Imaging Biomarkers and Prevalence of Complex Aortic Plaque in Cryptogenic Stroke: A Systematic Review

Atherosclerosis; Imaging; StrokeAterosclerosis; Imágenes; IctusAterosclerosi; Imatges; IctusBackground Complex aortic plaque (CAP) is a potential embolic source in patients with cryptogenic stroke (CS). We review CAP imaging criteria for transesophageal echocardiogram (TEE), computed tomography angiography (CTA), and magnetic resonance imaging and calculate CAP prevalence in patients with acute CS. Methods and Results PubMed and EMBASE databases were searched up to December 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guideline. Two independent reviewers extracted data on study design, imaging techniques, CAP criteria, and prevalence. The Cochrane Collaboration tool and Guideline for Reporting Reliability and Agreement Studies were used to assess risk of bias and reporting completeness, respectively. From 2293 studies, 45 were reviewed for CAP imaging biomarker criteria in patients with acute CS (N=37 TEE; N=9 CTA; N=6 magnetic resonance imaging). Most studies (74%) used ≥4 mm plaque thickness as the imaging criterion for CAP although ≥1 mm (N=1, CTA), ≥5 mm (N=5, TEE), and ≥6 mm (N=2, CTA) were also reported. Additional features included mobility, ulceration, thrombus, protrusions, and assessment of plaque composition. From 23 prospective studies, CAP was detected in 960 of 2778 patients with CS (0.32 [95% CI, 0.24–0.41], I2=94%). By modality, prevalence estimates were 0.29 (95% CI, 0.20–0.40; I2=95%) for TEE; 0.23 (95% CI, 0.15–0.34; I2=87%) for CTA and 0.22 (95% CI, 0.06–0.54; I2=92%) for magnetic resonance imaging. Conclusions TEE was commonly used to assess CAP in patients with CS. The most common CAP imaging biomarker was ≥4 mm plaque thickness. CAP was observed in one‐third of patients with acute CS. However, high study heterogeneity suggests a need for reproducible imaging methods.The work is supported by the National Heart, Lung, and Blood Institute (R01 HL147355, Z.F.), American Heart Association Career Development Awards (938082 to J.W.S.; 23CDA1053561 to J.W.), Vice Provost for University Research Foundation (J.W.S.), and Institute of Translational Medicine and Therapeutics (J.W.S.)

EARLYDRAIN- outcome after early lumbar CSF-drainage in aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Aneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.</p> <p>In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage has not been evaluated prospectively in a randomized controlled trial yet.</p> <p>Methods/Design</p> <p>This is a protocol for a 2-arm randomized controlled trial to compare an intervention group receiving early continuous lumbar CSF-drainage and standard neurointensive care to a control group receiving standard neurointensive care only. Adults suffering from a first aneurysmal subarachnoid hemorrhage whose aneurysm has been secured by means of coiling or clipping are eligible for trial participation. The effect of early CSF drainage (starting < 72 h after securing the aneurysm) will be measured in the following ways: the primary endpoint will be disability after 6 months, assessed by a blinded investigator during a personal visit or standardized telephone interview using the modified Rankin Scale. Secondary endpoints include mortality after 6 months, angiographic vasospasm, transcranial Doppler sonography (TCD) mean flow velocity in both middle cerebral arteries and rate of shunt insertion at 6 months after hospital discharge.</p> <p>Discussion</p> <p>Here, we present the study design of a multicenter prospective randomized controlled trial to investigate whether early application of a lumbar drainage improves clinical outcome after aneurysmal subarachnoid hemorrhage.</p> <p>Trial registration</p> <p>www.clinicaltrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01258257">NCT01258257</a></p

New therapeutic targets for hemorrhagic stroke

Patienten mit hämorrhagischem Schlaganfall erwartet ein hohes Maß an Morbidität und Mortalität. Die vorliegende Arbeit hatte zum Ziel, zum Verständnis von Zusammenhängen zwischen klinischen Variablen und Langzeit-Ergebnis beizutragen. In den vorgestellten Arbeiten wurden Schwerpunkte auf Identifikation, Charakterisierung bzw. Therapie solcher Variablen gelegt. In den Studien zur spontanen intrazerebralen Blutung (ICB) (Originalarbeiten 1 und 2) wurden die intraventrikuläre Blutungskomponente (IVB) und das perihämorrhagische Ödem (PHE) untersucht. Für beide wurde gezeigt, dass ihr Vorhandensein bzw. ihre Ausdehnung zeitabhängig sind, und das Blutungsstadium widerspiegeln. Für die IVB wurde gezeigt, dass sie ein Indikator für eine fortgeschrittene und schwere ICB darstellt und dass der verspätete Ventrikeleinbruch, vormals als häufiges Phänomen postuliert, selten ist. Für das PHE wurde konklusiv gezeigt, dass Statine als Hausmedikation keinen Einfluss auf seine Größe im Aufnahme-CT haben. Periodische EEG-Entladungen (PDs) nach spontaner Subarachnoidalblutung (SAB) gehen, abhängig von der Entladungs-Frequenz, mit Veränderungen von Sauerstoffpartialdruck und regionalem Blutfluß des Hirngewebes einher (Originalarbeit 3). Oberhalb einer PD-Frequenz von 2 Hertz stellt sich Hypoxie ein und die Veränderungen gleichen dann solchen, wie sie vormals während elektrographischer Anfälle nachgewiesen wurden. Die Studienergebnisse suggerieren, dass die antikonvulsive Behandlung hoch-frequenter PDs prospektiv untersucht werden sollte. Originalarbeit 4 beschreibt erstmals ein multimodales Prädiktions-Modell für Patienten mit SAB, welches in einer externen Patientenkohorte validiert wurde. Mit dem Modell können Behinderung, Kognition und Lebensqualität nach SAB prognostiziert werden. Die epidemiologische Originalarbeit 5 zeigt hohe Inzidenzen von Vorhofflimmern/-flattern bei Patienten nach Hospitalisierung im Rahmen eines hämorrhagischen Schlaganfalls, nahezu vergleichbar mit den Inzidenzen in den Kontrollgruppen (Patienten mit ischämischem Schlaganfall bzw. Hospitalisierte ohne Schlaganfall). Es besteht Bedarf, die Bedeutung intermittierenden VHF genauer zu charakterisieren, um Antikoagulations-Bedarf bei Patienten nach hämorrhagischem Schlaganfall zu definieren. Die vorgestellten Arbeiten charakterisieren Prädiktoren und Verschlechterungs-Mechanismen nach intrakraniellen Blutungen während der Hospitalisierungs- und Langzeit Follow-up Phase. Sie definieren somit Studien-Subpopulationen und neue Therapieziele, die nun prospektiv untersucht werden können

Neutrophil extracellular traps and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage

IMPORTANCE: Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage (aSAH) is unknown. OBJECTIVES: To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI). DESIGN, SETTING, AND PARTICIPANTS: Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU. MAIN OUTCOMES AND MEASURES: We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures. RESULTS: Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range [IQR], 18–43 ng/mL) at admission, and 22 ng/mL (IQR, 11–31 ng/mL) on day 4 (unpaired test; p = 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test; p = 0.036) but not in those without DCI (p = 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p = 0.006) but not in those without clinical vasospasm (p = 0.47). CONCLUSIONS AND RELEVANCE: This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further

Association Between Soluble Intercellular Adhesion Molecule-1 and Intracerebral Hemorrhage Outcomes in the FAST Trial

BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4-6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15-2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06-1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11-1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes

Always Look on the Bright Side: Associations of Optimism With Functional Outcomes After Stroke

Background Psychological health is as an important contributor to recovery after cardiovascular disease, but the roles of both optimism and depression in stroke recovery are not well characterized. Methods and Results A total of 879 participants in the SRUP (Stroke Recovery in Underserved Populations) 2005 to 2006 Study, aged ≥50 years, with incident stroke admitted to a rehabilitation facility were included. Optimism was assessed by the question: “Are you optimistic about the future?” Depression was defined by Center for Epidemiologic Studies Depression scale score >16. Participants were categorized into 4 groups: optimistic/without depression (n=581), optimistic/with depression (n=197), nonoptimistic/without depression (n=36), and nonoptimistic/with depression (n=65). Functional Independence Measure scores were used to assess stroke outcomes at discharge, 3 months after discharge, and 1 year after discharge with adjusted linear mixed models to estimate score trajectories. Participants were a mean age of 68 years (SD, 13 years), 52% were women, and 74% were White race. The optimistic/without depression group experienced the most recovery of total Functional Independence Measure scores in the first 3 months, 24.0 (95% CI, 22.5–25.4), followed by no change in the following 9 months, −0.3 (95% CI, −2.3 to 1.7), similar to the optimistic/with depression group with rapid recovery in 0 to 3 months, 21.1 (95% CI, 18.6–23.6) followed by minimal change in 3 to 12 months, 0.7 (95% CI, −2.8 to 4.1). The nonoptimistic groups demonstrated slow but continued recovery throughout the 12‐month period, with overall change, 25.4 (95% CI, 17.6–33.2) in the nonoptimistic/without depression group and 17.6 (95% CI, 12.0–23.1) in the nonoptimistic/with depression group. There was robust effect modification between optimism and depression (Pinteraction<0.001). Conclusions In this longitudinal cohort, optimism and depression are synergistically associated with functional recovery after stroke. Measuring optimism status may help identify individuals at risk for worse poststroke recovery

Association between Intraventricular Alteplase Use and Parenchymal Hematoma Volume in Patients with Spontaneous Intracerebral Hemorrhage and Intraventricular Hemorrhage

Importance: Intraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists. Objective: To evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes.Design, Setting, and Participants: This cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021. Exposure: Randomization to receive intraventricular alteplase.Main Outcomes and Measures: The primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location.Results: A total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P Conclusions and Relevance: This study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.</p

Early Deterioration, Hematoma Expansion, and Outcomes in Deep versus Lobar Intracerebral Hemorrhage: The FAST Trial

BACKGROUND: In patients with intracerebral hemorrhage (ICH), it is unclear whether early neurological deterioration, hematoma expansion (HE), and outcome vary by supratentorial ICH location (deep versus lobar). Herein, we assessed these relationships in a clinical trial cohort that underwent brain imaging early after symptom onset. We hypothesized that HE would occur more frequently, and outcome would be worse in patients with deep ICH. METHODS: We performed a post hoc analysis of the FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial including all patients with supratentorial hemorrhage. Enrolled patients underwent brain imaging within 3 hours of symptom onset and 24 hours after randomization. Multivariable regression was used to test the association between ICH location and 3 outcomes: HE (increase of ≥33% or 6mL), early neurological deterioration (decrease in Glasgow Coma Scale score ≥2 points or increase in National Institutes of Health Stroke Scale ≥4 points within 24 hours of admission), and 90-day outcome (modified Rankin Scale). RESULTS: Of 841 FAST trial patients, we included 728 (mean age 64 years, 38% women) with supratentorial hemorrhages (deep n=623, lobar n=105). HE (44 versus 27%, =0.001) and early neurological deterioration (31 versus 17%, =0.001) were more common in lobar hemorrhages. Deep hemorrhages were smaller than lobar hemorrhages at baseline (12 versus 35mL, \u3c0.001) and 24 hours (14 versus 38mL, \u3c0.001). Unadjusted 90-day outcome was worse in lobar compared with deep ICH (median modified Rankin Scale score 5 versus 4, =0.03). However, when adjusting for variables included in the ICH score including ICH volume, deep location was associated with worse and lobar location with better outcome (odds ratio lobar location, 0.58 [95% CI, 0.38-0.89]; =0.01). CONCLUSIONS: In this secondary analysis of randomized trial patients, lobar ICH location was associated with larger ICH volume, more HE and early neurological deterioration, and worse outcome than deep ICH. After adjustment for prognostic variables, however, deep ICH was associated with worse outcome, likely due to their proximity to eloquent brain structures

Medical Treatment Failure for Symptomatic Vasospasm After Subarachnoid Hemorrhage Threatens Long-Term Outcome

Background and Purpose- Symptomatic vasospasm is a common cause of morbidity and mortality after subarachnoid hemorrhage. We sought to identify predictors and the long-term impact of treatment failure with hypertensive therapy for symptomatic vasospasm. Methods- We performed a retrospective analysis of 1520 subarachnoid hemorrhage patients prospectively enrolled in the Columbia University SAH Outcomes Project between August 1996 and August 2012. One hundred ninety-eight symptomatic vasospasm patients were treated with vasopressors to raise arterial blood pressure, with and without volume expansion. Treatment response, defined as complete or near-complete resolution of the initial neurological deficit, was adjudicated in weekly meetings of the study team based on serial clinical examination after hypertensive treatment. Outcome was evaluated at 1 year with the modified Rankin Scale. Results- Twenty-one percent of the 198 patients who received hypertensive therapy did not respond to treatment. Treatment failure was associated with an increased risk of death or severe disability at 1 year (modified Rankin Scale score of 4-6; 62% versus 25%; P0.3 μg/L (64% versus 28%; P=0.001), aneurysm coiling (43% versus 20%; P=0.004), and involvement of \u3e1 symptomatic vascular territory at onset (39% versus 22%; P=0.02). In multivariable analysis, treatment failure was independently associated only with troponin I elevation (adjusted odds ratio, 4.30; 95% CI, 1.69-11.09; P=0.002). Conclusions- Failure to respond to induced hypertension for symptomatic vasospasm threatens 1-year outcome. Subarachnoid hemorrhage patients with symptomatic vasospasm who have elevated initial troponin I levels, indicative of neurogenic cardiac injury, are at twice the risk of medical treatment failure. Expedited endovascular therapy should be considered in these patients

Imaging Biomarkers and Prevalence of Complex Aortic Plaque in Cryptogenic Stroke: A Systematic Review

Background Complex aortic plaque (CAP) is a potential embolic source in patients with cryptogenic stroke (CS). We review CAP imaging criteria for transesophageal echocardiogram (TEE), computed tomography angiography (CTA), and magnetic resonance imaging and calculate CAP prevalence in patients with acute CS. Methods and Results PubMed and EMBASE databases were searched up to December 2022 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guideline. Two independent reviewers extracted data on study design, imaging techniques, CAP criteria, and prevalence. The Cochrane Collaboration tool and Guideline for Reporting Reliability and Agreement Studies were used to assess risk of bias and reporting completeness, respectively. From 2293 studies, 45 were reviewed for CAP imaging biomarker criteria in patients with acute CS (N=37 TEE; N=9 CTA; N=6 magnetic resonance imaging). Most studies (74%) used ≥4 mm plaque thickness as the imaging criterion for CAP although ≥1 mm (N=1, CTA), ≥5 mm (N=5, TEE), and ≥6 mm (N=2, CTA) were also reported. Additional features included mobility, ulceration, thrombus, protrusions, and assessment of plaque composition. From 23 prospective studies, CAP was detected in 960 of 2778 patients with CS (0.32 [95% CI, 0.24–0.41], I2=94%). By modality, prevalence estimates were 0.29 (95% CI, 0.20–0.40; I2=95%) for TEE; 0.23 (95% CI, 0.15–0.34; I2=87%) for CTA and 0.22 (95% CI, 0.06–0.54; I2=92%) for magnetic resonance imaging. Conclusions TEE was commonly used to assess CAP in patients with CS. The most common CAP imaging biomarker was ≥4 mm plaque thickness. CAP was observed in one‐third of patients with acute CS. However, high study heterogeneity suggests a need for reproducible imaging methods