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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., Competing Interests: Dr. Holland reports grants from NINDS, during the conduct of the study. Dr. Ritter has nothing to disclose., (Thieme. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Central nervous system comorbidities have been identified in patients with epilepsy. Several of these comorbidities have been correlated with poor surgery outcomes in patient cohorts. The authors sought to determine if prevalence of comorbidities in pediatric epilepsy surgery patients and their families correlate with long-term seizure outcome in a cross-sectional analysis. Three-generation pedigrees were elicited to compare family history of epilepsy, ADHD, anxiety, autism, bipolar disorder, cognitive disability, depression, migraine, and motor disability to surgery outcomes in 52 patients. Proportions of affected patients and relatives were compared to general population comorbidity rates and the patients' most recent seizure outcome classification. Patients and families had significantly higher rates of comorbidities than the general population. Poorer long-term seizure outcomes following resective surgery were associated with autism or cognitive disability in patients. Together these data support evidence for a common pathophysiological mechanism between epilepsy and central nervous system comorbidities.

Objective: Insomnia, especially maintenance insomnia, is widely prevalent in epilepsy. Although melatonin is commonly used, limited data address its efficacy. We performed a randomized, double-blind, placebo-controlled, crossover study to identify the effects of melatonin on sleep and seizure control in children with epilepsy., Methods: Eleven prepubertal, developmentally normal children aged 6-11 years with epilepsy were randomized by a software algorithm to receive placebo or a 9-mg sustained release (SR) melatonin formulation for four weeks, followed by a one-week washout and a four-week crossover condition. The pharmacy performed blinding; patients, parents, and study staff other than a statistician were blinded. The primary outcomes were sleep onset latency and wakefulness after sleep onset (WASO) measured on polysomnography. The secondary outcomes included seizure frequency, epileptiform spike density per hour of sleep on electroencephalogram (EEG), and reaction time (RT) measures on psychomotor vigilance task (PVT). Statistical tests appropriate for crossover designs were used for the analysis., Results: Data were analyzed from 10 subjects who completed the study. Melatonin decreased sleep latency (mean difference, MD, of 11.4 min and p = 0.02) and WASO (MD of 22 min and p = 0.04) as compared to placebo. No worsening of spike density or seizure frequency was seen. Additionally, slow-wave sleep duration and rapid eye movement (REM) latency were increased with melatonin and REM sleep duration was decreased. These changes were statistically significant. Worsening of headache was noted in one subject with migraine on melatonin., Conclusion: SR melatonin resulted in statistically significant decreases in sleep latency and WASO. No clear effects on seizures were observed, but the study was too small to allow any conclusions to be drawn in this regard., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: Children suffering from epilepsy with suspected low-grade tumors may benefit from a surgical approach that considers the epileptogenic zone, which can be more extensive than the tumor region. This study aimed to determine the prevalence of epilepsy in children undergoing supratentorial tumor resection and the factors predictive of postoperative seizure freedom in children with low-grade tumors., Methods: Subjects 3 months to 21 years undergoing supratentorial brain tumor resection between 2007 and 2011 were included in this retrospective study. Children with supratentorial, cortically based tumors and a preoperative diagnosis of epilepsy were considered epilepsy surgery candidates. Pre- and postoperative MRI were reviewed and scored for extent of resection, adjacent dysplasia, and remaining abnormal cortex postoperatively., Results: The prevalence of seizures in all cases of supratentorial tumors was 46/87 (53 %). Eighteen were epilepsy surgery candidates. Eight of 18 (44 %) were seizure-free postoperatively with a mean follow-up of 39 months. Children who were seizure free postoperatively had tried fewer anticonvulsants than those with continued seizures (1.7 v. 2.9, p = 0.01). Presurgical evaluation was nonstandardized, and a more extensive workup and resection were performed in children who continued to have seizures postoperatively., Conclusions: All epilepsy surgery candidates had low-grade tumors on histological evaluation, indicating that a surgical approach that takes into consideration the epileptogenic zone is reasonable in this population. Gross total resection should be the goal, with additional attention to resection of the epileptogenic zone when located in the noneloquent cortex.

Purpose: Acute post-operative seizures (APOS) after epilepsy surgery, previously believed to be benign, are increasingly associated with poor long-term prognosis. Prior literature has focused primarily on adult temporal lobe epilepsy. This retrospective study aimed to identify the prevalence, prognostic significance and risk factors for APOS in pediatric epilepsy surgery at a single center., Method: Retrospective chart review of all children aged 0-21 years undergoing resective surgery for epilepsy between 2009 and 2012 at a single center. APOS were defined as seizures within 30 days of resection. Surgical outcome was determined, using a minimum of 12 months postoperative follow-up for inclusion., Results: APOS, defined as a seizure within 30 days of resection, were identified in 50/112 (44%) of patients. APOS were a significant predictor of poor postoperative seizure outcome (ILAE 4-6); only 26% of those with APOS had a good outcome (ILAE 1-3), compared to 76% without APOS. Timing of postoperative seizure was not correlated with outcome. Most (54%) with APOS and good outcome had continued seizures between 14-30 days postoperatively. Patients with APOS after temporal (p=0.05) and extratemporal (p<0.001) resections had a significantly worse prognosis. APOS after hemispherectomy were not associated with a worse prognosis (p=0.22). Key risk factors for APOS include lack of ictal EEG lateralization to operated hemisphere/side of MRI abnormality., Conclusion: This study shows an association between APOS and poor outcome in both temporal and extratemporal pediatric epilepsy surgery. Findings support the expansion of APOS duration to 30 days., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

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., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Background: Functional hemispherectomy is effective in carefully selected patients, resulting in a reduction of seizure burden up to complete resolution, improvement of intellectual development, and developmental benefit despite possible additional neurological deficit. Despite apparent hemispheric pathology on brain magnetic resonance imaging (MRI) or other imaging tests, scalp electroencephalography (EEG) could be suggestive of bilateral ictal onset or even ictal onset contralateral to the dominant imaging abnormality. We aimed to investigate the role of scalp EEG lateralization pre-operatively in predicting outcome., Methods: We retrospectively reviewed 54 patients who underwent hemispherectomy between 1991 and 2009 at Medical College of Georgia (1991-2006) and Cincinnati Children's Hospital Medical Center (2006-2009) and had at least one year post-operative follow-up. All preoperative EEGs were reviewed, and classified as either lateralizing or nonlateralizing, for both ictal and interictal EEG recordings., Results: Of 54 patients, 42 (78%) became seizure free. Twenty-four (44%) of 54 had a nonlateralizing ictal or interictal EEG. Further analysis was based on etiology of epilepsy, including malformation of cortical development (MCD), Rasmussen syndrome (RS), and stroke (CVA). EEG nonlateralization did not predict poor outcome in any of the etiology groups evaluated., Conclusion: Scalp EEG abnormalities in contralateral or bilateral hemispheres do not, in isolation, predict a poor outcome from hemispherectomy. Results of other non-invasive and invasive evaluations should be used to determine candidacy., (2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the diagnostic value of individual noninvasive presurgical modalities and to study their role in surgical management of nonlesional pediatric epilepsy patients., Methods: We retrospectively studied 14 children (3-18 years) with nonlesional intractable focal epilepsy. Clinical characteristics, surgical outcome, localizing features on 3 presurgical diagnostic tests (subtraction peri-ictal SPECT coregistered to MRI [SISCOM], statistical parametric mapping [SPM] analysis of [18F] FDG-PET, magnetoencephalography [MEG]), and intracranial EEG (iEEG) were reviewed. The localization of each individual test was determined for lobar location by visual inspection. Concordance of localization between each test and iEEG was scored as follows: 2=lobar concordance; 1=hemispheric concordance; 0=discordance or nonlocalization. Total concordance score in each patient was measured by the summation of concordance scores for all 3 tests., Results: Seven (50%) of 14 patients were seizure-free for at least 12 months after surgery. One (7%) had only rare seizures and 6 (43%) had persistent seizures. MEG (79%, 11/14) and SISCOM (79%, 11/14) showed greater lobar concordance with iEEG than SPM-PET (13%, 3/14) (p<0.05). SPM-PET provided hemispheric lateralization (71%, 10/14) more often than lobar localization. Total concordance score tended to be greater for seizure-free patients (4.7) than for non-seizure-free patients (3.9)., Conclusions: Our data suggest that MEG and SISCOM are better tools for lobar localization than SPM analysis of FDG-PET in children with nonlesional epilepsy. A multimodality approach may improve surgical outcome as well as selection of surgical candidates in patients without MRI abnormalities.

Epilepsy is frequent in early childhood, but poorly understood. Management of very young children with refractory epilepsy is particularly challenging, but recent advances in classification, medical therapy, and surgical treatment are helping. We summarize work in each area, focusing on developments in the past 2 years. Classification schemes unique to the needs of very young children will likely improve our ability to accurately diagnose and treat those with refractory seizures. Medication studies are now being done that address some of the specific epilepsy syndromes seen in infants and young children, with promising results in some circumstances. Progress is also being made in the identification of good candidates for early, effective epilepsy surgery. For a variety of reasons and incentives, it is likely that research focusing on infants and young children will continue at a brisk pace.

This article discusses the factors involved in the appropriate selection of anticonvulsant medications. The clinical use of commonly used traditional antiepileptic drugs and the newly marketed antiepileptic drugs is discussed. This includes the specific indications for use, adverse effects, and dosing of each drug. Drug interactions, mechanisms of action, and pharmacological properties of each drug is also reviewed.

Anticonvulsant properties of alpha-ethyl-alpha-methyl-gamma-thiobutyrolactone (alpha-EMTBL) were compared with those of the antiepileptic drugs ethosuximide (ESM) and valproate (VPA) by testing their ability to block seizures in mice caused by maximal electroshock (MES), pentylenetetrazol (PTZ), picrotoxin (PICRO), bicuculline (BIC), methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-D,L-aspartate (NMDA), aminophylline (AMPH), strychnine (STR), beta-ethyl-beta-methyl-gamma-thiobutyrolactone (beta-EMTBL), and t-butylbicyclophosphorothionate (TBPS). ESM was able to prevent PTZ-, PICRO-, DMCM-, and beta-EMTBL-induced seizures. In contrast, VPA and alpha-EMTBL blocked all of these plus MESTBPS-, and BIC-induced convulsions. Only VPA prevented AMPH-induced seizures. None of the anticonvulsants blocked STR or NMDA seizures. Rotorod testing for acute neurotoxicity demonstrated that ESM was the least toxic and alpha-EMTBL and VPA were equivalent. Animals treated daily with high doses of alpha-EMTBL for a 2-week period appeared healthier and had a higher survival rate than animals treated with VPA in the same manner. After a single intraperitoneal (i.p.) injection, the duration of anticonvulsant action of alpha-EMTBL was 1.3 and 4 times longer than that of ESM and VPA, respectively. These results indicate that alpha-EMTBL has a wide spectrum of anticonvulsant action like VPA but may be less toxic and longer acting. We suggest that alpha-EMTBL is a compound worthy of further testing and development as an antiepileptic drug (AED).

Holland KD, Monahan S, Morita D, Vartzelis G, Glauser TA. Valproate in children with newly diagnosed idiopathic generalized epilepsy. Acta Neurol Scand: 2010: 121: 149–153. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – Sparse information on dose–response characteristics for initial antiepileptic drug monotherapy in children with idiopathic generalized epilepsy (IGE) is available. The aim of this study is to characterize the therapeutic dose of valproate in children with newly diagnosed IGE. Materials and methods – Effect of initial valproate monotherapy and doses associated with seizure freedom were examined in consecutive children with IGE identified from a New Onset Seizure Clinic. Results – Of 84 patients identified, 48 (57%) became seizure-free on valproate monotherapy and another 10 patients became seizure-free but discontinued VPA because of adverse effects. The mean dose in seizure-free children was 15.7 mg/kg/day and over 95% of IGE patients will respond below 25 mg/kg/day. Conclusions – Half of children became seizure-free on valproate monotherapy and did so at modest doses. [ABSTRACT FROM AUTHOR]