Search

Improgan is a compound developed from histamine antagonists which shows the pre-clinical profile of a highly effective, non-opioid analgesic when administered into the rodent CNS. Pharmacological studies suggest that improgan activates descending pain-relieving circuits, but the brain and spinal sites of action of this drug have not been previously studied. Presently, the effects of intracerebral and intrathecal microinjections of improgan were evaluated on thermal nociceptive responses in rats. Improgan produced large, dose- and time-related reductions in nociceptive responses following administration into the ventrolateral periaqueductal gray (PAG), the dorsal PAG, and the rostral ventromedial medulla (RVM). The drug had no measurable effects after injections into the caudate nucleus, basolateral amygdala, hippocampus, ventromedial hypothalamus, superior colliculi, ventrolateral medulla, or the spinal subarachnoid space. Inactivation of the RVM by muscimol microinjections completely attenuated antincociceptive responses produced by intraventricular improgan. These findings, taken with earlier results, show that, like opioids and cannabinoids, improgan acts in the PAG and RVM to activate descending analgesic systems. Unlike these other analgesics, improgan does not act in the spinal cord or in CNS areas outside of the brain stem. [Copyright &y& Elsevier]

Objective: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis., Methods: Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout., Results: Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation., Significance: These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant., Competing Interests: Declaration of competing interest All the authors have approved the manuscript and agree with submission to Experimental Neurology. There are no conflicts of interest to declare. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 Elsevier Inc. All rights reserved.)

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes., (© 2024 International League Against Epilepsy.)

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an artificial intelligence (AI) model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a microaveraged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the microaveraged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in clinical settings and drug trials. Further prospective studies are needed to confirm its ability to improve patient care., (© 2024. The Author(s).)

Purpose: Communication failure is one of the most significant causes of medical errors. Providing care to patients with seizures at comprehensive epilepsy centers requires uninterrupted coverage and a multidisciplinary approach. However, handoff practices in these settings have not been comprehensively assessed, and recommendations for their standardization are currently lacking. The aim of this observational study was to define the scope of existing practices for patient handoffs across epilepsy centers in the United States and provide relevant recommendations., Methods: A 79-question survey was developed to establish the patterns of transition of care for patients undergoing continuous EEG recording, including the periodicity of handoffs and specifics of the relevant workflow. With permission from the National Association of Epilepsy Centers (NAEC), the survey was distributed to the medical directors of all Level 3 and 4 NAEC-accredited epilepsy centers in the United States., Results: The responses were obtained from 70 institutions yielding a survey response rate of 26%. Of these, more than 77% had established weekly handoff processes for both the epilepsy monitoring unit and continuous EEG (cEEG) monitoring services. However, only 53% and 43% of centers had procedures for daily service transfers for the patients admitted to the epilepsy monitoring unit or the patients undergoing cEEG, respectively. The patterns of handoffs were complex and utilized group handoffs in < 50% of institutions. In most centers (>70%), patient data transmitted through handoffs included history, clinical information, and EEG findings. However, templates were not applied to standardize this information. All participants agreed or strongly agreed that a culture of patient safety was maintained in their place of practice; however, 12% of participants felt that insufficient time was allowed to discuss these patients or carry out the handoffs without interruptions., Conclusions: Existing handoff practices are not uniform or fully established across epilepsy centers in the United States. This study recommends that guidelines for formal handoff procedures be developed and introduced as a quality metric for all NAEC-accredited epilepsy centers., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 by the American Clinical Neurophysiology Society.)

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions., (© 2024 International League Against Epilepsy.)

Background: In intensive care units (ICUs), critically ill patients are monitored with electroencephalography (EEG) to prevent serious brain injury. EEG monitoring is constrained by clinician availability, and EEG interpretation can be subjective and prone to interobserver variability. Automated deep-learning systems for EEG could reduce human bias and accelerate the diagnostic process. However, existing uninterpretable (black-box) deep-learning models are untrustworthy, difficult to troubleshoot, and lack accountability in real-world applications, leading to a lack of both trust and adoption by clinicians., Methods: We developed an interpretable deep-learning system that accurately classifies six patterns of potentially harmful EEG activity - seizure, lateralized periodic discharges (LPDs), generalized periodic discharges (GPDs), lateralized rhythmic delta activity (LRDA), generalized rhythmic delta activity (GRDA), and other patterns - while providing faithful case-based explanations of its predictions. The model was trained on 50,697 total 50-second continuous EEG samples collected from 2711 patients in the ICU between July 2006 and March 2020 at Massachusetts General Hospital. EEG samples were labeled as one of the six EEG patterns by 124 domain experts and trained annotators. To evaluate the model, we asked eight medical professionals with relevant backgrounds to classify 100 EEG samples into the six pattern categories - once with and once without artificial intelligence (AI) assistance - and we assessed the assistive power of this interpretable system by comparing the diagnostic accuracy of the two methods. The model's discriminatory performance was evaluated with area under the receiver-operating characteristic curve (AUROC) and area under the precision-recall curve. The model's interpretability was measured with task-specific neighborhood agreement statistics that interrogated the similarities of samples and features. In a separate analysis, the latent space of the neural network was visualized by using dimension reduction techniques to examine whether the ictal-interictal injury continuum hypothesis, which asserts that seizures and seizure-like patterns of brain activity lie along a spectrum, is supported by data., Results: The performance of all users significantly improved when provided with AI assistance. Mean user diagnostic accuracy improved from 47 to 71% (P<0.04). The model achieved AUROCs of 0.87, 0.93, 0.96, 0.92, 0.93, and 0.80 for the classes seizure, LPD, GPD, LRDA, GRDA, and other patterns, respectively. This performance was significantly higher than that of a corresponding uninterpretable black-box model (with P<0.0001). Videos traversing the ictal-interictal injury manifold from dimension reduction (a two-dimensional representation of the original high-dimensional feature space) give insight into the layout of EEG patterns within the network's latent space and illuminate relationships between EEG patterns that were previously hypothesized but had not yet been shown explicitly. These results indicate that the ictal-interictal injury continuum hypothesis is supported by data., Conclusions: Users showed significant pattern classification accuracy improvement with the assistance of this interpretable deep-learning model. The interpretable design facilitates effective human-AI collaboration; this system may improve diagnosis and patient care in clinical settings. The model may also provide a better understanding of how EEG patterns relate to each other along the ictal-interictal injury continuum. (Funded by the National Science Foundation, National Institutes of Health, and others.).

Objective: We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis., Methods: Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88 -/- ) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively., Results: As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3-25 in 2 weeks). In contrast, only three of 14 MyD88 -/- mice (21.4%) had seizures (0, IQR = 0-.25, p = .01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88 -/- mice treated with anti-NMDAR antibodies (p = .03) or control antibodies (p = .04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88 -/- mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p = .0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88 -/- mice treated with anti-NMDAR or control antibodies., Significance: These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Magnetoencephalography (MEG) is clinically used to localize interictal spikes in discrete brain areas of epilepsy patients through the equivalent current dipole (ECD) method, but does not account for the temporal dynamics of spike activity. Recent studies found that interictal spike propagation beyond the temporal lobe may be associated with worse postsurgical outcomes, but studies using whole-brain data such as in MEG remain limited. In this pilot study, we developed a tool that visualizes the spatiotemporal dynamics of interictal MEG spikes normalized to spike-free sleep activity to assess their onset and propagation patterns in patients with temporal lobe epilepsy (TLE). We extracted interictal source data containing focal epileptiform activity in awake and asleep states from seven patients whose MEG ECD clusters localized to the temporal lobe and normalized the data against spike-free sleep recordings. We calculated the normalized activity over time per cortical label, confirmed maximal activity at onset, and mapped the activity over a 10 ms interval onto each patient's brain using a custom-built Multi-Modal Visualization Tool. The onset of activity in all patients appeared near the clinically determined epileptogenic zone. By 10 ms, four of the patients had propagated source activity restricted to within the temporal lobe, and three had propagated source activity spread to extratemporal regions. Using this tool, we show that noninvasively identifying the onset and propagation of interictal spike activity in MEG can be achieved, which may help provide further insight into epileptic networks and guide surgical planning and interventions in patients with TLE., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The Critical Care EEG Monitoring Research Consortium (CCEMRC) is an international research group focusing on critical care EEG and epilepsy. As CCEMRC grew to include 50+ institutions over the past decade, members met to establish research priorities., Methods: The authors used an analytical hierarchy process-based research prioritization method, adapted from an approach previously applied to a Department of Defense health-related research program. Forty-six CCEMRC members identified and scored a set of eight clinical problems (CPs) and 15 research topic areas (RTAs) at an annual CCEMRC meeting. Members scored CPs on three criteria using a five-point ordinal scale: Incidence, Impact, and Gap Size; and RTAs on four additional criteria: Niche, Feasibility, Scientific Importance, and Medical Importance, each of which was assigned a weight. The first three RTA criteria were scored using a five-point scale, and CPs were mapped to RTAs using a four-point scale. The Medical Importance score was a weighted average of its mapping scores and the CP score. Finally, a Priority score was calculated for each RTA as a product of the four RTA criteria scores., Results: The CPs with the highest scores were "Altered mental status" and "Long-term neurologic disability after hospital discharge." The RTAs with the highest priority scores were "Development of risk prediction tools," "Multicenter observational studies," and "Outcome prediction.", Conclusions: Research prioritization helped CCEMRC evaluate its current research trajectory, identify high-priority near-term research pursuits, and create a roadmap for future research plans aligned with its mission. This approach may be helpful to other academic consortia and research programs., (Copyright © 2022 by the American Clinical Neurophysiology Society.)

New onset refractory status epilepticus (NORSE), including its subtype with a preceding febrile illness known as febrile infection-related epilepsy syndrome (FIRES), is one of the most severe forms of status epilepticus. The exact causes of NORSE are currently unknown, and there is so far no disease-specific therapy. Identifying the underlying pathophysiology and discovering specific biomarkers, whether immunologic, infectious, genetic, or other, may help physicians in the management of patients with NORSE. A broad spectrum of biomarkers has been proposed for status epilepticus patients, some of which were evaluated for patients with NORSE. Nonetheless, none has been validated, due to significant variabilities in study cohorts, collected biospecimens, applied analytical methods, and defined outcome endpoints, and to small sample sizes. The NORSE Institute established an open NORSE/FIRES biorepository for health-related data and biological samples allowing the collection of biospecimens worldwide, promoting multicenter research and sharing of data and specimens. Here, we suggest standard operating procedures for biospecimen collection and biobanking in this rare condition. We also propose criteria for the appropriate use of previously collected biospecimens. We predict that the widespread use of standardized procedures will reduce heterogeneity, facilitate the future identification of validated biomarkers for NORSE, and provide a better understanding of the pathophysiology and best clinical management for these patients., (© 2023 International League Against Epilepsy.)

Background and Objectives: The validity of brain monitoring using electroencephalography (EEG), particularly to guide care in patients with acute or critical illness, requires that experts can reliably identify seizures and other potentially harmful rhythmic and periodic brain activity, collectively referred to as "ictal-interictal-injury continuum" (IIIC). Previous interrater reliability (IRR) studies are limited by small samples and selection bias. This study was conducted to assess the reliability of experts in identifying IIIC., Methods: This prospective analysis included 30 experts with subspecialty clinical neurophysiology training from 18 institutions. Experts independently scored varying numbers of ten-second EEG segments as "seizure (SZ)," "lateralized periodic discharges (LPDs)," "generalized periodic discharges (GPDs)," "lateralized rhythmic delta activity (LRDA)," "generalized rhythmic delta activity (GRDA)," or "other." EEGs were performed for clinical indications at Massachusetts General Hospital between 2006 and 2020. Primary outcome measures were pairwise IRR (average percent agreement [PA] between pairs of experts) and majority IRR (average PA with group consensus) for each class and beyond chance agreement (κ). Secondary outcomes were calibration of expert scoring to group consensus, and latent trait analysis to investigate contributions of bias and noise to scoring variability., Results: Among 2,711 EEGs, 49% were from women, and the median (IQR) age was 55 (41) years. In total, experts scored 50,697 EEG segments; the median [range] number scored by each expert was 6,287.5 [1,002, 45,267]. Overall pairwise IRR was moderate (PA 52%, κ 42%), and majority IRR was substantial (PA 65%, κ 61%). Noise-bias analysis demonstrated that a single underlying receiver operating curve can account for most variation in experts' false-positive vs true-positive characteristics (median [range] of variance explained ([Formula: see text]): 95 [93, 98]%) and for most variation in experts' precision vs sensitivity characteristics ([Formula: see text]: 75 [59, 89]%). Thus, variation between experts is mostly attributable not to differences in expertise but rather to variation in decision thresholds., Discussion: Our results provide precise estimates of expert reliability from a large and diverse sample and a parsimonious theory to explain the origin of disagreements between experts. The results also establish a standard for how well an automated IIIC classifier must perform to match experts., Classification of Evidence: This study provides Class II evidence that an independent expert review reliably identifies ictal-interictal injury continuum patterns on EEG compared with expert consensus., (© 2022 American Academy of Neurology.)

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., (© 2023 American Academy of Neurology.)

Objectives: Delayed management of nonconvulsive status epilepticus (NCSE) can lead to an increased morbidity and mortality. We previously established that inefficient treatment of NCSE at our institution stemmed from delayed initiation of emergent anti-seizure medications (ASM). In the present study, we assessed the trajectories of these time parameters and determined patient outcomes following the specific quality improvement (QI) interventions., Methods: The QI interventions, including the revision of the educational content for trainees and pharmacy workflow optimization were implemented between January 2019 and September 2021 by a dedicated multidisciplinary task force. The times needed to initiate and administer the ASMs for patients with NCSE as well as patient mortality were assessed in comatose and noncomatose patients and compared with the corresponding values prior to the interventions., Results: There were 79 occurrences of NCSE in 74 patients. The median time from seizure detection on EEG to the order of the first and second ASM for NCSE was reduced by 4 (p = 0.83) and 8 min (p = 0.52), respectively compared to the times prior to the initiation of interventions. The median times from the order to administration of the first and third ASM for all NCSE occurrences were reduced by 8 and 10 min, respectively (p = 0.28 and p = 0.10). In the present cohort of comatose patients, the median time spent to order the first ASM was reduced by 16.5 min and the time to administer it reduced by 35 min compared to that in our previous study. The overall patient mortality was decreased by 11.1%., Significance: More efficient delivery of rescue ASMs in patients with NCSE and improvement in their mortality can be achieved with multidisciplinary team efforts aimed at streamlining the functioning of pharmacy and strengthening the education of trainees and nurses., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Long-term sequelae of the new onset refractory status epilepticus (NORSE) include the development of epilepsy, cognitive deficits, and behavioral disturbances. The prevalence of these complications has been previously highlighted in case reports and case series: however, their full scope has not been comprehensively assessed., Methods: We conducted a systematic review of the literature (PROSPERO ID CRD42022361142) regarding neurological and functional outcomes of NORSE at 30 days or longer following discharge from the hospital. A systematic review protocol was developed using guidance from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)., Results: Of the 1,602 records for unique publications, 33 reports on adults and 52 reports on children met our inclusion criteria. They contained the description of 280 adults and 587 children of whom only 75.7 and 85% of patients, respectively had data on long-term follow-up. The mean age of adult and pediatric patients was 34.3 and 7.9 years, respectively; and the longest duration of follow up were 11 and 20 years, respectively. Seizure outcomes received major attention and were highlighted for 93.4 and 96.6% of the adult and pediatric NORSE patients, respectively. Seizures remained medically refractory in 41.1% of adults and 57.7% of children, while seizure freedom was achieved in only 26 and 23.3% of these patients, respectively. The long-term cognitive outcome data was provided for just 10.4% of the adult patients. In contrast, cognitive health data were supplied for 68.9% of the described children of whom 31.9% were moderately or severely disabled. Long-term functional outcomes assessed with various standardized scales were reported in 62.2 and 25.5% of the adults and children, respectively with majority of patients not being able to return to a pre-morbid level of functioning. New onset psychiatric disorders were reported in 3.3% of adults and 11.2% of children recovering from NORSE., Conclusion: These findings concur with previous observations that the majority of adult and pediatric patients continue to experience recurrent seizures and suffer from refractory epilepsy. Moderate to severe cognitive disability, loss of functional independence, and psychiatric disorders represent a hallmark of chronic NORSE signifying the major public health importance of this disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Taraschenko, Pavuluri, Schmidt, Pulluru and Gupta.)

Rasmussen encephalitis is a devastating progressive inflammatory disorder that leads to debilitating neurologic deficits and intractable epilepsy. Surgical treatment of the dominant hemisphere has been attempted with hesitation, given the lack of effective diagnostic tools to determine the potential functional deficits from disconnection procedures., (© 2022 American Academy of Neurology.)

Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis., (© 2022. The Author(s).)

New-onset movement disorders have been frequently reported in association with the use of antiseizure medications (ASMs). The frequency of specific motor manifestations and the spectrum of their semiology for various ASMs have not been well characterized. We carried out a systematic review of literature and conducted a search on CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus from inception to April 2021. We compiled the data for all currently available ASMs using the conventional terminology of movement disorders. Among 5123 manuscripts identified by the search, 437 met the inclusion criteria. The largest number of reports of abnormal movements were in association with phenobarbital, valproic acid, lacosamide, and perampanel, and predominantly included tremor and ataxia. The majority of attempted interventions for all agents were discontinuation of the offending drug or dose reduction which led to the resolution of symptoms in most patients. Familiarity with the movement disorder phenomenology previously encountered in relation with specific ASMs facilitates early recognition of adverse effects and timely institution of targeted interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Prefabricated arrays with a limited number of electrodes offer an opportunity to hasten the diagnosis of seizures; however, their accuracy to detect seizures is unknown. We examined the utility of two limited-montage EEG setups for the detection of nonconvulsive seizures., Methods: Thirty previously interpreted EEG segments with nonconvulsive seizures from 30 patients and 60 segments with background slowing or normal EEG from 60 patients were rendered in a bipolar "double banana" montage, a double distance "neonatal" montage, and a circumferential "hatband" montage. Experts reviewed 60 to 180 seconds long segments to determine whether seizures were present and if the EEG data provided were sufficient to make a decision on escalation of clinical care by ordering an additional EEG or prescribing anticonvulsants. The periodic patterns on the ictal-interictal continuum were specifically excluded for this analysis to keep the focus on definite electrographic seizures., Results: The sensitivities for seizure of the neonatal and hatband montages were 0.96 and 0.84, respectively, when compared with full montage EEG, whereas the specificities were 0.94 and 0.98, respectively. Appropriate escalation of care was suggested for 96% and 92% of occurrences of seizure patterns in neonatal and hatband montages, respectively. When compared with clinical EEG, the sensitivities of the neonatal and hatband montages for seizure diagnosis were 0.85 and 0.69, respectively., Conclusions: Nonconvulsive seizures were detected with high accuracy using the limited electrode array configuration in the neonatal and hatband montages. The sensitivity of the neonatal montage EEG in detecting seizures was superior to that of a hatband montage. These findings suggest that in some patients with nonconvulsive seizures, limited-montage EEG may allow to differentiate ictal and slow patterns., Competing Interests: S. Kedar has a licensed technology through EON Reality Inc. for the Advanced Pupil Simulator. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Objective: Anti-seizure medications (ASMs) are discontinued in the course of intracranial EEG (iEEG) monitoring for presurgical evaluation. The ASM withdrawal facilitates an emergence of seizures but may also precipitate seizure clusters (SC) and status epilepticus (SE). The aim of this study was to compare the rates of SC and SE during the ultra-rapid withdrawal (URW) and rapid withdrawal (RW) of ASMs during iEEG., Methods: We performed a retrospective observational study of all consecutive patients with drug resistant epilepsy who completed iEEG at our comprehensive epilepsy center from 2012-2018. SC was defined as three or more seizures in 24 h with a return to baseline between the events. SE was defined as ≥ 5 min of clinical seizure or ≥ 10 min of ictal electrographic activity or series of seizures with no return to the neurological baseline between the events., Results: Of 107 patients who completed iEEG with intracranial grid or strip electrodes, 46 (43%) were male. Median age at the time of iEEG was 35.4 years (interquartile range [IQR], 26.4 - 44.9). Ninety patients (84.1%) had all AEDs held on admission, while 16 patients (15%) underwent a rapid taper. The median time to first seizure was 15.1 (8.2 - 22.6) h. Sixty-two patients (57.9%) developed SC, while 10 (9.4%) developed SE. Twenty-six patients (36.1%) with these complications required intravenous lorazepam or other rescue ASMs, while the remaining patients had spontaneous resolution of seizures; intubations were not required. While there were differences in the proportions in patients who experienced SC, SE, or neither in the URW and RW groups, these differences were not significant at the 0.05 alpha level., Significance: Ultra-rapid and rapid ASM withdrawal are accompanied by SC and SE the majority of which terminate spontaneously. These data support the use of either approach of the medication taper for seizure provocation in iEEG., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis manifests with precipitous cognitive decline, abnormal movements, and severe seizures that can be challenging to control with conventional anti-seizure medications. We previously demonstrated that intracerebroventricular (i.c.v.) administration of cerebrospinal fluid from affected patients, or purified NMDA receptor antibodies from encephalitis patients to mice precipitated seizures, thereby confirming that antibodies are directly pathogenic for seizures. Although different repertoires of anti-NMDA receptor antibodies could contribute to the distinct clinical manifestations in encephalitis patients, the role of specific antibodies in the expression of seizure, motor, and cognitive phenotypes remains unclear. Using three different patient-derived monoclonal antibodies with distinct epitopes within the N-terminal domain (NTD) of the NMDA receptor, we characterized the seizure burden, motor activity and anxiety-related behavior in mice. We found that continuous administration of 5F5, 2G6 or 3C11 antibodies for 2 weeks precipitated seizures, as measured with continuous EEG using cortical screw electrodes. The seizure burden was comparable in all three antibody-treated groups. The seizures were accompanied by increased hippocampal C-C chemokine ligand 2 (CCL2) mRNA expression 3 days after antibody infusion had stopped. Antibodies did not affect the motor performance or anxiety scores in mice. These findings suggest that neuronal antibodies targeting different epitopes within the NMDA receptor may result in a similar seizure phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Taraschenko, Fox, Eldridge, Wang, Dowd, Al-Saleem, Kattala, Dessain and Dingledine.)

Background: In this pilot study, we examined the characteristics of patients with and without central nervous system (CNS) malignancies who developed immune checkpoint inhibitor (ICI)-induced encephalopathy., Methods: We identified adult patients treated with ICIs between 1 January 2013 and 9 May 2018 at our tertiary care center who developed encephalopathy within 30 days of the last dose of ICI without other explained causes. Demographic and clinical features were compared between patients with primary and metastatic malignant CNS tumors and those without., Results: Of the 480 patients treated with ICIs, 14 (2.9%) developed encephalopathy induced by nivolumab (8), pembrolizumab (4), and combined ipilimumab-nivolumab (2). Median age was 64.5 years. Patients with CNS malignancies tolerated more treatment cycles and developed encephalopathy later than patients without CNS lesions (20 and 32 days, respectively, p = 0.04) following ICI initiation. Four of seven patients with CNS tumors developed new contrast-enhancing lesions on brain imaging despite having no changes on imaging for a median of 61 (30-545) days. Electroencephalogram (EEG) revealed features of generalized dysfunction in patients in both cohorts. Two patients without and three with CNS malignancies were treated with steroids. Two thirds of patients without and 29% of those with CNS malignancies expired during ICI therapy or shortly thereafter., Conclusions: Lack of the uniform evaluation limits the definitive conclusion of the cause of encephalopathy in some patients but reflects the standard of care at the time of their assessment. ICI-associated neurotoxicity presenting with encephalopathy is an ominous complication of ICI therapy, especially if left untreated. Prompt recognition and involvement of multidisciplinary care, including neurologists, would facilitate timely administration of recommended therapies., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Neuroinflammation associated with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may facilitate seizures. We previously showed that intraventricular administration of cerebrospinal fluid from patients with anti-NMDAR encephalitis to mice precipitates seizures, thereby confirming that antibodies are directly pathogenic. To determine whether interleukin (IL)-1-mediated inflammation exacerbates autoimmune seizures, we asked whether blocking the effects of IL-1 by anakinra, a selective IL-1 receptor antagonist, blunts antibody-induced seizures., Methods: We infused C57BL/6 mice intraventricularly with purified serum IgG from patients with anti-NMDAR encephalitis or monoclonal anti-NMDAR IgG; subdural electroencephalogram was continuously recorded. After a 6-day interval, mice received anakinra (25 mg/kg sc, twice daily) or vehicle for 5 days. Following a 4-day washout period, we performed behavioral tests to assess motor function, anxiety, and memory, followed by hippocampus tissue analysis to assess astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adapter molecule [Iba]-1) activation., Results: Of 31 mice infused with purified patient NMDAR-IgG (n = 17) or monoclonal NMDAR-IgG (n = 14), 81% developed seizures. Median baseline daily seizure count during exposure to antibodies was 3.9; most seizures were electrographic. Median duration of seizures during the baseline was 82.5 s. Anakinra administration attenuated daily seizure frequency by 60% (p = .02). Anakinra reduced seizure duration; however, the effect was delayed and became apparent only after the cessation of treatment (p = .04). Anakinra improved novel object recognition in mice with antibody-induced seizures (p = .03) but did not alter other behaviors. Anakinra reduced the expression of GFAP and Iba-1 in the hippocampus of mice with seizures, indicating decreased astrocytic and microglial activation., Significance: Our evidence supports a role for IL-1 in the pathogenesis of seizures in anti-NMDAR encephalitis. These data are consistent with therapeutic effects of anakinra in other severe autoimmune and inflammatory seizure syndromes. Targeting inflammation via blocking IL-1 receptor-mediated signaling may be promising for developing novel treatments for refractory autoimmune seizures., (© 2021 International League Against Epilepsy.)

Objective: To assess feasibility, patient satisfaction, and financial advantages of telemedicine for epilepsy ambulatory care during the current COVID-19 pandemic., Methods: The demographic and clinical characteristics of all consecutive patients evaluated via telemedicine at a level 4 epilepsy center between March 20 and April 20, 2020 were obtained retrospectively from electronic medical records. A telephone survey to assess patient satisfaction and preferences was conducted within one month following the initial visit., Results: Among 223 telehealth patients, 85.7% used both synchronous audio and video technology. During the visits, 39% of patients had their anticonvulsants adjusted while 18.8% and 11.2% were referred to laboratory/diagnostic testing and specialty consults, respectively. In a post-visit survey, the highest degree of satisfaction with care was expressed by 76.9% of patients. The degree of satisfaction tended to increase the further a patient lived from the clinic (p = 0.05). Beyond the pandemic, 89% of patients reported a preference for continuing telemedicine if their epilepsy symptoms remained stable, while only 44.4% chose telemedicine should their symptoms worsen. Inclement weather and lack of transportation were factors favoring continued use of telemedicine. An estimated cost saving to patient attributed to telemedicine was $30.20 ± 3.8 per visit., Significance: Our findings suggest that epilepsy care via telemedicine provided high satisfaction and economic benefit, without compromising patients' quality of care, thereby supporting the use of virtual care during current and future epidemiological fallouts. Beyond the current pandemic, patients with stable seizure symptoms may prefer to use telemedicine for their epilepsy care., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Epilepsy is diagnosed in 20% of patients with psychogenic nonepileptic spells (PNES). The semiology of PNES and epileptic seizures (ES) overlaps in some patients. It is unclear whether the motor phenotype of PNES predicts the type of ES., Methods: Video segments of EEGs in patients with PNES and ES treated in the Epilepsy Monitoring Unit at the University of Nebraska Medical Center were reviewed. Videos were categorized according to the validated motor-based classification of PNES. Ratings of kinetic PNES events were analyzed to determine if there was an association with focal or generalized ES. If available, the video segments of ES were categorized as hypokinetic or hyperkinetic based on the constellation of focal or generalized movements and other semiological features., Results: Among 43 patients with documented PNES-ES (median age 34, interquartile range (IQR) 26-45), 27.9% were male. The largest proportion of patients (39.5%) had focal temporal epilepsy (TE). Other diagnostic groups included focal frontal (FE, 25.6%), generalized (GE, 25.6%), or other (9.3%) epilepsies. Thirty-three PNES patients (82.5%) were rated as having a hypokinetic phenotype. On average, hypokinetic PNES patients were receiving a median of 3 (IQR 2-4) anticonvulsants, compared to a median of 2 (IQR 2-3) in hyperkinetic PNES patients (p = 0.06). While the group with coexisting FE had a higher prevalence of hyperkinetic semiology (45.4%) than either the TE (11.7%) or GE (18.1%) patients, there was no significant association between the ES type and kinetic status of PNES. Among 20 patients who had video recordings of both PNES and ES, 40% displayed the concordant hypokinetic phenotypes for PNES and seizures while 15% had hyperkinetic presentation of both event types. Among additional 16 patients with scalp EEG-negative suspected nonepileptic events and documented ES, 6 had the recordings of seizures and 3 have presented with concordant hypokinetic PNES and ES., Conclusion: In patients with PNES and ES, the hypokinetic semiology of PNES prevails over hyperkinetic semiology in TE and GE syndromes. The motor status of PNES does not predict the phenotype of coexisting ES. The concordant kinetic semiology is present in more than half of the patients with dual diagnosis and available video data., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We sought to determine if global cognitive function in patients with epilepsy (PWE) differs when electroencephalographic (EEG) abnormalities are present during concurrent neuropsychological (NP) evaluation., Methods: We explored the association between subclinical epileptiform discharges (sEDs) and interictal epileptiform discharges (IEDs) and global aspects of cognition in 79 consecutive PWE who underwent continuous EEG monitoring during NP evaluation for diagnostic (15%) or presurgical (85%) purposes while on their standard antiseizure medication (ASM) regimens. As some researchers have suggested that the apparent link between IEDs and cognition represent epiphenomena of an underlying damaged neural substrate, we used functional status as a stratifying covariate to allow us to address this position., Results: Despite being on their standard ASM regimen, EEG was abnormal in 68% of patients. Epileptiform abnormalities (IEDs, sEDs, or both) were seen in isolation or coupled with diffuse or focal slowing in 38% of patients. Individuals with IEDs occurring during their NP evaluation demonstrated poorer scores in attention/working memory (forward and backward digit span), processing speed (symbol searching and coding), and speeded components of language (semantic fluency) tests compared with those with normal EEG tracings matched by their real-world, functional status. In two high functioning patients, performance was significantly better when these individuals were tested in the absence of IEDs, with performances appearing invalid when tested during periods of IED activity. No significant association was found between NP performance and nonepileptiform EEG abnormalities., Significance: A substantial proportion of PWE undergoing NP evaluation manifest concurrent EEG abnormalities, with epileptiform abnormalities associated with poorer global cognitive performance. As this pattern was observed regardless of functional status, this association appears to represent more than unrelated features coincidentally shared by the lowest functioning cohort. Coupled with our individual case data, our findings suggest that NP testing may be adversely affected by IEDs and sEDs going unrecognized in the absence of simultaneous EEG recordings, and set the stage for future studies to definitively establish this possible relationship., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Data on the timeliness of emergent medication delivery for nonconvulsive status epilepticus (NCSE) are currently lacking., Methods: Retrospective chart reviews (between 2015 and 2018) and analyses of all patients with NCSE were performed at the University of Nebraska Medical Center, a level 4 epilepsy center, to determine the latencies to order and administration of the first, second, and third antiepileptic drugs (AEDs). Recurrent NCSE cases were considered independently and classified as comatose and noncomatose., Results: There were 77 occurrences of NCSE in 53 patients. The first, second, and third AEDs were delivered with substantial delays at median times of 80 (25%-75% interquartile range, 44-166), 126 (interquartile range, 67-239), and 158 minutes (interquartile range, 89-295), respectively, from seizure detection. The median times to the order of the first and second AEDs were 33 and 134.5 minutes longer in comatose NCSE patients compared with those with noncomatose forms, respectively (P = 0.001 and 0.004, respectively). The median times between the AED orders and their administration in these two groups were the same (P = 0.60 and 0.37, respectively). With bivariate analysis, the median latencies to administration of the first, second, and third AEDs were significantly increased by 33, 109.5, and 173 minutes, respectively, in patients who died within 30 days compared with those who survived (P = 0.047, P = 0.02, P = 0.0007, respectively)., Conclusions: The administration of the first, second, and third AEDs for NCSE was delayed. Slow initiation of acute treatment in comatose patients was caused by delays in the placement of the medication order.

Use of non-vitamin K antagonist oral anticoagulants (NOACs), including dabigatran etexilate, rivaroxaban, apixaban, edoxaban or betrixaban provides a safe and convenient alternative to the traditional anticoagulation with vitamin K antagonists or heparin derivatives. Many patients receiving long-term seizure prophylaxis with antiepileptic drugs (AEDs) may require anticoagulation with NOACs. Providers caring for these patients need to be informed about potential interactions between AEDs and NOACs and the relevant clinical consequences. A systematic review of the existing literature was conducted to elucidate current knowledge on the clinically relevant interactions between AEDs and NOACs and highlight areas in which further research is needed. The systematic review protocol was developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Ovid MEDLINE, Embase, The Cochrane Library and SciFinder were searched. Of the 630 non-duplicate items identified by the search, 13 met eligibility criteria. These 13 items included 8 case reports, 2 letters to the editor and 3 nonrandomized studies. The majority of pharmacokinetic interactions between NOACs and first generation AEDs occurred via the induction of the hepatic enzyme system and competition for the P-glycoprotein transporter and lead to decreased NOAC plasma levels and consequent thrombotic events. Only one article, a case report, was identified that focused on interactions between the second generation AED and a NOAC. At the present time, the limited evidence suggests that enzyme-inducing or inhibiting AEDs reduce the effectiveness of anticoagulation produced by several NOACs. This information may help providers anticipate possible interactions and guide therapy appropriately., Competing Interests: Declarations of Competing Interest Mohamed Taha, Wenyang Li, Cynthia M. Schmidt and Marco Gonzalez-Castellon have no financial interests or conflicts of interest to declare. Olga Taraschenko has received research support from the American Epilepsy Society and speaker honoraria from the American Clinical Neurophysiology Society., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Seizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures., Methods: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures., Results: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice., Significance: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: Psychogenic nonepileptic spells (PNES) are paroxysmal movements or sensory events that resemble epileptic seizures but lack corresponding ictal electrographic changes. A confirmed diagnosis of PNES is only accomplished via video electroencephalogram (vEEG) monitoring. Prior to diagnosis, patients are often assessed with neurodiagnostic imaging and their conditions treated with anticonvulsant medications, both of which are of limited clinical value and contribute to the higher cost of care. In this study, we assessed the relationship between the semiological features of PNES, medication regimen, or psychiatric comorbidities and the frequency of referrals for brain imaging tests prior to diagnosis of PNES., Methods: This is a retrospective chart review of 224 adult patients diagnosed as having PNES at a level 4 epilepsy care center from 2012 to 2017. Patients with coexisting epilepsy were excluded. The 882 segments of vEEG records were reviewed for semiology of spells, and patients were categorized into one of seven distinct phenotypic classes according to the accepted clinical classification. The frequency of neurodiagnostic tests completed for each patient prior to vEEG was correlated with PNES phenotype and other clinical characteristics., Results: There were 68 (30%) males and 156 (70%) females diagnosed as having PNES with a median age of 36 years. Seventy-four percent of patients were receiving one or several anticonvulsant medications, and 67% of patients were treated with psychotropic medications other than benzodiazepines. The most prevalent PNES events were characterized by semirhythmic small amplitude movements in the extremities (class 2; 34%) followed by those resembling tonic-clonic seizures (class 4; 28%). Neurodiagnostic imaging tests including computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were performed at least once in 60% of patients and 4 times or more in 11% prior to vEEG. There was a significant association between the frequency of neurodiagnostic tests and the PNES phenotype (p = 0.02). Specifically, patients with sensory changes (class 6) had more imaging tests than those with primitive gesturing and truncal posturing (classes 1 and 5, respectively). Additionally, patients diagnosed with 3 or more psychiatric disorders underwent significantly more neurodiagnostic tests relative to patients diagnosed with two or fewer psychiatric disorders (p = 0.03). Furthermore, patients whose conditions were treated with anticonvulsant medications tended to undergo more imaging scans prior to vEEG as compared with the patients whose conditions were not being treated with anticonvulsants., Conclusions: These findings suggest that the frequency of brain imaging obtained prior to the definitive diagnosis of PNES is influenced by semiology of spells and the psychiatric health of patients. Patients who demonstrate minimal paroxysmal movements in the settings of multiple psychiatric comorbidities represent a particularly challenging patient phenotype which is linked to more frequent referrals for brain imaging. These patients should be promptly referred for vEEG to improve diagnostic accuracy and prevent treatment with anticonvulsants as well as referrals for serial neurodiagnostic tests., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Driving restrictions in epilepsy are intended to safeguard public and personal safety; however, these limitations inhibit socialization, restrict employment, and reduce self-esteem in patients with seizures. A large proportion of patients with seizures continue to drive, and factors leading to noncompliance with driving regulations are poorly understood. Thus, the patients' perspective on driving safety is not incorporated into the existing counseling tools on driving safety in epilepsy. The present study assessed social, economic, and psychological perceptions related to driving restrictions in patients with refractory and pharmacotherapy-controlled seizures at the single epilepsy center and identified impediments for safe driving., Methods: Data were obtained from an anonymous survey completed by 25 adult patients in the presurgical group (PG) with refractory epilepsy and 46 patients in the ambulatory group (AG) with confirmed epilepsy which did not meet criteria for refractoriness. The questionnaire (administered via Research Electronic Data Capture (REDCap)) addressed seizure and driving history, knowledge of driving restrictions, and social consequences of losing driving privileges., Results: Eighty-seven percent of all responders experienced seizures with alteration of awareness; however, 34% of patients continued to drive during the time when they were legally restricted, and 6% had accidents related to seizures. All responders reported their seizure status accurately to the treating physician, and 93% understood state-based driving restrictions. The median time from the last seizure was shorter, and the duration of last driving restriction was longer in the PG compared with the AG (1 vs. 20weeks, and 12 vs. 24weeks, respectively). Despite that, the proportions of patients driving at the time of survey were not significantly different between the two groups. Nearly 80% of all patients stated that driving restrictions reduced their quality of life, and 70% believed that these restrictions carry a social stigma. Employment was chosen to be the most affected by driving restrictions from a list of four social domains by the majority of patients in both groups. Notably, the employment rate was 26% higher in the AG compared with the PG. The lack of public transportation was regarded as a hurdle by more than 60% of patients in each group with greater than two-thirds of patients relying on other drivers for transportation., Conclusions: These findings suggest that patients with refractory and pharmacotherapy-controlled seizures are similarly likely to drive a vehicle, disregarding a practitioner's advice and state restrictions. The lack of public transportation is a shared constraint and likely leads to reduced compliance with driving regulations. Driving restrictions carry social stigma and limit the employment of patients with epilepsy, regardless of the refractory seizure status., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Histamine-synthesizing neurons in the brain may play an important role in cognition, and a histaminergic deficit has been found in Alzheimer's disease (AD). The AD medication tacrine was previously shown to inhibit some forms of rodent histamine-N-methyltransferase (HNMT), but the effects of AD drugs have not been investigated on human HNMT activity. Presently, the effects of tacrine and galanthamine (another AD medication) were studied on the activity of several forms of human and rat HNMT. Tacrine (0.01-10 microM) inhibited both human and rat HNMT activity in a concentration-dependent manner, but was less potent on both human embryonic kidney and recombinant human brain HNMT than on rat kidney HNMT (IC50 values were 0.46 and 0.70 microM vs. 0.29 microM, respectively). Galanthamine (up to 10 microM) did not influence the activity of rat kidney or human HNMT. Tacrine, but not galanthamine, may achieve brain levels sufficient to influence histamine metabolism in some patients treated for AD.