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Objective: Conventional randomized controlled trials (RCTs) have long served as the foundation of research in clinical psychology; however, most treatments for eating disorders show only modest effects on reduction of symptoms and maintenance of long‐term remission. New options for psychotherapy treatment development research, beyond continuing to pursue additive or subpopulation approaches, are needed. Methods: One option is to apply dose–response designs, which are commonplace in studies of pharmacology, toxicology, and medical research, and characterized by the evaluation of the amount of exposure (dose) to an intervention, and the resulting changes in body function or health (response). Results: Eating disorder interventions are particularly well‐suited for dose–response treatment designs. The deadly nature of eating disorders makes it imperative that patients are not turned away for not being "ready" to engage with treatment. By identifying optimal doses, research will likely yield a more parsimonious course of treatment, which will lend itself to reduced costs, greater uptake, and reduced drop‐out. Discussion: Limited use of within‐subject designs in trials for patients with eating disorders has produced fast‐track efficacy studies and omitted key elements in the treatment development pathway. To decrease reliance on RCT's, dose–response methods should be applied as an alternative study design. Public Significance: Eating disorders are associated with medical and psychiatric comorbidities, poor quality of life, and high mortality. Access to evidence‐based services for patients with eating disorders is limited, and identifying additional effective treatment options can be difficult because of challenges inherent to randomized‐controlled trials. This manuscript describes an alternative trial methodology to maximize the information that can be gathered prior to utilizing a standard large‐scale efficacy design. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore youth with disabilities' perspectives of their experiences in integrated physical education classes in the United States. Participants were three youth with visual impairments and three youth with orthopedic impairments (ages 10-17 years). Data sources were written prompts, audio-recorded, semistructured virtual interviews, and reflective notes. Based on a six-step thematic analysis method, four themes were developed: (a) "I couldn't do most things:" lack of accommodations; (b) "They had absolutely no clue:" the teacher's role; (c) "I'm a scared boy:" concerns about injuries and unsafe activities; and (d) "I get to hang out with my friends:" interpersonal relationships and feelings of inclusion. Participants recalled feeling a sense of belonging, acceptance, and value when experiencing positive interpersonal relationships. In contrast, a lack of accommodations, safety measures, and a perceived lack of teacher preparation made these feelings uncommon. [ABSTRACT FROM AUTHOR]

This study explored the experiences of students with orthopedic impairments in integrated physical education (PE) classes. An interpretative phenomenological analysis research approach was used, and six students with orthopedic impairments (age = 10–14 years) served as participants. Data sources were semistructured, audiotaped interviews and reflective interview notes. Based on data analysis, three themes were developed—"Without it, they probably would like, just treat me normal," visibility, disclosure, and expectations; "I sit out," limited participation and a lack of modifications/accommodations; and "PE doesn't feel great," social interactions and perception of self. The experiences portrayed throughout these themes highlight the marginalization and lack of access that the participants encountered in their integrated PE classes. The findings indicated that PE professionals working with students with orthopedic impairments may benefit from reflecting on personal biases and their instructional practices in an effort to improve the quality of PE experiences for these students. [ABSTRACT FROM AUTHOR]

This study examined how students with orthopedic impairments experienced strategies identified in the literature to support 'inclusion'. An interpretative phenomenological analysis research approach was used, and six students with orthopedic impairments (age 10–14 years) served as participants. Data sources were written prompts, semi-structured, audiotaped interviews, and reflective interview notes. Based on thematic data analysis, four themes were constructed: "It's kind of embarrassing": experiences with support; "I don't want to be different": equipment, activity, and rule modifications; "I like to be a part of the conversation": autonomy and choice in PE; and "I would rather be like the other students": discussing disability. The experiences portrayed through these themes highlighted the differential effects of these explicated strategies, where each strategy contributed to feelings of inclusion, as well as marginalization among participants. As such, the findings indicated that 'inclusive' strategies should not be considered as blanket recommendations; instead, attempts to promote 'inclusion' of students with disabilities should start with a reflexive look at the unique needs of each individual student. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe the reflections of adults with visual impairments about learning to run during K–12 physical education. An interpretative phenomenological analysis research approach was used, and eight adults (age 22–35 years) with visual impairments served as participants. Primary data sources were semistructured, audiotaped telephone interviews and reflective interview notes. Based on a thematic data analysis process, two themes were developed: (a) "I wouldn't expect anything better from you": running instruction in physical education and (b) "You look like the guy in the crosswalk signal": making up for the shortcomings of physical education. The narratives portraying these themes highlight the lack of instruction that took place in physical education, and the fact that no running instruction occurred at all. These findings indicate that professionals working with individuals with visual impairments should use instructional strategies that will allow for maximum access to learning fundamental movement skills such as running. [ABSTRACT FROM AUTHOR]

To assess the vascularity of the tumour preoperatively, digital subtraction angiography was also performed which demonstrated displacement of the anterior cerebral arteries to the left side, consistent with mass effect secondary to tumour, but minimal tumour "blush" following contrast phasing through the brain centrally. In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Here, the molecular confirmation of the novel I MN1 i - I GTSE1 i gene fusion, diagnostic of astroblastoma, supported the team in recommending 3-monthly follow-up, rather than the standard 6-monthly approach which would be more typical for a glioneuronal tumour. A rare case of paediatric astroblastoma with concomitant MN1-GTSE1 and EWSR1-PATZ1 gene fusions altering management. [Extracted from the article]

Because of next-generation sequencing and the discovery of many new causative genes, genetic testing in epilepsy patients has become widespread. Pathologic variants resulting in epilepsy cause a variety of changes that can be broadly classified into syndromic disorders (i.e., chromosomal abnormalities), metabolic disorders, brain malformations, and abnormal cellular signaling. Here, we review the available genetic testing, reasons to pursue genetic testing, common genetic causes of epilepsy, the data behind what patients are found to have genetic epilepsies based on current testing, and discussing these results with patients. We propose an algorithm for testing patients with epilepsy to maximize yield and limit costs based on their phenotype (including electroencephalography and magnetic resonance imaging findings), age of seizure onset, and presence of other neurologic comorbidities. Being able to discern which type of genetic testing to order, using that information to give targeted and cost-effective patient care, and interpreting results accurately will be a crucial skill for the modern neurologist. [ABSTRACT FROM AUTHOR]

Research indicates that although students with disabilities, including those with autism spectrum disorder (ASD), can be successful in acquiring motor and sport-related skills during physical education, they tend to struggle with generalizing those skills to other settings. Difficulties with generalization of physical education skills may contribute to low levels of physical activity and sport participation by individuals with ASD outside of physical education. Since generalization is unlikely to occur automatically, physical education teachers must plan and teach for generalized outcomes. Several strategies exist that can be used by educators to promote the generalization of skills to other settings or with other people. Physical education teachers can promote the use of motor skills and participation in physical activities in environments outside of school by embedding these strategies into their curriculum for the benefit of all students. The purpose of this article is to provide physical educators with practical generalization programming interventions for students with ASD. [ABSTRACT FROM AUTHOR]

Studies show that obesity rates among children with disabilities are significantly higher than children without disabilities (Neter et al., 2011). Walking, one of the most natural forms of movement (Morris & Hardman, 1997), is one activity that can promote physical activity and help decrease obesity rates. Schools, specifically physical education classes, provide an ideal setting for activity promotion among youth (Lubans et al., 2015). The purpose of this paper is to provide a framework for a year-long walking program for self-contained PE classes that is informed by the self-regulation construct of the social cognitive theory in an effort to increase physical activity levels for students with disabilities and their families. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels have been implicated in numerous inherited paroxysmal disorders of the nervous system, muscle, and heart. Our goal is to provide a framework that helps neurologists understand the clinical and treatment implications of sodium channel variants they encounter in clinical practice. This will be accomplished through our objectives of (1) recognizing the relationship between location of a missense sodium channel gene variant and its effect on channel function, and (2) categorizing clinical phenotype based on functional effect of a variant. The relationship between location, function, and treatment response is also discussed. These interactions can be illustrated by the sodium channelopathies seen in people with epilepsy but generalize beyond that disorder. Ann Neurol 2018;83:1-9. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the outcome, including drug-resistant epilepsy (DRE) in children with newly diagnosed partial onset epilepsy treated with carbamazepine (CBZ).Methods: A retrospective medical records review and telephone questionnaire were undertaken on a total of 100 subjects.Results: Long-term follow-up was obtained on 79 children with a mean duration of 7.1 years from CBZ initiation. A total of 66 (83.5%) subjects achieved 2-year seizure remission, 48 (72.7%) subjects did so with CBZ monotherapy. Seven (10.6%) had seizure recurrence after 2-year seizure remission. DRE was diagnosed in seven (8.9%) subjects and five subjects had epilepsy surgery. The mean duration from seizure onset to epilepsy surgery was 5.3 (±2.1) years. Contributing factors for the prolonged duration from seizure onset to epilepsy surgery were identified including: relapsing–remitting course of seizure, family reluctance for epilepsy surgery and uncontrolled psychological problems.Conclusions: Over 80% of children with newly diagnosed partial onset epilepsy who were initially treated with CBZ achieved 2-year seizure remission, and more than 70% of this group did so with CBZ monotherapy. The majority of these patients maintained seizure remission overtime. However, 8.9% of this population met the criteria for DRE and most of them had epilepsy surgery. The duration from seizure onset to epilepsy surgery is an important potential area for improvement in DRE patient care. [ABSTRACT FROM PUBLISHER]

Objective Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel ( SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. Methods Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. Results Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M- CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92. Significance Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90. [ABSTRACT FROM AUTHOR]

Objective: To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE).Methods: Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide.Results: Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25-5.56; p = 0.026, OR = 2.38, 95% CL = 1.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of CaV 3.2 was significantly less for P640L channel compared to wild-type channel.Interpretation: Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444-453. [ABSTRACT FROM AUTHOR]

Abstract: The role of neuronal voltage-gated sodium channel, α-1 subunit (SCN1A) gene mutations in Dravet syndrome is well-established. With a broader phenotype than initially described, some patients lack features of Dravet syndrome as defined by the International League Against Epilepsy. We evaluated the predictive value of International League Against Epilepsy criteria for a positive mutation in a cohort of consecutively tested children. Mutations of SCN1A were evident in 16 of 69 children. Exhibiting ≥4 International League Against Epilepsy criteria demonstrated 100% sensitivity. Seven criteria (resistance to multiple antiepileptic drugs, multiple seizure types, abnormal electroencephalogram features, exacerbation with hyperthermia, normal development before seizure onset, seizures beginning before age 1 year, and psychomotor retardation) were present in ≥85% of mutation-positive cases. The three criteria that best predicted a mutation in SCN1A included exacerbation with hyperthermia, normal development before seizure onset, and the appearance of ataxia, pyramidal signs, or interictal myoclonus. We have demonstrated a high-sensitivity testing strategy for detecting mutations of SCN1A in children with suspected Dravet syndrome. [Copyright &y& Elsevier]

The aim of this study was to determine the incidence and describe the factors influencing ictal cardiac arrhythmias in children with epilepsy. A 2-year review within a pediatric epilepsy monitoring unit revealed 2066 electrographically confirmed seizures in 139 patients. Demographic, seizure, and cardiac variables were collected for each patient. Fisher''s exact test, Wilcoxon rank-sum test, and Spearman''s rank correlation coefficient were used to identify significant differences and associations at the seizure and patient levels. In 244 seizures meeting inclusion criteria, ictal cardiac arrhythmias were seen in 45% of the seizures (40% of the patients). The most common arrhythmia was benign respiratory sinus arrhythmia (78% of seizures with arrhythmias, 70% of patients with arrhythmias). Potentially serious arrhythmias included irregular variable arrhythmias, and abnormal QRS intervals were seen in 12% of all the patients. In seizures with ictal arrhythmias, 64% occurred in male patients (P = 0.016) and 78% occurred in white patients (P = 0.013). This study estimates the incidence of ictal arrhythmias within the pediatric population that need further medical attention and management. [Copyright &y& Elsevier]

Abstract: Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy. [Copyright &y& Elsevier]

Abstract: Few randomized, controlled trials evaluating antiepileptic drug (AED) efficacy and tolerability have focused solely on patients with juvenile myoclonic epilepsy (JME). We conducted a pilot, randomized controlled trial comparing topiramate (N =19) and valproate (N =9) in adolescents/adults with JME to evaluate clinical response when these broad-spectrum agents are titrated to optimal effect. Rating scales were used to systematically assess tolerability. Among patients completing 26 weeks of treatment, 8 of 12 (67%) in the topiramate group and 4 of 7 (57%) in the valproate group were seizure-free during the 12-week maintenance period. Median daily dose was 250mg topiramate or 750mg valproate. Two (11%) topiramate-treated patients and one (11%) valproate-treated patient discontinued due to adverse events. Systemic toxicity scores, but not neurotoxicity scores, differed substantially between the two groups; greater systemic toxicity was associated with valproate. Our preliminary findings that topiramate may be an effective, well-tolerated alternative to valproate warrant validation in a double-blind trial. [Copyright &y& Elsevier]

OBJECTIVES. Our goals were to determine the effect of epilepsy surgery in infants (<3 years of age) on development and describe factors associated with postoperative developmental outcome. METHODS. We identified 50 infants among 251 consecutive pediatric patients (<18 years old) undergoing epilepsy surgery. Charts were reviewed for clinical data and neurodevelopmental testing with the Bayley Scales of Infant Development. A developmental quotient was calculated to compare scores of children at different ages. RESULTS. Complete data were available on 24 of 50 infants. Surgeries included 14 hemispherectomies and 10 focal resections. Seventeen patients became seizure free; 5 patients had >90% seizure reduction, 1 had >50% seizure reduction, and 1 had no change. The developmental quotient indicated modest postoperative improvement of mental age. The preoperative and postoperative development quotients correlated well. Younger infants had a higher increase in developmental quotient after surgery. Patients with epileptic spasms were younger and had a lower developmental quotient at presentation, but increase in developmental quotient was higher in this subgroup. CONCLUSIONS. After surgery, seizure frequency and developmental quotient improved. Developmental status before surgery predicted developmental function after surgery. Patients who were operated on at younger age and with epileptic spasms showed the largest increase in developmental quotient after surgery. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine physical education (PE) experiences from the perspective of an adult with Bardet-Biedl syndrome. An interpretative phenomenological analysis (IPA) research approach was used, and one male (age 32) with Bardet-Biedl syndrome acted as the participant. Sources of data included a semi-structured, audiotaped telephone interview and reflective interview notes. The interview was transcribed verbatim and data were analyzed thematically using a two-step approach informed by the IPA. Three themes emerged from the data: (a) "We were pretty much good friends": The teacher's influence, (b) "You're different, must destroy": Bullying and negative peer interactions, and (c) "I could never see the damn thing coming": Inappropriate and inaccessible activities. These themes provide unique insights into how an individual with Bardet-Biedl syndrome experienced PE. Generally, the participant recalled negative experiences with regards to peer interaction and an inability to participate, but positive memories of one physical educator. [ABSTRACT FROM AUTHOR]

• Stimulation within auditory cortex produced facial expressions and perioral motor responses in approximately one-third of patients. • Cortical sites with motor and language responses within transverse temporal gyrus and adjacent cortex (TGG+) showed different yet overlapping neurophysiologic characteristics. • TTG+ likely participates in non-verbal responses to low-level auditory and/or emotional cues during a communicative discourse. We investigated the role of transverse temporal gyrus and adjacent cortex (TTG+) in facial expressions and perioral movements. In 31 patients undergoing stereo-electroencephalography monitoring, we describe behavioral responses elicited by electrical stimulation within the TTG+. Task-induced high-gamma modulation (HGM), auditory evoked responses, and resting-state connectivity were used to investigate the cortical sites having different types of responses on electrical stimulation. Changes in facial expressions and perioral movements were elicited on electrical stimulation within TTG+ in 9 (29%) and 10 (32%) patients, respectively, in addition to the more common language responses (naming interruptions, auditory hallucinations, paraphasic errors). All functional sites showed auditory task induced HGM and evoked responses validating their location within the auditory cortex, however, motor sites showed lower peak amplitudes and longer peak latencies compared to language sites. Significant first-degree connections for motor sites included precentral, anterior cingulate, parahippocampal, and anterior insular gyri, whereas those for language sites included posterior superior temporal, posterior middle temporal, inferior frontal, supramarginal, and angular gyri. Multimodal data suggests that TTG+ may participate in auditory-motor integration. TTG+ likely participates in facial expressions in response to emotional cues during an auditory discourse. [ABSTRACT FROM AUTHOR]

The novel neurological mutant Cincinatti arose by genomic duplication of exon 5 in the glycine receptor gene Glra1. The mutant transcript results in premature protein truncation. A direct repeat of the pentamer GGGGC is present adjacent to the breakpoints and may have mediated the duplication event by a replication slippage mechanism. [ABSTRACT FROM AUTHOR]

Background: Variants in KCNQ2 and KCNQ3 may cause benign neonatal familial seizures and early infantile epileptic encephalopathy. Previous reports suggest that in silico models cannot predict pathogenicity accurately enough for clinical use. Here we sought to establish a model to accurately predict the pathogenicity of KCNQ2 and KCNQ3 missense variants based on available in silico prediction models.Methods: ClinVar and gnomAD databases of reported KCNQ2 and KCNQ3 missense variants in patients with neonatal epilepsy were accessed and classified as benign, pathogenic, or of uncertain significance. Sensitivity, specificity, and classification accuracy for prediction of pathogenicity were determined and compared for 10 widely used prediction algorithms program. A mathematical model of the variants (KCNQ Index) was created using their amino acid location and prediction algorithm scores to improve prediction accuracy.Results: Using clinically characterized variants, the free online tool PROVEAN accurately predicted pathogenicity 92% of the time and the KCNQ Index had an accuracy of 96%. However, when including the gnomAD database as benign variants, only the KCNQ Index was able to predict pathogenicity with an accuracy greater than 90% (sensitivity = 93% and specificity = 98%). No model could accurately predict the phenotype of variants.Conclusion: We show that KCNQ channel variant pathogenicity can be predicted by a novel KCNQ Index in neonatal epilepsy. However, more work is needed to accurately predict the patient's epilepsy phenotype from in silico algorithms. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe the experiences of adults with visual impairments regarding fitness testing during their integrated physical education experiences. An interpretative phenomenological analysis research approach was used and 11 adults (ages 20–35 years) with visual impairments acted as participants. The primary sources of data were semi-structured audiotaped telephone interviews and reflective interview notes. Thematic development was undertaken using a three-step analytical process. Based on the data analysis, the following three interrelated themes were constructed from the data: (a) 'decent at sit-ups, but the others were embarrassing': mixed feelings about performance; (b) 'I couldn't reach my full potential': forced exclusion/inclusion; and (c) 'I felt like a museum exhibit': navigating unwanted social attention. These themes extend the current literature by describing salient features of fitness testing that influence the meaning that individuals with visual impairments place on those experiences. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to adopt an explicitly intersectional approach to examine the experiences of women identifying as having a visual impairment and as being overweight or obese in integrated physical education (PE). Method: An interpretative phenomenological analysis (IPA) research approach was used, and six women (ages 25-34) with visual impairments who identified as being overweight or obese acted as participants. The sources of data included semistructured audiotaped telephone interviews and reflective interview notes. Data were analyzed thematically using a three-step analytic process informed by IPA. Results: Based on the data analysis, three inter-related themes emerged. The first theme, restricted/reluctant participation, described participants' experiences with PE activity restrictions and the influence of visual impairment and overweight or obesity on these restrictions. The second theme, teacher discrimination, described participants' recollection of discriminatory practices by physical educators that were influenced by perceptions of inability. Finally, the third theme, isolation, teasing and surveillance issues, described challenging social instances and how those instances were influenced by body size and disability status. Conclusions: Using an IPA approach, three themes emerged that exposed central experiences that were informed by the participants' identities as individuals with visual impairments and being overweight or obese. Through the lens of intersectionality, these themes contribute to our understanding of how these identities interacted to contribute to disadvantaging experiences in PE. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to electroencephalography (EEG) monitoring with subdural grid electrodes in a 2013 issue.

A letter to the editor is presented in response to the article "Genetic Screening of Scandinavian Families With Febrile Seizures and Epilepsy or GEFS+," by K.K. Selmer, T. Egeland, M.H. Solaas, K.O. Nakken, M.J. Kjeldsen, M.L. Friis, K. Brandal, L.A. Corey and D.E. Undlien, published in issue 117 of "Acta Neurologica Scandinavia."

Objective: Electrical stimulation mapping (ESM) is the clinical standard for functional localization with subdural electrodes (SDE). As stereoelectroencephalography (SEEG) has emerged as an alternative option, we compared functional responses, afterdischarges (ADs), and unwanted ESM‐induced seizures (EISs) between the two electrode types. Methods: Incidence and current thresholds for functional responses (sensory, motor, speech/language), ADs, and EISs were compared between SDE and SEEG using mixed models incorporating relevant covariates. Results: We identified 67 SEEG ESM and 106 SDE ESM patients (7207 and 4980 stimulated contacts, respectively). We found similar incidence of language and motor responses between electrode types; however, more SEEG patients reported sensory responses. ADs and EISs occurred less commonly with SEEG than SDE. Current thresholds for language, face motor, and upper extremity (UE) motor responses and EIS significantly decreased with age. However, they were not affected by electrode type, premedication, or dominant hemispheric stimulation. AD thresholds were higher with SEEG than with SDE. For SEEG ESM, language thresholds remained below AD thresholds up to 26 years of age, whereas this relationship was inverse for SDE. Also, face and UE motor thresholds fell below AD thresholds at earlier ages for SEEG than SDE. AD and EIS thresholds were not affected by premedication. Significance: SEEG and SDE have clinically relevant differences for functional brain mapping with electrical stimulation. Although evaluation of language and motor regions is comparable between SEEG and SDE, SEEG offers a higher likelihood of identifying sensory areas. A lower incidence of ADs and EISs, and a favorable relationship between functional and AD thresholds suggest superior safety and neurophysiologic validity for SEEG ESM than SDE ESM. [ABSTRACT FROM AUTHOR]

• Primary hub was significantly closer to the stereotactic EEG-defined seizure onset zone compared to the center of ECD cluster. • Both ECD cluster and network analyses suggested that spatially restricted region correlate with better seizure outcomes. • Our findings suggest that magnetoencephalography network analysis could be a valuable complement to the conventional ECD method. To clinically validate the connectivity-based magnetoencephalography (MEG) analyses to identify seizure onset zone (SOZ) with comparing to equivalent current dipole (ECD). The ECD cluster was quantitatively analyzed by calculating the centroid of the cluster and maximum distance (the largest distance between all dipoles). The "primary hub" was determined by the highest eigencentrality. The distribution of nodes in the top 5% of eigenvector centrality values was quantified by generating the convex hull between each node. Thirty-one patients who underwent MEG, stereotactic-EEG, and focal surgery were included. The primary hub was significantly closer to the sEEG-defined SOZ compared to ECD (p = 0.009). The seizure freedom positive and negative predictive values of complete ECD cluster and primary hub resections did not significantly differ, although complete resection of the primary hub showed slightly better negative predictive value (ECD: 50.0% NPV, hub: 64.7% NPV). Both quantitative ECD and functional connectivity analyses suggested that spatially restricted dipole distributions and higher connectivity in a smaller region correlate with better seizure outcomes. Our findings suggest that MEG network analysis could be a valuable complement to the ECD methods. The results of this study are an important step towards using non-invasive neurophysiologic recordings to accurately define the epileptic network. [ABSTRACT FROM AUTHOR]

Objective: Accreditation Council for Graduate Medical Education (ACGME)‐accredited epilepsy fellowships, like other ACGME accredited training programs, use Milestones to establish learning objectives and to evaluate how well trainees are achieving these goals. The ACGME began developing the second iteration of the Milestones 6 years ago, and these are now being adapted to all specialties. Here, we describe the process by which Epilepsy Milestones 2.0 were developed and summarize them. Methods: A work group of nine board‐certified, adult and pediatric epileptologists reviewed Epilepsy Milestones 1.0 and revised them using a modified Delphi approach. Results: The new Milestones share structural changes with all other specialties, including a clearer stepwise progression in professional development and the harmonized Milestones that address competencies common to all medical fields. Much of the epilepsy‐specific content remains the same, although a major addition is a set of Milestones focused on reading and interpreting electroencephalograms (EEGs), which the old Milestones lacked. Epilepsy Milestones 2.0 includes a Supplemental Guide to help program directors implement the new Milestones. Together, Epilepsy Milestones 2.0 and the Supplemental Guide recognize advances in epilepsy, including stereo‐EEG, neurostimulation, genetics, and safety in epilepsy monitoring units. Significance: Epilepsy Milestones 2.0 address the shortcomings of the old Milestones and should facilitate the assessment of epilepsy fellowships and fellows by program directors, faculty, and fellows themselves. [ABSTRACT FROM AUTHOR]

Abstract: Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy. [Copyright &y& Elsevier]

• During visual naming, high-gamma modulation occurs in a posteroanterior sequential pattern with overlapping temporal profiles. • Cortical activations during visual naming represent cognitive sub-components with different relative contributions from the left and right cerebral hemispheres. • Post-surgical neuropsychological deficits correlated with the location of resected parcels within the visual naming network. Cerebral spatiotemporal dynamics of visual naming were investigated in epilepsy patients undergoing stereo-electroencephalography (SEEG) monitoring. Brain networks were defined by Parcel-Activation-Resection-Symptom matching (PARS) approach by matching high-gamma (50–150 Hz) modulations (HGM) in neuroanatomic parcels during visual naming, with neuropsychological outcomes after resection/ablation of those parcels. Brain parcels with >50% electrode contacts simultaneously showing significant HGM were aligned, to delineate spatiotemporal course of naming-related HGM. In 41 epilepsy patients, neuroanatomic parcels showed sequential yet temporally overlapping HGM course during visual naming. From bilateral occipital lobes, HGM became increasingly left lateralized, coursing through limbic system. Bilateral superior temporal HGM was noted around response time, and right frontal HGM thereafter. Correlations between resected/ablated parcels, and post-surgical neuropsychological outcomes showed specific regional groupings. Convergence of data from spatiotemporal course of HGM during visual naming, and functional role of specific parcels inferred from neuropsychological deficits after resection/ablation of those parcels, support a model with six cognitive subcomponents of visual naming having overlapping temporal profiles. Cerebral substrates supporting visual naming are bilaterally distributed with relative hemispheric contribution dependent on cognitive demands at a specific time. PARS approach can be extended to study other cognitive and functional brain networks. [ABSTRACT FROM AUTHOR]

Purpose: Determine if blood messenger RNA (mRNA) expression patterns in children with newly diagnosed untreated idiopathic epilepsy are different from those in healthy controls. Determine the differential expression patterns between epilepsy patients with generalized onset or partial onset seizures compared to healthy controls. Methods: Whole blood was obtained from otherwise healthy pediatric patients with newly diagnosed untreated idiopathic epilepsy along with healthy pediatric controls. mRNA was isolated and hybridized to Affymetrix HGU 133 2.0+ microarrays. Analysis was performed using Genespring. Differentially expressed gene lists resulted from comparison of (1) epilepsy and control groups and (2) seizure type subgroups with controls. Tissue expression and gene ontology analysis was performed using DAVID. Key Findings: Thirty-seven epilepsy patients and 28 controls were included. Overall, 575 genes were differentially expressed in subjects with epilepsy compared to controls. The generalized seizure subgroup versus control (GvC) gene list and the partial seizure subgroup versus control (PvC) gene list were different (p < 0.05). Tissue expression analysis identified almost half of the genes in GvC and PvC as brain based. Functional group analysis identified several biologically relevant pathways. In GvC, these included mitochondria and lymphocyte activation. In PvC, we identified apoptosis, inflammatory defense, and cell motion pathways. Significance: A unique, biologically meaningful mRNA expression pattern is detectable in whole blood of pediatric subjects with new-onset and untreated epilepsy. This analysis finds many similar pathways to those identified in brain studies examining lesional intractable epilepsy. Blood mRNA expression patterns show promise as a target for biomarker development in pediatric epilepsy. [ABSTRACT FROM AUTHOR]

Background: Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex. Methods: Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter. Results: We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, −1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported. Conclusions: Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.) N Engl J Med 2010;363:1801-11. [ABSTRACT FROM AUTHOR]

To evaluate the need for antiepileptic drugs after successful epilepsy surgery in pediatric patients, we retrospectively reviewed patients who had epilepsy surgery and were seizure free or had rare nondisabling auras during the first 6 postoperative months. Association between drug discontinuation and seizure recurrence was evaluated using Cox proportional hazards multivariable survival analysis. Medications were withdrawn in 68 of 97 patients, seizure free (or with rare nondisabling auras) for >6 months after surgery; 57 of the 68 (84%) remained seizure free; the other 11 (16%) had seizure recurrence after 68 months (median). Seizure recurrence was controlled with medication in 7 of the 11 patients (3 have rare seizures, 1 frequent auras). Discontinuing medications at <6 mo, compared with later or no withdrawal, had significant risk for seizure recurrence (hazard ratio 5.8; 95% confidence interval 1.8, 17.5; P = 0.003). Of 29 patients who continued drugs, 28 (97%) remained seizure free after 37 months (median). Freedom from seizures 6 months after surgery predicted good outcome (95% seizure free, with or without medication). If discontinuation is offered after 6 months, the majority of patients (84%) can be expected to remain seizure free with no further need for medication. Although seizure breakthrough is possible in a smaller percentage, restarting drugs is likely to restore seizure control. [Copyright &y& Elsevier]

• An approach for analysis of task-related high-gamma modulation in stereo-EEG using distribution of power differential clusters is described. • Stereo-EEG high-gamma language mapping effectively localized reference neuroanatomy (Neurosynth). • Stereo-EEG high-gamma language mapping also adequately classified electrical stimulation mapping speech/language sites. A novel analytic approach for task-related high-gamma modulation (HGM) in stereo-electroencephalography (SEEG) was developed and evaluated for language mapping. SEEG signals, acquired from drug-resistant epilepsy patients during a visual naming task, were analyzed to find clusters of 50–150 Hz power modulations in time–frequency domain. Classifier models to identify electrode contacts within the reference neuroanatomy and electrical stimulation mapping (ESM) speech/language sites were developed and validated. In 21 patients (9 females), aged 4.8–21.2 years, SEEG HGM model predicted electrode locations within Neurosynth language parcels with high diagnostic odds ratio (DOR 10.9, p < 0.0001), high specificity (0.85), and fair sensitivity (0.66). Another SEEG HGM model classified ESM speech/language sites with significant DOR (5.0, p < 0.0001), high specificity (0.74), but insufficient sensitivity. Time to largest power change reliably localized electrodes within Neurosynth language parcels, while, time to center-of-mass power change identified ESM sites. SEEG HGM mapping can accurately localize neuroanatomic and ESM language sites. Predictive modelling incorporating time, frequency, and magnitude of power change is a useful methodology for task-related HGM, which offers insights into discrepancies between HGM language maps and neuroanatomy or ESM. [ABSTRACT FROM AUTHOR]

• Stereo-EEG sensorimotor mapping was prospectively compared with reference neuroanatomy. • Electrical stimulation mapping localized anatomic sensorimotor parcels with high accuracy. • Sensorimotor thresholds below after-discharge thresholds suggest safety of stereo-EEG ESM. We evaluated stereo-EEG electrical stimulation mapping (ESM) for localization of anatomic sensorimotor parcels in pediatric patients with drug-resistant epilepsy. We also analyzed sensorimotor and after-discharge thresholds, and the somatotopy of sensorimotor responses. ESM was performed with 50 Hz, biphasic, 2–3 s trains, using 1–9 mA current. Pre- and post-implant neuroimaging was co-registered and intersected with Neurosynth reference, to classify each electrode contact as lying within/outside an anatomic sensorimotor parcel. Indices of diagnostic performance were computed. Sensorimotor and after-discharge thresholds were analyzed using multivariable linear mixed models. In 15 patients (6 females), aged 5.5–21.2 years, ESM showed high accuracy (0.80), high specificity (0.86), and diagnostic odds ratio (11.4, p < 0.0001) for localization of sensorimotor parcels. Mean sensorimotor threshold (3.4 mA) was below mean after-discharge threshold (4.2 mA, p = 0.0004). Sensorimotor and after-discharge thresholds showed a significant decrease with increasing intelligence quotient. Somatotopy of sensorimotor responses was mapped to standardized brain parcels. We provide evidence for diagnostic validity and safety of stereo-EEG sensorimotor ESM. The somatotopy of sensorimotor responses elicited with electrical stimulation provide new insights into mechanisms of motor control and sensory perception. [ABSTRACT FROM AUTHOR]

Background: Many neonates with hypoxic ischemic encephalopathy and seizures do not respond to the first line antiepileptic drug, phenobarbital. Little is known about what factors are associated with its failure. Objective: To examine factors associated with failure of phenobarbital therapy in neonates with hypoxic ischemic encephalopathy and seizures. Design/Methods: A single-center retrospective review of 50 term (>35 weeks) neonates with hypoxic ischemic encephalopathy and seizures treated with phenobarbital as the first-line antiepileptic. Neonates were classified into either responders (n = 30) or nonresponders (n = 20). Nonresponse was defined as continued seizures after maximum dosing of phenobarbital or an additional antiepileptic. Subjects with acceptable magnetic resonance imaging (MRI) scans obtained within 2 weeks of birth were included in the study and rated using an MRI injury scoring system. Charts were reviewed for demographic, clinical, and laboratory variables. Resuscitation and seizure scores were also calculated. Electroencephalographic (EEG) background activity was reviewed in 2 different time epochs (12-24 hours and 24-36 hours of life) and graded as per ACNS guidelines. Results: There were no significant group differences in demographic, clinical, and laboratory variables except nonresponders, who had higher mean seizure score (P =.01) and significantly more injury on MRI scan for white matter (P =.004), parenchymal cortex (P =.027), and watershed (P =.009) regions. Neonates with moderately abnormal or severely abnormal background EEG responded poorly to phenobarbital. Conclusion: In the presence of above factors, one can anticipate that additional antiepileptic medication may be needed. These data also support that larger studies should be done to look prospectively at using alternative agents first line in patients with severe injury. [ABSTRACT FROM AUTHOR]

Highlights • Resection of HGM language sites is associated with worse neuropsychological outcomes. • Working memory was significantly worse in patients with resection of HGM naming sites. • Neuropsychological evaluation of children with epilepsy should include multiple cognitive and language domains. Abstract Background Language mapping with high-gamma modulation (HGM) has compared well with electrical cortical stimulation mapping (ESM). However, there is limited prospective data about its functional validity. We compared changes in neuropsychological evaluation (NPE) performed before and 1-year after epilepsy surgery, between patients with/without resection of cortical sites showing HGM during a visual naming task. Methods Pediatric drug-resistant epilepsy (DRE) patients underwent pre-surgical language localization with ESM and HGM using a visual naming task. Surgical decisions were based solely on ESM results. NPE difference scores were compared between patients with/without resection of HGM naming sites using principal component (PC) analysis. Follow-up NPE scores were modeled with resection group as main effect and respective pre-surgical score as a covariate, using analysis of covariance. Results Seventeen native English speakers (12 females), aged 6.5–20.2 years, were included. One year after epilepsy surgery, first PC score increased by (mean ± standard deviation) 14.4 ± 16.5 points in patients without resection, whereas it decreased by 7.6 ± 24.6 points in those with resection of HGM naming sites (p = 0.040). This PC score represented verbal comprehension, working memory, perceptual reasoning (Wechsler subscales); Woodcock-Johnson Tests of Achievement; and Peabody Picture Vocabulary Test. Subsequent analysis showed significant difference in working memory score between patients with/without resection of HGM naming sites (−15.2 points, 95% confidence limits −29.7 to −0.7, p = 0.041). Conclusion We highlight the functional consequences of resecting HGM language sites, and suggest that NPE of DRE patients should include comprehensive assessment of multiple linguistic and cognitive domains besides naming ability. [ABSTRACT FROM AUTHOR]

Summary: Objective: We studied age‐related dynamics of information sharing among cortical language regions with electrocorticographic high‐gamma modulation during picture‐naming and story‐listening tasks. Methods: Seventeen epilepsy patients aged 4‐19 years, undergoing extraoperative monitoring with left‐hemispheric subdural electrodes, were included. Mutual information (MI), a nondirectional measure of shared information, between 16 pairs of cortical regions of interest, was computed from trial‐averaged 70–150 Hz power modulations during language tasks. Impact of age on pairwise MI between language regions and their determinants were ascertained with regression analysis. Results: During picture naming, significant increase in MI with age was seen between pairwise combinations of Broca's area, inferior precentral gyrus (iPreC), and frontal association cortex (FAC); Wernicke's area and posterior association cortex (PAC); and Broca's and Wernicke's areas. During story listening, significant age‐related increase in MI was seen between Wernicke's area and either Broca's area, FAC, or PAC; and between Broca's area and FAC. Significant impact of baseline intelligence quotient was seen on the relationship between age and MI for all pairs, except between Broca's area and iPreC. The mean MI was higher during naming compared to listening for pairs including iPreC with Broca's area, FAC, or PAC and was lower for pairs of Wernicke's area or PAC with anterior language regions. Significance: Information sharing matures with age "within" frontal and temporoparietal language cortices, and "between" Broca's and Wernicke's areas. This study provides evidence for distinct patterns of developmental plasticity within perisylvian language cortex and has implications for planning epilepsy surgery. [ABSTRACT FROM AUTHOR]

Objective We evaluated the impact of radiotracer injection latency and post-injection seizure duration on subtraction ictal SPECT co-registered to MRI (SISCOM) test performance in identifying the epileptogenic zone (EZ) in children with drug-resistant epilepsy who had undergone a resective epilepsy surgery. Methods SISCOM concordance with the EZ was retrospectively reviewed to evaluate its performance in 113 children. The impact of radiotracer injection latency and post-injection seizure duration was evaluated for their predictive value of SISCOM localization accuracy. Results The overall sensitivity and specificity of SISCOM in identifying an EZ was 64.8% (95%CI = 50.6–77.3) and 40.7% (95%CI = 28.1–54.3). The positive likelihood ratio and diagnostic odd ratio was 1.09 (95%CI = 0.80–1.48) and 1.26 (95%CI = 0.59–2.71), respectively. Logistic regression showed that injection latency and post-injection seizure duration did not significantly predict the probability of true positive SISCOM (p-value = 0.45 and 0.29, respectively). Conclusion Radiotracer injection latency and post-injection seizure duration were not shown to have a statistical significant impact on SISCOM performance in identifying the EZ. Significance This study demonstrates that further study of factors contributing to the performance of SISCOM in EZ identification in children is needed. [ABSTRACT FROM AUTHOR]

Summary: Objective: This prospective study compared the topography of high‐gamma modulation (HGM) during a story‐listening task requiring negligible patient cooperation, with the conventional electrical stimulation mapping (ESM) using a picture‐naming task, for presurgical language localization in pediatric drug‐resistant epilepsy. Methods: Patients undergoing extraoperative monitoring with subdural electrodes were included. Electrocorticographic signals were recorded during quiet baseline and a story‐listening task. The likelihood of 70‐ to 150‐Hz power modulation during the listening task relative to the baseline was estimated for each electrode and plotted on a cortical surface model. Sensitivity, specificity, accuracy, and diagnostic odds ratio (DOR) were estimated compared to ESM, using a meta‐analytic framework. Results: Nineteen patients (10 with left hemisphere electrodes) aged 4‐19 years were analyzed. HGM during story listening was observed in bilateral posterior superior temporal, angular, supramarginal, and inferior frontal gyri, along with anatomically defined language association areas. Compared to either cognitive or both cognitive and orofacial sensorimotor interference with naming during ESM, left hemisphere HGM showed high specificity (0.82‐0.84), good accuracy (0.66‐0.70), and DOR of 2.23 and 3.24, respectively. HGM was a better classifier of ESM language sites in the left temporoparietal cortex compared to the frontal lobe. Incorporating visual naming with the story‐listening task substantially improved the accuracy (0.80) and DOR (13.61) of HGM mapping, while the high specificity (0.85) was retained. In the right hemisphere, no ESM sites for aphasia were seen, and the results of HGM and ESM comparisons were not significant. Significance: HGM associated with story listening is a specific determinant of left hemisphere ESM language sites. It can be used for presurgical language mapping in children who cannot cooperate with conventional language tasks requiring active engagement. Incorporation of additional language tasks, if feasible, can further improve the diagnostic accuracy of language localization with HGM. [ABSTRACT FROM AUTHOR]

Purpose We studied the effect of fosphenytoin (FOS) pre-medication on the incidence and thresholds of after-discharges (ADs), seizures, and functional responses during electrical stimulation mapping (ESM). Methods As individualized by the attending epileptologist, FOS was given intravenously at 2 mg-phenytoin-equivalents (PE)/kg/min or 150 mg-PE/min (whichever slower). Patients who received and did not receive FOS were compared for the incidence and thresholds of ADs, seizures, and functional responses. Results Before ESM, 40 and 82 patients respectively were pre-medicated/not pre-medicated with FOS. The incidence of ESM-induced seizures was significantly lower in FOS pre-medicated patients (22.5% vs. 42.7%, p = 0.044), whereas temporal language threshold was higher (9.2 vs. 6.5 mA, p = 0.032). FOS was more efficacious in preventing ESM-induced seizures in patients with symptomatogenic zone ipsilateral to the side of ESM. Although FOS dose had no significant effect on minimum language, minimum motor, or AD thresholds; seizure and temporal language thresholds showed trends approaching significance, intersecting at 12.2 mg-PE/kg. The incidence of ESM-induced seizures was significantly lower in those who received FOS at a dose of ≤12 mg/kg (9.1%) compared to those who did not receive any FOS (42.7%, p = 0.046), while the temporal language thresholds were not significantly different (6.3 vs. 6.5 mA, p = 0.897). Conclusions This study provides class III evidence that FOS pre-medication before ESM decreases the incidence of ESM-induced seizures, but increases temporal language threshold. FOS pre-medication may thus be considered before ESM. Future studies should prospectively verify these observations and characterize dose-response relationships. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to quantify the accuracy of 24-hour video electroencephalography (vEEG) for the diagnosis of epilepsy when a patient's typical paroxysmal event was not captured (no-event vEEG).Methods: We performed a retrospective chart review of all first-time 24 hour no-event vEEG studies at Cincinnati Children's Hospital Medical Center. Clinician diagnosis of epilepsy with a minimum of one year follow-up was used as the reference standard to calculate diagnostic accuracy. Sensitivity and specificity of routine EEG (rEEG) and vEEG were compared in patients with both studies, and factors affecting the accuracy of vEEG were explored with a multivariable analysis.Results: No-event vEEG showed sensitivity of 0.54 (95% confidence interval [CI] 0.44 to 0.64) and specificity of 0.88 (95% CI 0.84 to 0.92) respectively, with a diagnostic odds ratio of 7.53 (95% CI 4.45 to 12.76). The sensitivity of vEEG was statistically superior to that of rEEG, whereas specificity was comparable. Age emerged as the only factor that affected the diagnostic accuracy of no-event vEEG.Conclusion: Even in the absence of a typical seizure or spell, video EEG is a useful test for predicting or excluding epilepsy, with diagnostic accuracy that is superior to rEEG and unaffected by the presence of a chronic neurological condition. [ABSTRACT FROM AUTHOR]

Summary: Objective: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ‐aminobutyric acid (GABA) receptors and T‐type calcium channels implicated in the disorder. Previous studies of T‐type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T‐type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. Methods: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single‐compartment neurons, implemented with Hodgkin‐Huxley model ion channels and connected by AMPA, GABAA, and GABAB synapses. Network behavior was simulated for different combinations of T‐type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. Results: Decreasing cortical GABAA conductance and increasing T‐type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. Significance: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE. [ABSTRACT FROM AUTHOR]

Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity. Significance statement Hyperactivation of the mTOR pathway is associated with numerous neurological diseases, including autism and epilepsy. Here, we demonstrate that deletion of the mTOR negative regulator, PTEN, from a subset of hippocampal dentate granule impairs dendritic patterning, increases excitatory input and decreases inhibitory input. We further demonstrate that while granule cells from female mice receive more excitatory and inhibitory input than males, PTEN deletion produces mostly similar changes in both sexes. Together, these studies provide new insights into how the relatively small number (≈ 200,000) of PTEN knockout granule cells instigates the development of the profound epilepsy syndrome evident in both male and female animals in this model. [ABSTRACT FROM AUTHOR]

Objective This study examined the incidence, thresholds, and determinants of electrical cortical stimulation (ECS)-induced after-discharges (ADs) and seizures. Methods Electrocorticograph recordings were reviewed to determine incidence of ECS-induced ADs and seizures. Multivariable analyses for predictors of AD/seizure occurrence and their thresholds were performed. Results In 122 patients, the incidence of ADs and seizures was 77% (94/122) and 35% (43/122) respectively. Males (odds ratio [OR] 2.92, 95% CI 1.21–7.38, p = 0.02) and MRI-negative patients (OR 3.69, 95% CI 1.24–13.7, p = 0.03) were found to have higher odds of ECS-induced ADs. A significant trend for decreasing AD thresholds with age was seen (regression co-efficient −0.151, 95% CI −0.267 to −0.035, p = 0.011). ECS-induced seizures were more likely in patients with lateralized functional imaging (OR 6.62, 95% CI 1.36–55.56, p = 0.036, for positron emission tomography) and presence of ADs (OR 3.50, 95% CI 1.12–13.36, p = 0.043). Conclusions ECS is associated with a high incidence of ADs and seizures. With age, current thresholds decrease and the probability for AD/seizure occurrence increases. Significance ADs and seizures during ECS brain mapping are potentially hazardous and affect its functional validity. Thus, safer method(s) for brain mapping with improved neurophysiologic validity are desirable. [ABSTRACT FROM AUTHOR]

Objective To examine current thresholds and their determinants for language and motor mapping with extra-operative electrical cortical stimulation (ECS). Methods ECS electrocorticograph recordings were reviewed to determine functional thresholds. Predictors of functional thresholds were found with multivariable analyses. Results In 122 patients (age 11.9 ± 5.4 years), average minimum, frontal, and temporal language thresholds were 7.4 (± 3.0), 7.8 (± 3.0), and 7.4 (± 3.1) mA respectively. Average minimum, face, upper and lower extremity motor thresholds were 5.4 (± 2.8), 6.1 (± 2.8), 4.9 (± 2.3), and 5.3 (± 3.3) mA respectively. Functional and after-discharge (AD)/seizure thresholds were significantly related. Minimum, frontal, and temporal language thresholds were higher than AD thresholds at all ages. Minimum motor threshold was higher than minimum AD threshold up to 8.0 years of age, face motor threshold was higher than frontal AD threshold up to 11.8 years age, and lower subsequently. UE motor thresholds remained below frontal AD thresholds throughout the age range. Conclusions Functional thresholds are frequently above AD thresholds in younger children. Significance These findings raise concerns about safety and neurophysiologic validity of ECS mapping. Functional and AD/seizure thresholds relationships suggest individual differences in cortical excitability which cannot be explained by clinical variables. [ABSTRACT FROM AUTHOR]