). There was no evidence for a relationship between mean NUCOG score and overall subjective cognitive difficulties for the older group (r = 0.03, p = 0.83). Among older adults, those diagnosed with PNES had more experiences of childhood trauma. Measures of dissociation, depression, or general anxiety did not differ between PNES and non-PNES diagnoses in the older group.Psychiatric comorbidities are common among older adults admitted for VEM. The psychological impact of epilepsy and risk factors for PNES seen in younger patients are also applicable in the older group. The older group demonstrated more cognitive impairments than the younger group, although these were usually unrecognized by individuals. Older adults admitted to VEM will benefit from psychiatric and neuropsychological input to ensure a comprehensive care approach to evaluation and management.

Purpose To explore the efficacy and tolerability of adjuvant perampanel (PER) and their associated risk factors in late add-on drug-resistant epilepsy. Method Retrospective multicenter ‘real-world’ observational study. Consecutively identified patients commenced on PER, with mixed epilepsy syndromes, from nine Australian epilepsy centers. Primary efficacy endpoints were at least 50% reduction in seizure frequency (responders), seizure freedom, and retention at 6 and 12 months, following a 3-month titration period. Tolerability endpoints were cessation of PER for any reason, cessation of PER due to treatment-emergent adverse events (TEAE), or cessation due to inefficacy. Outcomes were assessed for a-priori risk factors associated with efficacy and tolerability. Results Three-hundred and eighty seven adults were identified and followed up for a median of 12.1 months (IQR 7.0–25.2). Focal epilepsy accounted for 79.6% (FE), idiopathic generalized epilepsy (IGE), 10.3% and developmental epileptic encephalopathy (DEE) 10.1%, of the cohort. All patients had drug-resistant epilepsy, 71.6% had never experienced six months of seizure freedom, and the mean number of antiepileptic medications (AEDs) prior to starting PER was six. At 12 months, with missing cases classified as treatment failure, retention was 40.0%, responder 21.7%, and seizure freedom 9.0%, whereas, using last outcome carried forward (LOCF), responder and seizure freedom rates were 41.3% and 14.7%, respectively. Older age of epilepsy onset was associated with a marginal increase in the likelihood of seizure freedom at 12-month maintenance (OR 1.04, 95% CI 1.02, 1.06). Male sex (adjusted OR [aOR] 2.06 95% CI 1.33, 3.19), lower number of prior AEDs (aOR 0.84, 95% CI 0.74, 0.96) and no previous seizure-free period of at least 6-month duration (aOR 2.04 95% CI 1.21, 3.47) were associated with retention. Perampanel combined with a GABA receptor AED was associated with a lower responder rate at 12 months but reduced cessation of PER. The most common TEAEs were neuropsychiatric (18.86%), followed by dizziness (13.70%), and sleepiness (5.68%). Conclusions Adjuvant PER treatment, even in late-add on drug-resistant epilepsy is an effective and well-tolerated treatment for drug-resistant epilepsy.

Objective This study aimed to investigate the factors influencing the level of social anxiety in patients with epilepsy (PWE) in Northeast China. We also identified the effect of social anxiety on the quality of life in these patients. Methods A consecutive cohort of 148 adult PWE from The First Hospital of Jilin University were recruited. In this sample, 116 patients had focal epilepsy, 20 had generalized epilepsy, and 12 had unclassified epilepsy. Depressive symptoms, social anxiety, and quality of life were evaluated using the Chinese version of the Patient Health Questionnaire 9 (PHQ-9), 20-item Social Phobia Scale (SPS), 20-item Social Interaction Anxiety Scale (SIAS), and Quality-of-Life Inventory in Epilepsy-31 (QOLIE-31), respectively. Multivariate linear regression analyses were employed to identify independent factors influencing SPS scores and SIAS scores. Results Correlation analysis suggested that sex, age at onset, seizure frequency over the last year, AED treatment model, >50% nocturnal seizures, PHQ-9 score, and QOLIE-31 score had a significant correlation with the SPS score. The age at onset, seizure frequency over the last year, AED treatment model, PHQ-9 score, and QOLIE-31 score correlated with the SIAS score. Multiple linear regression analysis showed that the total QOLIE-31 score (β = − 0.481; p = 0.001) was inversely associated with the SPS score in PWE. Additionally, earlier age of onset (β = −0.156; p = 0.022) and low total QOLIE-31 score (β = −0.457; p = 0.001) were risk factors for high SIAS scores. Conclusion We found that social anxiety was independently associated with poor quality of life. Earlier age of onset was also a risk factor for social anxiety. Future studies with large sample sizes are required to confirm our findings.

Introduction The differentiation between focal and generalized epilepsies based on clinical and electroencephalographic features is difficult and sometimes confusing. Objective To review the EEG findings in patients with focal epilepsy. Methods An extensive literature review was done. We used the following Pubmed and Medline descriptors alone and in different combinations for database searching: focal, partial, epilepsy, electroencephalographic findings, and EEG. Additional filters included review, original articles, and language limited to Spanish and English. Using the above criteria, a total of 69 articles showed the interictal and ictal EEG findings in focal epilepsy. Development Focal epileptiform discharges and persistence of focal abnormalities, characterize the interictal EEG findings in focal epilepsies. To distinguish SBS from primary generalized spike waves are required to note: (a) a lead-in time of at least 2 s, (b) the morphology of the focal triggering spikes clearly differ from that of the bisynchronous epileptiform paroxysms, and (c) the morphology of triggering spikes resemble that of other focal spikes from the same region. Focal and Generalized Epilepsy can coexist. Delayed Lateralization on EEG with inconclusive onset and bizarre semiology confusing semiology should not be confused with generalized onset seizures with focal evolution. Conclusions A close attention to localization and morphology of epileptiform discharges, the correct interpretation of secondary bilateral synchrony, and provocative maneuvers help to correctly identify the EEG findings leading to diagnose focal epilepsies. The presence of generalized epileptiform activity does not rule out the existence of a focal epilepsy.

Idiopathic generalized epilepsy (IGE) is an epileptic condition with good response to antiepileptic drugs (AED). Major syndromes are epilepsy with generalized tonic-clonic seizures (GTCS) alone, absence epilepsy and juvenile myoclonic epilepsy. However, clinical practice shows drug-resistant patients. Endpoint is to identify clinical features related with refractoriness in IGE and in its each individual syndrome.We retrospectively collected 279 consecutive patients with IGE assessed in the Epilepsy Clinic of our institution. We defined drug-resistant epilepsy as a failure of adequate trials of 2 tolerated and appropriately chosen and used AED schedules. We classified patients in two groups: drug-resistant and drug-responsive. Clinical features were compared among these groups, in the whole IGE group as well as in each syndrome.There were 122 drug-resistant, 105 drug- responsive; 52 were undefined and excluded from the analysis. After multivariate analysis, early seizures onset (age13), long-time epilepsy, several generalized seizure types, status epilepticus, EEG with generalized epileptiform activity, mainly polyspikes, and side effects with AED brought up as poor outcome factors. Additionally, 50.6% identified modifiable seizure triggers. Regarding syndromes, epilepsy with generalized tonic-clonic seizures alone had the same factors except several seizure types; presence of additional GTCS, polyspikes, history of AED side effects and psychiatric disorder were poor factors for absence epilepsy; only psychiatric comorbidity revealed significance in juvenile myoclonic epilepsy.Refractoriness in IGE and its major syndromes is associated with clinical and electrographic parameters. Moreover, lifestyle advices from neurologists to the patients might help them to achieve a better seizure control.

Ethnic variation in epilepsy classification was reported in the Epilepsy Phenome/Genome Project. This study aimed to determine the ethnic variation in the prevalence of genetic (idiopathic) generalized epilepsy (GGE) and GGE with family history in a multi-ethnic Asian population in Malaysia.In this cross-sectional study, 392 patients with a clinical diagnosis of GGE were recruited in the neurology outpatient clinic, University of Malaya Medical Centre (UMMC), from January 2011 till April 2016.In our epilepsy cohort (n=2100), 18.7% were diagnosed to have GGE. Of those, 28.6%(N=112) had family history of epilepsy with a mean age of seizure onset of 16.5 years old, and 42.0% had myoclonic seizures (N=47). The lifetime prevalence of epilepsy among first-degree relative of those with GGE and positive family history was 15.0%. Analysis according to ethnicity showed that Malaysian Chinese had the lowest percentage of GGE among those with epilepsy (12.3%), as compared with Indian and Malay (25.3% and 21.3%, p0.001). In addition, 32.1% of these Indian patients with GGE had positive family history, which is more than the Malay (26.4%) and Chinese (27.5%) ethnic groups. Consanguineous marriage was noted in 5 Indian families with positive family history (9.6%).There was ethnic variation in the prevalence of GGE, whereby the Malaysian Chinese had the lowest percentage of GGE as compared with Indian and Malay. A substantial proportion of GGE had positive family history among the three ethnics groups.

Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore, we tested the hypothesis that pre-treatment with FDA-approved antiepileptic drugs could prevent seizure onset in hyperoxia at 5 atmospheres absolute. We selected drugs from two putative functional categories, Na+-channel antagonists and GABA enhancers, each administered intraperitoneally at four doses in separate groups of C57BL/6 mice. The drugs varied in efficacy at the doses used. Of the five tested Na+-channel antagonists, carbamazepine and lamotrigine more than tripled seizure latency compared to values seen in vehicle controls. Primidone, zonisamide and oxcarbazepine were less effective. Of the four GABA reuptake inhibitors, tiagabine and vigabatrin also increased seizure latency by more than three times control values; valproic acid was less effective, and the GABA synthesis promoter gabapentin was intermediate in effectiveness. We infer that Na+-channel function and GABA neurotransmission may be critical targets in the pathophysiology of CNS O2 toxicity. Because these essential components of neuronal excitation and inhibition are also implicated in the pathogenesis of other seizure disorders, including generalized epilepsy, we propose that, at some level, common pathways are involved in these pathologies, although the initiating insults differ. Furthermore, hyperoxic exposures are not known to cause the spontaneously-recurring seizures that characterize true clinical epilepsy. Nonetheless, experimental studies of hyperbaric oxygen toxicity could provide new insights into molecular mechanisms of seizure disorders of various etiologies. In addition, the neuropathology of hyperbaric oxygen is particularly relevant to the hypothesis held by some investigators that oxidative stress is an etiological factor in clinical epilepsies.