Faculty Bibliography

OBJECTIVE:This study aims to better characterize the long-term neurological quality of life (QOL) outcomes (using the Neuro-QOL scale) in survivors of new onset refractory status epilepticus (NORSE), including its subtype febrile infection-related epilepsy syndrome (FIRES), and provide guidance for psychological and social support strategies. METHODS:Utilizing data from a multicenter prospective study of NORSE/FIRES led by Yale University, we enrolled patients who completed the validated, patient-reported Neuro-QOL scale at least once at 3-6 months (n = 37), 12 months (n = 29), 24 months (n = 23), or ≥36 months (n = 9) following discharge. The Neuro-QOL scale assesses physical, mental, and social health in patients with neurological disorders. QOL impairment (QOL-I) scores were calculated, with higher scores indicating greater impairment. T-scores enabled comparisons with reference populations. RESULTS:In adults, median QOL-I improved from 44.1% at 3-6 months to 37.6% at 36+ months. Paired analysis showed significant improvement in QOL-I between 3-6 and 24 months (p = .016), with specific improvements in communication, satisfaction with social roles, fatigue, and mobility. Greater improvement was also observed for participation in social roles (5.5-point T-score gain) compared to the reference population, suggesting meaningful change. A gradual improvement in overall QOL-I scores was also observed in pediatric participants, despite a modest sample size (n = 5 with data at 3-6 and 12 months). Measures of fatigue and anxiety persisted in adults, and cognitive difficulties persisted in both adults and children. In adults, longer status epilepticus duration and intensive care unit stay were associated with poorer QOL. Additionally, a higher number of antiseizure medications was associated with more depression, cognitive impairments, and perceived stigma. SIGNIFICANCE/CONCLUSIONS:These findings highlight the potential for recovery following an acute episode of NORSE, although many patients continue to face challenges requiring ongoing support, and the clinical meaning of the reported QOL improvement remains unclear. Furthermore, the findings underscore the importance of strategic multidisciplinary support systems in the years following discharge.

The Global Navigation Satellite System (GNSS) is commonly used for outdoor positioning. However, its effectiveness diminishes in urban canyons and indoor environments attributed to signal blockage. This study aims to explore the potential of GNSS signals penetrating indoor spaces through windows and to enhance indoor positioning with Three-Dimensional Mapping-Aided (3DMA) GNSS, a concept generally applied outdoors. The research employs a 3D model of a corridor with manually labeled window locations to predict satellite visibility within indoor areas. The study integrates Pedestrian Dead Reckoning (PDR) with an indoor Shadow-matching (I-SM) technique, utilizing an Extended Kalman Filter (EKF) to improve positioning accuracy. One of the findings indicates that the proposed method significantly enhances positioning performance and its availability, achieving a root mean square error (RMSE) that is 2 m better than using PDR alone or single epoch I-SM. The study concludes that integrating GNSS with I-SM technique and PDR can optimize an indoor positioning solution and highlights the potential for improved navigation solutions in complex urban environments.

The frequency and nature of neurological exams (neuro-checks) in patients with severe acquired brain injury resulting in coma or disorders of consciousness (DoC) remain variable, with limited evidence guiding practice and poor understanding of their role in predicting and preventing neurological deterioration, functional recovery and adverse effects such as delirium. This scoping review aims to explore the frequency of bedside neurological exams within the first 7 days of injury impact on clinical outcomes in adult patients with severe acquired brain injury including mortality, neurological deterioration, long-term function, and delirium. METHODS: A comprehensive literature search was conducted using the PubMed, CINAHL, Medline and EMBASE databases from 2003 to 2023. Search terms captured a range of acute brain injuries and neuro-assessment tools. Eligible studies included adult patients with severe traumatic or non-traumatic brain injury or stroke that addressed frequency of bedside neurological exams within the first 7 days of admission. RESULTS: Of 1327 studies screened, 20 met inclusion criteria, representing over 16,000 patients across 14 countries. Assessment tools varied, but use of the Glasgow Coma Scale was prevalent. Frequency of neuro-checks ranged from hourly to daily. Multiple outcome measures were utilized. Some studies found that continuing hourly neuro-checks beyond the first 48 hours did not provide additional clinical benefit. Others associated excessive assessment with increased stress or delirium. CONCLUSION: There is very low evidence supporting an association between the frequency of neuro-checks and functional outcomes, mortality, length of stay, or delirium. Although early assessments may aid prognostication, excessive exams may not improve outcomes and may contribute to harm. The heterogeneity, lack of evidence, and limited standardization of neuro-check frequency highlight the need for clinical research to guide future practice.

OBJECTIVE/UNASSIGNED:Carotid webs, first described in 1968, are increasingly recognized as a surgically treatable cause of ischemic stroke, particularly in young patients. Despite growing attention, the literature remains fragmented. We conducted the first advanced bibliometric analysis of carotid web research to map its historical foundations, identify key contributors, and illustrate emerging trends. METHODS/UNASSIGNED:The Web of Science database (inception-2025) was queried for carotid web publications. Articles and metadata were analyzed using Bibliometrix (R) and Python libraries. Reference publication year spectroscopy (RPYS) was employed to analyze the field's roots by analyzing citation frequency by publication year. RESULTS/UNASSIGNED:A total of 281 publications from 109 sources and 1,129 authors were identified. Annual publication growth averaged 6.15%, with 90% published after 2016. International collaboration was modest (9-11%), led by the U.S., China, France, and Canada. Shifts in keyword frequency reflected the field's evolution from early nosological uncertainty toward recognition of carotid webs as a distinct, high-risk lesion underlying ischemic stroke. Stroke and Journal of Vascular Surgery emerged as early key sources. Author analysis identified the most prolific contributors, though coauthorship networks remained small. RPYS revealed 19 seminal studies (1968-2021) that shaped the field's progression from early pathology descriptions to recognition of carotid webs as high-risk lesions for stroke. CONCLUSIONS/UNASSIGNED:Carotid web research has rapidly expanded, evolving into a multidisciplinary field. RPYS identified 19 seminal publications tracing the intellectual trajectory of the field. Ongoing challenges include limited collaboration, unresolved questions of pathogenesis, and variability in terminology and diagnostic criteria.

IMPORTANCE/UNASSIGNED:Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene. OBJECTIVE/UNASSIGNED:To evaluate the long-term effects of tofersen in adults with SOD1-ALS. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024). INTERVENTION AND EXPOSURE/UNASSIGNED:Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival. RESULTS/UNASSIGNED:VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.

BACKGROUND:Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) risk. Racial-, ethnic-, and sex-specific mechanisms of OSA and AD risk were examined. METHODS:We analyzed data from 3978 polysomnography patients without cognitive decline aged ≥ 60 including 663 OSA+ patients (284 non-Hispanic White, 207 Black, 172 Hispanic) matched to OSA- cohorts (1:1, n = 663; 1:4, n = 2652) and followed for AD through 2013. RESULTS:During the 8.5 (standard deviation 1.4) year period, 358 patients developed AD. AD risk was higher for Black (adjusted hazard ratio [aHR] 2.24 [1.24-2.71]), Hispanic (aHR 1.73, [1.38-3.51]), White (aHR 1.83, [1.21-3.37]), male (aHR 2.38, [1.31-3.47]), and female (aHR 1.37, [1.14-2.41]) patients. Hypoxia, sleep fragmentation, and sleep duration (p < 0.01) were associated with increased risk. Black and Hispanic, and female patients showed stronger effects for hypoxia and duration, and fragmentation, respectively. DISCUSSION/CONCLUSIONS:Hypoxia, fragmentation, and duration may underlie racial-, ethnic-, and sex-specific effects of AD risk.

OBJECTIVES/UNASSIGNED:To investigate the relationship between short and long sleep duration and subjective cognitive decline (SCD) in a diverse cohort of cognitively normal mid- to older-age adults. METHODS/UNASSIGNED:We conducted a cross-sectional analysis of the 2022 Behavioral Risk Factor Surveillance System (BRFSS) data, including 63,948 adults aged 40-70. SCD was assessed using BRFSS survey queries. Multivariable logistic regression models examined the association between sleep duration ( < 7, 7, ≥8 hours) and SCD, adjusting for age, sex, race/ethnicity, education, and history of depression. RESULTS/UNASSIGNED:Both short and long sleep durations were associated with higher odds of SCD. The association between short sleep and SCD was strongest among individuals in their 40s at the start of midlife. Findings were consistent across all ages for non-Hispanic Whites (NHW) and for Hispanics/Latinos in their 50s and 70s. Black/African American (B/AA) adults exhibited a stronger relationship between both short and long sleep duration and SCD as they aged from midlife into their 80s, compared to NHWs. CONCLUSIONS/UNASSIGNED:Short sleep duration is more strongly associated with subjective cognitive decline in midlife, particularly among B/AA adults. Addressing sleep disparities may help mitigate the risk of SCD.

Neurodegeneration, along with amyloid and tau, define the AT(N) framework of Alzheimer's disease that has shaped the development of diagnostics and therapeutics. Yet, biomarker development for neurodegeneration has lagged behind that for amyloid and tau, with limited definition of its heterogeneous microstructural aspects that may each serve as critical measures. In this issue of the JCI, Gong et al. leveraged diffusion MRI to derive a unique measure of axonal injury or axonal density index (ADI). Through cross-sectional and longitudinal analyses, they demonstrated that the ADI has superior performance in detecting, tracking, and predicting clinical impairment compared with prior diffusion MRI methods to evaluate axonal health and standard biomarkers of amyloid and tau. As such, the ADI measure may serve as an important expansion of the neurodegeneration biomarker repertoire.