BACKGROUND & AIMS: :We hypothesized that neonatal seizures lead to increased Ca(2+) influx (nCa(2+)I) in neuronal nuclei of newborn rats and that such increase is nitric-oxide mediated. Neuronal nuclear (45)Ca(2+) influx (nCa(2+)I) was measured in neuronal nuclei of 25 10-day-old male rat-pups newborn brains. They were divided into five groups (n = 5/group). (I) control; (II) hypoxia without seizures; (III) hypoxia with seizures; (IV) kainate, 2 mg/kg intraperitoneal (i.p.)-induced seizures and (V) 7-nitroindazole (7-NINA), 1 mg/kg i.p. pretreated, kainate-induced seizures. nCa(2+)I was significantly (P < 0.05) increased following hypoxia or seizures (hypoxic- or kainate-induced). Post-hypoxic seizures further enhanced nCa(2+)I increase induced by hypoxia (P < 0.05). 7-NINA abated the nCa(2+)I increase induced by kainate. We conclude that (1) kainate or hypoxia-induced seizures in newborn rats modify the neuronal nuclear membrane function, resulting in increased nCa(2+)I, (2) seizures exacerbate the hypoxia-induced increased nCa(2+)I incurred after hypoxia and (3) intranuclear calcium surges during kainate-induced neonatal seizures are nitric oxide-mediated.

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BACKGROUND & AIMS: OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.

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BACKGROUND & AIMS: INTRODUCTION:The present study examined seizure clusters as a primary outcome in patients receiving treatment for PNES. Cluster reduction is examined longitudinally using frequency threshold and statistical definitions of seizure cluster for patients. Possible risk factors for clustering will be examined along with clustering as a risk factor for poorer secondary outcomes. METHODS:Participants were from a pilot randomized treatment trial for PNES where they received cognitive behavioral therapy-informed psychotherapy (CBT-ip), sertraline, combination therapy, or treatment as usual. Seizure data are from patients' seizure dairies. RESULTS:Cluster reduction was observed for those receiving CBT-ip or combination treatment using all definitions of daily clusters and weekly clusters. No risk factors of clustering were observed. Those who were identified as having clusters during the trial had poorer secondary outcomes on several measures at baseline relative to those who were not identified as having clusters. DISCUSSION:This is the first study known to the authors to not only examined seizure clusters as a primary outcome for those with PNES, but also the first study to suggest that CBT-ip and combination therapy may be effective in reducing the frequency of clusters.

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BACKGROUND & AIMS: :Magnetic resonance imaging (MRI) is recommended for patients with epileptic seizures to rule out an underlying focal lesion. However, the radiological characteristics of epilepsy are not well elucidated. Transient periictal MRI abnormality (TPMA) refers to reversible MRI signal changes observed in epileptic patients. A 32-year-old man presented with a 2-week history of epileptic seizures, which initially manifested as focal aware seizures and progressed to a generalized tonic-clonic seizure on the third day. Electroencephalography showed sharp waves, sharp and slow wave complexes, and irregular δ waves over bilateral temporal lobes. After admission, brain MRI showed abnormal signals in the bilateral frontoparietal lobes. He was administered oral oxcarbazepine (75  mg twice daily). During follow-up he was seizure-free; the abnormal MRI signals persisted at 2 weeks, but were completely resolved at 4 months. The possibility of TPMA should be considered in patients with epileptic disorders, and differentiated from a potential epileptogenic lesion.

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BACKGROUND & AIMS: :It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals' performance in behavioral tests that often accompany acute and chronic seizure testing.

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BACKGROUND & AIMS: :Benzodiazepines have been used for decades as first-line treatment for status epilepticus (SE). For reasons that are not fully understood, the efficacy of benzodiazepines decreases with increasing duration of seizure activity. This often forces clinicians to resort to more drastic second- and third-line treatments that are not always successful. The antiseizure properties of benzodiazepines are mediated by γ-aminobutyric acid type A (GABA(A) ) receptors. Decades of research have focused on the failure of GABAergic inhibition after seizure onset as the likely cause of the development benzodiazepine resistance during SE. However, the details of the deficits in GABA(A) signaling are still largely unknown. Therefore, it is necessary to improve our understanding of the mechanisms of benzodiazepine resistance so that more effective strategies can be formulated. In this review we discuss evidence supporting the role of altered GABA(A) receptor function as the major underlying cause of benzodiazepine-resistant SE in both humans and animal models. We specifically address the prevailing hypothesis, which is based on changes in the number and subtypes of GABA(A) receptors, as well as the potential influence of perturbed chloride homeostasis in the mature brain.

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BACKGROUND & AIMS: :One of the considerations when a child presents with paroxysmal events is psychogenic nonepileptic seizures (PNES). PNES are discernible changes in behavior or consciousness that resemble epileptic seizures but are not accompanied by electrophysiologic changes. They are usually understood as the manifestation of a conversion disorder that reflects underlying psychological distress. There is a lack of population-based data on the prevalence or incidence of PNES in pediatric populations. The prevalence of PNES in children would appear to be lower than that in the adult population, but the prevalence of PNES seems to increase with age, and nonepileptic paroxysmal events are more likely to be PNES in adolescence than earlier in childhood. In terms of manifestation, PNES in childhood have been described using various categorizations and terminology, making comparisons across studies difficult. There is some evidence that events are more likely to involve unresponsiveness in younger children and prominent motor symptoms in older children. The most common precipitating factors would appear to be school-related difficulties and interpersonal conflict within the child's family. In terms of psychopathology, children with PNES are at high risk for symptoms of depression and anxiety. Accurate diagnosis of PNES in children is likely to involve taking a comprehensive description of the episodes, garnering the child's medical/developmental history, video-electroencephalography (video-EEG) to rule out epileptic seizures, and an evaluation of family functioning. The importance of effective and sensitive communication of the diagnosis of PNES has been emphasized and management approaches will typically involve multidisciplinary efforts to safely manage the events at home and at school. Interventions to reduce the effect of precipitating psychosocial stressors and the involvement of a mental health professional to treat comorbid psychopathology will also form part of an effective management plan. Outcome at follow-up is reported to be largely positive, although studies have not been able to follow all children, and few studies have focused on predictors of a good outcome. Future controlled intervention studies using a range of outcome measures are needed to identify efficacious approaches and predictors of best outcome.

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BACKGROUND & AIMS: OBJECTIVE:This paper explores the issues that arise from the discussion of administering rescue medication to children who experience prolonged convulsive seizures in mainstream schools in the UK. SITUATION ANALYSIS:Current guidelines recommend immediate treatment of children with such seizures (defined as seizures lasting more than 5 min) to prevent progression to status epilepticus and neurological morbidity. As children are unconscious during prolonged convulsive seizures, whether or not they receive their treatment in time depends on the presence of a teacher or other member of staff trained and able to administer rescue medication. However, it is thought that the situation varies between schools and depends mainly on the goodwill and resources available locally. RECOMMENDATIONS:A more systematic response is needed to ensure that children receive rescue medication regardless of where their seizure occurs. Possible ways forward include: greater use of training resources for schools available from epilepsy voluntary sector organisations; consistent, practical information to schools; transparent guidance outlining a clear care pathway from the hospital to the school; and implementation and adherence to each child's individual healthcare plan. IMPLICATIONS:Children requiring emergency treatment for prolonged convulsive seizures during school hours test the goals of integrated, person-centred care as well as joined-up working to which the National Health Service (NHS) aspires. As changes to the NHS come into play and local services become reconfigured, every effort should be made to take account of the particular needs of this vulnerable group of children within broader efforts to improve the quality of paediatric epilepsy services overall.

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BACKGROUND & AIMS: PURPOSE:To identify barriers to implementation of an evidence based integrated care pathway (ICP) for seizure management in the Emergency Department (ED). METHODS:A site specific bespoke questionnaire was designed to solicit anonymous responses from all grades of ED medical and nursing staff to a series of questions regarding utility, feasibility, significance and implementation of a locally designed and championed ICP for seizure management and onward referral. RESULTS:While 95% of respondents agreed that the pathway ensured patients were treated according to best practice, a number of human factors were identified as barriers to use. These fell into three categories 1) environmental 2) pathway design/process and 3) user related issues. CONCLUSIONS:Most respondents understood and endorsed the evidence based utility of the pathway. Barriers to use, however, are broad with interactions involving many complex human factors. Nevertheless, solutions can be relatively easily formulated but departmental-wide effort is required to comprehensively address all issues.

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BACKGROUND & AIMS: :Seizures have both local and remote effects on nervous system function. Whereas propagated seizures are known to disrupt cerebral activity, little work has been done on remote network effects of seizures that do not propagate. Human focal temporal lobe seizures demonstrate remote changes including slow waves on electroencephalography (EEG) and decreased cerebral blood flow (CBF) in the neocortex. Ictal neocortical slow waves have been interpreted as seizure propagation; however, we hypothesize that they reflect a depressed cortical state resembling sleep or coma. To investigate this hypothesis, we performed multimodal studies of partial and secondarily generalized limbic seizures in rats. Video/EEG monitoring of spontaneous seizures revealed slow waves in the frontal cortex during behaviorally mild partial seizures, contrasted with fast polyspike activity during convulsive generalized seizures. Seizures induced by hippocampal stimulation produced a similar pattern, and were used to perform functional magnetic resonance imaging weighted for blood oxygenation and blood volume, demonstrating increased signals in hippocampus, thalamus and septum, but decreases in orbitofrontal, cingulate, and retrosplenial cortex during partial seizures, and increases in all of these regions during propagated seizures. Combining these results with neuronal recordings and CBF measurements, we related neocortical slow waves to reduced neuronal activity and cerebral metabolism during partial seizures, but found increased neuronal activity and metabolism during propagated seizures. These findings suggest that ictal neocortical slow waves represent an altered cortical state of depressed function, not propagated seizure activity. This remote effect of partial seizures may cause impaired cerebral functions, including loss of consciousness.

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BACKGROUND & AIMS: OBJECTIVE:Febrile seizures (FS) are the most common convulsions in childhood. Interleukin-1beta (IL-1β) is proposed to play an important role in the development of FS, from in vitro data and data from peripheral blood samples. IL-1β secretion is needed for activation of the NLR family, pyrin-domain containing 3(NLRP3) inflammasome. However, whether NLRP3 play a role in the development of FS remains unknown. This study aimed to investigate the role of NLRP3 in FS. METHODS:Thirty-two FS cases and twenty-two matched controls were included in this study. Control samples were collected from children with febrile illness without seizures. We detected their levels of IL-1β and NLRP3 by Enzyme linked immunosorbent assay and Western blot, respectively. RESULTS:Serum IL-1β levels weresignificantlyhigher in FS patients (Median = 301.64 pg/ml) than in fever only controls (Median = 159.48 pg/ml) (P < 0.05). Additionally, NLRP3 protein levels of peripheral blood mononuclear cells (PBMC) were significantly higher in typical FS than in fever only controls (P < 0.05). Moreover, serum levels of IL-1β were significantly correlated with levels of NLRP3 protein (r = 0.787, P < 0.001). CONCLUSIONS:In this study, our results firstly indicated that NLRP3 protein was significantly up-regulated in the typical FS children compared in fever only controls. Increased NLRP3 can mediate IL-1β secretion that is responsible for the occurrence of FS.

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BACKGROUND & AIMS: PURPOSE:This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332. METHODS:Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs). RESULTS:During the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel. CONCLUSION:In this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

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BACKGROUND & AIMS: :Systemic administration does not allow a clear differentiation between the anticonvulsant properties of GABAA (gamma-aminobutyric acid) modulators. For this reason, various GABAA modulators have previously been micro-infused into seizure controlling substrates (area tempestas, substantia nigra) in the rat brain as a screening method for potential systemic administration. The purpose of the present study was to examine the anticonvulsant impact of the GABAergic modulators muscimol, ethanol, and propofol (screened by micro-infusions) when each drug was combined with procyclidine and administered systemically. The results showed that all 3 combinations could effectively terminate soman-induced (100 microg/kg s.c.) seizures when administered 30-35 min after onset. Procyclidine and propofol were considered as the most relevant double regimen to replace a previous triple regimen (procyclidine, diazepam, pentobarbital) against soman-induced seizures. Additionally, it was shown that unilateral implantation of hippocampal electrodes resulted in increased resistance to aphagia/adipsia and neuropathology, but not to lethality following soman. Efficient pharmacological treatment of soman-induced seizures at an early stage (< 20 min) is crucial to avoid neuropathology and cognitive deficits.

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BACKGROUND & AIMS: :We have studied 342 patients who had their first seizures after the age of 60 years. The causes of seizures were identified in 305 patients (89%) with cerebrovascular disease accounting for 39%, head injury 21%, brain tumours 11%, metabolic disorders 7%, multifactorial aetiology 6%, and CNS infection 4%. The majority of patients (80%) had focal onset seizures that were secondarily generalized in 50%.

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BACKGROUND & AIMS: PURPOSE:To investigate spatial and metabolic changes associated with frontal lobe seizures. METHODS:Functional near-infrared spectroscopy combined with electroencephalography (EEG-fNIRS) recordings of patients with confirmed nonlesional refractory frontal lobe epilepsy (FLE). KEY FINDINGS:Eighteen seizures from nine patients (seven male, mean age 27 years, range 13-46 years) with drug-refractory FLE were captured during EEG-fNIRS recordings. All seizures were coupled with significant hemodynamic variations that were greater with electroclinical than with electrical seizures. fNIRS helped in the identification of seizures in three patients with more subtle ictal EEG abnormalities. Hemodynamic changes consisted of local increases in oxygenated (HbO) and total hemoglobin (HbT) but heterogeneous deoxygenated hemoglobin (HbR) behavior. Furthermore, rapid hemodynamic alterations were observed in the homologous contralateral region, even in the absence of obvious propagated epileptic activity. The extent of HbO activation adequately lateralized the epileptogenic side in the majority of patients. SIGNIFICANCE:EEG-fNIRS reveals complex spatial and metabolic changes during focal frontal lobe seizures. Further characterization of these changes could improve seizure detection, localization, and understanding of the impact of focal seizures.

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