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Background: Frailty is a prevalent state associated with several aging-related traits and conditions. The relationship between frailty and stroke remains understudied. Here we aim to investigate whether the hospital frailty risk score (HFRS) is associated with the risk of stroke and determine whether a significant association between genetically determined frailty and stroke exists. Design: Observational study using data from All of Us research program and Mendelian Randomization analyses. Methods: Participants from All of Us with available electronic health records were selected for analysis. All of Us began national enrollment in 2018 and is expected to continue for at least 10 years. All of Us is recruiting members of groups that have traditionally been underrepresented in research. All participants provided informed consent at the time of enrollment, and the date of consent was recorded for each participant. Incident stroke was defined as stroke event happening on or after the date of consent to the All of Us study HFRS was measured with a 3-year look-back period before the date of consent for stroke risk. The HFRS was stratified into 4 categories: no-frailty (HFRS=0), low (HFRS ≥1 and Results: Two hundred fifty-three thousand two hundred twenty-six participants were at risk of stroke. In multivariable analyses, frailty status was significantly associated with risk of any (ischemic or hemorrhagic) stroke following a dose-response way: not-frail versus low HFRS (HR, 4.9 [CI, 3.5–6.8]; P P P P value for all comparisons P =0.002). Conclusions: Frailty, based on the HFRS was associated with higher risk of any stroke. Mendelian Randomization analyses confirmed this association providing evidence to support a causal relationship. more...

Background: Mechanical thrombectomy (MT) has significantly improved clinical outcomes in acute ischemic stroke. We used single-cell RNA sequencing (scRNA-seq) to describe the landscape of human clots at single cell resolution seeking to provide greater mechanistic insight into stroke pathophysiology and to uncover an association with stroke origin. Methods: scRNA-seq was performed on 14 clots retrieved from 14 patients undergoing MT between October 2020-July 2022. We followed standard molecular biology and bioinformatics workflows for sample processing and data to characterize differences in cellular composition between clots of different stroke origin (atrial fibrillation (AF) and carotid atherosclerosis (CA)). Results: Clots revealed a significant heterogeneity of immune cells with major constituents including cells of the mononuclear phagocyte system (MPS) and neutrophils. The cellular populations most enriched in CA clots were B-cells and CD4+ T-cells. The cellular population most enriched in AF clots was red blood cells. When looking at cellular subpopulations of the MPS component, we found that CD16+ monocytes (intermediate and non-classical) were significantly more abundant than CD14+CD16- (classical) monocytes in all clots. Moreover, the proportions of CD16+ monocytes varied with stroke origin: the proportion of non-classical (CD14-CD16+) monocytes was higher in CA clots (p=0.05) whereas the proportion of intermediate monocytes (CD14+CD16+) was higher in FA clots (p=0.03). AF clots had upregulated biomarkers and pathways involved with AF or contractile dysfunction (IFI30, FABP4, PPAR, HOTAIR, ILK, Integrin). CA clots had upregulated biomarkers and pathways associated with cardiovascular diseases and atherogenesis (RNSE1, POLR2J3.1, PLTP, Sirtuin, FAK). (Figure) Conclusions: These results reveal a significant heterogeneity of immune cells and point to important differences in cellular composition associated with stroke etiology. more...

Introduction: Conventional MRI (cMRI) is not routinely available post-mechanical thrombectomy (MT), which can preclude accurate infarction assessment. Our objective was to evaluate the use of low-field portable MRI (pMRI) for bedside evaluation post-MT, including its use as a post-procedural baseline monitor. Methods: Low-field pMRI was used to obtain bedside imaging in post-MT patients between December 2021 to August 2022 at Yale-New Haven Hospital. All pMRI exams were conducted in the standard ferromagnetic environment of the IR suite. Volumetric analyses were performed by a neuroradiologist using 3D Slicer software. If cMRI was not available for comparison, a CT was used. Patients’ charts were reviewed for pre-revascularization MAP and occurrences of MAP dropping by 10% and 20% from individual baselines between the time of pMRI and delayed imaging. Results: A total of 25 patients (64% females, median age 77 years-old [IQR 69.5-84.5]) underwent bedside pMRIs in the IR suite post-MT. The median time from last known normal to access was 6 hours [IQR 4-17]. The median pMRI examination time was 30 minutes [IQR 17-32]. Of the 24 patients with available delayed imaging, 7 (29.2%) had infarct progression compared to immediate post-MT pMRI, while 15 patients (62.5%) had stable/decreased stroke volume. Two patients (8.3%) had parenchymal hemorrhage type 2 and were excluded from further analysis. There was no statistically significant difference between the proportions of favorable TICI scores (85.7% in the infarct progression group vs. 92.3% in the stable/decreased infarct group, p=1.00). Patients with infarct progression had comparable pre-revascularization MAP compared to those with stable/decreased delayed infarct volume (mean of 100.3±4.6 vs. 101.9±15.9 respectively, p=0.727) but had more occurrences of MAP dropping by 10% and 20% of their baseline between the time of pMRI and delayed imaging (mean of 35.0±23.3 vs. 14.7±11.3 occurrences, p=0.011; and mean of 21.7±16.5 vs. 8.5±9.5 occurrences, p=0.026, respectively). Conclusions: The use of low-field MRI in the post-MT setting can facilitate benchmark brain monitoring and serial examinations to evaluate the impact of potential physiological perturbations that may impact ongoing brain injury. more...

Objective Subdural hematoma (SDH), a form of traumatic brain injury, is a common disease that requires extensive patient management and resource utilization; however, there remains a paucity of national studies examining the likelihood of readmission in this patient population. The aim of this study is to investigate differences in 30- and 90-day readmissions for treatment of traumatic SDH using a nationwide readmission database. Methods The Nationwide Readmission Database years 2013–2015 were queried. Patients with a diagnosis of traumatic SDH and a primary procedure code for incision of cerebral meninges for drainage were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Patients were grouped by no readmission (Non-R), readmission within 30 days (30-R), and readmission within 31–90 days (90-R). Results We identified a total of 14,355 patients, with 3106 (21.6%) patients encountering a readmission (30-R: n = 2193 [15.3%]; 90-R: n = 913 [6.3%]; Non-R: n = 11,249). The most prevalent 30- and 90-day diagnoses seen among the readmitted cohorts were postoperative infection (30-R: 10.5%, 90-R: 13.0%) and epilepsy (30-R: 3.7%, 90-R: 1.1%). On multivariate logistic regression analysis, Medicare, Medicaid, hypertension, diabetes, renal failure, congestive heart failure, and coagulopathy were independently associated with 30-day readmission; Medicare and rheumatoid arthritis/collagen vascular disease were independently associated with 90-day readmission. Conclusions In this study, we determine the relationship between readmission rates and complications associated with surgical intervention for traumatic subdural hematoma. more...

Objective: The objective of this study is to assess the impact that the type and duration of DAPT has on aneurysm occlusion rates and iatrogenic complications following endoluminal flow diversion with a single flow diverting stent. Methods: A retrospective review of a multicenter aneurysm database was performed from 2012 to 2020 to identify unruptured intracranial aneurysms treated with single device flow diversion and >12-month follow-up. Clinical and radiologic data were analyzed with aneurysm occlusion as a function of DAPT duration serving as a primary outcome measure. Results: A total of 205 patients underwent flow diversion with a single pipeline embolization device. During the study period, 12.7% of treated aneurysms remained non-occluded. There were no significant differences in aneurysm morphology or type of DAPT used between occluded and non-occluded groups. Non-occluded aneurysms received a longer mean duration of DAPT (9.4 vs 7.1 mo, p=0.016) with ANOVA demonstrating a significant effect of DAPT duration on the observed aneurysm occlusion rate (F(2, 202)=4.2, p=0.016). An exploratory analysis demonstrated the optimum DAPT discontinuation time to minimize aneurysm non-occlusion rates was 7.9 months (95% CI: 6-11 months). There was no significant difference in the rate of complications or delayed ischemic strokes observed between patients receiving short (6 mo) DAPT (7.9% vs 9.3%, p=0.76). Conclusions: Following endovascular flow-diversion, an abbreviated duration of DAPT lasting 6 months may be most appropriate before transitioning to low-dose aspirin monotherapy to promote timely aneurysm occlusion while minimizing delayed thromboembolic complications. more...

Carotid revascularization is an important method of stroke prevention and includes carotid endarterectomy and transfemoral carotid angioplasty and stenting. More recently, a hybrid open-endovascular approach, termed transcarotid artery revascularization (TCAR), is garnering increased attention. Although fundamentally a ‘stenting procedure’, unlike transfemoral carotid angioplasty and stenting, TCAR allows for a proximal neuroprotection strategy based on flow reversal. In this technical video, we will review operative techniques and nuances of the TCAR procedure, with a particular focus on the neurovascular proceduralist looking to adopt this technique into routine clinical practice(video 1).Video 1TCAR Technical Video more...

Importance Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non-East Asian individuals. Objective To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. Design, setting, and participants A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. Main outcomes and measures Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. Results Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10-6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non-East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. Conclusions and relevance These findings provide the largest collection to date of non-East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications. more...

Intracranial high-resolution vessel wall MRI (VW-MRI) is an imaging paradigm that is useful in site-of-rupture identification in patients presenting with spontaneous subarachnoid hemorrhage and multiple intracranial aneurysms. Only a handful of case reports describe its potential utility in the evaluation of more complex brain vascular malformations. We report for the first time three patients with ruptured cranial dural arteriovenous fistulas (dAVFs) that were evaluated with high-resolution VW-MRI. The presumed site-of-rupture was identified based on contiguity of a venous ectasia with adjacent blood products and thick, concentric wall enhancement. This preliminary experience suggests a role for high-resolution VW-MRI in the evaluation of ruptured cranial dAVFs, in particular, site-of-rupture identification. It also supports an emerging hypothesis that all spontaneously ruptured, macrovascular lesions demonstrate avid vessel wall enhancement. more...

OBJECTIVEThe authors performed a study to evaluate the hemorrhagic rates of cerebral dural arteriovenous fistulas (dAVFs) and the risk factors of hemorrhage following Gamma Knife radiosurgery (GKRS).METHODSData from a cohort of patients undergoing GKRS for cerebral dAVFs were compiled from the International Radiosurgery Research Foundation. The annual posttreatment hemorrhage rate was calculated as the number of hemorrhages divided by the patient-years at risk. Risk factors for dAVF hemorrhage prior to GKRS and during the latency period after radiosurgery were evaluated in a multivariate analysis.RESULTSA total of 147 patients with dAVFs were treated with GKRS. Thirty-six patients (24.5%) presented with hemorrhage. dAVFs that had any cortical venous drainage (CVD) (OR = 3.8, p = 0.003) or convexity or torcula location (OR = 3.3, p = 0.017) were more likely to present with hemorrhage in multivariate analysis. Half of the patients had prior treatment (49.7%). Post-GRKS hemorrhage occurred in 4 patients, with an overall annual risk of 0.84% during the latency period. The annual risks of post-GKRS hemorrhage for Borden type 2–3 dAVFs and Borden type 2–3 hemorrhagic dAVFs were 1.45% and 0.93%, respectively. No hemorrhage occurred after radiological confirmation of obliteration. Independent predictors of hemorrhage following GKRS included nonhemorrhagic neural deficit presentation (HR = 21.6, p = 0.027) and increasing number of past endovascular treatments (HR = 1.81, p = 0.036).CONCLUSIONSPatients have similar rates of hemorrhage before and after radiosurgery until obliteration is achieved. dAVFs that have any CVD or are located in the convexity or torcula were more likely to present with hemorrhage. Patients presenting with nonhemorrhagic neural deficits and a history of endovascular treatments had higher risks of post-GKRS hemorrhage. more...

Many publications report laser-interstitial thermal therapy (LITT) as a viable alternative treatment to craniotomy for radiation necrosis (RN) and re-growing tumor occurring after stereotactic radiosurgery (SRS) for brain metastases. No studies to-date have compared the two options. The aim of this study was to retrospectively compare outcomes after LITT versus craniotomy for regrowing lesions in patients previously treated with SRS for brain metastases. Data were collected from a single-institution chart review of patients treated with LITT or craniotomy for previously irradiated brain metastasis. Of 75 patients, 42 had recurrent tumor (56%) and 33 (44%) had RN. Of patients with tumor, 26 underwent craniotomy and 16 LITT. For RN, 15 had craniotomy and 18 LITT. There was no significant difference between LITT and craniotomy in ability to taper off steroids or neurological outcomes. Progression-free survival (PFS) and overall survival (OS) were similar for LITT versus craniotomy, respectively: %PFS-survival at 1-year = 72.2% versus 61.1%, %PFS-survival at 2-years = 60.0% versus 61.1%, p = 0.72; %OS-survival at 1-year = 69.0% versus 69.3%, %OS-survival at 2-years = 56.6% versus 49.5%, p = 0.90. This finding persisted on sub-analysis of smaller lesions under < 3cm in diameter. Craniotomy resulted in higher rates of pre-operative deficit improvement than LITT (p < 0.01). On sub-group analysis, the single factor most significantly associated with OS and PFS was pathology of the lesion. About 40% of tumor lesions needed post-operative salvage with radiation after both craniotomy and LITT. LITT was as efficacious as craniotomy in achieving local control of recurrent irradiated brain metastases and facilitating steroid taper, regardless of pathology. Craniotomy appears to be more advantageous for providing symptom relief in those with pre-operative symptoms. more...

Introduction: Numerical classification systems for the internal carotid artery (ICA) are available, but modifications have added confusion to the numerical systems. Furthermore, previous classifications may not be applicable uniformly to microsurgical and endoscopic procedures. The purpose of this study was to develop a clinically useful classification system. Materials and Methods: We performed cadaver dissections of the ICA in 5 heads (10 sides) and evaluated 648 internal carotid arteries with computed tomography angiography. We identified specific anatomic landmarks to define the beginning and end of each ICA segment. Results: The ICA was classified into eight segments based on the cadaver and imaging findings: (1) Cervical segment; (2) cochlear segment (ascending segment of the ICA in the temporal bone) (relation of the start of this segment to the base of the styloid process: Above, 425 sides [80%]; below, 2 sides [0.4%]; at same level, 107 sides [20%]; P < 0.0001) (relation of cochlea to ICA: Posterior, 501 sides [85%]; posteromedial, 84 sides [14%]; P < 0.0001); (3) petrous segment (horizontal segment of ICA in the temporal bone) starting at the crossing of the eustachian tube superolateral to the ICA turn in all 10 samples; (4) Gasserian-Clival segment (ascending segment of ICA in the cavernous sinus) starting at the petrolingual ligament (PLL) (relation to vidian canal on imaging: At same level, 360 sides [63%]; below, 154 sides [27%]; above, 53 sides [9%]; P < 0.0001); in this segment, the ICA projected medially toward the clivus in 275 sides (52%) or parallel to the clivus with no deviation in 256 sides (48%; P < 0.0001); (5) sellar segment (medial loop of ICA in the cavernous sinus) starting at the takeoff of the meningeal hypophyseal trunk (ICA was medial into the sella in 271 cases [46%], lateral without touching the sella in 127 cases [23%], and abutting the sella in 182 cases [31%]; P < 0.0001); (6) sphenoid segment (lateral loop of ICA within the cavernous sinus) starting at the crossing of the fourth cranial nerve on the lateral aspect of the cavernous ICA and located directly lateral to the sphenoid sinus; (7) ring segment (ICA between the 2 dural rings) starting at the crossing of the third cranial nerve on the lateral aspect of the ICA; (8) cisternal segment starting at the distal dural ring. Conclusions: The classification may be applied uniformly to all skull base surgical approaches including lateral microsurgical and ventral endoscopic approaches, obviating the need for 2 separate classification systems. The classification allows extrapolation of relevant clinical information because each named segment may indicate potential surgical risk to specific structures. more...

INTRODUCTION: Both medical management with bevacizumab and surgical management via craniotomy or more recently with laser interstitial thermal ablation (LITT) have been shown to be efficacious in the management of radiation necrosis (RN) after radiosurgery for brain metastases (BM). Indications for how to choose medical versus surgical management however remains unclear. METHODS: Single-institution chart review was performed of all patients with biopsy or radiographically confirmed RN after radiosurgery for BM between 2011 and 2017. Progression-free survival (PFS) and overall survival (OS) were compared between those treated using bevacizumab versus surgical intervention. RESULTS: 15 patients underwent craniotomy, 18 patients underwent LITT, and 18 patients were treated with bevacizumab. Those treated with bevacizumab had significantly higher number of regrowing lesions (n >1) at time of intervention (50.0%) versus those treated with surgery (15.2%) (p< 0.05). Likewise, pre-treatment KPS was lower in the bevacizumab cohort (median: 60) vs the surgery cohort (median: 90) (p< 0.05). Patients treated with bevacizumab demonstrated significantly decreased PFS (%PFS at 1-year 16.7% vs 86.7% and 87.8% for craniotomy and LITT, respectively; %PFS at 2-years 0% vs 86.7% and 73.2% for craniotomy and LITT, respectively, p < 0.05). Similar results were observed for OS (%OS at 1-year for bevacizumab 33.3% vs 93.3% and 73.8% for craniotomy and LITT, respectively; %OS at 2-years for bevacizumab 11.1% vs 64.6% and 63.2% for craniotomy and LITT, respectively, p< 0.05). CONCLUSIONS: Preliminary analysis shows that bevacizumab therapy in our institution is being chosen for patients with lower KPS and multiple regrowing lesions while surgical intervention is being chosen for patients with good KPS and single, symptomatic regrowing lesions. While the comparative outcomes after bevacizumab appear to be significantly worse than surgical management, it remains unknown if the difference is more related to its true efficacy or the significant discrepancy between the comparison groups. more...

Purpose To characterize smoking and alcohol use, and to describe predictors of oral cancer knowledge among a predominantly African-American population. Methods A cross-sectional study was conducted between September, 2013 among drag racers and fans in East St. Louis. Oral cancer knowledge was derived from combining questionnaire items to form knowledge score. Covariates examined included age, sex, race, marital status, education status, income level, insurance status, tobacco and alcohol use. Adjusted linear regression analysis measured predictors of oral cancer knowledge. Results Three hundred and four participants completed questionnaire; 72.7% were African Americans. Smoking rate was 26.7%, alcohol use was 58.3%, and mean knowledge score was 4.60 ± 2.52 out of 17. In final adjusted regression model, oral cancer knowledge was associated with race and education status. Compared with Caucasians, African Americans were 29% less likely to have high oral cancer knowledge (β = -0.71; 95% CI: -1.35, -0.07); and participants with a high school diploma or less were 124% less likely to have high oral cancer knowledge compared with college graduates (β = -1.24; 95% CI: -2.44, -0.41). Conclusions There was lower oral cancer knowledge among African Americans and those with low education. The prevalence of smoking was also very high. Understanding predictors of oral cancer knowledge is important in future design of educational interventions specifically targeted towards high-risk group for oral cancer. more...

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans. We showed previously that HCV induces autophagy for viral persistence by preventing the innate immune response. Knockdown of autophagy reduces extracellular HCV release, although the precise mechanism remains unknown. In this study, we observed that knockdown of autophagy genes enhances intracellular HCV RNA and accumulates infectious virus particles in cells. Since HCV release is linked with the exosomal pathway, we examined whether autophagy proteins associate with exosomes in HCV-infected cells. We observed an association between HCV and the exosomal marker CD63 in autophagy knockdown cells. Subsequently, we observed that levels of extracellular infectious HCV were significantly lower in exosomes released from autophagy knockdown cells. To understand the mechanism for reduced extracellular infectious HCV in the exosome, we observed that an interferon (IFN)-stimulated BST-2 gene is upregulated in autophagy knockdown cells and associated with the exosome marker CD63, which may inhibit HCV assembly or release. Taken together, our results suggest a novel mechanism involving autophagy and exosome-mediated HCV release from infected hepatocytes. IMPORTANCE Autophagy plays an important role in HCV pathogenesis. Autophagy suppresses the innate immune response and promotes survival of virus-infected hepatocytes. The present study examined the role of autophagy in secretion of infectious HCV from hepatocytes. Autophagy promoted HCV trafficking from late endosomes to lysosomes, thus providing a link with the exosome. Inhibition of HCV-induced autophagy could be used as a strategy to block exosome-mediated virus transmission. more...