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The subspecialty of Experimental Neurotherapeutics trains neurologists in discovering and developing new treatments for neurologic diseases. Based on development of exciting new treatments for genetic and inflammatory diseases, we predict that there will be many other breakthroughs. The job market has expanded rapidly in academia, the pharmaceutical industry, government, and not-for-profit sectors; many new opportunities can be anticipated. The burgeoning opportunities in the field mandate that training address the challenges of overcoming obstacles in therapeutic discovery, implementation science, and development of affordable and equitably available treatments. This article is protected by copyright. All rights reserved.

BACKGROUND AND OBJECTIVES: Seizures (SZs) and other SZ-like patterns of brain activity can harm the brain and contribute to in-hospital death, particularly when prolonged. However, experts qualified to interpret EEG data are scarce. Prior attempts to automate this task have been limited by small or inadequately labeled samples and have not convincingly demonstrated generalizable expert-level performance. There exists a critical unmet need for an automated method to classify SZs and other SZ-like events with expert-level reliability. This study was conducted to develop and validate a computer algorithm that matches the reliability and accuracy of experts in identifying SZs and SZ-like events, known as “ictal-interictal-injury continuum” (IIIC) patterns on EEG, including SZs, lateralized and generalized periodic discharges (LPD, GPD), and lateralized and generalized rhythmic delta activity (LRDA, GRDA), and in differentiating these patterns from non-IIIC patterns. METHODS: We used 6,095 scalp EEGs from 2,711 patients with and without IIIC events to train a deep neural network, SPaRCNet, to perform IIIC event classification. Independent training and test data sets were generated from 50,697 EEG segments, independently annotated by 20 fellowship-trained neurophysiologists. We assessed whether SPaRCNet performs at or above the sensitivity, specificity, precision, and calibration of fellowship-trained neurophysiologists for identifying IIIC events. Statistical performance was assessed by the calibration index and by the percentage of experts whose operating points were below the model's receiver operating characteristic curves (ROCs) and precision recall curves (PRCs) for the 6 pattern classes. RESULTS: SPaRCNet matches or exceeds most experts in classifying IIIC events based on both calibration and discrimination metrics. For SZ, LPD, GPD, LRDA, GRDA, and “other” classes, SPaRCNet exceeds the following percentages of 20 experts—ROC: 45%, 20%, 50%, 75%, 55%, and 40%; PRC: 50%, 35%, 50%, 90%, 70%, and 45%; and calibration: 95%, 100%, 95%, 100%, 100%, and 80%, respectively. DISCUSSION: SPaRCNet is the first algorithm to match expert performance in detecting SZs and other SZ-like events in a representative sample of EEGs. With further development, SPaRCNet may thus be a valuable tool for an expedited review of EEGs. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with epilepsy or critical illness undergoing EEG monitoring, SPaRCNet can differentiate (IIIC) patterns from non-IIIC events and expert neurophysiologists.

Temporal lobe epilepsy (TLE) is one of the most common causes of medically refractory focal epilepsy. Anterior temporal lobectomy (ATL) leads to improved seizure control in patients with medically refractory TLE. Various auras are associated with TLE; however, the relationships between aura type and outcome after ATL are poorly understood. Our objective was to investigate the associations among clinical features, aura type, and seizure outcome after ATL.The records of patients who underwent ATL between 1993 and 2016 at a single institution (N = 174) were retrospectively reviewed. Demographic and clinical variables were compared among aura types using analysis of variance and logistic regression analysis. A multiple regression analysis was conducted to determine whether aura type predicted seizure outcome after ATL.Mesial temporal sclerosis (MTS) on magnetic resonance imaging inversely correlated with cephalic auras (P = 0.0090). Affective auras (P = 0.014) and somatosensory auras (P = 0.021) were correlated with findings of MTS on pathology, whereas this finding was inversely correlated with the presence of auditory auras (P = 0.0056). On multiple regression analysis, predictors of worse seizure outcome after ATL were cephalic auras (P = 0.0048), gustatory auras (P = 0.029), visual auras (P = 0.049), and tonic-clonic seizures (P = 0.047). Fewer preoperative antiepileptic medications (P = 0.0032), and presence of multiple auras (P = 0.011) were associated with better outcome.Cephalic auras, gustatory auras, and visual auras were associated with worse seizure outcome after ATL.

Background and ObjectivesTo explore efficacy/safety of natalizumab, a humanized monoclonal anti–α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy.MethodsParticipants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed.ResultsOf 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was −14.4% (95% confidence interval [CI] –46.1%–36.1%; p = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64–6.85; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo.DiscussionAlthough the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted.Trial Registration InformationThe ClinicalTrials.gov registration number is NCT03283371.Classification of EvidenceThis study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab.

This study was undertaken to determine the dose-response relation between epileptiform activity burden and outcomes in acutely ill patients.A single center retrospective analysis was made of 1,967 neurologic, medical, and surgical patients who underwent16 hours of continuous electroencephalography (EEG) between 2011 and 2017. We developed an artificial intelligence algorithm to annotate 11.02 terabytes of EEG and quantify epileptiform activity burden within 72 hours of recording. We evaluated burden (1) in the first 24 hours of recording, (2) in the 12-hours epoch with highest burden (peak burden), and (3) cumulatively through the first 72 hours of monitoring. Machine learning was applied to estimate the effect of epileptiform burden on outcome. Outcome measure was discharge modified Rankin Scale, dichotomized as good (0-4) versus poor (5-6).Peak epileptiform burden was independently associated with poor outcomes (p 0.0001). Other independent associations included age, Acute Physiology and Chronic Health Evaluation II score, seizure on presentation, and diagnosis of hypoxic-ischemic encephalopathy. Model calibration error was calculated across 3 strata based on the time interval between last EEG measurement (up to 72 hours of monitoring) and discharge: (1) 5 days between last measurement and discharge, 0.0941 (95% confidence interval [CI] = 0.0706-0.1191); 5 to 10 days between last measurement and discharge, 0.0946 (95% CI = 0.0631-0.1290);10 days between last measurement and discharge, 0.0998 (95% CI = 0.0698-0.1335). After adjusting for covariates, increase in peak epileptiform activity burden from 0 to 100% increased the probability of poor outcome by 35%.Automated measurement of peak epileptiform activity burden affords a convenient, consistent, and quantifiable target for future multicenter randomized trials investigating whether suppressing epileptiform activity improves outcomes. ANN NEUROL 2021;90:300-311.

No clear evidence‐based treatment paradigm currently exists for refractory and super‐refractory status epilepticus, which can result in significant mortality and morbidity. While patients are typically treated with antiepileptic drugs and anesthetics, neurosurgical neuromodulation techniques can also be considered. We present a novel case in which responsive neurostimulation was used to effectively treat a patient who had developed super‐refractory status epilepticus, later consistent with epilepsia partialis continua, that was refractory to antiepileptic drugs, immunomodulatory therapies, and transcranial magnetic stimulation. This case demonstrates how regional therapy provided by responsive neurostimulation can be effective in treating super‐refractory status epilepticus through neuromodulation of seizure networks.

We sought to investigate electroencephalographers’ real-world behaviors and opinions concerning reading routine EEG (rEEG) with or without clinical information. An eight-question, anonymous, online survey targeted at electroencephalographers was disseminated on social media from the authors’ personal accounts and emailed to authors’ select colleagues. A total of 389 responses were included. Most respondents reported examining clinical information before describing rEEG findings. Nonetheless, only a minority of respondents believe that EEG analysis/description should be influenced by clinical information. We recommend reviewing clinical data only after an unbiased EEG read to prevent history bias and ensure generation of reliable electrodiagnostic information.

ObjectiveTo examine the relationship between scalp EEG biomarkers of hyperexcitability in Alzheimer disease (AD) and to determine how these electric biomarkers relate to the clinical expression of seizures in AD.MethodsIn this cross-sectional study, we performed 24-hour ambulatory scalp EEGs on 43 cognitively normal elderly healthy controls (HC), 41 participants with early-stage AD with no history or risk factors for epilepsy (AD-NoEp), and 15 participants with early-stage AD with late-onset epilepsy related to AD (AD-Ep). Two epileptologists blinded to diagnosis visually reviewed all EEGs and annotated all potential epileptiform abnormalities. A panel of 9 epileptologists blinded to diagnosis was then surveyed to generate a consensus interpretation of epileptiform abnormalities in each EEG.ResultsEpileptiform abnormalities were seen in 53% of AD-Ep, 22% of AD-NoEp, and 4.7% of HC. Specific features of epileptiform discharges, including high frequency, robust morphology, right temporal location, and occurrence during wakefulness and REM, were associated with clinical seizures in AD. Multiple EEG biomarkers concordantly demonstrated a pattern of left temporal lobe hyperexcitability in early stages of AD, whereas clinical seizures in AD were often associated with bitemporal hyperexcitability. Frequent small sharp spikes were specifically associated with epileptiform EEGs and thus identified as a potential biomarker of hyperexcitability in AD.ConclusionEpileptiform abnormalities are common in AD but not all equivalent. Specific features of epileptiform discharges are associated with clinical seizures in AD. Given the difficulty recognizing clinical seizures in AD, these EEG features could provide guidance on which patients with AD are at high risk for clinical seizures.

Today's modalities for short-term monitoring of EEG are primarily meant for supporting clinical diagnosis of epilepsy or classifying seizures and interictal epileptiform discharges while long-term EEG adds the value of differential diagnosis investigation or pre-surgical evaluation. However, longitudinal epilepsy care relies on patient diaries, which is known to be unreliable for most patients and especially those with focal impaired awareness or nocturnal seizures. The subcutaneous ultra long-term EEG (ULT-EEG) systems alleviate those issue by enabling objective, continuous EEG monitoring for days, weeks, months, or years. Albeit a great advance in continuous EEG over extended periods, it comes with the caveat of limited spatial resolution of two channels. Therefore, the new subcutaneous EEG modality may be especially suited for a selected group of patients. We convened a panel of experienced epileptologists to consider the utility of a subcutaneous, two-channel ULT-EEG device with the goal of developing a consensus-based expert recommendation on selecting the optimal patient types for this investigative technique. The ideal patients to select for this type of monitoring would have focal impaired awareness seizures without predominant motor features and seizures with medium to high voltage patterns. As this technology matures and we learn more about its limitations and benefits we might find a wider array of use case scenarios as it is believed that the benefits for many patients are most likely to outweigh the risks and cost.

Responsive neurostimulation (RNS) has emerged as an adjunctive treatment modality for patients with intractable focal epilepsy who are not surgical candidates or have more than one ictal onset focus. We report a 34‐year‐old patient with intractable, childhood‐onset, genetic generalized epilepsy (GGE) with tonic, atonic, myoclonic and absence seizures treated with RNS. Strip electrodes over the right posterior frontal cortex and depth electrodes placed in the right anterior nucleus were used for event detection and responsive stimulation. Two‐year follow‐up revealed 90–95% clinical seizure reduction. This case suggests that refractory GGE may be effectively treated with RNS targeting thalamocortical networks.

BACKGROUND: Burst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified. METHODS: The dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding. RESULTS: The expected outcomes in a “counterfactual” Randomized Controlled Trial (cRCT) that assigned patients to mild vs. severe illness is expected to show a difference in burst suppression burden of 39%, 95% CI [8–66]%, and in mortality of 35% [29–41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7–17]% compared to 0% burden. Burst suppression mediates 10% [2–21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8–12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression. CONCLUSIONS: Our analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.

We hypothesize that epileptiform abnormalities (EAs) in the electroencephalogram (EEG) during the acute period following traumatic brain injury (TBI) independently predict first-year post-traumatic epilepsy (PTE1 ). We analyze PTE1 risk factors in two cohorts matched for TBI severity and age (n = 50). EAs independently predict risk for PTE1 (odds ratio [OR], 3.16 [0.99, 11.68]); subdural hematoma is another independent risk factor (OR, 4.13 [1.18, 39.33]). Differences in EA rates are apparent within 5 days following TBI. Our results suggest that increased EA prevalence identifies patients at increased risk for PTE1 , and that EAs acutely post-TBI can identify patients most likely to benefit from antiepileptogenesis drug trials. Ann Neurol 2018;83:858-862.

Objective In mesial temporal lobe (mTL) epilepsy, seizure onset can precede the appearance of a scalp EEG ictal pattern by many seconds. The ability to identify this early, occult mTL seizure activity could improve lateralization and localization of mTL seizures on scalp EEG. Methods Using scalp EEG spectral features and machine learning approaches on a dataset of combined scalp EEG and foramen ovale electrode recordings in patients with mTL epilepsy, we developed an algorithm, SCOPE-mTL, to detect and lateralize early, occult mTL seizure activity, prior to the appearance of a scalp EEG ictal pattern. Results Using SCOPE-mTL, 73% of seizures with occult mTL onset were identified as such, and no seizures that lacked an occult mTL onset were identified as having one. Predicted mTL seizure onset times were highly correlated with actual mTL seizure onset times (r = 0.69). 50% of seizures with early mTL onset were lateralizable prior to scalp ictal onset, with 94% accuracy. Conclusions SCOPE-mTL can identify and lateralize mTL seizures prior to scalp EEG ictal onset, with high sensitivity, specificity, and accuracy. Significance Quantitative analysis of scalp EEG can provide important information about mTL seizures, even in the absence of a visible scalp EEG ictal correlate.

Super‐refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120‐h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes.

SummaryObjective Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. Methods Patients with partial seizures of neocortical origin 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. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. Results There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were not greater than with other neurostimulation devices. Significance Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

SummaryObjective To evaluate published algorithms for the identification of epilepsy cases in medical claims data using a unique linked dataset with both clinical and claims data. Methods Using data from a large, regional health delivery system, we identified all patients contributing biologic samples to the health system's Biobank (n = 36K). We identified all subjects with at least one diagnosis potentially consistent with epilepsy, for example, epilepsy, convulsions, syncope, or collapse, between 2014 and 2015, or who were seen at the epilepsy clinic (n = 1,217), plus a random sample of subjects with neither claims nor clinic visits (n = 435); we then performed a medical chart review in a random subsample of 1,377 to assess the epilepsy diagnosis status. Using the chart review as the reference standard, we evaluated the test characteristics of six published algorithms. Results The best-performing algorithm used diagnostic and prescription drug data (sensitivity = 70%, 95% confidence interval [CI] 66–73%; specificity = 77%, 95% CI 73–81%; and area under the curve [AUC] = 0.73, 95%CI 0.71–0.76) when applied to patients age 18 years or older. Restricting the sample to adults aged 18–64 years resulted in a mild improvement in accuracy (AUC = 0.75,95%CI 0.73–0.78). Adding information about current antiepileptic drug use to the algorithm increased test performance (AUC = 0.78, 95%CI 0.76–0.80). Other algorithms varied in their included data types and performed worse. Significance Current approaches for identifying patients with epilepsy in insurance claims have important limitations when applied to the general population. Approaches incorporating a range of information, for example, diagnoses, treatments, and site of care/specialty of physician, improve the performance of identification and could be useful in epilepsy studies using large datasets.

Importance Interictal epileptiform discharges (IEDs) in electroencephalograms (EEGs) are a biomarker of epilepsy, seizure risk, and clinical decline. However, there is a scarcity of experts qualified to interpret EEG results. Prior attempts to automate IED detection have been limited by small samples and have not demonstrated expert-level performance. There is a need for a validated automated method to detect IEDs with expert-level reliability. Objective To develop and validate a computer algorithm with the ability to identify IEDs as reliably as experts and classify an EEG recording as containing IEDs vs no IEDs. Design, Setting, and Participants A total of 9571 scalp EEG records with and without IEDs were used to train a deep neural network (SpikeNet) to perform IED detection. Independent training and testing data sets were generated from 13 262 IED candidates, independently annotated by 8 fellowship-trained clinical neurophysiologists, and 8520 EEG records containing no IEDs based on clinical EEG reports. Using the estimated spike probability, a classifier designating the whole EEG recording as positive or negative was also built. Main Outcomes and Measures SpikeNet accuracy, sensitivity, and specificity compared with fellowship-trained neurophysiology experts for identifying IEDs and classifying EEGs as positive or negative or negative for IEDs. Statistical performance was assessed via calibration error and area under the receiver operating characteristic curve (AUC). All performance statistics were estimated using 10-fold cross-validation. Results SpikeNet surpassed both expert interpretation and an industry standard commercial IED detector, based on calibration error (SpikeNet, 0.041; 95% CI, 0.033-0.049; vs industry standard, 0.066; 95% CI, 0.060-0.078; vs experts, mean, 0.183; range, 0.081-0.364) and binary classification performance based on AUC (SpikeNet, 0.980; 95% CI, 0.977-0.984; vs industry standard, 0.882; 95% CI, 0.872-0.893). Whole EEG classification had a mean calibration error of 0.126 (range, 0.109-0.1444) vs experts (mean, 0.197; range, 0.099-0.372) and AUC of 0.847 (95% CI, 0.830-0.865). Conclusions and Relevance In this study, SpikeNet automatically detected IEDs and classified whole EEGs as IED-positive or IED-negative. This may be the first time an algorithm has been shown to exceed expert performance for IED detection in a representative sample of EEGs and may thus be a valuable tool for expedited review of EEGs.

Silent seizures were discovered in mouse models of Alzheimer's disease over 10 years ago, yet it remains unclear whether these seizures are a salient feature of Alzheimer's disease in humans. Seizures that arise early in the course of Alzheimer's disease most likely originate from the mesial temporal lobe, one of the first structures affected by Alzheimer's disease pathology and one of the most epileptogenic regions of the brain. Several factors greatly limit our ability to identify mesial temporal lobe seizures in patients with Alzheimer's disease, however. First, mesial temporal lobe seizures can be difficult to recognize clinically, as their accompanying symptoms are often subtle or even non-existent. Second, electrical activity arising from the mesial temporal lobe is largely invisible on the scalp electroencephalogram (EEG), the mainstay of diagnosis for epilepsy in this population. In this review, we will describe two new approaches being used to study silent mesial temporal lobe seizures in Alzheimer's disease. We will first describe the methodology and application of foramen ovale electrodes, which captured the first recordings of silent mesial temporal lobe seizures in humans with Alzheimer's disease. We will then describe machine learning approaches being developed to non-invasively identify silent mesial temporal lobe seizures on scalp EEG. Both of these tools have the potential to elucidate the role of silent seizures in humans with Alzheimer's disease, which could have important implications for early diagnosis, prognostication, and development of targeted therapies for this population.

Purpose Stereotactic radiosurgery (SRS) may be an alternative to anterior temporal lobectomy (ATL) for mesial temporal lobe epilepsy (MTLE). Visual field defects (VFD) occur in 9–100% of patients following open surgery for MTLE. Postoperative VFD after minimally invasive versus open surgery may differ. Methods This prospective trial randomized patients with unilateral hippocampal sclerosis and concordant video-EEG findings to SRS versus ATL. Humphries perimetry was obtained at 24 m after surgery. VFD ratios (VFDR = proportion of missing homonymous hemifield with 0 = no VFD, 0.5 = complete superior quadrantanopsia) quantified VFD. Regressions of VFDR were evaluated against treatment arm and covariates. MRI evaluated effects of volume changes on VFDR. The relationships of VFDR with seizure remission and driving status 3 years after surgery were evaluated. Results No patients reported visual changes or had abnormal bedside examinations, but 49 of 54 (91%) of patients experienced VFD on formal perimetry. Neither incidence nor severity of VFDR differed significantly by treatment arm. VFDR severity was not associated with seizure remission or driving status. Conclusion The nature of VFD was consistent with lesions of the optic radiations. Effective surgery (defined by seizure remission) of the mesial temporal lobe results in about a 90% incidence of typical VFD regardless of method.

A 64-year-old right-handed man presented to the emergency department with a 4-week history of bilateral blurred and distorted vision. He reported that objects in his central visual field appeared to change shape and were disproportionately large or small. He also reported intermittent flashes of light with altered color perception. His medical history was notable for prostate cancer treated with prostatectomy, Bell palsy at age 25, gastroesophageal reflux disease, and bilateral refractive errors. His family had also noted intermittent episodes of confusion and anger over the preceding weeks along with difficulty recognizing family members. He endorsed minimal right-sided periorbital headache but reported no diplopia, weakness, paresthesiae, numbness, speech changes, or history of similar symptoms. He had no recent history of fever, illness, or infectious exposures. He had no history of seizures or migraine. He was taking omeprazole and did not smoke or use alcohol or illicit drugs.

Background. The optimal surgery in lesional neocortical temporal lobe epilepsy is unknown. Hippocampal electrocorticography maximizes seizure freedom by identifying normal-appearing epileptogenic tissue for resection and minimizes neuropsychological deficit by limiting resection to demonstrably epileptogenic tissue. We examined whether standardized hippocampal electrocorticography (hippocampography) guides resection for more consistent hippocampectomy than unguided resection in conventional electrocorticography focused on the lesion. Methods. Retrospective chart reviews any kind of electrocorticography (including hippocampography) as part of combined lesionectomy, anterolateral temporal lobectomy, and hippocampectomy over 8 years . Patients were divided into mesial (i.e., hippocampography) and lateral electrocorticography groups. Primary outcome was deviation from mean hippocampectomy length. Results. Of 26 patients, fourteen underwent hippocampography-guided mesial temporal resection. Hippocampography was associated with 2.6 times more consistent resection. The range of hippocampal resection was 0.7 cm in the mesial group and 1.8 cm in the lateral group (p=0.01). 86% of mesial group versus 42% of lateral group patients achieved seizure freedom (p=0.02). Conclusions. By rationally tailoring excision to demonstrably epileptogenic tissue, hippocampography significantly reduces resection variability for more consistent hippocampectomy than unguided resection in conventional electrocorticography. More consistent hippocampal resection may avoid overresection, which poses greater neuropsychological risk, and underresection, which jeopardizes postoperative seizure freedom.

The aim of this study was to compare physician encounter documentation with patient perceptions of quality of epilepsy care and examine the association between quality and patient assessment of provider communication.We identified 505 adult patients with epilepsy aged 18years or older over a 3-year period in two large academic medical centers. We abstracted individual, clinical, and care measures from 2723 electronic clinical notes written by physicians. We then randomly selected 245 patients for a phone interview. We compared patient perceptions of care with the documented care for several established epilepsy quality measures. We also explored the association of patient's perception of provider communication with provider documentation of key encounter interventions.There were 88 patients (36%) who completed the interviews. Fifty-seven (24%) refused to participate, and 100 (40%) could not be contacted. Participants and nonparticipants were comparable in their demographic and clinical characteristics; however, participants were more often seen by epilepsy specialists than nonparticipants (75% vs. 61.9%, p0.01). Quality scores based on patient perceptions differed from those determined by assessing the documentation in the medical record for several quality measures, e.g., documentation of side effects of antiseizure therapy (p=0.05), safety counseling (p0.01), and counseling for women of childbearing potential with epilepsy (McNemar's p=0.03; intraclass correlation coefficient, ICC=0.07). There was a significant, positive association between patient-reported counseling during the encounter (e.g., personalized safety counseling) and patient-reported scores of provider communication (p=0.05).The association between the patient's recollection of counseling during the visit and his/her positive perception of the provider's communication skills highlights the importance of spending time counseling patients about their epilepsy and not just determining if seizures are controlled.

How the interactions between cortices through a specific white matter pathway change during cognitive processing in patients with epilepsy remains unclear. Here, we used surface-based structural connectivity analysis to examine the change in structural connectivity with Broca's area/the right Broca's homologue in the lateral temporal and inferior parietal cortices through the arcuate fasciculus (AF) in 17 patients with left temporal lobe epilepsy (TLE) compared with 17 healthy controls. Then, we investigated its functional relevance to the changes in task-related responses and task-modulated functional connectivity with Broca's area/the right Broca's homologue during a semantic classification task of a single word. The structural connectivity through the AF pathway and task-modulated functional connectivity with Broca's area decreased in the left midtemporal cortex. Furthermore, task-related response decreased in the left mid temporal cortex that overlapped with the region showing a decrease in the structural connectivity. In contrast, the region showing an increase in the structural connectivity through the AF overlapped with the regions showing an increase in task-modulated functional connectivity in the left inferior parietal cortex. These structural and functional changes in the overlapping regions were correlated. The results suggest that the change in the structural connectivity through the left frontal-temporal AF pathway underlies the altered functional networks between the frontal and temporal cortices during the language-related processing in patients with left TLE. The left frontal-parietal AF pathway might be employed to connect anterior and posterior brain regions during language processing and compensate for the compromised left frontal-temporal AF pathway. Hum Brain Mapp 37:4425-4438, 2016. © 2016 Wiley Periodicals, Inc.

Objective The aim of this study was to assess medication prescribing and patient-reported outcomes among people with epilepsy (PWE) in Bhutan and introduce criteria for evaluating unmet epilepsy care needs, particularly in resource-limited settings. Methods People with epilepsy in Bhutan (National Referral Hospital, 2014–2015) completed a questionnaire, the Quality of Life in Epilepsy Inventory (QOLIE-31), and an electroencephalogram (EEG). Management gap was the proportion of participants meeting any of six prespecified criteria based on best practices and the National Institute for Health and Care Excellence (NICE) guidelines. Results Among 253 participants (53% female, median: 24 years), 93% (n = 235) were treated with antiepileptic drugs (AEDs). Seventy-two percent (n = 183) had active epilepsy (≥ 1 seizure in the prior year). At least one criterion was met by 55% (n = 138) of participants, whereas the treatment gap encompassed only 5% (n = 13). The criteria were the following: 1. Among 18 participants taking no AED, 72% (n = 13) had active epilepsy. 2. Among 26 adults on subtherapeutic monotherapy, 46% (n = 12) had active epilepsy. 3. Among 48 participants reporting staring spells, 56% (n = 27) were treated with carbamazepine or phenytoin. 4. Among 101 female participants aged 14–40 years, 23% (n = 23) were treated with sodium valproate. 5. Among 67 participants reporting seizure-related injuries, 87% (n = 58) had active epilepsy. 6. Among 111 participants with a QOLIE-31 score below 50/100, 77% (n = 86) had active epilepsy. Years since first AED treatment (odds ratio: 1.07, 95% CI: 1.03, 1.12) and epileptiform discharges on EEG (odds ratio: 1.95, 95% CI: 1.15, 3.29) were significantly associated with more criteria met. Conclusions By defining the management gap, subpopulations at greatest need for targeted interventions may be prioritized, including those already taking AEDs.

Ictal-interictal continuum (IIC) continuous EEG (cEEG) patterns including periodic discharges and rhythmic delta activity are associated with poor outcome and in the appropriate clinical context, IIC patterns may represent “electroclinical” status epilepticus (SE). To clarify the significance of IIC patterns and their relationship to “electrographic” SE, we investigated FDG-PET imaging as a complementary metabolic biomarker of SE among patients with IIC patterns. A single-center prospective clinical database was ascertained for patients undergoing FDG-PET during cEEG. Following MRI-PET co-registration, the maximum standardized uptake value in cortical and subcortical regions was compared to contralateral homologous and cerebellar regions. Consensus cEEG review and clinical rating of etiology and treatment response were performed retrospectively with blinding. Electrographic SE was classified as discrete seizures without interictal recovery or >3-Hz rhythmic IIC patterns. Electroclinical SE was classified as IIC patterns with electrographic and clinical response to anticonvulsants; clonic activity; or persistent post-ictal encephalopathy. Eighteen hospitalized subjects underwent FDG-PET during contemporaneous IIC patterns attributed to structural lesions (44 %), neuroinflammatory/neuroinfectious disease (39 %), or epilepsy (11 %). FDG-PET hypermetabolism was common (61 %) and predicted electrographic or electroclinical SE (sensitivity 79 % [95 % CI 53–93 %] and specificity 100 % [95 % CI 51–100 %]; p = 0.01). Excluding electrographic SE, hypermetabolism also predicted electroclinical SE (sensitivity 80 % [95 % CI 44–94 %] and specificity 100 % [95 % CI 51–100 %]; p = 0.01). In hospitalized patients with IIC EEG patterns, FDG-PET hypermetabolism is common and is a candidate metabolic biomarker of electrographic SE or electroclinical SE.

Extreme delta brush (EDB) is an EEG pattern unique to anti-NMDA encephalitis. It is correlated with seizures and status epilepticus in patients who have a prolonged course of illness. The etiology of the underlying association between EDB and seizures is not understood. We present a patient with anti-NMDA encephalitis who developed status epilepticus evolving from the high frequency activity of the extreme delta brush. This case demonstrates that EDB is not only a marker for a greater propensity for seizures but also directly implicated in seizure generation.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a promising immunotherapeutic approach in relapsed/refractory haematolgical malignancies. Broader application is limited by unique toxicities, notably, neurotoxicity (NTX). Language dysfunction is among the most frequent symptoms of NTX, the underlying mechanisms of which remain to be elucidated. Electroencephalogram (EEG) is an important tool to monitor for NTX and may provide insights into language dysfunction.AimWe aimed to characterise language dysfunction and define electroencephalographic signatures after CAR-T cell therapy.MethodsWe reviewed the clinical presentation and EEG findings of 20 adult patients presenting with language dysfunction after CAR-T cell infusion. The cohort included a subset of patients treated with investigational CD19-directed CAR-T cells for non-Hodgkin’s lymphoma (n=17), acute lymphoblastic leukaemia (n=1), follicular lymphoma (n=1) and chronic lymphocytic leukaemia (n=1).ResultsLanguage dysfunction presented within 14 days of CAR-T cell infusion in 16 (84%) patients. Ten (50%) patients had mild word-finding difficulties and 10 (50%) had marked dysphasia with profound word-finding difficulties; the latter were all associated with generalised rhythmic delta activity or generalised periodic discharges on EEG.ConclusionsLanguage dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities.

Importance The validity of using electroencephalograms (EEGs) to diagnose epilepsy requires reliable detection of interictal epileptiform discharges (IEDs). Prior interrater reliability (IRR) studies are limited by small samples and selection bias. Objective To assess the reliability of experts in detecting IEDs in routine EEGs. Design, Setting, and Participants This prospective analysis conducted in 2 phases included as participants physicians with at least 1 year of subspecialty training in clinical neurophysiology. In phase 1, 9 experts independently identified candidate IEDs in 991 EEGs (1 expert per EEG) reported in the medical record to contain at least 1 IED, yielding 87 636 candidate IEDs. In phase 2, the candidate IEDs were clustered into groups with distinct morphological features, yielding 12 602 clusters, and a representative candidate IED was selected from each cluster. We added 660 waveforms (11 random samples each from 60 randomly selected EEGs reported as being free of IEDs) as negative controls. Eight experts independently scored all 13 262 candidates as IEDs or non-IEDs. The 1051 EEGs in the study were recorded at the Massachusetts General Hospital between 2012 and 2016. Main Outcomes and Measures Primary outcome measures were percentage of agreement (PA) and beyond-chance agreement (Gwet κ) for individual IEDs (IED-wise IRR) and for whether an EEG contained any IEDs (EEG-wise IRR). Secondary outcomes were the correlations between numbers of IEDs marked by experts across cases, calibration of expert scoring to group consensus, and receiver operating characteristic analysis of how well multivariate logistic regression models may account for differences in the IED scoring behavior between experts. Results Among the 1051 EEGs assessed in the study, 540 (51.4%) were those of females and 511 (48.6%) were those of males. In phase 1, 9 experts each marked potential IEDs in a median of 65 (interquartile range [IQR], 28-332) EEGs. The total number of IED candidates marked was 87 636. Expert IRR for the 13 262 individually annotated IED candidates was fair, with the mean PA being 72.4% (95% CI, 67.0%-77.8%) and mean κ being 48.7% (95% CI, 37.3%-60.1%). The EEG-wise IRR was substantial, with the mean PA being 80.9% (95% CI, 76.2%-85.7%) and mean κ being 69.4% (95% CI, 60.3%-78.5%). A statistical model based on waveform morphological features, when provided with individualized thresholds, explained the median binary scores of all experts with a high degree of accuracy of 80% (range, 73%-88%). Conclusions and Relevance This study’s findings suggest that experts can identify whether EEGs contain IEDs with substantial reliability. Lower reliability regarding individual IEDs may be largely explained by various experts applying different thresholds to a common underlying statistical model.

ObjectiveTo compare the expected quality-adjusted life-years (QALYs) in adult patients undergoing immediate vs deferred antiepileptic drug (AED) treatment after a first unprovoked seizure.MethodsWe constructed a simulated clinical trial (Markov decision model) to compare immediate vs deferred AED treatment after a first unprovoked seizure in adults. Three base cases were considered, representing patients with varying degrees of seizure recurrence risk and effect of seizures on quality of life (QOL). Cohort simulation was performed to determine which treatment strategy would maximize the patient's expected QALYs. Sensitivity analyses were guided by clinical data to define decision thresholds across plausible measurement ranges, including seizure recurrence rate, effect of seizure recurrence on QOL, and efficacy of AEDs.ResultsFor patients with a moderate risk of recurrent seizures (52.0% over 10 years after first seizure), immediate AED treatment maximized QALYs compared to deferred treatment. Sensitivity analyses showed that for the preferred choice to change to deferred AED treatment, key clinical measures needed to reach implausible values were 10-year seizure recurrence rate ≤38.0%, QOL reduction with recurrent seizures ≤0.06, and efficacy of AEDs on lowering seizure recurrence rate ≤16.3%.ConclusionOur model determined that immediate AED treatment is preferable to deferred treatment in adult first-seizure patients over a wide and clinically relevant range of variables. Furthermore, our analysis suggests that the 10-year seizure recurrence rate that justifies AED treatment (38.0%) is substantially lower than the 60% threshold used in the current definition of epilepsy.

Objective Delayed cerebral ischemia (DCI) is a common, disabling complication of subarachnoid hemorrhage (SAH). Preventing DCI is a key focus of neurocritical care, but interventions carry risk and cannot be applied indiscriminately. Although retrospective studies have identified continuous electroencephalographic (cEEG) measures associated with DCI, no study has characterized the accuracy of cEEG with sufficient rigor to justify using it to triage patients to interventions or clinical trials. We therefore prospectively assessed the accuracy of cEEG for predicting DCI, following the Standards for Reporting Diagnostic Accuracy Studies. Methods We prospectively performed cEEG in nontraumatic, high-grade SAH patients at a single institution. The index test consisted of clinical neurophysiologists prospectively reporting prespecified EEG alarms: (1) decreasing relative alpha variability, (2) decreasing alpha-delta ratio, (3) worsening focal slowing, or (4) late appearing epileptiform abnormalities. The diagnostic reference standard was DCI determined by blinded, adjudicated review. Primary outcome measures were sensitivity and specificity of cEEG for subsequent DCI, determined by multistate survival analysis, adjusted for baseline risk. Results One hundred three of 227 consecutive patients were eligible and underwent cEEG monitoring (7.7-day mean duration). EEG alarms occurred in 96.2% of patients with and 19.6% without subsequent DCI (1.9-day median latency, interquartile range = 0.9-4.1). Among alarm subtypes, late onset epileptiform abnormalities had the highest predictive value. Prespecified EEG findings predicted DCI among patients with low (91% sensitivity, 83% specificity) and high (95% sensitivity, 77% specificity) baseline risk. Interpretation cEEG accurately predicts DCI following SAH and may help target therapies to patients at highest risk of secondary brain injury. Ann Neurol 2018;83:958-969.

ObjectiveTo investigate the correlation between characteristics of lateralized periodic discharges (LPDs) and glucose metabolism measured by 18F-fluorodeoxyglucose (FDG)–PET.MethodsWe retrospectively reviewed medical records to identify patients who underwent FDG-PET during EEG monitoring with LPDs present during the FDG uptake period. Two blinded board-certified neurophysiologists independently interpreted EEGs. FDG uptake was measured using standardized uptake value (SUV). Structural images were fused with PET images to aid with localization of SUV. Two PET readers independently measured maximum SUV. Relative SUV values were obtained by normalization of the maximum SUV to the SUV of pons (SUVRpons). LPD frequency was analyzed both as a categorical variable and as a continuous measure. Other secondary variables included duration, amplitude, presence of structural lesion, and “plus” EEG features such as rhythmic or fast sharp activity.ResultsNine patients were identified and 7 had a structural etiology for LPDs. Analysis using frequency as a categorical variable and continuous variable showed an association between increased LPD frequency and increased ipsilateral SUVRpons (p = 0.02). Metabolism associated with LPDs (0.5 Hz as a baseline) increased by a median of 100% at 1 Hz and for frequencies >1 Hz increased by a median of 309%. There were no statistically significant differences in SUVRpons for other factors including duration (p = 0.10), amplitude (p = 0.80), structural etiology (p = 0.55), or “plus” features such as rhythmic or fast sharp activity (p = 0.84).ConclusionsMetabolic activity increases monotonically with LPD frequency. LPD frequency should be a measure of interest when developing neuroprotection strategies in critical neurologic illness.

Objective To compare stereotactic radiosurgery (SRS) versus anterior temporal lobectomy (ATL) for patients with pharmacoresistant unilateral mesial temporal lobe epilepsy (MTLE). Methods This randomized, single-blinded, controlled trial recruited adults eligible for open surgery among 14 centers in the USA, UK, and India. Treatment was either SRS at 24 Gy to the 50% isodose targeting mesial structures, or standardized ATL. Outcomes were seizure remission (absence of disabling seizures between 25 and 36 months), verbal memory (VM), and quality of life (QOL) at 36-month follow-up. Results A total of 58 patients (31 in SRS, 27 in ATL) were treated. Sixteen (52%) SRS and 21 (78%) ATL patients achieved seizure remission (difference between ATL and SRS = 26%, upper 1-sided 95% confidence interval = 46%, P value at the 15% noninferiority margin = .82). Mean VM changes from baseline for 21 English-speaking, dominant-hemisphere patients did not differ between groups; consistent worsening occurred in 36% of SRS and 57% of ATL patients. QOL improved with seizure remission. Adverse events were anticipated cerebral edema and related symptoms for some SRS patients, and cerebritis, subdural hematoma, and others for ATL patients. Significance These data suggest that ATL has an advantage over SRS in terms of proportion of seizure remission, and both SRS and ATL appear to have effectiveness and reasonable safety as treatments for MTLE. SRS is an alternative to ATL for patients with contraindications for or with reluctance to undergo open surgery.

Chimeric antigen receptor (CAR) modified T cells emerged as promising immunotherapy in refractory lymphoid malignancies.1 Despite efficacy, toxicities include cytokine release syndrome (CRS) and neurotoxicity.1 We report EEG findings in patients with chemotherapy-refractory stage IV diffuse large B-cell lymphoma (DLBCL-4) who received CAR T cells and developed neurotoxicity.

Summary Objective The purpose of this study was to develop a quantitative framework to estimate the likelihood of multifocal epilepsy based on the number of unifocal seizures observed in the epilepsy monitoring unit (EMU). Methods Patient records from the EMU at Massachusetts General Hospital (MGH) from 2012 to 2014 were assessed for the presence of multifocal seizures as well the presence of multifocal interictal discharges and multifocal structural imaging abnormalities during the course of the EMU admission. Risk factors for multifocal seizures were assessed using sensitivity and specificity analysis. A Kaplan-Meier survival analysis was used to estimate the risk of multifocal epilepsy for a given number of consecutive seizures. To overcome the limits of the Kaplan-Meier analysis, a parametric survival function was fit to the EMU subjects with multifocal seizures and this was used to develop a Bayesian model to estimate the risk of multifocal seizures during an EMU admission. Results Multifocal interictal discharges were a significant predictor of multifocal seizures within an EMU admission with a p

Objective Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions. Methods Ambulatory ECoG was reviewed in patients with suspected bilateral MTL epilepsy who were among a larger cohort with intractable epilepsy participating in a randomized controlled trial of responsive neurostimulation. Subjects were implanted with bilateral MTL leads and a cranially implanted neurostimulator programmed to detect abnormal interictal and ictal ECoG activity. ECoG data stored by the neurostimulator were reviewed to determine the lateralization of electrographic seizures and the interval of time until independent bilateral MTL electrographic seizures were recorded. Results Eighty-two subjects were implanted with bilateral MTL leads and followed for 4.7 years on average (median 4.9 years). Independent bilateral MTL electrographic seizures were recorded in 84%. The average time to record bilateral electrographic seizures in the ambulatory setting was 41.6 days (median 13 days, range 0–376 days). Sixteen percent had only unilateral electrographic seizures after an average of 4.6 years of recording. Significance About one third of the subjects implanted with bilateral MTL electrodes required >1 month of chronic ambulatory ECoG before the first contralateral MTL electrographic seizure was recorded. Some patients with suspected bilateral MTL seizures had only unilateral electrographic seizures. Chronic ambulatory ECoG in patients with suspected bilateral MTL seizures provides data in a naturalistic setting, may complement data from inpatient video-EEG monitoring, and can contribute to treatment decisions.

The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures.All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy.The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%).The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures.This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Objective Brain connectivity at rest is altered in temporal lobe epilepsy (TLE), particularly in “hub” areas such as the posterior default mode network (DMN). Although both functional and anatomical connectivity are disturbed in TLE, the relationships between measures as well as to seizure frequency remain unclear. We aim to clarify these associations using connectivity measures specifically sensitive to hubs. Methods Connectivity between 1000 cortical surface parcels was determined in 49 TLE patients and 23 controls with diffusion and resting-state functional magnetic resonance imaging. Two types of hub connectivity were investigated across multiple brain modules (the DMN, motor system, etcetera): (1) within-module connectivity (a measure of local importance that assesses a parcel's communication level within its own subnetwork) and (2) between-module connectivity (a measure that assesses connections across multiple modules). Results In TLE patients, there was lower overall functional integrity of the DMN as well as an increase in posterior hub connections with other modules. Anatomical between-module connectivity was globally decreased. Higher DMN disintegration (DD) coincided with higher anatomical between-module connectivity, whereas both were associated with increased seizure frequency. DD related to seizure frequency through mediating effects of anatomical connectivity, but seizure frequency also correlated with anatomical connectivity through DD, indicating a complex interaction between multimodal networks and symptoms. Interpretation We provide evidence for dissociated anatomical and functional hub connectivity in TLE. Moreover, shifts in functional hub connections from within to outside the DMN, an overall loss of integrative anatomical communication, and the interaction between the two increase seizure frequency.

Objective Excitotoxic injury involving N-methyl-d-aspartate (NMDA) receptor hyperactivity contributes to epilepsy-related memory dysfunction (ERMD). Current treatment strategies for ERMD have limited efficacy and fail to target the underlying pathophysiology. The present pilot study evaluated the efficacy of memantine, an NMDA receptor antagonist, for the treatment of ERMD in adults with focal-onset seizures. Methods Subjects underwent cognitive testing at baseline, after a 13-week randomized, parallel-group, double-blinded phase (of memantine titrated to 10 mg bid or placebo), and following a 13-week open-label extension phase (of memantine titrated to 10 mg bid). The selective reminding test (SRT) continuous long-term retrieval (CLTR) score and 7/24 Spatial Recall Test learning score served as the primary outcome measures. Secondary measures included tests of attention span, fluency, visual construction, and response inhibition, as well as assessments of quality of life, depression, sleepiness, and side effects. Results Seventeen subjects contributed data to the blinded phase (n = 8 memantine, n = 9 placebo). No significant differences were seen between groups on the primary or secondary outcome measures. Pooled data at the end of the open-label phase from 10 subjects (initially randomized to memantine n = 3 or placebo n = 7) demonstrated statistically significant improvement from baseline in CLTR score, memory-related quality of life, spatial span, and response inhibition. No significant changes were evident in depression, sleepiness, side effects, or seizure frequency throughout the trial. Significance Results demonstrated no significant effect of memantine on cognition when assessed at the end of the blinded period. Pooled data at the end of the open-label phase showed significant improvement over baseline performance in measures of verbal memory, frontal-executive function, and memory-related quality of life. These improvements, however, may be due to practice effects and should be interpreted cautiously. Findings suggest a favorable safety profile of memantine in the setting of epilepsy.

SummaryObjective Evaluate 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. Methods Subjects 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. Results There 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). Significance Brain-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.

Background:Pressure ulcers resulting from continuous EEG (cEEG) monitoring in hospitalized patients have gained attention as a preventable medical complication. We measured their incidence and risk factors.Methods:We performed an observational investigation of cEEG-electrode-related pressure ulcers (EERPU) among acutely ill patients over a 22-month period. Variables analyzed included age, sex, monitoring duration, hospital location, application methods, vasopressor usage, nutritional status, skin allergies, fever, and presence/severity of EERPU. We examined risk for pressure ulcers vs monitoring duration using Kaplan-Meyer survival analysis, and performed multivariate risk assessment using Cox proportional hazard model.Results:Among 1,519 patients, EERPU occurred in 118 (7.8%). Most (n = 109, 92.3%) consisted of hyperemia only without skin breakdown. A major predictor was monitoring duration, with 3-, 5-, and 10-day risks of 16%, 32%, and 60%, respectively. Risk factors included older age (mean age 60.65 vs 50.3, p < 0.01), care in an intensive care unit (9.37% vs 5.32%, p < 0.01), lack of a head wrap (8.31% vs 27.3%, p = 0.02), use of vasopressors (16.7% vs 9.64%, p < 0.01), enteral feeding (11.7% vs 5.45%, p = 0.04), and fever (18.4% vs 9.3%, p < 0.01). Elderly patients (71–80 years) were at higher risk (hazard ratio 6.84 [1.95–24], p < 0.01), even after accounting for monitoring time and other pertinent variables in multivariate analysis.Conclusions:EERPU are uncommon and generally mild. Elderly patients and those with more severe illness have higher risk of developing EERPU, and the risk increases as a function of monitoring duration.

SUMMARY Objectives: Anterior temporal lobectomy is curative for many patients with disabling medically refractory temporal lobe epilepsy, but carries an inherent risk of disabling verbal memory loss. Although accurate prediction of iatrogenic memory loss is becoming increasingly possible, it remains unclear how much weight such predictions should have in surgical decision making. Here we aim to create a framework that facilitates a systematic and integrated assessment of the relative risks and benefits of surgery versus medical management for patients with left temporal lobe epilepsy. Methods: We constructed a Markov decision model to evaluate the probabilistic outcomes and associated health utilities associated with choosing to undergo a left anterior temporal lobectomy versus continuing with medical management for patients with medically refractory left temporal lobe epilepsy. Three base-cases were considered, representing a spectrum of surgical candidates encountered in practice, with varying degrees of epilepsy-related disability and potential for decreased quality of life in response to post-surgical verbal memory deficits. Results: For patients with moderately severe seizures and moderate risk of verbal memory loss, medical management was the preferred decision, with increased quality-adjusted life expectancy. However, the preferred choice was sensitive to clinically meaningful changes in several parameters, including quality of life impact of verbal memory decline, quality of life with seizures, mortality rate with medical management, probability of remission following surgery, and probability of remission with medical management. Significance: Our decision model suggests that for patients with left temporal lobe epilepsy, quantitative assessment of risk and benefit should guide recommendation of therapy. In particular, risk for and potential impact of verbal memory decline should be carefully weighed against the degree of disability conferred by continued seizures on a patient-by-patient basis.

Quantitatively evaluate whether screening with compressed spectral arrays (CSAs) is a practical and time-effective protocol for assisting expert review of continuous EEG (cEEG) studies in hospitalized adults.Three neurophysiologists reviewed the reported findings of the first 30 minutes of 118 cEEGs, then used CSA to guide subsequent review ("CSA-guided review" protocol). Reviewers viewed 120 seconds of raw EEG data surrounding suspicious CSA segments. The same neurophysiologists performed independent page-by-page visual interpretation ("conventional review") of all cEEGs. Independent conventional review by 2 additional, more experienced neurophysiologists served as a gold standard. We compared review times and detection rates for seizures and other pathologic patterns relative to conventional review.A total of 2,092 hours of cEEG data were reviewed. Average times to review 24 hours of cEEG data were 8 (±4) minutes for CSA-guided review vs 38 (±17) minutes for conventional review (p0.005). Studies containing seizures required longer review: 10 (±4) minutes for CSA-guided review vs 44 (±20) minutes for conventional review (p0.005). CSA-guided review was sensitive for seizures (87.3%), periodic epileptiform discharges (100%), rhythmic delta activity (97.1%), focal slowing (98.7%), generalized slowing (100%), and epileptiform discharges (88.5%).CSA-guided review reduces cEEG review time by 78% with minimal loss of sensitivity compared with conventional review.This study provides Class IV evidence that screening of cEEG with CSAs efficiently and accurately identifies seizures and other EEG abnormalities as compared with standard cEEG visual interpretation.

Aim. Caregiver burden (CB) in epilepsy constitutes an understudied area. Here we attempt to identify the magnitude of this burden, the factors associated with it, and its impact to caregiver quality of life (QOL). Methods. 48 persons with epilepsy (PWE) underwent video-EEG monitoring and their caregivers completed questionnaires providing demographic, disease-related, psychiatric, cognitive, sleep, QOL, and burden information. Results. On regression analysis, higher number of antiepileptic drugs, poorer patient neuropsychological performance, lower patient QOL score, and lower caregiver education level were associated with higher CB. Time allocated to patient care approximated but did not attain statistical significance. A moderate inverse correlation between CB and caregiver QOL physical component summary score and a stronger inverse correlation between CB and caregiver QOL mental component summary score were seen. Conclusion. In a selected cohort of PWE undergoing video-EEG monitoring, we identified modest degree of CB, comparable to that reported in the literature for other chronic neurological conditions. It is associated with specific patient and caregiver characteristics and has a negative effect on caregiver QOL.

Summary Objectives To determine the ability of foramen ovale electrodes (FOEs) to localize epileptogenic foci after inconclusive noninvasive investigations in patients with suspected mesial temporal lobe epilepsy (MTLE). Methods We identified patients with medically intractable epilepsy who had undergone FOE investigation for initial invasive monitoring at our institution between 2005 and 2012. Indications for initiating FOE investigation were grouped into four categories: (1) bilateral anterior temporal ictal activity on scalp electroencephalography (EEG), (2) unclear laterality of scalp EEG onset due to muscle artifact or significant delay following clinical manifestation, (3) discordance between ictal and interictal discharges, and (4) investigation of a specific anatomic abnormality or competing putative focus. The FOE investigation was classified as informative if it provided sufficient evidence to make a treatment decision. Results Forty-two consecutive patients underwent FOE investigation, which was informative in 38 patients (90.5%). Of these 38 patients, 24 were determined to be appropriate candidates for resective surgery. Five were localized sufficiently for surgery, but were considered high risk for verbal memory deficit, and nine were deemed poor surgical candidates because of bilateral ictal origins. The remaining 4 of 42 patients had inconclusive FOE studies and were referred for further invasive investigation. Of the 18 patients who underwent resective surgery, 13 (72%) were seizure-free (Engel class I) at last follow-up (mean 22.5 months). Significance More than 90% of our 42 FOE studies provided sufficient evidence to render treatment decisions. When undertaken with an appropriate hypothesis, FOE investigations are a minimally invasive and efficacious means for evaluating patients with suspected MTLE after an inconclusive noninvasive investigation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

The pathogenesis of disease progression in drug-refractory epilepsy is poorly understood. We report the case of a young woman with a four-year history of epilepsy that progressed rapidly as evidenced by the development of progressive focal cortical atrophy. She underwent biopsy that showed perinatal ischemia and a prominent inflammatory response, including T-cell infiltration and microglial activation. There was no consensus reached on the final diagnosis although the hypothesis of dual pathology (adult variant of Rasmussen's encephalitis and perinatal stroke) was considered. The possible role of inflammation in the progression of epilepsy caused by a “static” lesion (perinatal stroke) is discussed.