Nationwide diurnal pattern among intracerebral hemorrhage incidence and volume.

INTRODUCTION: Intracerebral hemorrhage (ICH) incidence follows both seasonal and diurnal patterns with greater severity reported in nighttime hemorrhages. These differences have been attributed to variations in the coagulation cascade, blood pressure, and sleep-wake cycle that all have their own rhythmicity. The purpose of this analysis was to validate these trends in a large nationwide database of automated ICH detection scans and evaluate for differences in hematoma volume by image acquisition time. METHODS: Serial non-contrast head CT (NCHCT) data, processed with an automated imaging software (iSchemaView), was acquired from U.S. hospitals between 1/1/2020 and 12/31/2021. Final exclusion criteria included: (1) patient age ≤ 25, (2) hematoma volume ≥ 100 ml, (3) hematoma volume ≤ 0.4 ml. Imaging time was subdivided into three epochs: (1) Night: 23:00h-06:59h, (2) Day: 07:00h-14:59h, and (3) Evening: 15:00h-22:59h. RESULTS: A total of 19,397 scans were included in the final analysis with a median ICH volume of 2.9 ml and mean volume of 13.23 mL; 15.6% of scans had volumes above 30 ml. Peak imaging occurred around noon. Hematoma volume was significantly different across timepoints (p = 0.003), with ICHs presenting at night (average volume 14.2 ml) larger than those presenting during the day (12.9 ml, p = 0.002) or evening (13.0 ml, p = 0.012). CONCLUSION: In this real world, multi-site data set, we show similar diurnal trends in ICH incidence as previously reported and detected subtle differences in volume based on time of imaging. Further research is required to elucidate the potential underlying mechanisms for these differences.

Decreasing false-positive detection of intracranial hemorrhage (ICH) using RAPID ICH 3.

INTRODUCTION: The prompt detection of intracranial hemorrhage (ICH) on a non-contrast head CT (NCCT) is critical for the appropriate triage of patients, particularly in high volume/high acuity settings. Several automated ICH detection tools have been introduced; however, at present, most suffer from suboptimal specificity leading to false-positive notifications. METHODS: NCCT scans from 4 large databases were evaluated for the presence of an ICH (IPH, IVH, SAH or SDH) of >0.4 ml using fully-automated RAPID ICH 3.0 as compared to consensus detection from at least two neuroradiology experts. Scans were excluded for (1) severe CT artifacts, (2) prior neurosurgical procedures, or (3) recent intravenous contrast. ICH detection accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios by were determined. RESULTS: A total of 881 studies were included. The automated software correctly identified 453/463 ICH-positive cases and 416/418 ICH-negative cases, resulting in a sensitivity of 97.84% and specificity 99.52%, positive predictive value 99.56%, and negative predictive value 97.65% for ICH detection. The positive and negative likelihood ratios for ICH detection were similarly favorable at 204.49 and 0.02 respectively. Mean processing time was <40 seconds. CONCLUSIONS: In this large data set of nearly 900 patients, the automated software demonstrated high sensitivity and specificity for ICH detection, with rare false-positives.

Safety and Feasibility of an Emergency Department-to-Outpatient Pathway for Patients With TIA and Nondisabling Stroke.

Background and Objectives: Evaluation of transient ischemic attack/nondisabling ischemic strokes (TIA/NDS) in the emergency department (ED) contributes to capacity issues and increasing health care expenditures, especially high-cost duplicative imaging. Methods: As an institutional quality improvement project, we developed a novel pathway to evaluate patients with TIA/NDS in the ED using a core set of laboratory tests and CT-based neuroimaging. Patients identified as 'low risk' through a safety checklist were discharged and scheduled for prompt outpatient tests and stroke clinic follow-up. In this prespecified analysis designed to assess feasibility and safety, we abstracted data from patients consecutively enrolled in the first 6 months. Results: We compared data from 106 patients with TIA/NDS enrolled in the new pathway from April through September 2020 (age 67.9 years, 45% female), against 55 unmatched historical controls with TIA encountered from April 2016 through March 2017 (age 68.3 years, 47% female). Both groups had similar median NIHSS scores (pathway and control 0) and ABCD2 scores (pathway and control 3). Pathway-enrolled patients had a 44% decrease in mean ED length of stay (pathway 13.7 hours, control 24.4 hours, p < 0.001) and decreased utilization of ED MRI-based imaging (pathway 63%, control 91%, p < 0.001) and duplicative ED CT plus MRI-based brain and/or vascular imaging (pathway 35%, control 53%, p = 0.04). Among pathway-enrolled patients, 89% were evaluated in our stroke clinic within a median of 5 business days; only 5.5% were lost to follow-up. Both groups had similar 90-day rates of ED revisits (pathway 21%, control 18%, p = 0.84) and recurrent TIA/ischemic stroke (pathway 1%, control 2%, p = 1.0). Recurrent ischemic events among pathway-enrolled patients were attributed to errors in following the safety checklist before discharge. Discussion: Our TIA/NDS pathway, implemented during the initial outbreak of COVID-19, seems feasible and safe, with significant positive impact on ED throughput and ED-based high-cost duplicative imaging. The safety checklist and option of virtual telehealth follow-up are novel features. Broader adoption of such pathways has important implications for value-based health care.

Larger ischemic cores and poor collaterals among large vessel occlusions presenting in the late evening.

BACKGROUND: Components critical to cerebral perfusion have been noted to oscillate over a 24-h cycle. We previously reported that ischemic core volume has a diurnal relationship with stroke onset time when examined as dichotomized epochs (i.e. Day, Evening, Night) in a cohort of over 1,500 large vessel occlusion (LVO) patients. In this follow-up analysis, our goal was to explore if there is a sinusoidal relationship between ischemic core, collateral status (as measured by HIR), and stroke onset time. METHODS: We retrospectively examined collection of LVO patients with baseline perfusion imaging performed within 24 h of stroke onset from four international comprehensive stroke centers. Both ischemic core volume and HIR, were utilized as the primary radiographic parameters. To evaluate for differences in these parameters over a continuous 24-h cycle, we conducted a sinusoidal regression analysis after linearly regressing out the confounders age and time to imaging. RESULTS: A total of 1506 LVO cases were included, with a median ischemic core volume of 13.0 cc (IQR: 0.0-42.0) and median HIR of 0.4 (IQR: 0.2-0.6). Ischemic core volume varied by stroke onset time in the unadjusted (p = 0.001) and adjusted (p = 0.003) sinusoidal regression analysis with a peak in core volume around 7:45PM. HIR similarly varied by stroke onset time in the unadjusted (p = 0.004) and adjusted (p = 0.002) models with a peak in HIR values at around 8:18PM. CONCLUSION: The results suggest that critical factors to the development of the ischemic core vary by stroke onset time and peak around 8PM. When placed in the context of prior studies, strongly suggest a diurnal component to the development of the ischemic core.

Automated cerebral hemorrhage volume calculation and stability detection using automated software.

Introduction: The measurement of intracerebral hemorrhage (ICH) volume is important for management, particularly in evaluating expansion on subsequent imaging. However manual volumetric analysis is time-consuming, especially in busy hospital settings. We aimed to use automated Rapid Hyperdensity software to accurately measure ICH volume across repeated imaging. Methods: We identified ICH cases, with repeat imaging conducted within 24 hours, from two randomized clinical trials where enrollment was not based on ICH volume. Scans were excluded if there was (1) severe CT artifacts, (2) prior neurosurgical procedures, (3) recent intravenous contrast, or (4) ICH < 1 ml. Manual ICH measurements were conducted by one neuroimaging expert using MIPAV software and compared to the performance of automated software. Results: 127 patients were included with median baseline ICH volume manually measured at 18.18 cc (IQR: 7.31 - 35.71) compared to automated detection of 18.93 cc (IQR: 7.55, 37.88). The two modalities were highly correlated (r = 0.994, p < 0.001). On repeat imaging, the median absolute difference in ICH volume was 0.68cc (IQR: -0.60-4.87) compared to automated detection at 0.68cc (IQR: -0.45-4.63). These absolute differences were also highly correlated (r = 0.941, p < 0.001), with the ability of the automated software to detect ICH expansion with a Sensitivity of 94.12% and Specificity 97.27%. Conclusion: In our proof-of-concept study, the automated software has high reliability in its ability to quickly determine IPH volume with high sensitivity and specificity and to detect expansion on subsequent imaging.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Infarct Core Growth During Interhospital Transfer For Thrombectomy Is Faster At Night.

BACKGROUND: Preclinical stroke models have recently reported faster infarct growth (IG) when ischemia was induced during daytime. Considering the inverse rest-activity cycles of rodents and humans, faster IG during the nighttime has been hypothesized in humans. METHODS: We retrospectively evaluated acute ischemic stroke patients with a large vessel occlusion transferred from a primary to 1 of 3 French comprehensive stroke center, with magnetic resonance imaging obtained at both centers before thrombectomy. Interhospital IG rate was calculated as the difference in infarct volumes on the 2 diffusion-weighted imaging, divided by the time elapsed between the 2 magnetic resonance imaging. IG rate was compared between patients transferred during daytime (7:00-22:59) and nighttime (23:00-06:59) in multivariable analysis adjusting for occlusion site, National Institutes of Health Stroke Scale score, infarct topography, and collateral status. RESULTS: Out of the 329 patients screened, 225 patients were included. Interhospital transfer occurred during nighttime in 31 (14%) patients and daytime in 194 (86%). Median interhospital IG was faster when occurring at night (4.3 mL/h; interquartile range, 1.2-9.5) as compared to the day (1.4 mL/h; interquartile range, 0.4-3.5; P<0.001). In multivariable analysis, nighttime transfer remained independently associated with IG rate (P<0.05). CONCLUSIONS: Interhospital IG appeared faster in patients transferred at night. This has potential implications for the design of neuroprotection trials and acute stroke workflow.

Elevated Hypoperfusion Intensity Ratio (HIR) observed in patients with a large vessel occlusion (LVO) presenting in the evening.

BACKGROUND: Circadian variability has been implicated in timing of stroke onset, yet the full impact of underlying biological rhythms on acute stroke perfusion patterns is not known. We aimed to describe the relationship between time of stroke onset and perfusion profiles in patients with large vessel occlusion (LVO). METHODS: A retrospective observational study was conducted using prospective registries of four stroke centers across North America and Europe with systematic use of perfusion imaging in clinical care. Included patients had stroke due to ICA, M1 or M2 occlusion and baseline perfusion imaging performed within 24h from last-seen-well (LSW). Stroke onset was divided into eight hour intervals: (1) Night: 23:00-6:59, (2) Day: 7:00-14:59, (3) Evening: 15:00-22:59. Core volume was estimated on CT perfusion (rCBF <30%) or DWI-MRI (ADC <620) and the collateral circulation was estimated with the Hypoperfusion Intensity Ratio (HIR = [Tmax>10s]/[Tmax>6s]). Non-parametric testing was conducted using SPSS to account for the non-normalized dependent variables. RESULTS: A total of 1506 cases were included (median age 74.9 years, IQR 63.0-84.0). Median NIHSS, core volumes, and HIR were 14.0 (IQR 8.0-20.0), 13.0mL (IQR 0.0-42.0), and 0.4 (IQR 0.2-0.6) respectively. Most strokes occurred during the Day (n = 666, 44.2%), compared to Night (n = 360, 23.9%), and Evening (n = 480, 31.9%). HIR was highest, indicating worse collaterals, in the Evening compared to the other timepoints (p = 0.006). Controlling for age and time to imaging, Evening strokes had significantly higher HIR compared to Day (p = 0.013). CONCLUSION: Our retrospective analysis suggests that HIR is significantly higher in the evening, indicating poorer collateral activation which may lead to larger core volumes in these patients.

Association of Soluble ST2 With Functional Outcome, Perihematomal Edema, and Immune Response After Intraparenchymal Hemorrhage.

BACKGROUND AND OBJECTIVES: Perihematomal edema (PHE) contributes to poor outcome after deep intraparenchymal hemorrhage (IPH), which is characterized by neuroinflammation and an influx of peripherally derived innate immune cells. We previously identified soluble ST2 (sST2) as a candidate for immune-mediated secondary brain injury. Leveraging prospectively collected cohorts from 2 centers, we sought to determine whether sST2 was associated with functional outcome, PHE, and the immune response following IPH. METHODS: Patients with deep IPH were enrolled within 36 hours of ictus, and blood was collected for sST2 and immune cell measurement. Hematoma volume and PHE were measured on serial CT scans. Good outcome was defined as a modified Rankin Scale score of 0-3 at 90 days. Linear mixed-effects models were used to analyze the relationship between sST2 and PHE over time. Flow cytometry was used to identify shifts in immune cell populations associated with sST2. Immunohistochemistry of human brain tissue was used to identify ST2-expressing cells in the perihematomal region. RESULTS: The 55 included patients had a median admission Glasgow Coma Scale score of 14 (interquartile range [IQR] 9-15), an intracerebral hemorrhage (ICH) score of 1 (IQR 1-2), and a hematoma volume of 8.6 mL (IQR 3.4-13.8 mL). Receiver operating curve analysis found the sST2 level to be predictive of poor outcome with an area under the curve of 0.763 (95% CI 0.632-0.894) and Youden optimum cut point of 61.8 ng/mL (p < 0.001). sST2 remained an independent predictor after adjustment for ICH score (adjusted odds ratio 2.53, 95% CI 1.03-6.19, p = 0.042). Measurement of PHE found those patients with high sST2 to have greater edema volume over time (ß = 1.07, 95% CI 0.51-1.63, p < 0.001). High sST2 was associated with a shift toward an innate peripheral immune response (monocytes and natural killer cells; 68.6% ± 5.1% vs 47.5% ± 4.0%; p = 0.003). DISCUSSION: Our findings demonstrate that elevated sST2 links the peripheral innate immune response to PHE volume and outcome after IPH. This knowledge is relevant to future studies that seek to identify patients with IPH at highest risk for immune-mediated injury or limit injury through targeted interventions.

Clinical Trial Publication Trends Within Neurology.

Timely dissemination of results from clinical studies is crucial for the advancement of knowledge and clinical decision making. A large body of research has shown that up to half of clinical trials do not publish their findings. In this study, we sought to determine whether clinical trial publication rates within neurology have increased over time. Focusing on neurology clinical trials completed between 2008 to 2014, we found that while the overall percentage of published trials has not changed (remaining at approximately 50%), time to publication has significantly decreased. Our findings suggest that clinical trials within neurology are being published in a more timely manner.

Functional Improvement Among Intracerebral Hemorrhage (ICH) Survivors up to 12 Months Post-injury.

BACKGROUND AND PURPOSE: As survival rates have increased for intracerebral hemorrhage (ICH) patients, there is limited information regarding recovery beyond 3-6 months. This study was conducted to examine recovery curves using the modified Rankin Scale (mRS) and Barthel Index (BI) up to 12 months post-injury. METHODS: We prospectively enrolled 173 patients admitted with ICH who were subsequently evaluated using the mRS and BI at discharge as well as 3, 6, and 12 months. Repeated measures nonparametric testing was conducted to assess functional trajectories across time. RESULTS: The mRS scores showed significant improvement between discharge (median 4) and 3 (median 4), 6 (median 4), and 12 months (median 3) (p values <0.001). However, the mRS scores did not differ between follow-up time-points (i.e., 3-6, 6-12 months). There was significant improvement in scores using the BI (p values <0.001), showing improvement between discharge (mean 43.0) and 3 (mean 73.0), 6 (mean 78.2), and 12 months (mean 83.4). Additionally, there were differences in the BI between 3 and 12 months (p = 0.013), as well as between 6 and 12 months (p = 0.025). CONCLUSIONS: The BI may be a more sensitive measure of long-term recovery post-injury than the mRS, which shows minimal improvement for some survivors after 3 months. BI scores indicate survivors continually improve till 12 months post-injury. These results may have implications for the prognostication of ICH and design of clinical trial outcome measures.

Intracerebral Hemorrhage Location and Functional Outcomes of Patients: A Systematic Literature Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) has the highest mortality rate among all strokes. While ICH location, lobar versus non-lobar, has been established as a predictor of mortality, less is known regarding the relationship between more specific ICH locations and functional outcome. This review summarizes current work studying how ICH location affects outcome, with an emphasis on how studies designate regions of interest. METHODS: A systematic search of the OVID database for relevant studies was conducted during August 2015. Studies containing an analysis of functional outcome by ICH location or laterality were included. As permitted, the effect size of individual studies was standardized within a meta-analysis. RESULTS: Thirty-seven studies met the inclusion criteria, the majority of which followed outcome at 3 months. Most studies found better outcomes on the Modified Rankin Scale (mRS) or Glasgow Outcome Score (GOS) with lobar compared to deep ICHs. While most aggregated deep structures for analysis, some studies found poorer outcomes for thalamic ICH in particular. Over half of the studies did not have specific methodological considerations for location designations, including blinding or validation. CONCLUSIONS: Multiple studies have examined motor-centric outcomes, with few studies examining quality of life (QoL) or cognition. Better functional outcomes have been suggested for lobar versus non-lobar ICH; few studies attempted finer topographic comparisons. This study highlights the need for improved reporting in ICH outcomes research, including a detailed description of hemorrhage location, reporting of the full range of functional outcome scales, and inclusion of cognitive and QoL outcomes.

TURN Score Predicts 24-Hour Cerebral Edema After IV Thrombolysis.

BACKGROUND AND PURPOSE: Cerebral edema is associated with poor outcome after IV thrombolysis. We recently described the TURN score (Thrombolysis risk Using mRS and NIHSS), a predictor of severe outcome after IV thrombolysis. Our purpose was to evaluate its ability to predict 24-h cerebral edema. METHODS: We retrospectively analyzed data from 303 patients who received IV rt-PA during the NINDS rt-PA trial. Measures of brain swelling included edema, mass effect and midline shift assessed at baseline, at 24 h and new onset at 24 h. Outcome was assessed using intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH), 90-day severe outcome, and 90-day mortality. Statistical associations were assessed by logistic regression reporting odds ratios (OR) and by areas under the receiver operating characteristic curves (AUROC). RESULTS: Baseline brain swelling did not predict poor outcome; however, 24-h brain swelling predicted ICH (OR 5.69, P < 0.001), sICH (OR 9.50, P = 0.01), 90-day severe outcome (OR 7.10, P < 0.001), and 90-day mortality (OR 5.65, P = 0.01). Similar results were seen for new brain swelling at 24 h. TURN predicted 24-hour brain swelling (OR 2.5, P < 0.001; AUROC 0.69, 95 % CI 0.63-0.75) and new brain swelling at 24 h (OR 2.1, P < 0.001; AUROC 0.67, 95 % CI 0.61-0.73). CONCLUSIONS: Cerebral edema at 24 h is associated with poor outcome and 90-day mortality. TURN predicts ischemic stroke patients who will develop 24-h cerebral edema after IV thrombolysis.

Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system.

Many neuropeptides are members of peptide families, with multiple structurally similar isoforms frequently found even within a single species. This raises the question of whether the individual peptides serve common or distinct functions. In the accompanying paper, we found high isoform specificity in the responses of the lobster (Homarus americanus) cardiac neuromuscular system to members of the pyrokinin peptide family: only one of five crustacean isoforms showed any bioactivity in the cardiac system. Because previous studies in other species had found little isoform specificity in pyrokinin actions, we examined the effects of the same five crustacean pyrokinins on the lobster stomatogastric nervous system (STNS). In contrast to our findings in the cardiac system, the effects of the five pyrokinin isoforms on the STNS were indistinguishable: they all activated or enhanced the gastric mill motor pattern, but did not alter the pyloric pattern. These results, in combination with those from the cardiac ganglion, suggest that members of a peptide family in the same species can be both isoform specific and highly promiscuous in their modulatory capacity. The mechanisms that underlie these differences in specificity have not yet been elucidated; one possible explanation, which has yet to be tested, is the presence and differential distribution of multiple receptors for members of this peptide family.