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- A comprehensive behavioral evaluation in the lithium-pilocarpine model in rats: Effects of carisbamate administration during status epilepticus. [JOURNAL ARTICLE]
- Epilepsia 2013 May 11.
PURPOSE:Administration of carisbamate during status epilepticus (SE) prevents the occurrence of motor seizures in the lithium-pilocarpine model and leads in a subpopulation of rats to spike-and-wave discharges characteristic of absence epilepsy. Widespread neuroprotection accompanied this change in seizure expression. To assess whether these carisbamate-induced changes affected comorbidity, we used a large battery of behavioral tests in rats that had developed temporal lobe or absence-like seizures.
METHODS:Lithium-pilocarpine or saline was administered to 60 adult rats. Carisbamate (90 mg/kg) or diazepam and saline was given 1 h after SE onset, and repeated 8 h later and twice daily over 6 more days. Rats were video-monitored for 2 months. Subsequently, locomotor activity, anxiety, and various types of memory were assessed. KEY
FINDINGS:In rats with motor seizures, treated or not with carisbamate, all features of behavior were impaired compared to controls. Rats exhibiting absence-like seizures after carisbamate treatment behaved as controls in all paradigms tested along with widespread neuroprotection.
SIGNIFICANCE:Carisbamate treatment leading to absence-like instead of temporal lobe seizures impressively prevented behavioral comorbidities reported by patients with epilepsy as the most disabling.
- Comprehensive evaluation of the psychosocial parameters of epilepsy-A representative population-based study in Prey Veng (Cambodia). [JOURNAL ARTICLE]
- Epilepsia 2013 May 11.
PURPOSE:We conducted a population-based study of epilepsy in Prey Veng (Cambodia) to explore self-esteem, fear, discrimination, knowledge-attitude-practice (KAP), social-support, stigma, coping strategies, seizure-provoking factors, and patient-derived factors associated with quality of life (QOL).
METHODS:The results are based on a cohort of 96 cases and matched controls (n = 192), randomly selected from the same source population. Various questionnaires were developed and validated for internal consistency (by split-half, Spearman-Brown prophecy, Kuder-Richardson 20), content clarity and soundness. Summary, descriptive statistics, classical tests of hypothesis were conducted. Uncorrected chi-square was used. Group comparison was done to determine statistically significant factors, for each domain, by conducting logistic regression; 95% confidence interval (CI) with 5% (two-sided) statistical significance was used. KEY
FINDINGS:All questionnaires had high internal consistency. Stress was relevant in 14.0% cases, concealment in 6.2%, denial in 8.3%, negative feelings in public in 3.0%. Mean self-esteem was 7.5, range 0-8, related to seizure frequency. Mean discrimination was least during social interactions. Coping strategies were positive (e.g. look for treatment). Postictal headache, anger, no nearby health facility, etc. were associated with QOL.
SIGNIFICANCE:The reliability of our questionnaires was high. A positive social environment was noted with many infrequent social and personal prejudices. Not all populations should (by default) be considered as stigmatized or equipped with poor KAP. We addressed themes that have been incompletely evaluated, and our approach could therefore become a model for other projects.
- A novel pedigree with familial cortical myoclonic tremor and epilepsy (FCMTE): Clinical characterization, refinement of the FCMTE2 locus, and confirmation of a founder haplotype. [JOURNAL ARTICLE]
- Epilepsia 2013 May 11.
PURPOSE:We describe the clinical, neurophysiologic, and genetic features of a new, large family with familial cortical myoclonic tremor and epilepsy (FCMTE).
METHODS:Reliable clinical information was obtained on the 127 members. Thirty-one collaborative individuals were assessed by a detailed clinical interview and a complete neurologic examination. A polygraphic study was conducted in 15 patients, back-averaging analysis and somatosensory evoked potentials with C-reflex study in four. The genetic study investigated 30 subjects with microsatellite markers at three loci on chromosomes 8q (FCMTE1), 2p (FCMTE2), and 5p (FCMTE3). KEY
FINDINGS:The pedigree included 25 affected members (M/F: 9/16). We studied 16 of the 19 living affected members (M/F: 5/11; mean age 47.8 years). Cortical myoclonic tremor (CMT) was associated with generalized seizures in 10 patients (62.5%). The mean age at onset of CMT and seizures was 28.1 and 33.8 years, respectively. Four patients (25%) reported a slow progression of CMT, with severe gait impairment in one. Psychiatric disorders of variable severity recurred in 37.5% of cases. Rhythmic bursts at 7-15 Hz were recorded in all 11 affected members tested. Additional neurophysiologic investigations disclosed a cortical origin of myoclonus in all patients tested. Generalized epileptiform discharges were recorded in 25% of cases, and a photoparoxysmal response in 31%. Genetic analysis established linkage to the FCMTE2 locus on chromosome 2p11.1-2q12.2 (OMIM 607876) and narrowed the critical interval to a 10.4 Mb segment. Haplotype analysis in the present family identified a founder haplotype identical to that previously observed in families from the same geographic area.
SIGNIFICANCE:This study confirms evidence of a founder effect in Italian families and reduces the number of positional candidate genes in the FCMTE2 locus to 59, thereby contributing to future gene identification by Next Generation Sequencing approaches.
- Visual field defects after radiosurgery for mesial temporal lobe epilepsy. [JOURNAL ARTICLE]
- Epilepsia 2013 May 10.
PURPOSE:Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE.
METHODS:This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY
FINDINGS:No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations.
SIGNIFICANCE:VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.
- Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. [JOURNAL ARTICLE]
- Epilepsia 2013 May 10.
PURPOSE:Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS.
METHODS:We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures. KEY
FINDINGS:In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase.
SIGNIFICANCE:We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.
- Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: A pooled analysis of three phase III studies. [JOURNAL ARTICLE]
- Epilepsia 2013 May 10.
PURPOSE:Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose.
METHODS:Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double-blind phase) and percentage of patients achieving ≥50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. KEY
FINDINGS:The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs.
SIGNIFICANCE:Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile.
- Psychiatric symptoms in children prior to epilepsy surgery differ according to suspected seizure focus. [JOURNAL ARTICLE]
- Epilepsia 2013 May 10.
PURPOSE:Children and adolescents with epilepsy have an overrepresentation of psychiatric illness. However, few studies in pediatrics have characterized specific psychiatric conditions associated with seizure localization. In addition, degree to which psychiatric illness may be more prominent in children refractory to standard medical treatment for epilepsy is not known. The aim of this study was to assess psychiatric symptoms in children with medically refractory epilepsy and ascertain whether symptoms were associated with specific localization.
METHODS:Case records were reviewed for 40 children with medically refractory epilepsy at the time of their referral for presurgical evaluation. Patients received a clinical psychiatric evaluation and parents completed the Child Behavioral Checklist (CBCL). Seizure localization was verified by pediatric epileptologists, and suitability for surgical procedures was verified by neurosurgical specialists. Groups were compared based on localization of seizure foci, either in the temporal lobe or predominantly extratemporal. KEY
FINDINGS:The majority of the sample had psychiatric diagnoses and behavior problems, well beyond the level reported in chronic epilepsy populations. In addition, children with temporal lobe seizure foci had more CBCL behavioral problem categories rated in the clinically significant range, and also were more likely to have clinical diagnoses of depression.
SIGNIFICANCE:Routine psychiatric evaluation prior to epilepsy surgery may be important for pediatric patients with medically refractory epilepsy. Psychiatric illness, particularly depression, may be especially prominent for those with temporal lobe seizure foci.
- Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy. [JOURNAL ARTICLE]
- Epilepsia 2013 May 10.
PURPOSE:Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously.
METHODS:We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. KEY
FINDINGS:We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients.
SIGNIFICANCE:Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing.
- Pharmacoresistant epilepsy: Unmet needs in solving the puzzle(s). [Journal Article]
- Epilepsia 2013 May.:80-5.
Pharmacoresistant epilepsy is a significant medical problem. The 2nd Halifax International Epilepsy Conference & Retreat identified crucial needs, which if successfully addressed, will aid in paving the way to improved lives for people with pharmacoresistant epilepsy. These are needs: (1) for an evidence-based and dynamic definition of pharmacoresistant epilepsy; (2) for a comprehensive description of the natural history of pharmacoresistant epilepsy; (3) for a comprehensive description of the complications and comorbidities of pharmacoresistant epilepsy; (4) for a rigorous delineation of the epidemiology and socioeconomic impact of pharmacoresistant epilepsy; (5) for clinically meaningful diagnostic and prognostic physiologically based electroencephalography (EEG) biomarkers; (6) for clinically meaningful diagnostic and prognostic anatomically based (MRI Imaging) biomarkers; (7) for biomolecular/biochemical mechanistic understanding of etiopathogenesis for pharmacoresistant epilepsy; (8) for representative animal models of pharmacoresistant epilepsy; (9) for new and effective drugs or other novel treatments for pharmacoresistant epilepsy; and (10) to promote continuing research and research funding targeting pharmacoresistant epilepsy.
- A conceptual framework for the use of neuroimaging to study and predict pharmacoresistance in epilepsy. [Journal Article]
- Epilepsia 2013 May.:75-9.
Twenty percent to 49% of newly treated patients with epilepsy will develop pharmacoresistance (PR). The mechanisms leading to PR are unclear. There is currently no unifying theory to explain the variety of presentations of PR and the diversity of potential contributing factors. Etiology of seizures seems to play a critical role in at least a subset of PR. Many magnetic resonance imaging (MRI) studies in the advanced stages of epilepsy suggest a strong association between lesions such as hippocampal sclerosis and focal cortical dysplasia and PR. Unfortunately, almost all of these studies are cross-sectional and retrospective. There is a need for a new perspective on the role of preexisting lesions in the evolution of epilepsy and PR. We propose in this article to study a unique population of drug-naive patients with either first seizure or new-onset epilepsy longitudinally with advanced MRI imaging techniques, including magnetic resonance spectroscopy and diffusion tensor imaging. We hope to be able to monitor imaging findings and the development of PR early in the course of the disease in a subset of these patients with temporal lobe epilepsy (TLE). Our goal is to understand the pathogenesis of PR, to dissect changes associated with the development of PR from changes associated with chronic seizures and medication, and ultimately to predict PR at the onset of disease.