Automated, machine learning-based alerts increase epilepsy surgery referrals: A randomized controlled trial.

OBJECTIVE: To determine whether automated, electronic alerts increased referrals for epilepsy surgery. METHODS: We conducted a prospective, randomized controlled trial of a natural language processing-based clinical decision support system embedded in the electronic health record (EHR) at 14 pediatric neurology outpatient clinic sites. Children with epilepsy and at least two prior neurology visits were screened by the system prior to their scheduled visit. Patients classified as a potential surgical candidate were randomized 2:1 for their provider to receive an alert or standard of care (no alert). The primary outcome was referral for a neurosurgical evaluation. The likelihood of referral was estimated using a Cox proportional hazards regression model. RESULTS: Between April 2017 and April 2019, at total of 4858 children were screened by the system, and 284 (5.8%) were identified as potential surgical candidates. Two hundred four patients received an alert, and 96 patients received standard care. Median follow-up time was 24 months (range: 12-36 months). Compared to the control group, patients whose provider received an alert were more likely to be referred for a presurgical evaluation (3.1% vs 9.8%; adjusted hazard ratio [HR] = 3.21, 95% confidence interval [CI]: 0.95-10.8; one-sided p = .03). Nine patients (4.4%) in the alert group underwent epilepsy surgery, compared to none (0%) in the control group (one-sided p = .03). SIGNIFICANCE: Machine learning-based automated alerts may improve the utilization of referrals for epilepsy surgery evaluations.

Neuropsychological outcomes after epilepsy surgery: A comparison of stereo electroencephalography and subdural electrodes.

BACKGROUND AND PURPOSE: We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language. METHODS: Drug-resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM. RESULTS: Ninety-nine patients aged 6-29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter-Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores. CONCLUSIONS: Intracranial evaluations with SEEG and SDE are comparable in terms of long-term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

Supporting treatment adherence regimens in children with epilepsy: A randomized clinical trial.

OBJECTIVE: This study was undertaken to examine the efficacy of a family-tailored education and problem-solving behavioral intervention, Supporting Treatment Adherence Regimens (STAR), in young children (2-12 years old) with new onset epilepsy compared to an attention control (i.e., education only [EO]) intervention. Participants randomized to the STAR intervention were hypothesized to demonstrate significantly improved adherence at postintervention and 3-, 6-, and 12-month follow-up visits compared to the EO intervention. Seizure and health-related quality of life (HRQOL) outcomes were also examined. METHODS: Two hundred children with new onset epilepsy and their caregivers were recruited during routine epilepsy clinic visits. Baseline questionnaires were completed, and electronic adherence monitors were provided. Participants with adherence less than 95% during the run-in period were randomized to either STAR or EO intervention. Active intervention was provided to both groups for 4 months. Questionnaires were completed at conclusion of the active intervention phase and three follow-up time points (3, 6, and 12 months). Group differences in adherence, seizure outcomes, and HRQOL were examined using regression-based analyses of covariance and longitudinal mixed effect linear or logistical models. RESULTS: Adherence at 12-month follow-up was significantly different between the STAR (mean = 82.34, SD = 21.29) and EO intervention groups (mean = 61.77, SD = 28.29), with the STAR group demonstrating 20.6% greater adherence (b = 19.11, p = .04, 95% confidence interval = 1.00-37.22, d = .83). No significant differences were found between groups in seizure and HRQOL outcomes. SIGNIFICANCE: A family-based behavioral adherence intervention demonstrated sustained adherence improvements 1 year following epilepsy diagnosis compared to an epilepsy-specific education intervention. STAR is an efficacious adherence intervention that can easily be implemented into routine epilepsy care.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

OBJECTIVE: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. METHODS: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. RESULTS: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. SIGNIFICANCE: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.

Early identification of epilepsy surgery candidates: A multicenter, machine learning study.

OBJECTIVES: Epilepsy surgery is underutilized. Automating the identification of potential surgical candidates may facilitate earlier intervention. Our objective was to develop site-specific machine learning (ML) algorithms to identify candidates before they undergo surgery. MATERIALS & METHODS: In this multicenter, retrospective, longitudinal cohort study, ML algorithms were trained on n-grams extracted from free-text neurology notes, EEG and MRI reports, visit codes, medications, procedures, laboratories, and demographic information. Site-specific algorithms were developed at two epilepsy centers: one pediatric and one adult. Cases were defined as patients who underwent resective epilepsy surgery, and controls were patients with epilepsy with no history of surgery. The output of the ML algorithms was the estimated likelihood of candidacy for resective epilepsy surgery. Model performance was assessed using 10-fold cross-validation. RESULTS: There were 5880 children (n = 137 had surgery [2.3%]) and 7604 adults with epilepsy (n = 56 had surgery [0.7%]) included in the study. Pediatric surgical patients could be identified 2.0 years (range: 0-8.6 years) before beginning their presurgical evaluation with AUC =0.76 (95% CI: 0.70-0.82) and PR-AUC =0.13 (95% CI: 0.07-0.18). Adult surgical patients could be identified 1.0 year (range: 0-5.4 years) before beginning their presurgical evaluation with AUC =0.85 (95% CI: 0.78-0.93) and PR-AUC =0.31 (95% CI: 0.14-0.48). By the time patients began their presurgical evaluation, the ML algorithms identified pediatric and adult surgical patients with AUC =0.93 and 0.95, respectively. The mean squared error of the predicted probability of surgical candidacy (Brier scores) was 0.018 in pediatrics and 0.006 in adults. CONCLUSIONS: Site-specific machine learning algorithms can identify candidates for epilepsy surgery early in the disease course in diverse practice settings.

Prospective validation of a machine learning model that uses provider notes to identify candidates for resective epilepsy surgery.

OBJECTIVE: Delay to resective epilepsy surgery results in avoidable disease burden and increased risk of mortality. The objective was to prospectively validate a natural language processing (NLP) application that uses provider notes to assign epilepsy surgery candidacy scores. METHODS: The application was trained on notes from (1) patients with a diagnosis of epilepsy and a history of resective epilepsy surgery and (2) patients who were seizure-free without surgery. The testing set included all patients with unknown surgical candidacy status and an upcoming neurology visit. Training and testing sets were updated weekly for 1 year. One- to three-word phrases contained in patients' notes were used as features. Patients prospectively identified by the application as candidates for surgery were manually reviewed by two epileptologists. Performance metrics were defined by comparing NLP-derived surgical candidacy scores with surgical candidacy status from expert chart review. RESULTS: The training set was updated weekly and included notes from a mean of 519 ± 67 patients. The area under the receiver operating characteristic curve (AUC) from 10-fold cross-validation was 0.90 ± 0.04 (range = 0.83-0.96) and improved by 0.002 per week (P < .001) as new patients were added to the training set. Of the 6395 patients who visited the neurology clinic, 4211 (67%) were evaluated by the model. The prospective AUC on this test set was 0.79 (95% confidence interval [CI] = 0.62-0.96). Using the optimal surgical candidacy score threshold, sensitivity was 0.80 (95% CI = 0.29-0.99), specificity was 0.77 (95% CI = 0.64-0.88), positive predictive value was 0.25 (95% CI = 0.07-0.52), and negative predictive value was 0.98 (95% CI = 0.87-1.00). The number needed to screen was 5.6. SIGNIFICANCE: An electronic health record-integrated NLP application can accurately assign surgical candidacy scores to patients in a clinical setting.

Differential antiseizure medication sensitivity of the Affective Reactivity Index: A randomized controlled trial in new-onset pediatric focal epilepsy.

BACKGROUND: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). METHOD: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. RESULTS: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. CONCLUSION: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

Investigation of bias in an epilepsy machine learning algorithm trained on physician notes.

Racial disparities in the utilization of epilepsy surgery are well documented, but it is unknown whether a natural language processing (NLP) algorithm trained on physician notes would produce biased recommendations for epilepsy presurgical evaluations. To assess this, an NLP algorithm was trained to identify potential surgical candidates using 1097 notes from 175 epilepsy patients with a history of resective epilepsy surgery and 268 patients who achieved seizure freedom without surgery (total N = 443 patients). The model was tested on 8340 notes from 3776 patients with epilepsy whose surgical candidacy status was unknown (2029 male, 1747 female, median age = 9 years; age range = 0-60 years). Multiple linear regression using demographic variables as covariates was used to test for correlations between patient race and surgical candidacy scores. After accounting for other demographic and socioeconomic variables, patient race, gender, and primary language did not influence surgical candidacy scores (P > .35 for all). Higher scores were given to patients >18 years old who traveled farther to receive care, and those who had a higher family income and public insurance (P < .001, .001, .001, and .01, respectively). Demographic effects on surgical candidacy scores appeared to reflect patterns in patient referrals.

Development of information sharing in language neocortex in childhood-onset drug-resistant epilepsy.

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

Electrical stimulation mapping of language with stereo-EEG.

OBJECTIVE: We prospectively validated stereo-electroencephalography (EEG) electrical stimulation mapping (ESM) of language against a reference standard of meta-analytic functional magnetic resonance imaging (fMRI) framework (Neurosynth). METHODS: Language ESM was performed using 50 Hz, biphasic, bipolar, stimulation at 1-8 mA, with a picture naming task. Electrode contacts (ECs) were scored as ESM+ if ESM interfered with speech/language function. For each patient, presurgical MRI was transformed to a standard space and coregistered with computed tomographic (CT) scan to obtain EC locations. After whole-brain parcellation, this fused image data were intersected with three-dimensional language fMRI (Neurosynth), and each EC was classified as lying within/outside the fMRI language parcel. Diagnostic odds ratio (DOR) and other indices were estimated. Current thresholds for language inhibition and after-discharges (ADs) were analyzed using multivariable linear mixed models. RESULTS: In 10 patients (5 females), aged 5.4-21.2 years, speech/language inhibition was noted with ESM on 87/304 (29%) ECs. Stereo-EEG language ESM was a valid classifier of fMRI (Neurosynth) language sites (DOR: 9.02, p < 0.0001), with high specificity (0.87) but poor sensitivity (0.57). Similar diagnostic indices were seen for ECs in frontal or posterior regions, and gray or white matter. Language threshold (3.1 ±â€¯1.5 mA) was lower than AD threshold (4.0 ±â€¯2.0 mA, p = 0.0001). Language and AD thresholds decreased with age and intelligence quotient. Electrical stimulation mapping triggered seizures/auras represented patients' habitual semiology with 1 Hz stimulation. CONCLUSIONS: Stereo-EEG ESM can reliably identify cerebral parcels with/without language function but may under detect all language sites. We suggest a 50-Hz stimulation protocol for language ESM with stereo-EEG.

Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.

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

Ictal connectivity in childhood absence epilepsy: Associations with outcome.

OBJECTIVE: The understanding of childhood absence epilepsy (CAE) has been revolutionized over the past decade, but the biological mechanisms responsible for variable treatment outcomes are unknown. Our purpose in this prospective observational study was to determine how pretreatment ictal network pathways, defined using a combined electroencephalography (EEG)-functional magnetic resonance imaging (EEG-fMRI) and magnetoencephalography (MEG) effective connectivity analysis, were related to treatment response. METHODS: Sixteen children with newly diagnosed and drug-naive CAE had 31 typical absence seizures during EEG-fMRI and 74 during MEG. The spatial extent of the pretreatment ictal network was defined using fMRI hemodynamic response with an event-related independent component analysis (eICA). This spatially defined pretreatment ictal network supplied prior information for MEG-effective connectivity analysis calculated using phase slope index (PSI). Treatment outcome was assessed 2 years following diagnosis and dichotomized to ethosuximide (ETX)-treatment responders (N = 11) or nonresponders (N = 5). Effective connectivity of the pretreatment ictal network was compared to the treatment response. RESULTS: Patterns of pretreatment connectivity demonstrated strongest connections in the thalamus and posterior brain regions (parietal, posterior cingulate, angular gyrus, precuneus, and occipital) at delta frequencies and the frontal cortices at gamma frequencies (P < .05). ETX treatment nonresponders had pretreatment connectivity, which was decreased in the precuneus region and increased in the frontal cortex compared to ETX responders (P < .05). SIGNIFICANCE: Pretreatment ictal connectivity differences in children with CAE were associated with response to antiepileptic treatment. This is a possible mechanism for the variable treatment response seen in patients sharing the same epilepsy syndrome.

The impact of nonadherence to antiseizure drugs on seizure outcomes in an animal model of epilepsy.

OBJECTIVE: Nonadherence to prescribed dosing regimens is a significant problem in the treatment of pediatric and adult chronic epilepsy, and can result in severe consequences to patient outcomes. In this first-of-kind preclinical study, the impact of nonadherence on seizure control was studied by simulating human patterns of nonadherence in an animal epilepsy model. METHODS: In study 1, three different patterns of nonadherence were modeled in newly diagnosed epileptic rats treated with carbamazepine: perfect adherence (100% of pellets contained carbamazepine), variable nonadherence (50% of pellets contained carbamazepine with different dosing patterns between animals), and complete nonadherence (0% of pellets contained carbamazepine). In study 2, a cohort of newly diagnosed epileptic rats were subjected to a "drug holiday" nonadherence paradigm, that is, a 2-week on (100%), 2-week off (0%), and 2-week on (100%) carbamazepine paradigm. RESULTS: In the first experiment, the 100% (0.3 ± 0.2 SD convulsive seizures per day) adherent cohort demonstrated better seizure control than either the 0% (1.1 ± 0.8 SD) or 50% (0.8 ± 0.6 SD) adherent cohorts, which had similar levels of seizure control. In the second study, poor seizure control was exhibited during the second 2 weeks; that is, the drug holiday epoch; however, this did not negatively affect restoration of seizure control upon reinstatement of CBZ. SIGNIFICANCE: The results from this pilot investigation suggest that nonadherence to carbamazepine is associated with significant negative but reversible effects on seizure control in an animal model of epilepsy. Furthermore, these results demonstrate that animal studies of nonadherence can yield potentially important and translatable insights into the consequences of nonadherence on seizure control.

Impact of frequency and lateralization of interictal discharges on neuropsychological and fine motor status in children with benign epilepsy with centrotemporal spikes.

Despite a positive prognosis for seizure remission, children with benign epilepsy with centrotemporal spikes (BECTS) have been reported to exhibit subtle neuropsychological difficulties. We examined the relationship between patterns of centrotemporal spikes (the typical electroencephalography [EEG] finding in BECTS) and neuropsychological and motor outcomes in children with new-onset BECTS. Thirty-four patients with new-onset BECTS (not taking antiepileptic medication) and 48 typically developing children participated in the study. In BECTS patients, centrotemporal spikes (CTS) were evaluated in the first hour awake and first 2 h of sleep in a 24-h EEG recording and left or right-sided origin was noted. General intellectual function, language, visuospatial skill, processing speed, and fine motor skill were assessed in all participants. We found no significant difference between BECTS patients and controls on measures of general intellectual function, or visuospatial or language testing. There were significant differences in processing speed index and nondominant hand fine motor scores between groups. Significant negative relationships were observed between rates of left-sided CTS and right hand fine motor scores. This suggests that psychomotor and fine motor speed are affected in BECTS, but the extent of affected domains may be more limited than previously suggested, especially in untreated patients early in the course of their epilepsy.

Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital.

OBJECTIVE: To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control. DESIGN: Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. SETTING: Nine pediatric hospitals in the United States. PATIENTS: In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. MAIN RESULTS: The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies. CONCLUSIONS: Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

Low- and high-frequency oscillations reveal distinct absence seizure networks.

OBJECTIVE: The aim of this study was to determine the frequency-dependent, spatiotemporal involvement of corticothalamic networks to the generation of absence seizures. METHODS: Magnetoencephalography recordings were obtained in 12 subjects (44 seizures) with untreated childhood absence seizures. Time-frequency analysis of each seizure was performed to determine bandwidths with significant power at ictal onset. Source localization was then completed to determine brain regions contributing to generalized spike and wave discharges seen on electroencephalogram. RESULTS: Significant power in the time-frequency analysis was seen within 1 to 20Hz, 20 to 70Hz, and 70 to 150Hz bandwidths. Source localization revealed that sources localized to the frontal cortex similarly for the low- and gamma-frequency bandwidths, whereas at the low-frequency bandwidth (3-20Hz) significantly more sources localized to the parietal cortex (odds ratio [OR] = 16.7). Cortical sources within the high-frequency oscillation (HFO) bandwidth (70-150Hz) localized primarily to the frontal region compared to the parietal (OR = 7.32) or temporal (OR = 2.78) areas. INTERPRETATION: Neuromagnetic activity within frontal and parietal cortical regions provides further confirmation of hemodynamic changes reported using functional magnetic resonance imaging that have been associated with absence seizures. The frequency-dependent nature of these networks has not previously been reported, and the presence of HFOs during absence seizures is a novel finding. Co-occurring frontal and parietal corticothalamic networks may interact to produce a pathological state that contributes to the generation of spike and wave discharges. The clinical and pathophysiological implications of HFOs within the frontal cortical region are unclear and should be further investigated.

Quantification of Interictal Neuromagnetic Activity in Absence Epilepsy with Accumulated Source Imaging.

Aberrant brain activity in childhood absence epilepsy (CAE) during seizures has been well recognized as synchronous 3 Hz spike-and-wave discharges on electroencephalography. However, brain activity from low- to very high-frequency ranges in subjects with CAE between seizures (interictal) has rarely been studied. Using a high-sampling rate magnetoencephalography (MEG) system, we studied ten subjects with clinically diagnosed but untreated CAE in comparison with age- and gender-matched controls. MEG data were recorded from all subjects during the resting state. MEG sources were assessed with accumulated source imaging, a new method optimized for localizing and quantifying spontaneous brain activity. MEG data were analyzed in nine frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), low-gamma (30-55 Hz), high-gamma (65-90 Hz), ripple (90-200 Hz), high-frequency oscillation (HFO, 200-1,000 Hz), and very high-frequency oscillation (VHFO, 1,000-2,000 Hz). MEG source imaging revealed that subjects with CAE had higher odds of interictal brain activity in 200-1,000 and 1,000-2,000 Hz in the parieto-occipito-temporal junction and the medial frontal cortices as compared with controls. The strength of the interictal brain activity in these regions was significantly elevated in the frequency bands of 90-200, 200-1,000 and 1,000-2,000 Hz for subjects with CAE as compared with controls. The results indicate that CAE has significantly aberrant brain activity between seizures that can be noninvasively detected. The measurements of high-frequency neuromagnetic oscillations may open a new window for investigating the cerebral mechanisms of interictal abnormalities in CAE.