Rajat Dhar

Background: The risk of vasospasm and delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is well characterized. However, the risk of these complications in cases of aneurysmal rupture causing intracerebral hemorrhage is less clear. Here, we characterized the incidence and radiographic features of aneurysmal ICH (aICH) and the associated risk of vasospasm and DCI. Methods: This is a retrospective single-center cohort study of 442 patients with aneurysmal hemorrhage from 2014 to 2021. Clinical and radiographic features were compared in those with versus without ICH and presence of ICH was analyzed as an independent risk factor for vasospasm and DCI. Further, the incidence of vasospasm/DCI in those with aneurysmal ICH without SAH was compared to those with ICH and cisternal SAH. Vasospasm and DCI were evaluated only in those surviving at least four days. Results: Overall, 83 of 442 patients (19%) had ICH, of whom only 8 (2%) had ICH without SAH. Among those surviving for 4 days, patients with ICH experienced higher rates of vasospasm (59% vs. 34%) and DCI (42% vs. 21%, both p = 0.0005) than those patients with SAH without ICH. Those with ICH without SAH experienced numerically lower rates of vasospasm than those with concomitant ICH and SAH (43% vs 62%) and DCI (14% vs. 46%). After adjustment for age, aneurysm size, WFNS grade, modified Fisher and IVH scores, ICH was an independent risk factor for vasospasm (OR 2.26, 95% CI 1.13–4.52) with a trend to higher risk of DCI (OR 1.83, 95% CI 0.90–3.68). Conclusion: Presence of ICH following aneurysmal rupture carries significantly higher risk of vasospasm with a trend to higher risk of DCI in survivors. In comparison, aneurysmal ICH without SAH is relatively rare but is still associated with vasospasm and DCI, though this estimate requires confirmation in larger cohorts.

Introduction: White matter hyperintensities (WMH) are key radiographic biomarkers of cerebral small vessel disease (CSVD) and have been associated with worse outcomes after stroke. Since CSVD may involve blood–brain barrier disruption, we hypothesized that worse outcomes in those with WMH may be mediated through more severe cerebral edema and hemorrhagic transformation (HT). Methods: In this retrospective multicenter cohort study, we studied patients from four multinational stroke cohorts who presented within 12 h of anterior circulation large vessel occlusion (LVO) stroke and received at least one follow-up computed tomography (CT) between 12 and 48 h. WMH were rated on baseline CTs using a Fazekas-derived system, with a subset also assessed with Fazekas grading on magnetic resonance imaging (MRI). Automated image analysis measured cerebrospinal fluid displacement (ΔCSF) and lesional-to-contralateral hemispheric CSF volumes (CSF-ratio) as quantitative edema biomarkers. We analyzed the association between WMH presence and edema severity, hemorrhagic transformation, and poor functional outcome (mRS 3–6), adjusting for key covariates, overall and in the subgroup undergoing thrombectomy and those with successful reperfusion. Results: Of 1290 patients with LVO, 782 were eligible for analysis. Of these, 19% had WMH on CT. Patients with WMH were older, more often female, and had a history of hypertension and higher presenting systolic blood pressure and glucose levels. WMH presence was associated with worse functional outcome, adjusting for age and additional covariates [OR 1.84 (1.06–3.22), p = 0.04] but lower risk of any HT [OR 0.48 (0.25–0.88), p = 0.03]. However, WMH presence by CT or MRI was not associated with edema (ΔCSF, CSF ratio, or midline shift) in the whole population or thrombectomy/reperfusion subgroups. Reperfusion was associated with less edema and improved recovery. Conclusions: Presence of CT-graded WMH was associated with worse outcome after LVO stroke, independent of age and other factors. However, this risk appears not to be mediated through greater risk of HT or cerebral edema formation.

INTRODUCTION: White Matter Hyperintensities (WMH) are key radiographic biomarkers of cerebral small vessel disease (CSVD) and have been associated with worse outcomes after stroke. Since CSVD may involve blood-brain barrier disruption, we hypothesized that worse outcomes in those with WMH may be mediated through more severe cerebral edema and hemorrhagic transformation. METHODS: In this retrospective multicenter cohort study, we studied patients from four multinational stroke cohorts who presented within 12 hours of anterior circulation large vessel occlusion (LVO) stroke and received at least one follow-up CT between 12–48 hours. WMH were rated on baseline CTs using a Fazekas-derived system, with a subset also assessed with Fazekas-grading on MRI. Automated image analysis measured cerebrospinal fluid displacement (ΔCSF) and lesional-to-contralateral hemispheric CSF volumes (CSF-ratio) as quantitative edema biomarkers. We analyzed the association between WMH presence and edema severity, hemorrhagic transformation and poor functional outcome (mRS 3–6), adjusting for key covariates, overall and in the subgroup undergoing thrombectomy and those with successful reperfusion. RESULTS: Of 1,290 LVO patients, 782 were eligible for imaging analysis. Of these, 19% had WMH on CT. Patients with WMH were older, more often female and had a history of hypertension, and higher presenting systolic blood pressure and glucose levels. WMH presence was associated with worse functional outcome, adjusting for age and additional covariates [OR 1.84 (1.06–3.22), p = 0.04] but lower risk of any HT [OR 0.48 (0.25–0.88), p = 0.03]. However, WMH presence by CT or MRI was not associated with edema (ΔCSF, CSF-ratio, or midline shift) in the whole population or thrombectomy/reperfusion subgroups. Reperfusion was associated with less edema and improved recovery. CONCLUSIONS: Presence of CT-graded WMH was associated with worse outcome after LVO stroke, independent of age and other factors. However, this risk appears not to be mediated through greater risk of HT or cerebral edema formation.

Imaging after ischemic and hemorrhagic stroke may allow measurement of key phenotypes of injury and recovery for which targeted therapies are still lacking. Such imaging endophenotypes provide quantifiable and heritable biomarkers that can represent mechanistic aspects of disease processes better than clinical measures. Artificial intelligence is allowing extraction of these imaging biomarkers in large cohorts, which can be paired with genomic and other omics data. This will allow the evaluation of what genetic and other biologic variations impact stroke injury and recovery. Integration of these analyses with bioinformatics tools (such as Mendelian randomization and multi-trait analysis) could further dissect how stroke complications overlap with other biologic processes and how they may be causally linked to risk factors. Further work is required to confirm the translational impact of these methods in elucidating mechanisms and drug targets for stroke. However, global collaborations are accelerating analyses on large multi-ethnic stroke cohorts, with availability of imaging data facilitated by federally-funded repositories such as the Imaging Repository for the Cerebrovascular Disease Knowledge Portal (iCDKP).

Background: Large middle cerebral artery (MCA) infarctions can result in life-threatening cerebral edema. Quantitative brain atrophy may improve risk stratification for severe edema. We examined whether quantitative brain atrophy is associated with severe midline shift after large ischemic stroke and whether incorporating atrophy improves prediction beyond established clinical and radiographic predictors. Methods: This was a retrospective observational cohort study of patients with ≥½ MCA ischemic infarction, presentation within 24 hours of last known well, and at least one follow-up head CT, admitted to two academic hospitals with comprehensive stroke centers between 2006 and 2024. The study was approved by the institutional review boards of both centers. Brain atrophy was quantified as the inverse of standardized brain volume on admission head CT. The primary outcome was severe radiographic mass effect, defined as midline shift ≥5 mm on follow-up CT. The secondary outcome was in-hospital mortality. Multivariable regression models assessed associations between quantified atrophy and outcomes. Incremental prognostic value was evaluated by comparing models with and without atrophy using measures of goodness of fit, calibration, and discrimination. Results: Among 565 patients (mean age 67.5±15.7 years; 49.9% female), 223 (39.5%) developed severe mass effect. Greater atrophy was associated with lower odds of midline shift ≥5 mm (OR 0.44, 95% CI 0.34-0.58), but not with in-hospital mortality. Incorporation of atrophy significantly improved prediction of severe mass effect compared to the baseline model (likelihood ratio test χ² (1) = 41, p <0.001; AIC 703 vs. 741; BIC 733 vs. 767; AUC 0.68 vs. 0.60). Conclusions: Quantified brain atrophy is independently associated with a reduced risk of severe mass effect after large MCA stroke and improved the performance of established predictive models. Incorporation of this imaging biomarker may enhance early risk stratification, monitoring, and intervention planning for patients at risk of life-threatening cerebral edema.

The optimal blood pressure (BP) target after endovascular thrombectomy (EVT) remains elusive. The aim of our study was to assess the relationship between individualized autoregulation-based BP thresholds, secondary brain injury, and functional outcomes. We conducted a prospective observational study of patients with acute ischemic stroke who underwent EVT. Simultaneous recordings of arterial BP and near-infrared spectroscopy were used to continuously monitor each patient's limits of autoregulation for up to 24 hours. Time outside limits of autoregulation was correlated with short-term clinical end points, radiographic biomarkers of secondary brain injury, and functional outcomes. Personalized BP targets were successfully computed in 199 patients. Percent time outside limits of autoregulation was independently associated with early neurologic deterioration (OR 1.2, 95% CI 1.1-1.4, p < 0.001) and worse modified Rankin Scale scores at 90 days (OR 1.22, 95% CI 1.09-1.36, p < 0.001). Patients with hemorrhagic transformation and symptomatic intracranial hemorrhage spent significantly more time above the upper limit of autoregulation compared with those without (18.7% vs 11%, p = 0.02, and 24.9% vs 12.3%, p = 0.024, respectively). Furthermore, time above the upper limit of autoregulation was correlated with net water uptake, a radiographic biomarker of cerebral edema (β = 1.6, 95% CI 0.4-2.8, p = 0.009). In nonrecanalized patients, every 60 minutes below the lower limit of autoregulation was associated with an infarct progression of 16.2 mL (p < 0.001). Deviations from personalized BP targets were associated with an increased risk of secondary brain injury and worse functional outcomes. The study proposes autoregulation-oriented BP management as a promising strategy for improving recovery after ischemic stroke.

Quantitative analysis of brain imaging after stroke provides a window into disease course and severity, critical factors for pathophysiology and outcome studies. While millions of patients experience a stroke each year, there are barriers to systematically analyzing the high volume of imaging studies across centers. This study demonstrates the capabilities of a cloud-based imaging repository and computational platform for extracting multi-dimensional imaging biomarkers from CT scans of ischemic and hemorrhagic stroke patients. The Stroke NeuroImaging Phenotype Repository (SNIPR) is built on the XNAT platform and has archived serial imaging data from several large stroke cohorts. The platform supports Docker-containerized analysis for the evaluation of lesion and edema volumes. This study outlines the deployment of these comprehensive image analysis pipelines, encompassing steps from brain scan classification to the segmentation of ischemic and hemorrhage regions and subsequent quantification of edema biomarkers, including net water uptake (NWU) and the ratio of hemispheric CSF volumes. Analysis pipelines were executed on 8029 CT sessions across ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage cohorts, yielding successful biomarker extraction in 91% of cases, demonstrating the platform's efficiency. Biomarker profiles extracted from these large cohorts illustrated the plausibility of big data analyses in stroke using SNIPR. The incorporation of containerized analysis pipelines into a stroke imaging platform significantly enhances the capacity for multi-centric collaborative stroke research, enabling the processing of thousands of brain CT images for biomarker extraction.

Background: Inflammation plays a critical role in brain injury following acute ischemic stroke (AIS). Transcutaneous auricular vagus nerve stimulation (taVNS) has shown anti-inflammatory properties in various conditions, but its efficacy in AIS remains unexplored. We investigated if taVNS could mitigate post-AIS inflammation and its safety. Methods: In this randomized, sham-controlled trial with blinded outcomes assessment, patients with anterior circulation large vessel occlusion (LVO) AIS were assigned to twice-daily taVNS or sham stimulation for five days or until discharge. Key inclusion criteria included age ≥18 years, National Institutes of Health Stroke Scale (NIHSS) ≥6, anterior circulation LVO, and enrollment within 36 hours of last known normal. Primary endpoints were changes in inflammatory biomarkers (white blood cells and cytokines including interleukins (IL)-1β, 6, 10, 17α, and tumor necrosis factor alpha (TNFα) measured at baseline and Days 1, 3, 5, and 7, and taVNS safety. Secondary exploratory endpoints included change in NIHSS, 90 day modified Rankin score (mRS), and safety (bradycardia, hypotension, infection, and death). Results: Thirty-five patients (17 taVNS, 18 sham) were enrolled. The taVNS group showed a significant rate of change in normalized aggregate pro-inflammatory cytokines and interleukin-6 levels compared to sham (p=0.04 and p<0.001, respectively). Each 1 pg/mL reduction in interleukin-6 correlated with a 0.798-point improvement in NIHSS in the taVNS group (95% confidence interval [0.077, 1.518], p = 0.031]), with no significant correlation in the sham group. IL-1β, 10, 17α, and TNFα showed reduction in cytokine levels, but did not reach statistical significance. There were no statistically significant differences amongst mRS and safety outcomes between both groups. Conclusions: taVNS safely reduced post-AIS inflammation in anterior circulation LVO stroke patients, demonstrating biological effects. Secondary analyses also found potential effects in NIHSS improvements. These promising findings warrant further investigation in larger trials. ClinicalTrials.gov ID: NCT05390580, https://clinicaltrials.gov/study/NCT05390580