Faculty Bibliography

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS:We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS/RESULTS:Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION/CONCLUSIONS:Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING/BACKGROUND:National Institutes of Health.

BACKGROUND:The risk of intracerebral hemorrhage (ICH) hematoma expansion (HE) is highest in the first hours after onset, and coagulopathy is believed to further increase this risk. However, there is a paucity of data comparing the risk of HE over time for various antithrombotic agents. METHODS:We conducted a retrospective study of spontaneous ICH patients enrolled at a comprehensive stroke center between December 2016 and May 2022, excluding those who underwent surgical evacuation. ICH volumes were calculated using ABC/2 methodology and HE was coded for a ≥ 33% and/or ≥ 6-mL increase in ICH volume. Multivariable logistic regression and Cox proportional hazards models were constructed to evaluate risk of HE among patients exposed to the following antithrombotics: aspirin, P2Y12 inhibitors, aspirin + P2Y12 inhibitors, warfarin, oral factor Xa inhibitors, direct thrombin inhibitors, full dose heparinoids, and combined antiplatelet + anticoagulant. RESULTS:Of 319 patients with ICH, 141 (44%) were on an antithrombotic at the time of ICH and 65 (20%) had HE in a median of 10 h (interquartile range (IQR) 7-21) from last known normal (LKN). In multivariable logistic regression analyses, the odds of HE decreased by 2% for every hour from LKN (adjusted odds ratio (aOR) 0.98, 95% CI 0.97-0.99, P = 0.038), and HE occurred significantly more often in patients taking combined antiplatelet + anticoagulant (9/24, 38%) compared with those who were not (56/295, 19%, aOR 2.71, 95% CI 1.09-6.73, P = 0.032). No other antithrombotic was significantly associated with HE. In multivariable Cox analysis adjusting for admission National Institutes of Health Stroke Scale (NIHSS), only antiplatelet + anticoagulant use was associated with significantly increased rates of HE (adjusted HR (aHR) 2.33, 95% CI 1.14-4.75, P = 0.020), with the highest probability of HE occurring immediately after ICH onset. CONCLUSIONS:Use of combined antiplatelet + anticoagulant was associated with a twofold increased hazard of HE, with the highest probability of expansion occurring early after ICH onset. No increased rate of HE was observed for other antithrombotics.

BACKGROUND:There are limited data to guide antiseizure medication (ASM) prophylaxis in patients with aneurysmal subarachnoid hemorrhage (SAH). This results in practice variation in the use and duration of ASM prophylaxis. METHODS:We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with aneurysmal SAH. The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM or no ASM be used in patients hospitalized for aneurysmal subarachnoid hemorrhage who have no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam or phenytoin/fosphenytoin be preferentially used? (3) If an ASM is used, should a long (> 3 days) or short (≤ 3 days) duration of prophylaxis be used? The main outcomes were early seizure (≤ 14 days), late seizures (> 14 days), adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1988 articles, of which 10 formed the basis of the recommendations: Regarding PICO 1, we did not find a significant difference in outcomes of early seizure, adverse events, mortality, or functional outcomes when comparing ASM to no ASM. In regard to PICO 2, we found fewer early seizures with phenytoin/fosphenytoin and lower risk for neurologic decline with levetiracetam; however, there was low certainty of evidence. There was no significant difference in mortality between the different treatment types. Regarding PICO 3, we found extended use of ASM may be associated with lower seizure risk, but at the same time be associated with higher risk for adverse effects. CONCLUSIONS:Overall, the quality of evidence is low, precluding strong recommendations. We suggest that ASM or no ASM may be used in patients hospitalized with aneurysmal subarachnoid hemorrhage (conditional recommendation, low quality of evidence). If used, we suggest either levetiracetam or phenytoin/fosphenytoin (conditional recommendation, very low quality of evidence) for a short or long duration (conditional recommendation, moderate quality of evidence).

Head computed tomography (CT) imaging is a widely used imaging modality with multitudes of medical indications, particularly in assessing pathology of the brain, skull and cerebrovascular system. It is commonly used as the first-line imaging in neurologic emergencies given its rapidity of image acquisition, safety, cost and ubiquity. Deep learning models may facilitate detection of a wide range of diseases. However, the scarcity of high-quality labels and annotations, particularly among less common conditions, substantially hinders the development of powerful models. To address this challenge, we introduce FM-HCT, a Foundation Model for Head CT for generalizable disease detection, trained using self-supervised learning. Our approach pretrains a deep learning model on a large, diverse dataset of 361,663 non-contrast 3D head CT scans without the need for manual annotations, enabling the model to learn robust, generalizable features. Our results demonstrate that the self-supervised foundation model substantially improves performance on downstream diagnostic tasks compared to models trained from scratch and previous 3D CT foundation models trained on scarce annotated datasets.

BACKGROUND:There is significant heterogeneity related to the use of prophylactic antiseizure medications (ASM) following supratentorial craniotomy. METHODS:We conducted a systematic review and meta-analysis assessing ASM primary prophylaxis in adults hospitalized following supratentorial neurosurgery with no prior seizure history. The following population, intervention, comparator, and outcome (PICO) questions were assessed: (1) Should ASM versus no ASM be used as seizure prophylaxis in adult patients undergoing supratentorial neurosurgery? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT) be preferentially used? and (3) Should a long (> 7 days) versus short (≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure (≤ 14 days), late seizures (> 14 days), adverse events, mortality, and functional and cognitive outcomes. We utilized Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1988 articles, and 16 formed the basis of the recommendations. PICO 1: while meta-analysis of randomized controlled trials (RCTs) demonstrated a significant benefit for early seizure prevention, meta-analyses including all study designs was nonsignificant. Further, there were no differences in late seizure or mortality rates, and there was a trend toward higher adverse event rates with ASM. PICO 2: LEV was associated with significantly lower early seizure rates than PHT, and there were trends toward fewer late seizures and adverse events with LEV. PICO 3: only three studies examined the duration of ASM treatment, and there was no significant difference in seizure events between subjects treated for a short versus long duration. CONCLUSIONS:We suggest that either prophylactic ASM or no ASM be used for seizure prophylaxis in patients undergoing supratentorial neurosurgery (conditional recommendation, low quality of evidence). If an ASM is used, we suggest LEV over PHT (conditional recommendation, very low quality of evidence) for a short duration (conditional recommendation, very low quality of evidence).

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.

INTRODUCTION/BACKGROUND:Though brain fog is common in Long-coronavirus disease 2019 (Long-COVID), the incidence of mild cognitive impairment (MCI) is unknown. METHODS:In an observational cohort study, recovered COVID-positive, Long-COVID, and COVID-negative subjects underwent blinded evaluation using National Alzheimer's Coordinating Center (NACC) and National Institute on Aging (NIA) -Alzheimer's Association diagnostic criteria for dementia and MCI. The cumulative incidence of MCI was calculated for each group, and the hazard of MCI was compared between groups. RESULTS:Among 260 subjects, the cumulative incidence of MCI over 4.4 years was higher with Long-COVID (27%) versus recovered-COVID (5%) or COVID-negative status (1%). There was a higher hazard of MCI for patients with Long-COVID compared to those without (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.86-8.31, p < 0.001), and specifically for the Alzheimer's disease (AD) -related MCI subtype (HR 3.20, 95% confidence interval [CI] 1.14-9.00, p = 0.027). DISCUSSION/CONCLUSIONS:The cumulative incidence and adjusted hazard of MCI (and specifically AD-related MCI) at 4.4 years was significantly higher among Long-COVID patients compared to recovered-COVID and COVID-negative controls.

INTRODUCTION/BACKGROUND:Choroid plexus (ChP) enlargement is a neuroimaging biomarker of neuroinflammation and neurodegeneration. However, evidence of ChP structural and perfusion alterations in long coronavirus disease (COVID) and their clinical relevance remains limited. METHODS:This study included 86 long COVID, 67 recovered COVID, and 26 COVID-negative healthy controls (HCs). ChP volume and cerebral blood flow (CBF) were quantified, and their associations with Alzheimer's disease (AD) symptoms and plasma biomarkers were examined. RESULTS:Both patient groups showed higher ChP volume and lower CBF than HC. Relative to recovered COVID, long COVID patients had a larger ChP volume, but no significant difference in CBF. ChP volume correlated positively with glial fibrillary acidic protein (r = 0.35) and phosphorylated tau217 (p-tau217; r = 0.54), while CBF correlated negatively with p-tau217 (r = -0.56). Both ChP volume and CBF were associated with cognitive decline measured with Mini-Mental State Examination and Clinical Dementia Rating. DISCUSSION/CONCLUSIONS:These findings suggest that ChP differences in long COVID are associated with AD-related cognitive decline and increased plasma biomarkers. HIGHLIGHTS/CONCLUSIONS:Long coronavirus disease (COVID) patients show choroid plexus (ChP) enlargement and reduced cerebral blood flow. ChP alterations are associated with Alzheimer's disease (AD)-related symptoms and plasma biomarker changes. ChP alterations on magnetic resonance imaging may serve as imaging markers for tracking neurological symptoms and AD-related pathology in post-COVID patients.

OBJECTIVES/OBJECTIVE:Cervical artery dissection (CeAD) is an important cause of ischemic stroke in young adults. Nearly 100 million annual chiropractic cervical manipulations are performed in the United States. The relationship between manipulation and CeAD remains controversial. METHODS:We analyzed patients in the multicenter STOP-CAD registry (n=4023) to identify CeAD cases diagnosed after chiropractic cervical manipulation. Demographics and clinical features were compared between manipulation-associated and nonmanipulation-associated cases using χ2 and t tests. Multivariable logistic regression identified key factors associated with manipulation-related CeAD. RESULTS:About 1 in 20 CeAD cases in this registry reported antecedent cervical manipulation. In multivariable binary logistic regression, compared with patients without prior manipulation, those with prior manipulation were younger (OR per year 0.98, 95% CI: 0.97-0.99, P=0.014), more often female (OR: 1.64, 95% CI: 1.21-2.23, P=0.001), less often diabetic (OR: 0.24, 95% CI: 0.08-0.78, P=0.018), presented with neck pain (OR: 2.80, 95% CI: 2.08-3.77, P<0.001), and had higher odds of isolated vertebral artery dissection (OR: 2.15, 95% CI: 1.57-2.94, P<0.001). Recurrent ischemic stroke rates were similar between groups. CONCLUSIONS:Given the very high number of manipulations performed annually, the absolute risk of secondary CeAD is extremely low. Manipulation-associated cases have distinct clinical features, occurring more often in younger women with vertebral dissections. Whether manipulation acts as a precipitating trigger or patients with early CeAD symptoms seek manipulation remains unresolved.