PurposeTo determine the frequency band-related local functional connectivity (BRLFC) of the seizure onset area (SOA) and areas removed from it, and the relationship between BRLFC and outcome of epilepsy surgery.MethodsThis study was conducted on 14 unselected adult patients with focal epilepsy undergoing icEEG monitoring for surgery. Intracranial EEG (icEEG) electrode contacts were located from post-implantation CT and MR images and registered to the MRI of a common brain to allow interpretation of results from all patients in the same space. Two 1 h icEEG epochs, recorded during wake and removed in time from seizure occurrence, were studied. One of these epochs was when the subject was on anti-seizure medications (ASMs), while the second was after ASM taper. Coherence was estimated for all pairs of electrode contacts ipsilateral to the SOA in delta, theta, alpha, beta, gamma and a high frequency band. The BRLFC of each electrode contact was estimated as the average band-related coherence between it and all electrode contacts within a spatial window.Key findingsBRLFC in the SOA and peri-SOA, for selected frequency bands, was greater in patients with excellent outcome after surgery in comparison to those with poor outcome. A graded relationship was observed between BRLFC and distance to the SOA of patients with excellent outcome to surgery such that contacts with the greatest connectivity were closer to the SOA and those with the lowest connectivity were several cm from the SOA. This relationship between distance to the SOA and connectivity was present primarily in the alpha, beta, gamma and high frequency bands and the BRLFC was greatest in the peri-SOA, within a distance of 5 cm from the SOA. This relationship was stable between on-ASMs and off-ASMs epochs.SignificanceThere is stable altered BRLFC in the SOA and peri-SOA expressed in the background icEEG of patients with focal epilepsy. This altered BRLFC may be a network marker of medically intractable focal epilepsy which is related to outcome of epilepsy surgery.

We provide an understanding of the network theory of epilepsy based on an interpretation of temporal, spatial, spectral and connectivity evaluations of background intracranial electroencephalogram (EEG) recordings. The background intracranial EEG recordings were acquired from patients with medically intractable epilepsy undergoing evaluation for epilepsy surgery. We argue that our results suggest, in the main, the presence of a two-node network with one of the nodes being the seizure onset area, and the second the thalamus. We hypothesize seizures arise from the interaction of these two nodes under a specific set of circumstances.

Over the last two decades, it has become increasingly clear that epilepsy is a network disorder. However, it is unclear whether these networks are established only during seizures or persist interictally. The goal of this study was to identify whether functional seizure networks exist interictally and evaluate if there is a structural basis to these networks. We identified four patients with mesial temporal lobe epilepsy who underwent resective epilepsy surgery. We estimated functional and structural connectivity across intracranial electrode contacts involved in seizure onset, early spread, and uninvolved controls. Across all interictal epochs considered, we found higher functional and white matter connectivity across cortical regions involved in seizure spread. Additionally, we observed that the patient in our cohort with the best seizure outcome had the highest functional connectivity across seizure contacts. Functional connectivity findings suggest the presence of an interictal seizure network that parallels underlying structural connectivity. Furthermore, our findings suggest that disruption or ablation of highly connected seizure regions may be necessary to achieve improved post-operative seizure freedom.

It is increasingly understood that the epilepsies are characterized by network pathology that can span multiple spatial and temporal scales. Recent work indicates that infraslow (<0.2 Hz) envelope correlations may form a basis for distant spatial coupling in the brain. We speculated that infraslow correlation structure may be preserved even with some time lag between signals. To this end, we studied intracranial EEG (icEEG) data collected from 22 medically refractory epilepsy patients. For each patient, we selected hour-long background, awake icEEG epochs before and after antiseizure medication (ASM) taper. For each epoch, we selected 5,000 random electrode contact pairs and estimated magnitude-squared coherence (MSC) below 0.15 Hz of band power time-series in the traditional EEG frequency bands. Using these same contact pairs, we shifted one signal of the pair by random durations in 15-s increments between 0 and 300 s. We aggregated these data across all patients to determine how infraslow MSC varies with duration of lag. We further examined the effect of ASM taper on infraslow correlation structure. We also used surrogate data to empirically characterize MSC estimator and to set optimal parameters for estimation specifically for the study of infraslow activity. Our empirical analysis of the MSC estimator showed that hour-long segments with MSC computed using 3-min windows with 50% overlap was sufficient to capture infraslow envelope correlations while minimizing estimator bias and variance. The mean MSC decreased monotonically with increasing time lag until 105 s of lag, then plateaued between 106 and 300 s. Significantly nonzero infraslow envelope MSC was preserved in all frequency bands until about 1 min of time lag, both pre- and post-ASM taper. We also saw a slight, but significant increase in infraslow MSC post-ASM taper, consistent with prior work. These results provide evidence for the feasibility of examining infraslow activity via its modulation of higher-frequency activity in the absence of DC-coupled recordings. The use of surrogate data also provides a general methodology for benchmarking measures used in network neuroscience studies. Finally, our study points to the clinical relevance of infraslow activity in assessing seizure risk.

After cessation of blood flow or similar ischaemic exposures, deleterious molecular cascades commence in mammalian cells, eventually leading to their death1,2. Yet with targeted interventions, these processes can be mitigated or reversed, even minutes or hours post mortem, as also reported in the isolated porcine brain using BrainEx technology3. To date, translating single-organ interventions to intact, whole-body applications remains hampered by circulatory and multisystem physiological challenges. Here we describe OrganEx, an adaptation of the BrainEx extracorporeal pulsatile-perfusion system and cytoprotective perfusate for porcine whole-body settings. After 1 h of warm ischaemia, OrganEx application preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs. Commensurately, single-nucleus transcriptomic analysis revealed organ- and cell-type-specific gene expression patterns that are reflective of specific molecular and cellular repair processes. Our analysis comprises a comprehensive resource of cell-type-specific changes during defined ischaemic intervals and perfusion interventions spanning multiple organs, and it reveals an underappreciated potential for cellular recovery after prolonged whole-body warm ischaemia in a large mammal.

A range of abnormal electrical activity patterns termed epileptiform discharges can occur in the brains of persons with epilepsy. These epileptiform discharges can be monitored and recorded with implanted devices that deliver therapeutic neurostimulation. These continuous recordings provide an opportunity to study the behavioral correlates of epileptiform discharges as the patients go about their daily lives. Here, we captured the smartphone touchscreen interactions in eight patients in conjunction with electrographic recordings (accumulating 35,714 h) and by using an artificial neural network model addressed if the behavior reflected the epileptiform discharges. The personalized model outputs based on smartphone behavioral inputs corresponded well with the observed electrographic data (R: 0.2-0.6, median 0.4). The realistic reconstructions of epileptiform activity based on smartphone use demonstrate how day-to-day digital behavior may be converted to personalized markers of disease activity in epilepsy.

BACKGROUND AND PURPOSE:The aim of this study was to evaluate the quality of smartphone videos (SVs) of neurologic events in adult epilepsy outpatients. The use of home video recording in patients with neurological disease states is increasing. Experts interpretation of outpatient smartphone videos of seizures and neurological events has demonstrated similar diagnostic accuracy to inpatient video-electroencephalography (EEG) monitoring.METHODS:A prospective, multicenter cohort study was conducted to evaluate SV quality in patients with paroxysmal neurologic events from August 15, 2015 through August 31, 2018. Epileptic seizures (ESs), psychogenic nonepileptic attacks (PNEAs), and physiologic nonepileptic events (PhysNEEs) were confirmed by video-EEG monitoring. Experts and senior neurology residents blindly viewed cloud-based SVs without clinical information. Quality ratings with regard to technical and operator-driven metrics were provided in responses to a survey.RESULTS:Forty-four patients (31 women, age 45.1 years [r = 20-82]) were included and 530 SVs were viewed by a mean of seven experts and six residents; one video per patient was reviewed for a mean of 133.8 s (r = 9-543). In all, 30 patients had PNEAs, 11 had ESs, and three had PhysNEEs. Quality was suitable in 70.8% of SVs (375/530 total views), with 36/44 (81.8%) patient SVs rated as adequate by the majority of reviewers. Accuracy improved with the presence of convulsive features from 72.4% to 98.2% in ESs and from 71.1% to 95.7% in PNEAs. An accurate diagnosis was given by all reviewers (100%) in 11/44 SVs (all PNEAs). Audio was rated as good by 86.2% of reviewers for these SVs compared with 75.4% for the remaining SVs (p = 0.01). Lighting was better in SVs associated with high accuracy (p = 0.06), but clarity was not (p = 0.59). Poor video quality yielded unknown diagnoses in 24.2% of the SVs reviewed. Features hindering diagnosis were limited interactivity, restricted field of view and short video duration.CONCLUSIONS:Smartphone video quality is adequate for clinical interpretation in the majority of patients with paroxysmal neurologic events. Quality can be optimized by encouraging interactivity with the patient, adequate duration of the SV, and enlarged field of view during videography. Quality limitations were primarily operational though accuracy remained for SV review of ESs and PNEAs.

Objective To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. Methods Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. Results Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). Conclusions Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. ClinicalTrials.gov identifier NCT00572195. Classification of evidence This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

The term 'implantation effect' is used to describe an immediate and transient improvement in seizure frequency following an intracranial study for seizure onset localization. We conducted a retrospective analysis of 190 consecutive patients undergoing intracranial electroencephalogram (EEG) monitoring, of whom 41 had no subsequent resection/ablation/stimulation; 33 had adequate data and follow-up time available for analysis. Analysis of seizure frequency following an intracranial study showed 36% (12/33) responder rate (>50% seizure reduction) at one year, decreasing and stabilizing at 20% from year 4 onwards. In addition, we describe three patients (9%) who had long term seizure freedom of more than five years following electrode implantation alone, two of whom had thalamic depth electrodes. Electrode implantation perhaps leads to a neuromodulatory effect sufficient enough to disrupt epileptogenic networks. Rarely, this may be significant enough to even result in long term seizure freedom, as seen in our three patients.

Importance Misdiagnosis of epilepsy is common. Video electroencephalogram provides a definitive diagnosis but is impractical for many patients referred for evaluation of epilepsy. Objective To evaluate the accuracy of outpatient smartphone videos in epilepsy. Design, Setting, and Participants This prospective, masked, diagnostic accuracy study (the OSmartViE study) took place between August 31, 2015, and August 31, 2018, at 8 academic epilepsy centers in the United States and included a convenience sample of 44 nonconsecutive outpatients who volunteered a smartphone video during evaluation and subsequently underwent video electroencephalogram monitoring. Three epileptologists uploaded videos for physicians from the 8 epilepsy centers to review. Main Outcomes and Measures Measures of performance (accuracy, sensitivity, specificity, positive predictive value, and negative predictive value) for smartphone video-based diagnosis by experts and trainees (the index test) were compared with those for history and physical examination and video electroencephalogram monitoring (the reference standard). Results Forty-four eligible epilepsy clinic outpatients (31 women [70.5%]; mean [range] age, 45.1 [20-82] years) submitted smartphone videos (530 total physician reviews). Final video electroencephalogram diagnoses included 11 epileptic seizures, 30 psychogenic nonepileptic attacks, and 3 physiologic nonepileptic events. Expert interpretation of a smartphone video was accurate in predicting a video electroencephalogram monitoring diagnosis of epileptic seizures 89.1% (95% CI, 84.2%-92.9%) of the time, with a specificity of 93.3% (95% CI, 88.3%-96.6%). Resident responses were less accurate for all metrics involving epileptic seizures and psychogenic nonepileptic attacks, despite greater confidence. Motor signs during events increased accuracy. One-fourth of the smartphone videos were correctly diagnosed by 100% of the reviewing physicians, composed solely of psychogenic attacks. When histories and physical examination results were combined with smartphone videos, correct diagnoses rose from 78.6% to 95.2%. The odds of receiving a correct diagnosis were 5.45 times greater using smartphone video alongside patient history and physical examination results than with history and physical examination alone (95% CI, 1.01-54.3; P = .02). Conclusions and Relevance Outpatient smartphone video review by experts has predictive and additive value for diagnosing epileptic seizures. Smartphone videos may reliably aid psychogenic nonepileptic attacks diagnosis for some people.

Tuesday, April 28April 14, 2020Free AccessComparison of Responsive Neurostimulation System Efficacy Between Different Electrographic Seizure Onset Patterns (1255)Paulina Henriquez-Rojas, Tara Torabi, Pue Farooque, Lawrence Hirsch, Robert Duckrow, Aline Herlopian, Dennis Spencer, Jason Gerrard, and Imran QuraishiAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1255 Letters to the Editor

Focal slowing (<4 Hz) of brain waves is often associated with focal cerebral dysfunction and is assumed to be increased closest to the location of dysfunction. Prior work suggests that slowing may be comprised of at least two distinct neural mechanisms: slow oscillation activity (<1 Hz) may reflect primarily inhibitory cortical mechanisms while power in the delta frequency (1–4 Hz) may correlate with local synaptic strength. In focal epilepsy patients, we examined slow wave activity near and far from the seizure onset zone (SOZ) during wake, sleep, and postictal states using intracranial electroencephalography. We found that slow oscillation (0.3–1 Hz) activity was decreased near the SOZ, while delta activity (2–4 Hz) activity was increased. This finding was most prominent during sleep, and accompanied by a loss of long-range intra-hemispheric synchrony. In contrast to sleep, postictal slowing was characterized by a broadband increase of spectral power, and showed a reduced modulatory effect of slow oscillations on higher frequencies. These results suggest slow oscillation focal slowing is reduced near the seizure onset zone, perhaps reflecting reduced inhibitory activity. Dissociation between slow oscillation and delta slowing could help localize the seizure onset zone from interictal intracranial recordings.

SummaryObjectiveStudies of infraslow amplitude modulations (<0.15 Hz) of band power time series suggest that these envelope correlations may form a basis for distant spatial coupling in the brain. In this study, we sought to determine how infraslow relationships are affected by antiepileptic drug (AED) taper, time of day, and seizure.MethodsWe studied intracranial electroencephalographic (icEEG) data collected from 13 medically refractory adult epilepsy patients who underwent monitoring at Yale–New Haven Hospital. We estimated the magnitude‐squared coherence (MSC) at <0.15 Hz of traditional EEG frequency band power time series for all electrode contact pairs to quantify infraslow envelope correlations between them. We studied, first, hour‐long background icEEG epochs before and after AED taper to understand the effect of taper. Second, we analyzed the entire record for each patient to study the effect of time of day. Finally, for each patient, we reviewed the clinical record to find all seizures that were at least 6 hours removed from other seizures and analyzed infraslow envelope MSC before and after them.ResultsInfraslow envelope MSC increased slightly, but significantly, after AED taper, and increased on average during the night and decreased during the day. It was also increased significantly in all frequency bands up to 3 hours preseizure and 1 hour postseizure as compared to background icEEG (61 seizures studied). These changes occurred for both daytime and nighttime seizures (28 daytime, 33 nighttime). Interestingly, there was significant spatial variability to these changes, with the seizure onset area peaking at 3 hours preseizure, then showing progressive desynchronization from 3 hours preseizure to 1 hour postseizure.SignificanceInfraslow envelope analysis may be used to understand long‐term changes over the course of icEEG monitoring, provide unique insight into interictal electrophysiological changes related to ictogenesis, and contribute to the development of novel seizure forecasting algorithms.

Increased slow wave activity is typically associated with decreased levels of awareness. Previous work has shown greater slow wave activity (1–2 Hz) in frontal and parietal areas during seizures that impair awareness than seizures that do not (Englot, 2010). During non-REM sleep, slowing was increased for patients with epilepsy compared to controls, including a local increase at the seizure onset zone (SOZ) (Boly, 2017). Here, we examined slow wave activity for patients with epilepsy in wake, sleep, and post-ictal states. Data were recorded with the Natus Neurolink IP 256 channel EEG amplifier (0.16 Hz High pass filter, 1024 Hz sampling frequency). Inclusion criteria were: (1) bilateral subdural electrode coverage (>30 electrode contacts per hemisphere), (2) no known hemispheric abnormalities or diffuse abnormalities affecting the frontal lobes, (3) well-defined SOZs in either the temporal or frontal regions, and (4) at least three recorded clinical seizures with impaired awareness without generalized convulsive activity. Intracranial data from five patients was studied. The patients had 237, 198, 238, 241, and 229 contacts and seizures emerging from regions in the left frontal (n = 2), left temporal (n = 1), and right temporal (n = 1) lobes. 15 min in the wake, non-REM sleep, and postictal states following each of three focal seizures was examined, for a total of 2.25 h of data per patient. Power was increased for all frequency band (0.1–50 Hz) in the postictal state (0-3 min following seizure cessation) compared to sleep, while low frequency power during sleep showed a peak at about 0.6 Hz. In the postictal state, power ipsilateral to the SOZ was increased for frequencies 2–50 Hz compared to the contralateral side. However, delta activity (0.5–4 Hz) normalized by beta (12–50 Hz) activity was increased for the contralateral side relative to the ipsilateral side. The average signal correlation for a given distance was increased for low frequency bands relative to high frequency bands but did not differ across patient states. Slow wave activity appears to be more uniformly increased during the postictal state as compared to sleep. Relative amounts of low frequency delta activity are decreased ipsilateral to the SOZ. These results suggest that delta activity (0.5–4 Hz) may represent different underlying physiology when comparing wake, sleep, and postictal states.

The responsive neurostimulation (RNS) system is used for cases of medically refractory focal epilepsy in which curative resection is not possible. Uniquely, the device provides long term ambulatory neurophysiologic data including counts of intracranial seizure onset patterns. We sought to determine whether this data could be useful in predicting the response to starting an anti-seizure drug (ASD). Currently, there are no metrics available to accurately predict ASD response in a relatively short amount of time following its initiation. We identified all patients with implanted RNS devices who were followed at the Yale Comprehensive Epilepsy Center between 2004 and 2016. 20 patients implanted with RNS had stable detection and stimulation settings suitable for further analysis. 21 instances of added medications during periods of stable detection settings were found. Medications that were not tolerated were not included. Daily detection outputs including “episode starts” and “long episodes” were compared before and after ASD initiation. Long episodes are electrocorticographic patterns that detection criteria for a provider-specified duration. Ratios of detection counts before and after each medication change were then compared with medication response outcomes. Medication success or failure was determined retrospectively based on provider documentation of improvement in seizures, whether or not the provider and patient chose to continue the medication long term, and patient-reported clinical efficacy including seizure diaries. Within 1 week of ASD initiation, relative to a 3-month baseline, long episode counts (p = 0.0008), but not total detection counts (p = 0.1733) were significantly different between instances of medication success and failure. Over a 3-month period after ASD initation, changes in long episode counts (p = 0.1258) and total detections (p = 0.6806) did not show a significant difference. Over the first week, a decrease in long episodes of 20% was an optimal cutoff point to determine efficacy. A decrease in long episodes of 20% or more predicted clinical efficacy with PPV = 100%. An increase in counts or a <20% decrease in long episode counts predicted lack of clinical efficacy (NPV = 70%). 5 cases were identified in which long episode counts dropped to zero over the first 7 days after starting an ASD; all of these cases were clinically efficaceous. In patients with RNS and stable detection settings, when new ASDs are started, a decrease in RNS long episode counts of 20% or more within the first week provides an early and accurate indication of individualized clinical efficacy.

ObjectiveTo study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. MethodsAll deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. ResultsThere were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SignificanceThe SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Evaluate the seizure‐reduction response and safety of brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of neocortical origin.

SummaryObjectiveEvaluate the seizure‐reduction response and safety of mesial temporal lobe (MTL) brain‐responsive stimulation in adults with medically intractable partial‐onset seizures of mesial temporal lobe origin.MethodsSubjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain‐responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2–6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events.ResultsThere were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy‐six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow‐up was 6.1 ± (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty‐nine percent of subjects experienced at least one seizure‐free period of 6 months or longer, and 15% experienced at least one seizure‐free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device‐related adverse event was soft tissue implant‐site infection (overall rate, including events categorized as device‐related, uncertain, or not device‐related: 0.03 per implant year, which is not greater than with other neurostimulation devices).SignificanceBrain‐responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

ObjectiveThe effect of electrical stimulation on brain glutamate release in humans is unknown. Glutamate is elevated at baseline in the epileptogenic hippocampus of patients with refractory epilepsy, and increases during spontaneous seizures. We examined the effect of 50 Hz stimulation on glutamate release and its relationship to interictal levels in the hippocampus of patients with epilepsy. In addition, we measured basal and stimulated glutamate levels in a subset of these patients where stimulation elicited a seizure.MethodsSubjects (n = 10) were patients with medically refractory epilepsy who were undergoing intracranial electroencephalography (EEG) evaluation in an epilepsy monitoring unit. Electrical stimulation (50 Hz) was delivered through implanted hippocampal electrodes (n = 11), and microdialysate samples were collected every 2 min. Basal glutamate, changes in glutamate efflux with stimulation, and the relationships between peak stimulation-associated glutamate concentrations, basal zero-flow levels, and stimulated seizures were examined.ResultsStimulation of epileptic hippocampi in patients with refractory epilepsy caused increases in glutamate efflux (p = 0.005, n = 10), and 4 of ten patients experienced brief stimulated seizures. Stimulation-induced increases in glutamate were not observed during the evoked seizures, but rather were related to the elevation in interictal basal glutamate (R-2 = 0.81, p = 0.001). The evoked-seizure group had lower basal glutamate levels than the no-seizure group (p = 0.04), with no stimulation-induced change in glutamate efflux (p = 0.47, n = 4). Conversely, increased glutamate was observed following stimulation in the no-seizure group (p = 0.005, n = 7). Subjects with an atrophic hippocampus had higher basal glutamate levels (p = 0.03, n = 7) and higher stimulation-induced glutamate efflux.SignificanceElectrical stimulation of the epileptic hippocampus either increased extracellular glutamate efflux or induced seizures. The magnitude of stimulated glutamate increase was related to elevation in basal interictal glutamate, suggesting a common mechanism, possibly impaired glutamate metabolism. Divergent mechanisms may exist for seizure induction and increased glutamate in patients with epilepsy. These data highlight the potential risk of 50 Hz stimulation in patients with epilepsy.

ObjectiveAberrant glutamate and γ‐aminobutyric acid (GABA) neurotransmission contribute to seizure generation and the epileptic state. However, whether levels of these neurochemicals are abnormal in epileptic patients is unknown. Here, we report on interictal levels of glutamate, glutamine, and GABA in epilepsy patients at seizure onset and nonepileptic sites, cortical lesions, and from patients with poorly localized neocortical epilepsies.MethodsSubjects (n = 79) were medically refractory epilepsy patients undergoing intracranial electroencephalogram evaluation. Microdialysis probes (n = 125) coupled to depth electrodes were implanted within suspected seizure onset sites and microdialysis samples were obtained during interictal periods. Glutamate, glutamine, and GABA were measured using high‐performance liquid chromatography. Probe locations were subsequently classified by consensus of expert epileptologists.ResultsGlutamate levels were elevated in epileptogenic (p = 0.03; n = 7), nonlocalized (p < 0.001), and lesional cortical sites (p < 0.001) when compared to nonepileptogenic cortex. Glutamate was also elevated in epileptogenic (p < 0.001) compared to nonepileptogenic hippocampus. There were no statistical differences in GABA or glutamine, although GABA levels showed high variability across patients and groups.InterpretationOur findings indicate that chronically elevated extracellular glutamate is a common pathological feature among epilepsies with different etiology. Contrary to our predictions, GABA and glutamine levels were not decreased in any of the measured areas. Whereas variability in GABA levels may in part be attributed to the use of GABAergic antiepileptic drugs, the stability in glutamine across patient groups indicate that extracellular glutamine levels are under tighter metabolic regulation than previously thought. Ann Neurol 2016;80:35–45