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Efficacy of Levetiracetam, Fosphenytoin, and Valproate for Established Status Epilepticus by Age Group (ESETT): A Double-Blind, Responsive-Adaptive, Randomised Controlled Trial.Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP, Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E, Connor JT, and Silbergleit R, Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators. Lancet. 2020;395(10231):1217-1224. doi:https://europepmc.org/article/med/32203691Background:Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying etiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT), we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here, we describe our results after extending enrolment in children to compare outcomes in 3 age groups.Methods:In this multicenter, double-blind, response-adaptive, randomized controlled trial, we recruited patients from 58 hospital emergency departments across the United States. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalized convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 minutes after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods, and stratified by age-group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional anti-seizure medication at 1 hour from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analyzed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.Findings:Between November 3, 2015, and December 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). One hundred seventy-five (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenytoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age-group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age-group.Interpretation:Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the 3 drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.Randomized Trial of Three Anticonvulsant Medications for Status EpilepticusKapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R, NETT, and PECARN Investigators. N Engl J Med. 2019;381(22):2103-2113. doi:10.1056/NEJMoa1905795Background:The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.Methods:In a randomized, blinded, adaptive trial, we compared the efficacy and safety of 3 intravenous anticonvulsive agents—levetiracetam, fosphenytoin, and valproate—in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.Results:A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39-55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36-54), and 56 patients assigned to valproate (46%; 95% credible interval, 38-55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically, more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.Conclusions:In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the 3 drugs were associated with similar incidences of adverse events (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

The Effects of Direct Brain Stimulation in Humans Depend on Frequency, Amplitude, and White-Matter Proximity Mohan U, Watrous A, Miller J, et al. Brain Stimul. 2020;13(5):1183-1195. doi:10.1016/j.brs.2020.05.009Background:Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes.Objective:The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain.Methods:To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically across a range of parameters and locations.Results:Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity.Conclusion:By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

Association of Levels of Specialized Care With Risk of Premature Mortality in Patients With Epilepsy Lowerison MW, Josephson CB, Jetté N, et al. JAMA Neurol. 2019;76:1352-1358.Importance:Patients with epilepsy are at an elevated risk of premature mortality. Interventions to reduce this risk are crucial.Objective:To determine if the level of care (non-neurologist, neurologist, or comprehensive epilepsy program) is negatively associated with the risk of premature mortality.Design, Setting, and Participants:In this retrospective open cohort study, all adult patients 18 years or older who met the administrative case definition for incident epilepsy in linked databases (Alberta Health Services administrative health data and the Comprehensive Calgary Epilepsy Programme Registry [CEP]) inclusive of the years 2002 to 2016 were followed up until death or loss to follow-up. The final analyses were performed on May 1, 2019.Exposures:Evaluation by a non-neurologist, neurologist, or epileptologist.Main Outcomes and Measures:The outcome was all-cause mortality. We used extended Cox models treating exposure to a neurologist or the CEP as time-varying covariates. Age, sex, socioeconomic deprivation, disease severity, and comorbid burden at index date were modeled as fixed-time coefficients.Results:A total 23 653 incident cases were identified (annual incidence of 89 per 100 000); the mean age (SD) at index date was 50.8 (19.1) years and 12 158 (50.3%) were women. A total of 14 099 (60%) were not exposed to specialist neurological care, 9554 (40%) received care by a neurologist, and 2054 (9%) received care in the CEP. In total, 4098 deaths (71%) occurred in the nonspecialist setting, 1481 (26%) for those seen by a neurologist, and 176 (3%) for those receiving CEP care. The standardized mortality rate was 7.2% for the entire cohort, 9.4% for those receiving nonspecialist care, 5.6% for those seen by a neurologist, and 2.8% for those seen in the CEP. The hazard ratio (HR) of mortality was lower in those receiving neurologist (HR, 0.85; 95% CI, 0.77-0.93) and CEP (HR, 0.49; 95% CI, 0.38-0.62) care. In multivariable modeling, specialist care, the age at index, and disease severity were retained in the final model of the association between specialist care and mortality.Conclusions and Relevance:Exposure to specialist care is associated with incremental reductions in the hazard of premature mortality. Those referred to a comprehensive epilepsy program received the greatest benefit.

Diagnostic Exome Sequencing in 100 Consecutive Patients With Both Epilepsy and Intellectual Disability Snoeijen-Schouwenaars FM, van Ool JS, Verhoeven JS, et al. Epilepsia. 2019;60(1):155-164. doi:10.1111/epi.14618. Epub December 7, 2018. PMID: 30525188.Objective:Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole-exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy.Methods:One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. Whole-exome sequencing analysis was performed in 2 steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so-called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. Results: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 (40%) of 25 patients with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future.Significance:This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. Diagnostic Yield of Genetic Tests in Epilepsy: A Meta-Analysis and Cost-Effectiveness Study Sánchez Fernández I, Loddenkemper T, Gaínza-Lein M, Sheidley BR, Poduri A. Neurology. 2019. Epub ahead of print. pii: 10.1212/WNL.0000000000006850. doi:10.1212/WNL.0000000000006850. PMID: 30610098 Objective:To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.Methods:This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing”“ as a point of comparison.Results:Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57; 0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29) and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of US$15 000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: US$15 848/diagnosis) followed by WES (ICER: US$34 500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: US$15 336/diagnosis); although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: US$18 385/diagnosis). Although the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.Conclusion:Whole-exome sequencing and EP are the most cost-effective genetic tests for epilepsy. Our analyses support for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage AdjustmentAícua-Rapún I, André P, Rossetti AO, et al. Ann Neurol. 2020;87(1):22-29. doi:10.1002/ana.25641.Objective:Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy. Methods: We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study end point was reached (inefficacy or adverse events). The primary outcome was the proportion of participants who followed 1 year without reaching one of the predefined end points. Results: A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, P = .6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit. Interpretation: This study provides class A evidence that systematic drug-level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues.

Abnormal Temporal Lobe Morphology in Asymptomatic Relatives of Patients With Hippocampal Sclerosis: A Replication Study Yaakub SN, Barker GJ, Carr SJ, et al. Epilepsia. 2019;60(1):e1-e5. doi:10.1111/epi.14575. We investigated gray and white matter morphology in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE + HS) and first-degree asymptomatic relatives of patients with mTLE+HS. Using T1-weighted magnetic resonance imaging (MRI), we sought to replicate previously reported findings of structural surface abnormalities of the anterior temporal lobe in asymptomatic relatives of patients with mTLE+HS in an independent cohort. We performed whole-brain MRI in 19 patients with mTLE+HS, 14 first-degree asymptomatic relatives of patients with mTLE+HS, and 32 healthy control participants. Structural alterations in patients and relatives compared to controls were assessed using automated hippocampal volumetry and cortical surface-based morphometry. We replicated previously reported cortical surface area contractions in the ipsilateral anterior temporal lobe in both patients and relatives compared to healthy controls, with asymptomatic relatives showing similar but less extensive changes than patients. These findings suggest morphologic abnormality in asymptomatic relatives of patients with mTLE+HS, suggesting an inherited brain structure endophenotype.

Randomized Placebo-Controlled Trial of Intravenous Immunoglobulin in Autoimmune LGI1/CASPR2 Epilepsy Dubey D, Britton J, Mckeon A, et al. Ann Neurol. 2019;87(2):313-323. doi:10.1002/ana.25655.Objective:Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1) immunoglobulin (IgG)-associated and contactin-associated protein-like 2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency.Methods:Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per week. Patients were randomized to receive IVIG (0.5 g/kg, day 1; 1 g/kg, day 2; 0.6 g/kg weeks 3 and 5) or volume-matched IV normal saline. Following the blinded phase, the nonresponders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks.Results:After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated due to slow enrollment. Six of 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (P = .044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). For the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders, compared to 0 of 6 in the placebo group. Two LGI1-IgG-seropositive patients receiving IVIG, but none receiving placebo, were seizure-free at the end of the blinded phase. Four of the 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses.Interpretation:Superiority of IVIG to placebo reached statistical significance for the primary end point for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size.

Background: Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. Methods: We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Findings: Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p

Association of Cortical Stimulation-Induced Seziure With Surgical Outcome in Patients With Focal Drug-Resistant EpilepsyCuello Oderiz C, von Ellenrieder N, Dubeau F, et al. JAMA Neurol. 2019.Import...

EEG Reactivity as Predictor of Neurological Outcome in Postanoxic Coma: A Multicenter Prospective Cohort StudyAdmiraal MM, van Rootselaar AF, Hofmeijer J, Hoedemaekers CWE, van Kaam CR, Keijzer HM,...

Safety and Efficacy of Midazolam Nasal Spray in the Outpatient Treatment of Patients With Seizure Clusters—A Randomized, Double-Blind, Placebo-Controlled Trial. Detyniecki K, Van Ess PJ, Sequeira DJ, Wheless JW, Meng TC, Pullmnaan WE. Epilepsia. 2019. doi:10.1111/epi.15159. Epub ahead of print.Objective:To evaluate the safety and efficacy of a novel formulation of midazolam administered as a single-dose nasal spray (MDZ-NS) in the outpatient treatment of patients experiencing seizure clusters (SCs).Methods:This was a phase III, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov NCT01390220) with patients aged ≥12 years on a stable regimen of antiepileptic drugs. Following an in-clinic test dose phase (TDP), patients entered an outpatient comparative phase (CP) and were randomized (2:1) to receive double-blind MDZ-NS 5 mg or placebo nasal spray, administered by caregivers when they experienced an SC. The primary efficacy end point was treatment success (seizure termination within 10 minutes and no recurrence 10 minutes to 6 hours after trial drug administration). Secondary efficacy end points were proportion of patients with seizure recurrence 10 minutes to 4 hours and time to next seizure >10 minutes after double-blind drug administration. Safety was monitored throughout.Results:Of 292 patients administered a test dose, 262 patients were randomized and 201 received double-blind treatment for an SC (n = 134 MDZ-NS, n = 67 placebo, modified intent-to-treat population). A significantly greater proportion of MDZ-NS than placebo-treated patients achieved treatment success (53.7% vs 34.4%; P = .0109). Significantly, fewer MDZ-NS- than placebo-treated patients experienced seizure recurrence (38.1% vs 59.7%; P = .0043). Time-to-next seizure analysis showed early separation (within 30 minutes) between MDZ-NS and placebo that was maintained throughout the 24-hour observation period (21% difference at 24 hours; P = .0124). Sixteen (5.5%) patients discontinued because of a treatment-emergent adverse event (TEAE) during the TDP and none during the CP. During the CP, 27.6% and 22.4% of patients in the MDZ-NS and placebo groups, respectively, experienced ≥1 TEAE.Significance:The MDZ-NS was superior to placebo in providing rapid, sustained seizure control when administered to patients experiencing an SC in the outpatient setting and was associated with a favorable safety profile.

Levetiracetam Versus Phenytoin for Second-Line Treatment of Pediatric Convulsive Status Epilepticus (EcLiPSE): A Multicentre, Open-Label, Randomized Trial Lyttle MD, Rainford NEA, Gamble C, Messahel S, Humphreys A, Woolfall K, Roper L, Nablet J, Lee ED, Potter S, Tate P, Iyer A, Evans V, Appleton RE. Lancet. 2019;393:2125-34. doi:10.1016/S0140-6736(19)30724-X.Background:Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the United Kingdom; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of pediatric convulsive status epilepticus.Methods:This open-label, randomized clinical trial was undertaken at 30 United Kingdom emergency departments at secondary and tertiary care centers. Participants aged 6 months to less than 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomization schedule to receive levetiracetam (40 mg/kg over 5 minutes) or phenytoin (20 mg/kg over at least 20 minutes), stratified by centre. The primary outcome was time from randomization to cessation of convulsive status epilepticus, analyzed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomization and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings:Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomized participants were treated and had available data: 152 allocated to levetiracetam and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomization to cessation of convulsive status epilepticus was 35 minutes (interquartile range: 20 to not assessable) in the levetiracetam group and 45 minutes (24 to not assessable) in the phenytoin group (hazard ratio: 1.20, 95% confidence interval: 0·91-1.60; P = .20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral edema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]).Interpretation:Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of pediatric convulsive status epilepticus. Levetiracetam Versus Phenytoin for Second-Line Treatment of Convulsive Status Epilepticus in Children (ConSEPT): An Open-Label, Multicentre, Randomized Controlled Trial Dalziel SR, Borland ML, Furyk J, Bonisch M, Neutze J, Donath S, Francis KL, Sharpe C, Harvey AS, Davidson A, Craig S, Phillips N, George S, Rao A, Cheng N, Zhang M, Kochar A, Brabyn C, Oakley E, Babl FE. Lancet. 2019;393:2135-45. doi:10.1016/S0140-6736(19)30722-6.Background:Phenytoin is the current standard of care for second-line treatment of pediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for pediatric convulsive status epilepticus.Methods:ConSEPT was an open-label, multicenter, randomized controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus who failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes: 2 and 4) randomization sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 minutes) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 minutes). The primary outcome was clinical cessation of seizure activity 5 minutes after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583.Findings:Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 minutes after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference: −9.2% [95% confidence interval: −21.9 to 3.5]; P = .16). One participant in the phenytoin group died at 27 days because of hemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events.Interpretation:Levetiracetam is not superior to phenytoin for second-line management of pediatric convulsive status epilepticus.

Effects of Surgical Targeting in Laser Interstitial Thermal Therapy for Mesial Temporal Lobe Epilepsy: A Multicenter Study of 234 Patients Wu C, Jermakowicz WJ, Chakravorti S, Cajigas I, Sharan AD, Jagid JR, Matias CM, Sperling MR, Buckley R, Ko A, Ojemann JG, Miller JW, Youngerman B, Sheth SA, McKhann GM, Laxton AW, Couture DE, Popli GS, Smith A, Mehta AD, Ho AL, Halpern CH, Englot DJ, Neimat JS, Konrad PE, Neal E, Vale FL, Holloway KL, Air EL, Schwalb J, Dawant BM, D′Haese PF. Epilepsia. 2019;60(6):1171-1183. doi:10.1111/epi.15565.Objective:Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78%, with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited 3-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE.Methods:This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively.Results:Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome.Significance:Laser interstitial thermal therapy is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control.

We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability.Thirty-five adults (mean age: 37.5 ± 10.9 years, 13 males) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative magnetic resonance imaging tissue map comparison. This mask provided the following: (a) resection volume, (b) overlap between resection and preoperative activation, and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance.Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjustedResection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection.

Blood Markers of Cardiac Stress After Generalized Convulsive Seizures. Nass RD, Motloch LJ, Paar V, Lichtenauer M, Baumann J, Zur B, Hoppe UC, Holdenrieder S, Elger CE, Surges R.Adult patients with refractory epilepsy who underwent video-electroencephalography monitoring along with simultaneous one-lead electrocardiography recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high-sensitivity troponin T [hsTNT]; N-terminal prohormone of brain natriuretic peptide; copeptin; suppression of tumorigenicity-2 [SST-2]; growth differentiation factor 15, [GDF-15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart-type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Peri-ictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals (QTc).Thirty-six GCS (6 generalized-onset tonic-clonic seizures and 30 focal to bilateral tonic-clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than 2-fold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 (10%) of 30 patients and 6 (26%) of 23 patients, respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST-2, HFABP, and GDF-15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient.The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. Soluble urokinase plasminogen activator receptor may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS but specificity needs to be tested.

Infantile spasms of unknown cause: predictors of outcome and genotype-phenotype correlation Yuskaitis CJ, Ruzhnikov MRZ, Howell KB, et al. Pediatr Neurol. 2018;87:48–56. doi:10.1016/j.pediatrneurol.2018.04.012. Epub 2018 May 7.Background:No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project (EPGP) aimed to characterize IS of unknown cause by phenotype and genotype analysis.Methods:We undertook a retrospective multicenter observational cohort of 133 individuals within the EPGP database met criteria for IS of unknown cause with at least 6 months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined.Results:Normal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS (P < .001), older age of IS onset (median 6 months old), and resolution of IS after initial treatment (P < .001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS (P = .018), earlier age of IS onset (median 5 months old), and refractory IS (P = .008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes (P = .035).Conclusions:The current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.

Long-Term Outcomes of Reoperations in Epilepsy Surgery Yardi R, Morita-Sherman ME, Fitzgerald Z, et al. Epilepsia. 2020;61(3):465-470. https://pubmed.ncbi.nlm.nih.gov/32108946/ Objective:To analyze longitudinal seizure outcomes following epilepsy surgery, including reoperations, in patients with intractable focal epilepsy.Methods:Clinicoradiological characteristics of patients who underwent epilepsy surgery from 1995 to 2016 with follow-up of ≥1 year were reviewed. In patients undergoing reoperations, the latest resection was considered the index surgery. The primary outcome was complete seizure freedom (Engel I) at last follow-up. Potentially significant outcome variables were first identified using univariate analyses and then fit in multivariate Cox proportional hazards models.Results:Of 898 patients fulfilling study criteria, 110 had reoperations: 92 had one resection prior to the index surgery and 18 patients had 2 or more prior resective surgeries. Two years after the index surgery, 69% of patients with no prior surgeries had an Engel score of I, as opposed to only 42% of those with one prior surgery, and 33% of those with 2 or more prior resections (P < .001). Among surgical outcome predictors, the number of prior epilepsy surgeries, female sex, lesional initial magnetic resonance imaging, no prior history of generalization, and pathology correlated with better seizure outcomes on univariate analysis. However, only sex (P = .011), history of generalization (P = .016), and number of prior surgeries (P = .002) remained statistically significant in the multivariate model.Significance:Although long-term seizure control is possible in patients with failed prior epilepsy surgery, the chances of success diminish with every subsequent resection. Outcome is additionally determined by inherent biological markers (sex and secondary generalization tendency), rather than traditional outcome predictors, supporting a hypothesis of “surgical refractoriness.”

Neurofeedback Impacts Cognition and Quality of Life in Pediatric Focal Epilepsy: An Exploratory Randomized Double-Blinded Sham-Controlled Trial Morales-Quezada L, Martinez D, El-Hagrassy MM, et al. Epilepsy Behav. 2019;101(pt A):106570. doi:10.1016/j.yebeh.2019.106570.Objective:Children with epilepsy experience cognitive deficits and well-being issues that have detrimental effects on their development. Pharmacotherapy is the standard of care in epilepsy; however, few interventions exist to promote cognitive development and to mitigate disease burden. We aimed to examine the impact of 2 different modalities of neurofeedback (NFB) on cognitive functioning and quality of life (QOL) measurements in children and adolescents with controlled focal epilepsy. The study also explored the effects of NFB on clinical outcomes and electroencephalography (EEG) quantitative analysis.Methods:Participants (n = 44) with controlled focal epilepsy were randomized to 1 of 3 arms: sensorimotor rhythm (SMR) NFB (n = 15), slow cortical potentials (SCP) NFB (n = 16), or sham NFB (n = 13). All participants received 25 sessions of intervention. The attention switching task (AST), Liverpool Seizure Severity Scale, seizure frequency, EEG power spectrum, and coherence were measured at baseline, postintervention, and at 3-month follow-up.Results:In children and adolescents with controlled focal epilepsy, SMR training significantly reduced reaction time in the AST (P = .006), and this was correlated with the difference of change for θ power on EEG (P = .03); only the SMR group showed a significant decrease in β coherence (P = .03). All groups exhibited improvement in QOL (P ≤ .05).Conclusions:This study provides the first data on 2 NFB modalities (SMR and SCP) including cognitive, neurophysiological, and clinical outcomes in pediatric epilepsy. Sensorimotor rhythm NFB improved cognitive functioning, while all the interventions showed improvements in QOL, demonstrating a powerful placebo effect in the sham group.

The aim of epilepsy surgery in patients with focal, pharmacoresistant epilepsies is to remove the complete epileptogenic zone to achieve long-term seizure freedom. In addition to a spectrum of diagnostic methods, magnetoencephalography focus localization is used for planning of epilepsy surgery. We present results from a retrospective observational cohort study of 1000 patients, evaluated using magnetoencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecutive cases were included in the study, evaluated at the University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to 20 years. Sensitivity for interictal epileptic activity was evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar level. We evaluate magnetoencephalography characteristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In operated patients, resection of magnetoencephalography localizations were related to postsurgical seizure outcomes, including long-term results after several years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic accuracy were calculated for magnetoencephalography resection and lesionectomy. Sensitivity for interictal epileptic activity was 72% with significant differences between temporal and extra-temporal lobe epilepsy. Magnetoencephalography was concordant with the presurgical consensus in 51% and showed additional or more focal involvement in an additional 32%. Patients who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography results. Complete magnetoencephalography resection was associated with significantly higher chances to achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and extra-temporal lobe cases, but was significantly higher in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-lesional versus lesional cases (42.0 versus 6.2). The results show that magnetoencephalography provides non-redundant information, which significantly contributes to patient selection, focus localization and ultimately long-term seizure freedom after epilepsy surgery. Specifically in extra-temporal lobe epilepsy and non-lesional cases, magnetoencephalography provides excellent accuracy.

Electromagnetic Source Imaging in Presurgical Workup of Patients With Epilepsy: A Prospective Study. Duez L, Tankisi H, Hansen PO, et al. Neurology. 2019;92(6):e576-e586. doi:10.1212/WNL.0000000000006877. Epub 2019 Jan 4. PMID: 30610090Objective:To determine the diagnostic accuracy and clinical utility of electromagnetic source imaging (EMSI) in presurgical evaluation of patients with epilepsy.Methods:We prospectively recorded magnetoencephalography (MEG) simultaneously with electroencephalogram (EEG) and performed EMSI, comprising electric source imaging, magnetic source imaging, and analysis of combined MEG-EEG data sets, using 2 different software packages. As reference standard for irritative zone (IZ) and seizure onset zone (SOZ), we used intracranial recordings and for localization accuracy outcome 1 year after operation.Results:We included 141 consecutive patients. Electromagnetic source imaging showed localized epileptiform discharges in 94 (67%) patients. Most (72%) of the epileptiform discharge clusters were identified by both modalities, 15% only by EEG, and 14% only by MEG. Agreement was substantial between inverse solutions and moderate between software packages. Electromagnetic source imaging provided new information that changed the management plan in 34% of the patients, and these changes were useful in 80%. Depending on the method, EMSI had a concordance of 53% to 89% with IZ and 35% to 73% with SOZ. Localization accuracy of EMSI was between 44% and 57% which was not significantly different from magnetic resonance imaging (49%-76%) and PET (54%-85%). Combined EMSI achieved significantly higher odds ratio compared to electric source imaging and magnetic source imaging.Conclusion:Electromagnetic source imaging has accuracy similar to established imaging methods and provides clinically useful, new information in 34% of the patients.Classification of evidence:This study provides class IV evidence that EMSI had a concordance of 53% to 89% and 35% to 73% (depending on analysis) for the localization of epileptic focus when compared to intracranial recordings (IZ and SOZ), respectively.

Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies Lagarde S, Roehri N, Lambert I, et al. Brain. 2018;141(10):2966-2980.Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional magnetic resonance imaging (MRI)-based functional connectivity. Few studies have used electrophysiology, despite its high-temporal capacities. In particular, stereotactic-electroencephalogram (EEG) is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed toward temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with postsurgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using nonlinear correlation. We focused on 3 zones defined by stereotactic-EEG ictal activity: the epileptogenic zone (EZ), the propagation zone (PZ), and the noninvolved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analyzed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially postsurgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (1) a gradual decrease in the within-zone functional connectivity with higher values for EZ and PZ, and lower for noninvolved zones; (2) preferential coupling between structures of the EZ; (3) preferential coupling between EZ and PZ; and (4) poorer postsurgical outcome in patients with higher functional connectivity of non-involved zone (within-noninvolved zone, between noninvolved zone, and PZ functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (EZ and PZ) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer postsurgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures. Dynamic brain network states in human generalized spike-wave discharges Tangwiriyasakul C, Perani S, Centeno M, et al. Brain. 2018;141(10):2981-2994.Generalized spike-wave discharges in idiopathic generalized epilepsy are conventionally assumed to have abrupt onset and offset. However, in rodent models, discharges emerge during a dynamic evolution of brain network states, extending several seconds before and after the discharge. In human idiopathic generalized epilepsy, simultaneous EEG and functional MRI shows cortical regions may be active before discharges, and network connectivity around discharges may not be normal. Here, in human idiopathic generalized epilepsy, we investigated whether generalized spike-wave discharges emerge during a dynamic evolution of brain network states. Using EEG-functional MRI, we studied 43 patients and 34 healthy control subjects. We obtained 95 discharges from 20 patients. We compared data from patients with discharges with data from patients without discharges and healthy controls. Changes in MRI (blood oxygenation level dependent) signal amplitude in discharge epochs were observed only at and after EEG onset, involving a sequence of parietal and frontal cortical regions then thalamus (P < .01, across all regions and measurement time points). Examining MRI signal phase synchrony as a measure of functional connectivity between each pair of 90 brain regions, we found significant connections (P < .01, across all connections and measurement time points) involving frontal, parietal and occipital cortex during discharges, and for 20 seconds after EEG offset. This network prominent during discharges showed significantly low synchrony (below 99% confidence interval for synchrony in this network in nondischarge epochs in patients) from 16 seconds to 10 seconds before discharges, then ramped up steeply to a significantly high level of synchrony 2 seconds before discharge onset. Significant connections were seen in a sensorimotor network in the minute before discharge onset. This network also showed elevated synchrony in patients without discharges compared to healthy controls (P = .004). During 6 seconds prior to discharges, additional significant connections to this sensorimotor network were observed, involving prefrontal, and precuneus regions. In healthy subjects, significant connections involved a posterior cortical network. In patients with discharges, this posterior network showed significantly low synchrony during the minute prior to discharge onset. In patients without discharges, this network showed the same level of synchrony as in healthy controls. Our findings suggest persistently high sensorimotor network synchrony, coupled with transiently (at least 1 minute) low posterior network synchrony, may be a state predisposing to generalized spike-wave discharge onset. Our findings also show that EEG onset and associated MRI signal amplitude change is embedded in a considerably longer period of evolving brain network states before and after discharge events.

Standards for testing and clinical validation of seizure detection Beniczky S, Ryvlin P. Epilepsia. 2018;59(S1):9-13. https://doi.org/10.1111/epi.14049To increase the quality of studies on seizure detection devices, we propose standards for testing and clinical validation of such devices. We identified 4 key features that are important for studies on seizure detection devices: subjects, recordings, data analysis and alarms, and reference standard. For each of these features, we list the specific aspects that need to be addressed in the studies, and depending on these, studies are classified into 5 phases (0-4). We propose a set of outcome measures that need to be reported, and we propose standards for reporting the results. These standards will help in designing and reporting studies on seizure detection devices, they will give readers clear information on the level of evidence provided by the studies, and they will help regulatory bodies in assessing the quality of the validation studies. These standards are flexible, allowing classification of the studies into one of the 5 phases. We propose actions that can facilitate development of novel methods and devices. User-based evaluation of applicability and usability of a wearable accelerometer device for detecting bilateral tonic-clonic seizures: a field study Meritam P, Ryvlin P, Beniczky S. Epilepsia. 2018;59(S1):48-52. https://doi.org/10.1111/epi.14051Clinical validation studies of seizure detection devices conducted in epilepsy monitoring units (EMUs) can be biased by the artificial environment. We report a field (phase 4) study of a wearable accelerometer device (Epi-Care) that has previously been validated in EMUs for detecting bilateral tonic–clonic seizures (BTCS). Seventy-one patients using the device (or their caregivers) completed the modified Post-Study System Usability Questionnaire. Median time patients had been using the device was 15 months (range = 24 days to 6 years). In 10% of cases, patients stopped using the device due to reasons related to the device. The median sensitivity (90%) and false alarm rate (0.1/day) were similar to what had been determined in EMUs. Patients and caregivers were overall satisfied with the device (median = 5.5 on the 7-point Likert scale), considered the technical aspects satisfactory, and considered the device comfortable and efficient. Adverse effects occurred in 11% but were only mild: skin irritation at the wrist and interference with home electronic appliances. In 55%, the device influenced the number of seizures logged into the seizure diary, and in 40%, it contributed to fewer seizure-related injuries. This field study demonstrates the applicability and usability of the wearable accelerometer device for detecting BTCS. Wearable devices for sudden unexpected death in epilepsy prevention Ryvlin P, Ciumas C, Wisniewski I, Beniczky S. Epilepsia. 2018;59(S1):61-66. https://doi.org/10.1111/epi.14054Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic–clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. Generalized tonic–clonic seizures–triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP. The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS, duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia. The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. N Engl J Med. 2018;378:1888-1897.Background:Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.Methods:In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2-55 years) who had had 2 or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of 20 mg/kg of body weight (20-mg cannabidiol group) or 10 mg/kg (10-mg cannabidiol group) or matching placebo, administered in 2 equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.Results:A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percentage reduction from baseline in drop seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P = .005 for the 20-mg cannabidiol group vs placebo group, and P = .002 for the 10-mg cannabidiol group vs placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.Conclusions:Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 or 20 mg/kg/d to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560.) Long-Term Safety and Treatment Effects of Cannabidiol in Children and Adults With Treatment-Resistant Epilepsies: Expanded Access Program Results Szaflarski JP, Bebin EM, Comi AM, et al; CBD EAP Study Group. Epilepsia. 2018;59(8):1540-1548.Objective:Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.Methods:Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2 to 10 mg/kg/d, titrated to a maximum dose of 25 to 50 mg/kg/d. Patient visits were every 2 to 4 weeks through 16 weeks and every 2 to 12 weeks thereafter. Efficacy end points included the percentage change from baseline in median monthly convulsive and total seizure frequency and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures versus baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.Results:Of 607 patients in the safety data set, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. Cannabidiol was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).Significance:Results from this ongoing EAP support previous observational and clinical trial data, showing that add-on CBD may be an efficacious long-term treatment option for TRE. Randomized, Dose-Ranging Safety Trial of Cannabidiol in Dravet Syndrome Devinsky O, Patel AD, Thiele EA, et al; GWPCARE1 Part A Study Group. Neurology. 2018;90(14):e1204-e1211.Objective:To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.Methods:Patients aged 4 to 10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, electrocardiograms, adverse events (AEs), seizure frequency, and suicidality.Results:Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose proportional (AUC0-t). Cannabidiol did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.Conclusions:Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. Cannabidiol resulted in more AEs than placebo but was generally well tolerated.Classification of Evidence:This study provides class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well tolerated.

To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE).The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure.A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]).Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE.NCT00088452.This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.

Determine the accuracy and confidence of critical care medicine providers to identify seizures using amplitude-integrated electroencephalography versus amplitude-integrated electroencephalography combined with color density spectral array electroencephalography (aEEG + CDSA).Tutorial and questionnaire.PICU.Pediatric critical care providers (attendings, fellows, and nurses).A standardized powerpoint tutorial on amplitude-integrated electroencephalography and color density spectral array followed by classification of 100 amplitude-integrated electroencephalography images and 100 amplitude-integrated electroencephalography combined with color density spectral array as displaying seizures or not displaying seizures.Electroencephalography tracings were obtained from children monitored with continuous electroencephalography after cardiac arrest. The gold standard for seizure identification was continuous electroencephalography interpretation by a pediatric electroencephalographer. The same electroencephalography tracings were used to generate images containing only amplitude-integrated electroencephalography or aEEG + CDSA. Twenty-three critical care medicine providers underwent a 30-minute tutorial on amplitude-integrated electroencephalography and color density spectral array interpretation. They were then asked to determine if there were seizures on 100 amplitude-integrated electroencephalography images and 100 aEEG + CDSA. Amplitude-integrated electroencephalography seizure detection sensitivity was 77% (95% CI, 73%-80%), specificity of 65% (95% CI, 62%-67%), negative predictive value of 88% (95% CI, 86%-90%), and positive predictive value of 46% (95% CI, 43%-49%). For aEEG + CDSA, sensitivity was 77% (95% CI, 74%-81%), specificity of 68% (95% CI, 66%-71%), negative predictive value of 89% (95% CI, 87%-90%), and positive predictive value of 49% (95% CI, 46%-52%). Sensitivity for status epilepticus detection was 77% (95% CI, 71%-82%) with amplitude-integrated electroencephalography and 75% (95% CI, 69%-81%) with aEEG + CDSA. The addition of color density spectral array to amplitude-integrated electroencephalography did not improve seizure detection. However, 87% of critical care medicine providers qualitatively felt that combining both modalities increased their ability to detect seizures.Amplitude-integrated electroencephalography and aEEG + CDSA offer reasonable sensitivity and negative predictive value for seizure detection by critical care medicine providers. aEEG + CDSA did not improve seizure detection over amplitude-integrated electroencephalography alone although critical care medicine providers felt more confident using both tools combined. Amplitude-integrated electroencephalography and color density spectral array require further evaluation as a tool for screening for seizures and should only be used in conjunction with professional continuous electroencephalography review.

See Kleen and Kirsch (doi:10.1093/awx178) for a scientific commentary on this article.Cognitive deficits are common among epilepsy patients. In these patients, interictal epileptiform discharges, also termed spikes, are seen routinely on electroencephalography and believed to be associated with transient cognitive impairments. In this study, we investigated the effect of spikes on memory encoding and retrieval, taking into account the spatial distribution of spikes in relation to the seizure onset zone as well as anatomical regions of the brain. Sixty-seven patients with medication refractory epilepsy undergoing continuous intracranial electroencephalography monitoring engaged in a delayed free recall task to test short-term memory. In this task, subjects were asked to memorize and recall lists of common nouns. We quantified the effect of each spike on the probability of successful recall using a generalized logistic mixed model. We found that in patients with left lateralized seizure onset zones, spikes outside the seizure onset zone impacted memory encoding, whereas those within the seizure onset zone did not. In addition, spikes in the left inferior temporal gyrus, middle temporal gyrus, superior temporal gyrus, and fusiform gyrus during memory encoding reduced odds of recall by as much as 15% per spike. Spikes also reduced the odds of word retrieval, an effect that was stronger with spikes outside of the seizure onset zone. These results suggest that seizure onset regions are dysfunctional at baseline, and support the idea that interictal spikes disrupt cognitive processes related to the underlying tissue.

Declining Trend in Valproate Use in Finland Among Females of Childbearing Age in 2012–2016 – A Nationwide Registry-Based Outpatient Study.Virta LJ, Kalviainen R, Villikka K, Keranen T Eur J Neurol ...

Find the optimal continuous electroencephalographic (CEEG) monitoring duration for seizure detection in critically ill patients.We analyzed prospective data from 665 consecutive CEEGs, including clinical factors and time-to-event emergence of electroencephalographic (EEG) findings over 72 hours. Clinical factors were selected using logistic regression. EEG risk factors were selected a priori. Clinical factors were used for baseline (pre-EEG) risk. EEG findings were used for the creation of a multistate survival model with 3 states (entry, EEG risk, and seizure). EEG risk state is defined by emergence of epileptiform patterns.The clinical variables of greatest predictive value were coma (31% had seizures; odds ratio [OR] = 1.8, p 0.01) and history of seizures, either remotely or related to acute illness (34% had seizures; OR = 3.0, p 0.001). If there were no epileptiform findings on EEG, the risk of seizures within 72 hours was between 9% (no clinical risk factors) and 36% (coma and history of seizures). If epileptiform findings developed, the seizure incidence was between 18% (no clinical risk factors) and 64% (coma and history of seizures). In the absence of epileptiform EEG abnormalities, the duration of monitoring needed for seizure risk of5% was between 0.4 hours (for patients who are not comatose and had no prior seizure) and 16.4 hours (comatose and prior seizure).The initial risk of seizures on CEEG is dependent on history of prior seizures and presence of coma. The risk of developing seizures on CEEG decays to5% by 24 hours if no epileptiform EEG abnormalities emerge, independent of initial clinical risk factors. Ann Neurol 2017;82:177-185.

Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence.We identified 1,899,654 individuals born between 1987 and 2006 via national Swedish registers and linked each individual to his or her biological relatives. We used logistic regression to estimate the association between epilepsy and ADHD within individual and across relatives. Quantitative genetic modeling was used to decompose the cross-disorder covariance into genetic and environmental factors.Individuals with epilepsy had a statistically significant increased risk of ADHD (odds ratio [OR] = 3.47, 95% confidence interval [CI] = 3.33-3.62). This risk increase extended to children whose mothers had epilepsy (OR = 1.85, 95% CI = 1.75-1.96), children whose fathers had epilepsy (OR = 1.64, 95% CI = 1.54-1.74), full siblings (OR = 1.56, 95% CI = 1.46-1.67), maternal half siblings (OR = 1.28, 95% CI = 1.14-1.43), paternal half siblings (OR = 1.10, 95% CI = 0.96-1.25), and cousins (OR = 1.15, 95% CI = 1.10-1.20). The genetic correlation was 0.21 (95% CI = 0.02-0.40) and explained 40% of the phenotypic correlation between epilepsy and ADHD, with the remaining variance largely explained by nonshared environmental factors (49%, nonshared environmental correlation = 0.36, 95% CI = 0.23-0.49). The contribution of shared environmental factors to the cross-disorder overlap was not statistically significant (11%, shared environmental correlation = 0.32, 95% CI = -0.16-0.79).This study demonstrates a strong and etiologically complex association between epilepsy and ADHD, with shared familial factors and risk factors unique to the individual contributing to co-occurrence of the disorders. Our findings suggest that epilepsy and ADHD may share less genetic risk as compared with other neurodevelopmental disorders.

To determine the accuracy of automated detection of generalized tonic-clonic seizures (GTCS) using a wearable surface EMG device.We prospectively tested the technical performance and diagnostic accuracy of real-time seizure detection using a wearable surface EMG device. The seizure detection algorithm and the cutoff values were prespecified. A total of 71 patients, referred to long-term video-EEG monitoring, on suspicion of GTCS, were recruited in 3 centers. Seizure detection was real-time and fully automated. The reference standard was the evaluation of video-EEG recordings by trained experts, who were blinded to data from the device. Reading the seizure logs from the device was done blinded to all other data.The mean recording time per patient was 53.18 hours. Total recording time was 3735.5 hours, and device deficiency time was 193 hours (4.9% of the total time the device was turned on). No adverse events occurred. The sensitivity of the wearable device was 93.8% (30 out of 32 GTCS were detected). Median seizure detection latency was 9 seconds (range -4 to 48 seconds). False alarm rate was 0.67/d.The performance of the wearable EMG device fulfilled the requirements of patients: it detected GTCS with a sensitivity exceeding 90% and detection latency within 30 seconds.This study provides Class II evidence that for people with a history of GTCS, a wearable EMG device accurately detects GTCS (sensitivity 93.8%, false alarm rate 0.67/d).

To evaluate health-related quality of life (HRQOL) and emotional well-being in resective epilepsy surgery and nonoperated patients at long-term follow-up.This is a prospective cohort study where patients undergoing presurgical work-up during 1995-1998 completed the Short-Form Health Survey (SF-36) and the Hospital Anxiety and Depression scale (HAD) at baseline, and 2 and 14 years after resective surgery or presurgical evaluation (nonoperated patients). SF-36 scores were compared to a normative population. Proportions of patients reaching HRQOL changes of minimum clinically important difference (MCID) were calculated.At 14-year follow-up, operated patients scored equal to or better than the normative sample on all SF-36 domains except Social Functioning and Mental Health. Physical component summary (PCS) was better and mental component summary (MCS) was worse than for the normative sample. Nonoperated patients scored worse than the normative sample on five of eight domains, and on PCS and MCS. Change in seizure status from 2 to 14 years did not affect PCS or MCS means. Improvement reaching MCID from baseline to long-term was seen in 50% (PCS) and 47% (MCS) of operated and in 33% (PCS) and 38% (MCS) of nonoperated patients. Worsening was seen in 18% (PCS) and 22% (MCS) of operated and in 38% (PCS) and 38% (MCS) of nonoperated patients. Differences between groups were nonsignificant. HAD scores did not differ between groups, and the numbers of possible or probable cases were low. Patient satisfaction with surgery was higher in operated seizure-free patients. Only 5% of all operated patients considered surgery not to be overall beneficial.At the group level, HRQOL was stable 14 years after surgery compared to after 2 years. Social Functioning and Mental Health were still below, but other domains were similar to the normative sample. Individual patterns did not follow seizure outcome changes, indicating that multiple factors are important for long-term HRQOL.

The aim of this study was to determine the potential risk factors for de novo psychiatric syndromes after epilepsy surgery.Refractory epilepsy surgery candidates were recruited from our Refractory Epilepsy Reference Centre. Psychiatric evaluations were made before surgery and every year, during a 3-year follow-up period. Demographic, psychiatric, and neurological data were recorded. The types of surgeries considered were resective surgery (resection of the epileptogenic zone) and palliative surgery (deep brain stimulation of the anterior nuclei of the thalamus [ANT-DBS]). A survival analysis model was used to determine pre- and postsurgical predictors of de novo psychiatric events after surgery.One hundred and six people with refractory epilepsy submitted to epilepsy surgery were included. Sixteen (15%) people developed psychiatric disorders that were never identified before surgery. Multilobar epileptogenic zone (People with more generalized epileptogenic activity and those who undergo ANT-DBS seem to present an increased susceptibility for the development of mental disorders, after neurosurgical interventions, for the treatment of refractory epilepsy. People considered to be at higher risk should be submitted to more frequent routine psychiatric assessments."

Effective Connectivity Within the Default Mode Network in Left Temporal Lobe Epilepsy: Findings From the Epilepsy Connectome Project Cook CJ, Hwang G, Mathis J, et al. Brain Connect. 2018. doi:10.1089/brain.2018.0600. [Epub ahead of print]; PMID: 30398367 The Epilepsy Connectome Project examines the differences in connectomes between patients with temporal lobe epilepsy (TLE) and healthy controls. Using these data, the effective connectivity of the default mode network (DMN) in patients with left TLE compared to healthy controls was investigated using spectral dynamic causal modeling of resting state functional magnetic resonance imaging data. Group comparisons were made using 2 parametric empirical Bayes (PEB) models. The first level of each PEB model consisted of each participant's spectral dynamic causal modeling. Two different second-level models were constructed: the first comparing effective connectivity of the groups directly and the second using the Rey Auditory Verbal Learning Test (RAVLT) delayed free recall index as a covariate at the second level in order to assess effective connectivity controlling for the poor memory performance of patients with left TLE. After an automated search over the nested parameter space and thresholding parameters at 95% posterior probability, both models revealed numerous connections in the DMN that lead to inhibition of the left hippocampal formation. Left hippocampal formation inhibition may be an inherent result of the left temporal epileptogenic focus as memory differences were controlled for in one model and the same connections remained. An excitatory connection from the posterior cingulate cortex to the medial prefrontal cortex was found to be concomitant with left hippocampal formation inhibition in patients with TLE when including RAVLT delayed free recall at the second level.

Effects of Carbamazepine and Lamotrigine on Functional Magnetic Resonance Imaging Cognitive Networks Xiao F, Caciagli L, Wandschneider B, Sander JW, Sidhu M, Winston G, Burdett J, Trimmel K, Hill A, Vollmar C, Vos SB, Ourselin S, Thompson PJ, Zhou D, Duncan JS, Koepp MJ. Epilepsia. 2018;59:1362-1371. Objective To investigate the effects of sodium channel-blocking antiepileptic drugs (AEDs) on functional magnetic resonance imaging (fMRI) language network activations in patients with focal epilepsy. Methods In a retrospective study, we identified patients who were treated at the time of language fMRI scanning with either carbamazepine (CBZ; n = 42) or lamotrigine (LTG; n = 42), but not another sodium channel-blocking AED. We propensity-matched 42 patients taking levetiracetam (LEV) as "patient-controls" and included further 42 age- and gender-matched healthy controls. After controlling for age, age at onset of epilepsy, gender, and antiepileptic comedications, we compared verbal fluency fMRI activations between groups and out-of-scanner psychometric measures of verbal fluency. Results Patients on CBZ performed less well on a verbal fluency tests than those taking LTG or LEV. Compared to either LEV-treated patients or controls, patients taking CBZ showed decreased activations in left inferior frontal gyrus and patients on LTG showed abnormal deactivations in frontal and parietal default mode areas. All patient groups showed fewer activations in the putamen bilaterally compared to controls. In a post hoc analysis, out-of-scanner fluency scores correlated positively with left putamen activation. Significance Our study provides evidence of AED effects on the functional neuroanatomy of language, which might explain subtle language deficits in patients taking otherwise well-tolerated sodium channel-blocking agents. Patients on CBZ showed dysfunctional frontal activation and more pronounced impairment of performance than patients taking LTG, which was associated only with failure to deactivate task-negative networks. As previously shown for working memory, LEV treatment did not affect functional language networks.

Association Between Midlife Risk Factors and Late-Onset Epilepsy: Results From the Atherosclerosis Risk in Communities Study Johnson EL, Krauss GL, Lee AK, Schneider ALC, Dearborn JL, Kucharska-Newton AM, Huang J, Alonso A, Gottesman RF. JAMA Neurol. 2018 Jul 23 [Epub ahead of print]Importance: The incidence of epilepsy is higher in older age than at any other period of life. Stroke, dementia, and hypertension are associated with late-onset epilepsy; however, the role of other vascular and lifestyle factors remains unclear. Objective: To identify midlife vascular and lifestyle risk factors for late-onset epilepsy. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study is a prospective cohort study of 15 792 participants followed up since 1987 to 1989 with in-person visits, telephone calls, and surveillance of hospitalizations (10 974 invited without completing enrollment). The ARIC is a multicenter study with participants selected from 4 US communities. This study included 10 420 black or white participants from ARIC with at least 2 years of Medicare fee-for-service coverage and without missing baseline data. Data were analyzed between April 2017 and May 2018. Exposures: Demographic, vascular, lifestyle, and other possible epilepsy risk factors measured at baseline (age 45-64 years) were evaluated in multivariable survival models including demographics, vascular risk factors, and lifestyle risk factors. Main Outcomes and Measures: Time to development of late-onset epilepsy (2 or more International Classification of Diseases, Ninth Revision codes for epilepsy or seizures starting at 60 years or older in any claim [hospitalization or outpatient Medicare through 2013]), with first code for seizures after at least 2 years without code for seizures. Results: Of the 10 420 total participants (5878 [56.4%] women and 2794 [26.8%] black participants; median age 55 years at first visit), 596 participants developed late-onset epilepsy (3.33 per 1000 person-years). The incidence was higher in black than in white participants (4.71; 95% confidence interval [CI], 4.12-5.40 vs 2.88; 95% CI, 2.60-3.18 per 1000 person-years). In multivariable analysis, baseline hypertension (hazard ratio [HR], 1.30; 95% CI, 1.09-1.55), diabetes (HR, 1.45; 95% CI, 1.17-1.80), smoking (HR, 1.09; 95% CI, 1.01-1.17), apolipoprotein E ε4 (APOE ε4) genotype (1 allele HR, 1.22; 95% CI, 1.02-1.45; 2 alleles HR, 1.95; 95% CI, 1.35-2.81), incident stroke (HR, 3.38; 95% CI, 2.78-4.10), and dementia (HR, 2.56; 95% CI, 2.11-3.12) were associated with an increased risk of late-onset epilepsy, while higher levels of physical activity (HR, 0.90; 95% CI, 0.83-0.98) and moderate alcohol intake (HR, 0.72; 95% CI, 0.57-0.90) were associated with a lower risk. Results were similar after censoring individuals with stroke or dementia. Conclusions and Relevance: Potentially modifiable risk factors in midlife and the APOE ε4 genotype were positively associated with risk of developing late-onset epilepsy. Although stroke and dementia were both associated with late-onset epilepsy, vascular and lifestyle risk factors were significant even in the absence of stroke or dementia.

To evaluate a novel approach to control epileptic drop attacks through a selective posterior callosotomy, sparing all prefrontal interconnectivity.Thirty-six patients with refractory drop attacks had selective posterior callosotomy and prospective follow-up for4 years. Falls, episodes of aggressive behavior, and IQ were quantified. Autonomy in activities of daily living, axial tonus, and speech generated a functional score ranging from 0 to 13. Subjective effect on patient well-being and caregiver burden was also assessed.Median monthly frequency of drop attacks decreased from 150 to 0.5. Thirty patients (83%) achieved either complete or90% control of the falls. Need for constant supervision decreased from 90% to 36% of patients. All had estimated IQ below 85. Median functional score increased from 7 to 10 (p = 0.03). No patient had decrease in speech fluency or hemiparesis. Caregivers rated the effect of the procedure as excellent in 40% and as having greatly improved functioning in another 50%. Clinical, EEG, imaging, and cognitive variables did not correlate with outcome.This cohort study with objective outcome assessment suggests that selective posterior callosotomy is safe and effective to control drop attacks, with functional and behavioral gains in patients with intellectual disability. Results are comparable to historical series of total callosotomy and suggest that anterior callosal fibers may be spared.This study provides Class III evidence that selective posterior callosotomy reduces falls in patients with epileptic drop attacks.

Epilepsy has an impact on the reproductive system. Males with epilepsy have lower fertility rates, hypo-sexuality and reduced potency compared with the general population. Anti-epileptic drugs and epilepsy itself are thought to be responsible for this reduced fertility. LEV is a second-generation anti-epileptic agent with low incidences of both adverse effects and drug-drug interactions. In this study, we have investigated the effects of LEV treatment on sex hormones and sperm parameters in newly diagnosed epilepsy patients.We recruited 26 males with newly diagnosed epilepsy and introduced LEV monotherapy. Patients were divided into two groups depending on whether they had partial or generalized seizures. We acquired the results of pre- and post-treatment sperm analyses and serum sex hormone levels. We also recorded the maximum dose, daily dose and treatment duration for each individual. Pre- and post-treatment comparisons and correlations between both sperm and sex hormone parameters and both treatment duration and dose were determined.Pre- and post-treatment sex hormone levels were not significantly different. The total sperm count, percentage of normal morphology and functional sperm count tested after treatment were significantly lower in both groups compared with pre-treatment values (p0.05). There was a moderate correlation between daily dose and reduction in functional sperm count (r: 0.41, p: 0.034).Our findings confirm that LEV treatment of newly diagnosed epilepsy patients decreases sperm parameters without altering sex hormone levels. Our results may guide the choice of anti-epileptic drug treatment among men with epilepsy.

Presurgical language assessment can help minimize damage to eloquent cortex during resective epilepsy surgery. Two methods for presurgical language mapping are functional MRI (fMRI) and direct cortical stimulation (DCS) of implanted subdural electrodes. We compared fMRI results to DCS to help optimize noninvasive language localization and assess its validity.We studied 19 patients referred for presurgical evaluation of drug-resistant epilepsy. Patients completed four language tasks during preoperative fMRI. After subdural electrode implantation, we used DCS to localize language areas. For each stimulation site, we determined whether language positive electrode pairs intersected with significant fMRI activity clusters for language tasks.Sensitivity and specificity depended on electrode region of interest radii and statistical thresholding. For patients with at least one language positive stimulation site, an auditory description decision task provided the best trade-off between sensitivity and specificity. For patients with no language positive stimulation sites, fMRI was a dependable method of excluding eloquent language processing.Language fMRI is an effective tool for determining language lateralization before electrode implantation and is especially useful for excluding unexpected critical language areas. It can help guide subdural electrode implantation and narrow the search for eloquent cortical areas by DCS. Ann Neurol 2017;81:526-537.

Around half of all patients fail to achieve seizure freedom after temporal lobe resection. Keller et al. show that postoperative seizures after amygdalohippocampectomy are associated with regional tissue abnormalities and insufficient resection of temporal lobe white matter tracts. These results hold promise as imaging prognostic markers of postoperative seizure outcome., Approximately one in every two patients with pharmacoresistant temporal lobe epilepsy will not be rendered completely seizure-free after temporal lobe surgery. The reasons for this are unknown and are likely to be multifactorial. Quantitative volumetric magnetic resonance imaging techniques have provided limited insight into the causes of persistent postoperative seizures in patients with temporal lobe epilepsy. The relationship between postoperative outcome and preoperative pathology of white matter tracts, which constitute crucial components of epileptogenic networks, is unknown. We investigated regional tissue characteristics of preoperative temporal lobe white matter tracts known to be important in the generation and propagation of temporal lobe seizures in temporal lobe epilepsy, using diffusion tensor imaging and automated fibre quantification. We studied 43 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis and 44 healthy controls. Patients underwent preoperative imaging, amygdalohippocampectomy and postoperative assessment using the International League Against Epilepsy seizure outcome scale. From preoperative imaging, the fimbria-fornix, parahippocampal white matter bundle and uncinate fasciculus were reconstructed, and scalar diffusion metrics were calculated along the length of each tract. Altogether, 51.2% of patients were rendered completely seizure-free and 48.8% continued to experience postoperative seizure symptoms. Relative to controls, both patient groups exhibited strong and significant diffusion abnormalities along the length of the uncinate bilaterally, the ipsilateral parahippocampal white matter bundle, and the ipsilateral fimbria-fornix in regions located within the medial temporal lobe. However, only patients with persistent postoperative seizures showed evidence of significant pathology of tract sections located in the ipsilateral dorsal fornix and in the contralateral parahippocampal white matter bundle. Using receiver operating characteristic curves, diffusion characteristics of these regions could classify individual patients according to outcome with 84% sensitivity and 89% specificity. Pathological changes in the dorsal fornix were beyond the margins of resection, and contralateral parahippocampal changes may suggest a bitemporal disorder in some patients. Furthermore, diffusion characteristics of the ipsilateral uncinate could classify patients from controls with a sensitivity of 98%; importantly, by co-registering the preoperative fibre maps to postoperative surgical lacuna maps, we observed that the extent of uncinate resection was significantly greater in patients who were rendered seizure-free, suggesting that a smaller resection of the uncinate may represent insufficient disconnection of an anterior temporal epileptogenic network. These results may have the potential to be developed into imaging prognostic markers of postoperative outcome and provide new insights for why some patients with temporal lobe epilepsy continue to experience postoperative seizures.

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients. (C) 2016 Elsevier B.V. All rights reserved.

SummaryObjective Following a sudden death at a residential care unit, the Dutch Health and Care Inspectorate advised intensification of the use of video monitoring (VM) at the unit. We assessed whether VM resulted in increased identification of seizures that required clinical intervention. Methods The unit provides care for 340 individuals with refractory epilepsy and severe learning disabilities. Acoustic detection systems (ADSs) cover all individuals; 37 people also have a bed motion sensor (BMS) and 46 people with possible nocturnal seizures are now monitored by VM. During a 6-month period, in all cases of a suspected seizure we asked the caregivers to specify which device alerted them and to indicate whether this led to an intervention. Staff costs of VM were estimated using payroll information. Results We identified 1,208 seizures in 37 individuals: 4 had no nocturnal seizures and 393 (33%) seizures were seen only on video. In 169 (14%) of 1,208 seizures an intervention was made and this included 39 (10%) of 393 seizures seen only on video. When compared to seizures observed with an ADS or BMS, seizures seen only on video were more often tonic seizures (71% vs. 22%, p < 0.001) and occurred mostly in the beginning or at the end of the night (40% vs. 26%, p < 0.001). The extra staff costs of monitoring was 7,035 euro per seizure seen only on video and leading to an intervention. Significance VM facilitates nocturnal surveillance, but the costs are high. This underscores the need for development of reliable seizure detection devices.

Objective:To determine the outcome of patients with psychogenic pseudosyncope (PPS) after communication of the diagnosis.Methods:This was a retrospective cohort study of patients with PPS referred in 2007 to 2015 to a tertiary referral center for syncope. We reviewed patient records and studied attack frequency, factors affecting attack frequency, health care use, and quality of life using a questionnaire. We explored influences on attack freedom and attack frequency in the 6 months before follow-up for age, sex, education level, duration until diagnosis, probability of diagnosis, additional syncope, and acceptance of diagnosis.Results:Forty-seven of 57 patients with PPS could be traced, of whom 35 (74%) participated. Twelve (34%) were attack-free for at least 6 months. The median time from diagnosis to follow-up was 50 months (range 6–103 months). Communicating and explaining the diagnosis resulted in immediate reduction of attack frequency (p = 0.007) from the month before diagnosis (median one attack, range 0–156) to the month after (median one attack, range 0–16). In the 6 months before follow-up, the number of admissions decreased from 19 of 35 to 0 of 35 (p = 0.002). The use of somatic and mental health care shifted toward the latter (p < 0.0001). Quality of life at follow-up (Short Form Health Survey 36) showed lower scores for 7 of 8 domains compared to matched Dutch control values; quality of life was not influenced by attack freedom.Conclusions:After communication of the diagnosis in PPS, attack frequency decreased and health care use shifted toward mental care. Low quality of life underlines that PPS is a serious condition.

Decades of experience with intracranial recordings in patients with epilepsy have demonstrated that seizures can occur in deep cortical regions such as the mesial temporal lobes without showing any obvious signs of seizure activity on scalp electroencephalogram. Predicated on the idea that these seizures are purely focal, currently, the only way to detect these 'scalp-negative seizures' is with intracranial recordings. However, intracranial recordings are only rarely performed in patients with epilepsy, and are almost never performed outside of the context of epilepsy. As such, little is known about scalp-negative seizures and their role in the natural history of epilepsy, their effect on cognitive function, and their association with other neurological diseases. Here, we developed a novel approach to non-invasively identify scalp-negative seizures arising from the mesial temporal lobe based on scalp electroencephalogram network connectivity measures. We identified 25 scalp-negative mesial temporal lobe seizures in 10 patients and obtained control records from an additional 13 patients, all of whom underwent recordings with foramen ovale electrodes and scalp electroencephalogram. Scalp data from these records were used to train a scalp-negative seizure detector, which consisted of a pair of logistic regression classifiers that used scalp electroencephalogram coherence properties as input features. On cross-validation performance, this detector correctly identified scalp-negative seizures in 40% of patients, and correctly identified the side of seizure onset for each seizure detected. In comparison, routine clinical interpretation of these scalp electroencephalograms failed to identify any of the scalp-negative seizures. Among the patients in whom the detector raised seizure alarms, 80% had scalp-negative mesial temporal lobe seizures. The detector had a false alarm rate of only 0.31 per day and a positive predictive value of 75%. Of the 13 control patients, false seizure alarms were raised in only one patient. The fact that our detector specifically recognizes focal mesial temporal lobe seizures based on scalp electroencephalogram coherence features, lends weight to the hypothesis that even focal seizures are a network phenomenon that involve widespread neural connectivity. Our scalp-negative seizure detector has clear clinical utility in patients with temporal lobe epilepsy, and its potential easily translates to other neurological disorders, such as Alzheimer's disease, in which occult mesial temporal lobe seizures are suspected to play a significant role. Importantly, our work establishes a novel approach of using computational approaches to non-invasively detect deep seizure activity, without the need for invasive intracranial recordings.

For 20 million people with drug-resistant epilepsy, recurring, spontaneous seizures have a devastating impact on daily life. The ecacy of surgical treatment for controlling seizures is hindered by a poor understanding of how some seizures spread to and synchronize surrounding tissue while others remain focal. To pinpoint network regions that regulate seizure evolution, we present a novel method to assess changes in synchronizability in response to virtually lesioning cortical areas in a validated computational network model. In human patients implanted with electrocorticographic sensors, we apply our virtual cortical resection technique to time-varying functional networks and identify control regions that synchronize or desynchronize cortical areas using an antagonistic push-pull control scheme to raise or lower synchronizability. Our results suggest that synchronizability before seizures predicts seizure evolution: in focal seizures, the strongest controllers are located outside seizure-generating areas. These methods,while applied here to epilepsy, are generalizable to other brain networks, and have wide applicability in isolating and mapping functional drivers of brain dynamics in health and disease. dynamic network neuroscience | epileptic network | synchronizability | push-pull control | diffusion | seizure evolution