Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Systematic screening can help identify antiseizure medication (ASM)-associated adverse events (AEs) that may preclude patients from reaching effective doses or completing adequate trial periods. The Adverse Event Profile (AEP) is a self-completed instrument to identify the frequency of common AEs associated with ASM use. This study aimed to compare the AE profile of commonly used ASMs in adults with newly diagnosed focal epilepsy. METHODS:The Human Epilepsy Project is a prospective, international, observational study investigating markers of treatment response in newly diagnosed focal epilepsy. Participants were enrolled within 4 months of treatment initiation. Adult participants on levetiracetam, lamotrigine, carbamazepine, or oxcarbazepine monotherapy who completed the AEP and Mini International Neuropsychiatric Interview at enrollment were included. Multivariable generalized linear and penalized logistic regression models assessed differences in total and itemized marginal AEP scores and dichotomized responses ("never/rarely" vs "sometimes/always"). RESULTS:= 0.047) than lamotrigine users. Carbamazepine and oxcarbazepine had the highest rates of discontinuation (42.1%, each), followed by levetiracetam (34.8%) and lamotrigine (16.4%). Levetiracetam users had the highest proportion of discontinuations because of AEs alone (18%), and lamotrigine had the lowest (5%). DISCUSSION/CONCLUSIONS:Systematic screening for AEs in adults with newly diagnosed focal epilepsy on ASM monotherapy showed that those with comorbid psychiatric conditions report greater AEs overall, irrespective of ASM. Levetiracetam was associated with >3-fold risk of psychiatric AEs and half the risk of experiencing unsteadiness than lamotrigine. Levetiracetam had the highest proportion of discontinuations because of AEs alone, while lamotrigine had the lowest.

OBJECTIVES/OBJECTIVE:Cervical artery dissection (CeAD) accounts for 25% of ischemic strokes in young adults. This study evaluated the benefits and harms of intravenous thrombolysis (IVT) in patients presenting with spontaneous CeAD and acute ischemic stroke symptoms. METHODS:This analysis used data from the retrospective STOP-CAD study and included patients with spontaneous CeAD who presented within 1 day of acute ischemic stroke symptoms. Patients were dichotomized into those who received IVT and those managed without IVT. We assessed the association between IVT and 90-day functional independence (modified Rankin Scale scores 0-2) and the incidence of symptomatic intracranial hemorrhage (ICH, defined as ICH causing new or worsening neurologic symptoms within 72 hours after CeAD diagnosis). RESULTS:= 0.215). DISCUSSION/CONCLUSIONS:In patients with spontaneous CeAD and suspected ischemic stroke, IVT improved functional outcomes, without increasing symptomatic ICH risk. These findings support current guideline recommendations to consider thrombolysis for otherwise eligible patients with CeAD. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that IVT significantly increases the probability of 90-day functional independence in patients with CeAD.

Exposure to repetitive head impacts (RHIs) in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE) which currently can be diagnosed only at postmortem. American football players are at higher risk of developing CTE given their exposure to RHIs. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at postmortem in living individuals using structural magnetic resonance imaging (MRI). MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 58 age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each Traumatic Encephalopathy Syndrome (TES) diagnosis core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula temporal pole and superior frontal gyrus. Post-hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus amygdala entorhinal cortex parahippocampal gyrus insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe age-by-group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggest that MRI morphometrics detects abnormalities in individuals with a history of RHI exposure that resemble the anatomic distribution of pathological findings from postmortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggests that brain morphometry must be complemented by other types of measures to characterize individuals with RHIs.

Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)-a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8-immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.

IMPORTANCE/UNASSIGNED:The lack of an in vivo measure for α-synuclein (α-syn) pathology until recently has limited thorough characterization of its brain atrophy pattern, especially during early disease stages. OBJECTIVE/UNASSIGNED:To assess the association of state-of-the-art cerebrospinal fluid (CSF) seed amplification assays (SAA) α-syn positivity (SAA α-syn+) with magnetic resonance imaging (MRI) structural measures, across the continuum from clinically unimpaired (CU) to cognitively impaired (CI) individuals, in 3 independent cohorts, and separately in CU and CI individuals, the latter reflecting a memory clinic population. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:Cross-sectional data were used from the Swedish BioFINDER-2 study (inclusion, 2017-2023) as the discovery cohort and the Swedish BioFINDER-1 study (inclusion, 2007-2015) and Alzheimer's Disease Neuroimaging Initiative (ADNI; inclusion 2005-2022) as replication cohorts. All cohorts are from multicenter studies, but the BioFINDER cohorts used 1 MRI scanner. CU and CI individuals fulfilling inclusion criteria and without missing data points in relevant metrics were included in the study. All analyses were performed from 2023 to 2024. EXPOSURES/UNASSIGNED:Presence of α-syn pathology, estimated by baseline CSF SAA α-syn. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcomes were cross-sectional structural MRI measures either through voxel-based morphometry (VBM) or regions of interest (ROI) including an automated pipeline for cholinergic basal forebrain nuclei CH4/4p (nucleus basalis of Meynert [NBM]) and CH1/2/3. Secondary outcomes were domain-specific cross-sectional cognitive measures. Analyses were adjusted for CSF biomarkers of Alzheimer pathology. RESULTS/UNASSIGNED:A total of 2961 participants were included in this study: 1388 (mean [SD] age, 71 [10] years; 702 female [51%]) from the BioFINDER-2 study, 752 (mean [SD] age, 72 [6] years; 406 female [54%]) from the BioFINDER-1 study, and 821 (mean [SD] age, 75 [8] years; 449 male [55%]) from ADNI. In the BioFINDER-2 study, VBM analyses in the whole cohort revealed a specific association between SAA α-syn+ and the cholinergic NBM, even when adjusting for Alzheimer copathology. ROI-based analyses in the BioFINDER-2 study focused on regions involved in the cholinergic system and confirmed that SAA α-syn+ was indeed independently associated with smaller NBM (β = -0.271; 95% CI, -0.399 to -0.142; P <.001) and CH1/2/3 volumes (β = -0.227; 95% CI, -0.377 to -0.076; P =.02). SAA α-syn+ was also independently associated with smaller NBM volumes in the separate CU (β = -0.360; 95% CI, -0.603 to -0.117; P =.03) and CI (β = -0.251; 95% CI, -0.408 to -0.095; P =.02) groups. Overall, the association between SAA α-syn+ and NBM volume was replicated in the BioFINDER-1 study and ADNI cohort. In CI individuals, NBM volumes partially mediated the association of SAA α-syn+ with attention/executive impairments in all cohorts (BioFINDER-2, β = -0.017; proportion-mediated effect, 7%; P =.04; BioFINDER-1, β = -0.096; proportion-mediated effect, 19%; P =.04; ADNI, β = -0.061; proportion-mediated effect, 20%; P =.007). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, SAA α-syn+ was consistently associated with NBM atrophy already during asymptomatic stages. Further, in memory clinic CI populations, SAA α-syn+ was associated with NBM atrophy, which partially mediated α-syn-induced attention/executive impairment.

OBJECTIVE:To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS:Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS:Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE/CONCLUSIONS:While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

People with disorders of consciousness (DoC) are characteristically unable to synchronously participate in decision-making about clinical care or research. The inability to self-advocate exacerbates preexisting socioeconomic and geographic disparities, which include the wide variability observed across individuals, hospitals, and countries in access to acute care, expertise, and sophisticated diagnostic, prognostic, and therapeutic interventions. Concerns about equity for people with DoC are particularly notable when they lack a surrogate decision-maker (legally referred to as "unrepresented" or "unbefriended"). Decisions about both short-term and long-term life-sustaining treatment typically rely on neuroprognostication and individual patient preferences that carry additional ethical considerations for people with DoC, as even individuals with well thought out advance directives cannot anticipate every possible situation to guide such decisions. Further challenges exist with the inclusion of people with DoC in research because consent must be completed (in most circumstances) through a surrogate, which excludes those who are unrepresented and may discourage investigators from exploring questions related to this population. In this article, the Curing Coma Campaign Ethics Working Group reviews equity considerations in clinical care and research involving persons with DoC in the following domains: (1) access to acute care and expertise, (2) access to diagnostics and therapeutics, (3) neuroprognostication, (4) medical decision-making for unrepresented people, (5) end-of-life decision-making, (6) access to postacute rehabilitative care, (7) access to research, (8) inclusion of unrepresented people in research, and (9) remuneration and reciprocity for research participation. The goal of this discussion is to advance equitable, harmonized, guideline-directed, and goal-concordant care for people with DoC of all backgrounds worldwide, prioritizing the ethical standards of respect for autonomy, beneficence, and justice. Although the focus of this evaluation is on people with DoC, much of the discussion can be extrapolated to other critically ill persons worldwide.