Periodontitis in ischemic stroke: impact of Porphyromonas gingivalis on thrombus composition and ischemic stroke outcomes.

Background: Periodontitis is associated with an increased risk of ischemic stroke, but the mechanisms underlying this association remain unclear. Objectives: Our objective was to determine whether Porphyromonas gingivalis (Pg), a periodontal bacterium, could be detected within thrombus aspirates, modify thrombus composition, and endovascular therapy responses. Methods: The presence of Pg gingipain in 175 consecutive thrombi from patients with large vessel occlusion stroke enrolled in the multicenter research cohort compoCLOT was investigated by immunostaining. Thrombus blood cell composition according to gingipain status was analyzed in a subset of 63 patients. Results: Pg gingipain immunostaining was positive in 33.7% of thrombi (95% CI, 26.7%-40.8%). The percentage of near to complete reperfusion (modified Thrombolysis in Cerebral Infarction Score 2c/3) at the end of the procedure was lower in the Pgpos group than the Pgneg group (39.0% vs 57.8% respectively; adjusted odds ratio, 0.38; 95% CI, 0.19-0.77). At 3 months, 35.7% of patients in the Pgpos group had a favorable neurological outcome vs 49.5% in the Pgneg group (odds ratio, 0.65; 95% CI, 0.30-1.40). Quantitative analysis of a subset of 63 thrombi showed that neutrophil elastase content was significantly (P < .05) higher in Pgpos thrombi than in Pgneg thrombi. Conclusion: Our results indicate that intrathrombus Pg gingipain is associated with increased neutrophil content and resistance to endovascular therapy.

Neutrophil activation in patients treated with endovascular therapy is associated with unfavorable outcomes and mitigated by intravenous thrombolysis.

BACKGROUND: Accumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT. METHODS: A single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3-6 at 3 months. RESULTS: Between 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR -2.1-150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline -0.8 ng/mL (IQR -7.6-6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes. CONCLUSIONS: A peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.

High thrombus platelet content is associated with a lower rate of first pass effect in stroke treated by endovascular therapy.

Background and purpose: First pass effect (FPE), the occurrence of complete reperfusion after one pass with no rescue attempt during endovascular therapy (EVT), is associated with the best clinical outcome after an acute ischemic stroke (AIS). Previous studies evaluating FPE occurrence according to EVT technical strategies, occlusion locations, or thrombus composition have provided controversial results. Here, we performed a correlation analysis between FPE occurrence and AIS thrombus cellular composition, as assessed using quantitative biochemical assays. Patients and methods: Homogenates of AIS thrombi from 250 patients were prepared by mechanical grinding. Platelet, red blood cell (RBC), and leukocyte contents of AIS thrombi were respectively estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. FPE was defined as a modified Thrombolysis in Cerebral Infraction (mTICI) score of 2C or 3 after a single EVT device pass. Results: AIS thrombi successfully removed after a single pass were poorer in GPVI (0.098 ± 0.023 vs 0.111 ± 0.024 ng/mg, p < 0.001) compared to those whose removal had required several passes. GPVI content was also significantly associated with a higher number of device passes and a longer procedure time. No such significant correlation was found with DNA and heme content. Discussion and conclusion: Thrombus platelet content may hamper thrombus removal by EVT. This result suggests that adjunctive therapies or functionalization of retrieval devices targeting platelets may improve EVT efficacy.

Impact of COVID-19 on thrombus composition and response to thrombolysis: Insights from a monocentric cohort population of COVID-19 patients with acute ischemic stroke.

BACKGROUND: Resistance to fibrinolysis, levels of procoagulant/antifibrinolytic neutrophil extracellular traps (NETs), and the severity of acute ischemic stroke (AIS) are increased by COVID-19. Whether NETs are components of AIS thrombi from COVID-19 patients and whether COVID-19 impacts the susceptibility of these thrombi to thrombolytic treatments remain unknown, however. OBJECTIVES: We aimed to characterize AIS thrombi from COVID-19 patients by immunohistology and to compare their response to thrombolysis to that of AIS thrombi from non-COVID-19 patients. PATIENTS/METHODS: For this monocentric cohort study, 14 thrombi from COVID-19 AIS patients and 16 thrombi from non-COVID-19 patients, all recovered by endovascular therapy, were analyzed by immunohistology or subjected to ex vivo thrombolysis by tissue-type plasminogen (tPA)/plasminogen. RESULTS: COVID-19 AIS thrombi were rich in neutrophils and contained NETs, but not spike protein. Thrombolysis assays revealed a mean resistance profile to tPA/plasminogen of COVID-19 AIS thrombi similar to that of non-COVID-19 AIS thrombi. The addition of DNase 1 successfully improved thrombolysis by potentiating fibrinolysis irrespective of COVID-19 status. Levels of neutrophil, NETs, and platelet markers in lysis supernatants were comparable between AIS thrombi from non-COVID-19 and COVID-19 patients. CONCLUSIONS: These results show that COVID-19 does not impact NETs content or worsen fibrinolysis resistance of AIS thrombi, a therapeutic hurdle that could be overcome by DNase 1 even in the context of SARS-CoV-2 infection.

Endovascular treatment as the main approach for Spetzler-Martin grade III brain arteriovenous malformations.

BACKGROUND: Because Spetzler-Martin (SM) grade III brain arteriovenous malformations (bAVMs) constitute a heterogeneous group of lesions with various combination of sizes, eloquence, and venous drainage patterns, their management is usually challenging. The aim of this study is to evaluate the clinical/imaging outcomes and the procedural safety of endovascular approach as the main treatment for the cure of SM grade III bAVMs. METHODS: In this retrospective study, prospectively collected data of SM grade III bAVMs treated by endovascular techniques between 2010 and 2018 at our hospital were reviewed. Patients older than 16 years with angiographic follow-up of at least 6 months after endovascular treatment were entered in the study. The patients had a mean follow-up of 12 months. The data were assessed for clinical outcome (modified Rankin Scale), permanent neurological deficit, post-operative complications, and optimal imaging outcome, defined by complete exclusion of AVM. The independent predictive variables of poor outcome or hemorrhagic complication were assessed using binary logistic regression. RESULTS: Sixty-five patients with 65 AVMs were included in the study. Mean age of the patients was 40.0±14.4. Most common presentation was hemorrhage (61.5%). The patients underwent one to eight endovascular procedures (median=2). Mean nidus diameter was 30.2±13.0. A complete obliteration of AVM was achieved in 57 patients (87.7%). Post-procedure significant hemorrhagic and ischemic complications were seen in 13 (20%) and five (7.7%) patients respectively, leading to five (7.7%) transient and four (6.2%) permanent neurological deficits. Eight patients (12.3%) experienced worsening of mRS after embolization. Ten patients (15.4%) had poor outcome (mRS 3-5) at follow-up and two (3%) died. CONCLUSIONS: Endovascular treatment can achieve a high rate of complete exclusion of grade III AVM but may be associated (as in other treatment modalities) with significant important complications. CLINICAL TRIAL REGISTRATION NUMBER: NCT02879071.

Visual assessment of diffusion weighted imaging infarct volume lacks accuracy and reliability.

PURPOSE: The DAWN trial (Diffusion weighted imaging or CT perfusion Assessment with clinical mismatch in the triage of Wake-up and late presenting strokes undergoing Neurointervention with Trevo) has demonstrated the benefits of thrombectomy in patients with unknown or late onset strokes, using automated software (RAPID) for measurement of infarct volume. Because RAPID is not available in all centers, we aimed to assess the accuracy and repeatability of visual infarct volume estimation by clinicians and the consequences for thrombectomy decisions based on the DAWN criteria. MATERIALS AND METHODS: 18 physicians, who routinely depend on MRI for acute stroke imaging, assessed 32 MR scans selected from a prospective databaseover two independent sessions. Raters were asked to visually estimate the diffusion weighted imaging (DWI) infarct volume for each case. Sensitivity, specificity, and accuracy of the estimated volumes were compared with the available RAPID measurements for various volume cut-off points. Thrombectomy decisions based on DAWN criteria with RAPID measurements and raters' visual estimates were compared. Inter-rater and intra-rater agreement was measured using kappa statistics. RESULTS: The mean accuracy of raters was <90% for all volume cut-points. Inter-rater agreement was below substantial for each DWI infarct volume cut-off points. Intra-rater agreement was substantial for 55-83% of raters, depending on the selected cut-off points. Applying DAWN criteria with visual estimates instead of RAPID measurements led to 19% erroneous thrombectomy decisions, and showed a lack of reproducibility. CONCLUSION: The visual assessment of DWI infarct volume lacks accuracy and repeatability, and could lead to a significant number of erroneous decisions when applying the DAWN criteria.

Prognostic Significance of Pulse Pressure Variability During Mechanical Thrombectomy in Acute Ischemic Stroke Patients.

Background Studies on the role of blood pressure ( BP ) variability specifically during mechanical thrombectomy ( MT ) are sparse and limited. Moreover, pulse pressure ( PP ) has not been considered as a potent hemodynamic parameter to describe BP variability during MT . We assessed the impact of PP variability on functional outcome in acute ischemic stroke patients with large vessel occlusion during MT . Methods and Results Acute ischemic stroke patients presenting with large vessel occlusion from January 2012 to June 2016 were included. BP data during MT were prospectively collected in the ETIS (Endovascular Treatment in Ischemic Stroke) registry. Logistic regression models were used to assess the association between PP coefficients of variation and functional outcome at 3 months (modified Rankin Scale). Among the 343 included patients, PP variability was significantly associated with worse 3-month modified Rankin Scale in univariable (odds ratio [OR] =1.56, 95% confidence interval [CI]: 1.24-1.96 per 1-unit increase, P=0.0002) and multivariable ordinal logistic regression (adjusted OR =1.40, 95% CI : 1.09-1.79, P=0.008). PP variability was also associated with unfavorable outcome (modified Rankin Scale 3-6) in univariable ( OR =1.53, 95% CI : 1.17-2.01, P=0.002) and multivariable analysis (adjusted OR =1.42, 95% CI : 1.02-1.98, P=0.04). There was an association between PP variability and 3-month all-cause mortality in univariable analysis ( OR = 1.37, 95% CI : 1.01-1.85 per 1-unit increase of the coefficient of variation of the PP , P=0.04), which did not remain significant after adjustment for potential confounders. Conclusions PP variability during MT is an independent predictor of worse clinical outcome in acute ischemic stroke patients. These findings support the need for a close monitoring of BP variability during MT . Whether pharmacological interventions aiming at reducing BP variability during MT could impact functional outcome needs to be determined.

Gadolinium-Enhanced Extracranial MRA Prior to Mechanical Thrombectomy Is Not Associated With an Improved Procedure Speed.

Objectives: To assess whether performing a pre-intervention gadolinium-enhanced extracranial magnetic resonance angiogram (MRA) in addition to intracranial vascular imaging is associated with improved thrombectomy time metrics. Methods: Consecutive patients treated by MT at a large comprehensive stroke center between January 2012 and December 2017 who were screened using pre-intervention MRI were included. Patients characteristics and procedural data were collected. Univariate and multivariate analysis were performed to compare MT speed, efficacy, complications, and clinical outcomes between patients with and without pre-intervention gadolinium-enhanced extracranial MRA. Results: A total of 912 patients were treated within the study period, including 288 (31.6%) patients with and 624 (68.4%) patients without extracranial MRA. Multivariate analysis showed no significant difference between groups in groin puncture to clot contact time (RR = 0.93 [0.85-1.02], p = 0.14) or to recanalization time (RR = 0.92 [0.83-1.03], p = 0.15), rates of successful recanalization (defined as a mTICI 2b or 3, RR = 0.93 [0.62-1.42], p = 0.74), procedural complications (RR = 0.81 [0.51-1.27], p = 0.36), and good clinical outcome (defined by a mRS ≤ 2 at 3 months follow-up, RR = 1.05 [0.73-1.52], p = 0.79). Conclusion: Performing a pre-intervention gadolinium-enhanced extracranial MRA in addition to non-contrast intracranial MRA at stroke onset does not seem to be associated with a delay or shortening of procedure times.