Faculty Bibliography

OBJECTIVES/OBJECTIVE:Temporal lobe epilepsy (TLE) impacts multiple brain networks. Aberrant functional connectivity has been demonstrated in resting-state networks (RSNs) that mediate higher brain functions in TLE. This study aimed to identify the reproducible patterns of altered functional connectivity in TLE in a large, international cohort through ENIGMA-Epilepsy. METHODS:Resting-state functional MRI datasets from nine centers across North America, South America, Europe and South Africa, including 442 people with TLE and 387 healthy adults, were analyzed. We examined group differences in whole-brain connectivity in patients compared to controls in seven major RSNs. We also investigated whole-brain connectivity maps for key nodes within the default mode network (DMN). Furthermore, the associations between connectivity patterns and clinical variables were assessed. RESULTS:We found lower within-network connectivity scores (13.6% on average) and higher between-network connectivity scores (129% on average) in non-limbic RSN in TLE. This pattern was reproducible across all seven sites and most robust for DMN and visual networks. Patterns of connectivity were not associated with age of seizure onset or disease duration and were mostly similar in patients with left and right TLE with a few exceptions; isolated regions of high connectivity in left TLE and lower connectivity in right TLE compared to controls. SIGNIFICANCE/CONCLUSIONS:We show strong evidence of lower connectivity within most RSNs and higher connectivity outside of these networks that was highly consistent across geographically diverse sites, demonstrating the robustness and generalizability of our findings. The findings demonstrate a consistent disruption of network organization in TLE that may underlie cognitive co-morbidities and seizure propagation patterns observed in this patient population. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:In this international ENIGMA-Epilepsy study, resting-state fMRI data from 442 individuals with TLE showed reduced connectivity within major resting-state networks (about 14% lower) and markedly increased connectivity between networks (about 129% higher), compared to 387 healthy controls. These patterns were highly reproducible across sites. Connectivity alterations were not related to age of onset or disease duration and were largely similar across left and right TLE, aside from small, region-specific differences. Overall, the study demonstrates a robust, widespread reorganization of brain network connectivity in TLE, which may help explain associated cognitive difficulties and seizure spread.

OBJECTIVE:A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN/METHODS:Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING/METHODS:Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS/METHODS:A panel of multinational, multiprofessional, and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS/RESULTS:A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds) were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS:A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 µg per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Over 50% of persons living with dementia (PLWD) and their care partners (dyads) visit the emergency department (ED) every year. In the ED, healthcare professionals face complex challenges managing acute issues and symptoms of Alzheimer's disease and Alzheimer's disease-related dementias without provider training or in-ED structures to ensure a successful discharge. While many of these visits are for conditions more suitable for ambulatory care, as many as 50% of PLWD discharged from the ED return within 30 days, suggesting opportunities to improve ED care, and discharge processes. Emergency Care Redesign (ECR) includes intentional workflows where physicians, nurses, and social workers engage in a team-based approach with structured assessments to manage a myriad of potential psychosocial and behavioral issues contributing to the need for ED care. Three core components comprise this evidence-based, efficient pragmatic intervention for PLWD and their care partners: (1) problem identification, (2) problem prioritization, and (3) provision of non-pharmacologic solutions supported by community resources. Although these components are essential to provide optimal ED care and reduce revisits and other adverse outcomes, they require an embedded clinical decision support structure, focused training, and clear workflows. In this paper, we describe the ECR intervention as one of three being implemented in the cluster-randomized multifactorial pragmatic trial, Emergency Departments LEading Transformation of Alzheimer's and Dementia Care (ED-LEAD), designed to improve care for PLWD and their outcomes after discharge home within 15 health systems and 79 EDs across the United States.

BackgroundMisalignment between actual and perceived balance ability provides relevant information to understand functional deficits and fall risk. However, few studies have provided a continuous quantification of misalignment in neurological populations such as people with Parkinson's disease (PD).ObjectiveDetermine whether a continuous quantification of misalignment between actual and perceived balance ability, discordance, relates to functional outcomes such as quality of life and cognition.MethodsActual (gait velocity), and perceived (Activities of Balance Confidence) balance, cognition (measured via a computer-based cognitive assessment), and mobility-related quality of life were captured in a clinical sample of 95 people with PD. Primary outcomes were quality of life and cognitive domains frequently altered in people with PD (global cognition & executive function). Secondary cognitive domains assessed were attention, memory, visuo-spatial, verbal function, and information processing. Linear and non-linear models assessed the relationship between discordance, quality of life, and cognition.ResultsDiscordance related to mobility-related quality of life, such that under-confidence was related to poorer quality of life. Non-linear (quadratic) models were shown to fit the discordance-Global cognition (p = 0.02) data better than linear models such that over- and under-confidence related to poorer cognition. Secondary cognitive domains were not robustly related to discordance.ConclusionsIn a clinical sample of people with PD, discordance was related to mobility-related quality of life and global cognition. Global cognition further exhibited a possible non-linear relationship to discordance indicating that over- or under-confidence may relate to poorer cognition. This work underscores the functional relevance of misalignment of actual and balance abilities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Carotid webs are an underrecognized cause of ischemic stroke in young adults and are associated with a high risk of recurrence when managed with medical therapy alone. Although carotid endarterectomy (CEA) is increasingly performed, histopathological confirmation remains infrequently reported, and the underlying pathological substrate of symptomatic carotid webs is not well defined. In this study, we present the largest pathologically confirmed series of symptomatic carotid webs treated with CEA, providing a comprehensive clinicopathological characterization and evaluation of long-term surgical outcomes. METHODS:Patients with symptomatic carotid webs were retrospectively identified from institutional databases encompassing both inpatient and outpatient encounters. Clinical features, imaging characteristics, surgical findings, and histopathological results from CEA specimens are presented. RESULTS:Among 39 patients with symptomatic carotid web, 34 underwent CEA with histopathological confirmation of the diagnosis, characterized by focal eccentric intimal fibromyxoid tissue, fibromuscular dysplasia, hyperplasia, or thickening. Notably, concurrent atheromatous changes were noted in 6 patients. All webs were located within 3 cm of the carotid bifurcation, and most (76%) were localized on the posterior wall. Competing stroke mechanisms were identified in 15% of patients. Two-thirds of patients presented with a large or medium vessel occlusion and over half received acute reperfusion therapy (intravenous thrombolysis and/or mechanical thrombectomy). Two patients experienced transient, minor cranial nerves injuries (hypoglossal nerve and marginal mandibular branch) after CEA. At a median follow-up of 29 months, no patients experienced recurrent stroke (95% CI: 0%-10%), and the median modified Rankin Scale score was 1 (0-1). CONCLUSION/CONCLUSIONS:This study supports CEA as a safe and effective therapeutic option for patients with symptomatic carotid webs and demonstrates its diagnostic value through direct histopathological confirmation. By presenting the largest pathologically validated series to date, our findings further define the vascular pathology underlying carotid webs and underscore the diagnostic value of surgical resection for definitive diagnosis.

OBJECTIVE:A definition of refractory septic shock is necessary to guide diagnosis, management, prognostication, research, and future guidelines for this most severe form of the disease. We sought to achieve consensus on clinical criteria that would be used to define refractory septic shock. DESIGN/METHODS:Review of literature, expert panel position statements, and Delphi rounds with an international expert group. SETTING/METHODS:Consensus was defined as having at least 75% of panellists in agreement or disagreement on the three highest or lowest levels of a 7-point Likert scale or based on responses to single- or multiple-choice questions, respectively. SUBJECTS/METHODS:A panel of multinational, multiprofessional and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine (57 invitations and 56 participants). MEASUREMENTS AND MAIN RESULTS/RESULTS:A five-round Delphi process was conducted for consensus and stability. The steering committee proposed 34 statements, and five of them were rejected by panel experts after round 2. Among 29 statements selected from eight domains, consensus was reached for 13. The panel agreed on the need for a comprehensive consensus set of clinical criteria for refractory septic shock. Markers of organ dysfunction (75%, 2 rounds), tissue perfusion (91.1%, 2 rounds) including lactate (94.6%, 2 rounds) and capillary refill time (76.8%, 2 rounds), assessment of fluid-responsiveness after initial resuscitation (92.9%, 5 rounds), and use of vasoactive drugs at norepinephrine equivalents greater than 0.5 µg/kg/min (75.0%, 3 rounds), were selected as clinical criteria of refractory septic shock. The use of critical care ultrasound (CCUS) (92.9%, 3 rounds) was the single diagnostic modality that reached a consensus-based agreement. CONCLUSIONS:A consensus for 13 criteria to frame the definition of refractory septic shock was reached. Refractory septic shock is characterised by persistently elevated lactate concentrations and or prolonged capillary refill time in patients with septic shock who are fluid unresponsive, require a norepinephrine base equivalent dose greater than 0.5 micrograms per kilogram per minute, and undergo CCUS assessment when mixed shock is suspected.

Three-dimensional (3D) ex vivo imaging of cleared tissue from intact brains from animal models, human brain surgical specimens, and large postmortem human and non-human primate brain specimens is essential for understanding physiological neural connectivity and pathological alterations underlying neurological and neuropsychiatric disorders. Contemporary light-sheet microscopy enables rapid, high-resolution imaging of large, cleared samples but is limited by the orthogonal arrangement of illumination and detection optics, which constrains specimen size. Light-sheet theta microscopy (LSTM) overcomes this limitation by employing two oblique illumination paths while maintaining a perpendicular detection geometry. Here, we report the development of a next-generation, fully integrated and user-friendly LSTM system that enables uniform subcellular-resolution imaging (with subcellular resolution determined by the lateral performance of the system) throughout large specimens without constraining lateral (XY) dimensions. The system provides a seamless workflow encompassing image acquisition, data storage, pre- and post-processing, enhancement and quantitative analysis. Performance is demonstrated by high-resolution 3D imaging of intact mouse brains and human brain samples, including complete downstream analyses such as digital neuron tracing, vascular reconstruction and design-based stereological analysis. This enhanced and accessible LSTM implementation enables rapid quantitative mapping of molecular and cellular features in very large biological specimens.

OBJECTIVE:Cenobamate has been shown to be an effective antiseizure medication for some patients with drug-resistant focal epilepsy being considered for epilepsy surgery. This retrospective single-center study evaluated whether surgery was obtained within 12 months for patients who received cenobamate as a treatment during the presurgical evaluation and those who did not, comparing across years before and after cenobamate approval. METHODS:Patients undergoing surgical evaluation for drug-resistant focal epilepsy at the University of Colorado during 2018 and 2023 who had 12 months of follow-up data were analyzed. Comparison years were also chosen to avoid the confounding effect of the COVID-19 pandemic on surgical volume (2020-2021). This allowed for comparison times before and after cenobamate's US Food and Drug Administration approval. The primary outcome (surgery within 12 months) was modeled with potential explanatory variables using multiple logistic regression. A p-value of <.05 was considered significant. RESULTS:After controlling for potentially confounding clinical and demographic variables, cenobamate use during the presurgical evaluation period was associated with .13 lower odds of surgery within 12 months compared to not being prescribed this medication (95% confidence interval [CI] = .04-.42, p < .001). Being Hispanic or Latino was significantly associated with .23 lower odds of surgery within 12 months compared to patients who did not report being Hispanic or Latino (95% CI = .09-.61, p = .003). Year of evaluation (2023 vs. 2018), education level, age, and sex did not have significant associations with undergoing surgery within 12 months. SIGNIFICANCE/CONCLUSIONS:Patients with drug-resistant focal epilepsy undergoing evaluation for epilepsy surgery may benefit from cenobamate. In this study, patients who received cenobamate during the presurgical evaluation were less likely to undergo surgery within 12 months. The delay to surgery identified among Hispanic and Latino patients suggests potential barriers to care in this patient population warranting further investigation.

BACKGROUND:Many survivors of hemorrhagic stroke have impaired communication. We aimed to identify preadmission, admission, and post-discharge factors associated with self-reported impaired communication after hemorrhagic stroke. DESIGN/METHODS:Patients with intracerebral or subarachnoid hemorrhage (ICH or SAH) admitted at an urban academic medical center were assessed 3-months post-bleed using the communication Quality of Life in Neurological Disorders (Neuro-QoL) short form inventory. Multivariate analysis was performed to evaluate the relationship between impaired communication (Neuro-QoL scaled score < 100) and preadmission, admission, and post-discharge factors. RESULTS:Of 108 patients (68 ICH and 40 SAH), 59 (54.6%) had impaired communication 3-months post-bleed. On multivariate analysis of the full cohort, when controlling for NIHSS score on admission, impaired communication was associated with: retirement prior to admission (OR: 8.18, 95% CI 1.95-40.5, p = 0.005), hospital length-of-stay (OR: 1.11, 95% CI 1.03-1.22, p = 0.012), and cognitive impairment post-bleed (OR: 32.1, 95% CI 8.93-146, p < 0.001). There were 43 (63.2%) ICH patients with impaired communication 3-months post-bleed. On multivariate analysis, impaired communication was associated with: retirement prior to admission (OR: 9.46, 95% CI 1.76-71.8, p = 0.014), supratentorial location (OR: 8.93, 95% CI 1.22-93.6, p = 0.043), hospital length-of-stay (OR: 1.21, 95% CI 1.01-1.45, p = 0.018), and cognitive impairment post-bleed (OR: 16.3, 95% CI 3.58-102, p < 0.001). CONCLUSIONS:Impaired communication after hemorrhagic stroke is more common in patients who were retired prior to admission and who have post-bleed comorbid cognitive impairment. Increased surveillance is recommended for retired and cognitively impaired patients. Additional investigation into the relationship between communication and both retirement status and cognitive impairment is needed.