Faculty Bibliography

OBJECTIVE:Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS:A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS:Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE/CONCLUSIONS:This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.

The Victoria Symptom Validity Test (VSVT) is a performance validity test (PVT) with over two decades of empirical backing, although methodological limitations within the extant literature restrict its clinical and research generalizability. Chief among these constraints includes limited consensus on the most accurate index within the VSVT and the most appropriate cut-scores within each VSVT validity index. The current systematic review synthesizes existing VSVT validation studies and provides additional cross-validation in an independent sample using a known-groups design. We completed a systematic search of the literature, identifying 17 peer-reviewed studies for synthesis (7 simulation designs, 7 differential prevalence designs, and 3 known-groups designs). The independent cross-validation sample consisted of 200 mixed clinical neuropsychiatric patients referred for outpatient neuropsychological evaluation. Across all indices, Total item accuracy produced the strongest psychometric properties at an optimal cut-score of ≤ 40 (62% sensitivity/88% specificity). However, ROC curve analyses for all VSVT indices yielded statistically significant areas under the curve (AUCs; .73-81), suggestive of moderate classification accuracy. Cut-scores derived using the independent cross-validation sample converged with some previous findings supporting cut-scores of ≤ 22 for Easy item accuracy and ≤ 40 for Total item accuracy, although divergent findings were noted for Difficult item accuracy. Overall, VSVT validity indicators have adequate diagnostic accuracy across populations, with the current study providing additional support for its use as a psychometrically sound PVT in clinical settings. However, caution is recommended among patients with certain verified clinical conditions (e.g., dementia) and those with pronounced working memory deficits due to concerns for increased risk of false positives.

This paper addresses the absence of an international diagnostic taxonomy for cognitive disorders in patients with epilepsy. Initiated through the 2020 Memorandum of Understanding between the International League Against Epilepsy and the International Neuropsychological Society, neuropsychological representatives from both organizations met to address the problem and consequences of the absence of an international diagnostic taxonomy for cognitive disorders in epilepsy, overview potential solutions, and propose specific solutions going forward. The group concluded that a classification of cognitive disorders in epilepsy, including an overall taxonomy and associated operational criteria, was clearly lacking and sorely needed. This paper reviews the advantages and shortcomings of four existing cognitive diagnostic approaches, including taxonomies derived from the US National Neuropsychology Network, DSM-V Neurocognitive Disorders, the Mild Cognitive Impairment classification from the aging/preclinical dementia literature, and the Research Domain Criteria Initiative. We propose a framework to develop a consensus-based classification system for cognitive disorders in epilepsy that will be international in scope and be applicable for clinical practice and research globally and introduce the International Classification of Cognitive Disorders in Epilepsy (IC-CODE) project.

Thorough assessment of performance validity has become an established standard of practice in neuropsychological assessment. While there has been a large focus on the development and cross-validation of embedded performance validity tests (PVTs) in recent years, new freestanding PVTs have also been developed, including the Word Choice Test (WCT) as part of the Advanced Clinical Solutions Effort System. And, while the WCT's general utility for identifying invalid performance has been demonstrated in the ensuing decade since its initial publication, optimal cut-scores and associated psychometric properties have varied widely across studies. This study sought to synthesize the existing diagnostic accuracy literature regarding the WCT via a systematic review and to conduct a meta-analysis to determine the performance validity cut-score that best maximizes sensitivity while maintaining acceptable specificity. A systematic search of the literature resulted in 14 studies for synthesis, with eight of those available for meta-analysis. Meta-analytic results revealed an optimal cut-score of ≤ 42 with 54% sensitivity and 93% specificity for identifying invalid neuropsychological test performance. Collectively, the WCT demonstrated adequate diagnostic accuracy as a PVT across a variety of populations. Recommendations for future studies are also provided.

BACKGROUND AND PURPOSE/OBJECTIVE:Indirect consequences of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic include those related to failure of patients to seek or receive timely medical attention for seemingly unrelated disease. We report our experience with stroke code imaging during the early pandemic months of 2020. MATERIALS AND METHODS/METHODS:Retrospective review of stroke codes during the 2020 pandemic and both 2020 and matched 2019 prepandemic months was performed. Patient variables were age, sex, hospital location, and severity of symptoms based on the NIHSS. We reviewed the results of CT of the head, CTA, CTP, and MR imaging examinations and classified a case as imaging-positive if any of the imaging studies yielded a result that related to the clinical indication for the study. Both year-to-year and sequential comparisons were performed between pandemic and prepandemic months. RESULTS:= .03). CONCLUSIONS:During our pandemic period, there was a significantly decreased number of stroke codes but simultaneous increases in positivity rates, symptom severity, and inpatient codes. We postulate that this finding reflects the documented reluctance of patients to seek medical care during the pandemic, with the shift toward a greater proportion of inpatient stroke codes potentially reflecting the neurologic complications of the virus itself.

INTRODUCTION/BACKGROUND:The challenging environment of prehospital casualty care demands providers to make prompt decisions and to engage in lifesaving interventions, occasionally without them being adequately experienced. Telementoring based on augmented reality (AR) devices has the potential to decrease the decision time and minimise the distance gap between an experienced consultant and the first responder. The purpose of this study was to determine whether telementoring with AR glasses would affect chest thoracotomy performance and self-confidence of inexperienced trainees. METHODS:Two groups of inexperienced medical students performed a chest thoracotomy in an ex vivo pig model. While one group was mentored remotely using HoloLens AR glasses, the second performed the procedure independently. An observer assessed the trainees' performance. In addition, trainees and mentors evaluated their own performance. RESULTS:Quality of performance was found to be superior with remote guidance, without significant prolongation of the procedure (492 s vs 496 s, p=0.943). Moreover, sense of self-confidence among participant was substantially improved in the telementoring group in which 100% of the participants believed the procedure was successful compared with 40% in the control group (p=0.035). CONCLUSION/CONCLUSIONS:AR devices may have a role in future prehospital telementoring systems, to provide accessible consultation for first responders, and could thus positively affect the provider's confidence in decision-making, enhance procedure performance and ultimately improve patient prognosis. That being said, future studies are required to estimate full potential of this technology and additional adjustments are necessary for maximal optimisation and implementation in the field of prehospital care.

INTRODUCTION/BACKGROUND:According to evidence-based clinical practice guidelines, patients presenting with disabling stroke symptoms should be treated with intravenous tissue plasminogen activator (IV tPA) within 4.5 hours of time last known well. However, 25% of strokes are detected upon awakening ('wake-up strokes'; WUS) which renders patients ineligible for IV tPA administered via time-based treatment algorithms because it is impossible to establish a reliable time of symptom onset. We performed a systematic review and meta-analysis of the efficacy and safety of IV tPA compared with normal saline, placebo, or no treatment in patients with WUS using imaging-based treatment algorithms. METHODS:We searched Medline, Web of Science, and Scopus between January 1, 2006 and April 30, 2020. We included controlled trials (randomized or nonrandomized), observational cohort studies (prospective or retrospective), and single-arm studies in which adults with WUS were administered IV tPA after MR- or CT-based imaging. Our primary outcome was recovery at 90 days (defined as a modified Rankin Scale [mRS] score of 0-2) and our secondary outcomes were symptomatic intracranial hemorrhage (sICH) within 36 hours, mortality, and other adverse effects. RESULTS:We included 16 studies that enrolled a total of 14,017 patients. Most studies were conducted in Europe (37.5%) or North America (37.5%), and 1,757 patients (12.5%) received IV tPA. All studies used MRI-based (5 studies) or CT-based (10 studies) imaging selection and one study used a combination of modalities. Sixty-one percent of patients receiving IV tPA achieved mRS of 0-2 at 90 days (95% CI 51% to 70%; 12 studies), with a relative risk (RR) of 1.21 compared with patients not receiving IV tPA (95% CI 1.01 to 1.46; 4 studies). Three percent of patients receiving IV tPA experienced sICH within 36 hours (95% CI 2.5% to 4.1%; 16 studies), an RR of 4.00 compared with patients not receiving IV tPA (95% CI 2.85 to 5.61; 7 studies). CONCLUSIONS:This systematic review and meta-analysis suggests that IV tPA is associated with a better functional outcome at 90 days despite the increased but acceptable risk of sICH. Based on these results, IV tPA should be offered as a treatment for WUS patients with favorable neuroimaging findings.

De novo, heterozygous, loss of function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared to wild-type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome. This article is protected by copyright. All rights reserved.

Background and aims: The Work Productivity and Activity Impairment (WPAI) questionnaire is a patientreported outcome assessing percentage of work time missed, impairment while working, overall work impairment and activity impairment over seven days prior. We report 2-year changes in WPAI, and associations with the 29-item Multiple Sclerosis Impact Scale (MSIS-29) and SymptoMScreen (self-reported symptom burden) among patients with relapsing-remitting MS (RRMS) in the Phase IIIb CASTING trial (NCT02861014). Method(s): Patients (n=680; Expanded Disability Status Scale score <=4.0) with a suboptimal response to one or two prior disease-modifying therapies (DMTs) received intravenous ocrelizumab 600mg every 24 weeks for 96 weeks. WPAI, MSIS-29 and SymptoMScreen were completed at baseline, Week 24, Year 1 and Year 2. Spearman correlations were assessed between change in WPAI subscores from baseline to Year 2, MSIS-29 subscores, and SymptoMScreen total score. Result(s): WPAI improved from baseline to Year 2, with significant reduction in overall work impairment (-3.08, p=0.020) and activity impairment (-5.69, p<0.001), and consistent trends in work time missed (-2.54, p=0.102) and impairment while working (-1.66, p=0.129). Improvement in SymptoMScreen score correlated with reduction in all WPAI measures: work time missed (rs=0.196), impairment while working (rs=0.387), overall work impairment (rs=0.362) and activity impairment (rs=0.421) over two years (all p<0.01). MSIS-29 improvements correlated with WPAI improvements over two years (Table 1). Table 1 Conclusion(s): Patients with a suboptimal response to one or two prior DMTs who switched to ocrelizumab showed improvement in work productivity (WPAI), which correlated with improvement in physical/psychological impacts of MS (MSIS-29) and decrease in symptom burden (SymptoMScreen) over two years

Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival-is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events.