Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients.

Inflammation including immunothrombosis by neutrophil extracellular traps (NETs) has important implications in acute ischemic stroke and can affect reperfusion status, susceptibility to stroke associated infections (SAI) as well as functional clinical outcome. NETs were shown to be prevalent in stroke thrombi and NET associated markers were found in stroke patients' blood. However, little is known whether blood derived NET markers reflect the amount of NETs in thrombi. Conclusions from blood derived markers to thrombus composition might open avenues for novel strategies in diagnostic and therapeutic approaches. We prospectively recruited 166 patients with acute ischemic stroke undergoing mechanical thrombectomy between March 2018 and May 2021. Available thrombi (n = 106) were stained for NET markers DNA-histone-1 complexes and myeloperoxidase (MPO). Cell free DNA (cfDNA), deoxyribonuclease (DNase) activity, MPO-histone complexes and a cytokine-panel were measured before thrombectomy and after seven days. Clinical data, including stroke etiology, reperfusion status, SAI and functional outcome after rehabilitation, were collected of all patients. NET markers were present in all thrombi. At onset the median concentration of cfDNA in blood was 0.19 µg/ml increasing to 0.30 µg/ml at 7 days. Median DNase activity at onset was 4.33 pmol/min/ml increasing to 4.96 pmol/min/ml at 7 days. Within thrombi DNA-histone-1 complexes and MPO correlated with each other (ρ = 0.792; p < 0.001). Moreover, our study provides evidence for an association between the amount of NETs and endogenous DNase activity in blood with amounts of NETs in cerebral thrombi. However, these associations need to be confirmed in larger cohorts, to investigate the potential clinical implications for individualized therapeutic and diagnostic approaches in acute ischemic stroke.

Early clinical experience with the new generation Pipeline Vantage flow diverter in the treatment of unruptured saccular aneurysms using short-term dual antiplatelet therapy.

PURPOSE: The Pipeline Vantage flow diverter with Shield technology (PV) used in this study is a 4th-generation flow diverter (FD) designed to reduce thrombogenicity, promote endothelialization of the implant and increase efficiency in achieving aneurysm closure. In this study, we report the aneurysm occlusion rate, complication rate and clinical outcome with short-term dual antiplatelet therapy (DAPT) in the treatment of unruptured intracranial saccular aneurysms using the PV. METHODS: We retrospectively identified patients treated between September 2021 and January 2023 with the PV and subsequently underwent short-term DAPT for 3 months. Patient and aneurysm characteristics, peri- and post-procedural complications, clinical outcomes and the grade of aneurysm occlusion were documented. RESULTS: Thirty patients with 32 aneurysms were treated. Successful FD implantation was achieved in all cases (100%). No periprocedural complications were documented. The overall symptomatic complication rate was 10% and the neurologic, treatment-related symptomatic complication rate was 6.6%. Only one symptomatic complication (3.3%) was device-related. Permanent clinical deterioration occurred in 2/30 patients (6.6%), leading to deterioration of the mRS within the first 3 months after treatment. No mortality was documented. The rate of complete aneurysm occlusion after 3 months and after a mean imaging follow-up of 9.9 months was 65.6% and 75%, respectively. CONCLUSION: Implantation of the PV for the treatment of saccular intracranial aneurysms achieves a good aneurysm occlusion rate with a low rate of complications. In addition, the use of short-term DAPT after PV implantation appears to be safe.

Feasibility and safety of ADAPT in acute distal posterior cerebral artery occlusions.

PURPOSE: The direct aspiration first pass technique (ADAPT) is an effective and safe endovascular treatment for distal medium vessel occlusions (DMVO) of the anterior circulation. Clinical experience with ADAPT in the distal posterior circulation, however, is still limited and published data is scarce. In this original work, feasibility, safety and efficacy of ADAPT with distal access catheters (DAC) for treatment of acute distal posterior cerebral artery occlusions (DPCAOs) is evaluated. METHOD: All acute ischemic stroke patients between 2017 and 2022 with primary or secondary DPCAOs in the P2 or P3 segment, that underwent thrombectomy of the DPACO using ADAPT with DACs as frontline therapy, were identified. Demographic data, recanalization rates, procedural safety, and clinical outcome were assessed. RESULTS: Twenty-four patients with primary (n = 6) or secondary (n = 18) DPCAOs (P2: 21/24; P3: 3/24) were included. Median NIHSS score at admission was 14.5 (IQR 9.5). In all cases, the DPCAO could be reached with the DAC. Successful revascularization (DMVO-p-TICI ≥ 2b) with ADAPT was achieved in 79.2% (19/24), including a first pass effect of 62.5% (15/24), leading to complete recanalization (DMVO-p-TICI 3). Median number of passes was 1 (range 1-2). No complications related to distal PCA aspiration thrombectomy occurred. Median NIHSS and mRS scores at discharge were 4 (IQR 8) and 3 (IQR 2), respectively. CONCLUSIONS: ADAPT appears to be feasible, safe and effective for the treatment of acute DPCAOs in the setting of different occlusion patterns. High revascularization rates without procedural complications can be achieved. Further studies are needed to consolidate these results.

Endovascular treatment of distal medium vessel occlusions using microcatheter aspiration thrombectomy.

BACKGROUND AND PURPOSE: Recent studies suggest that endovascular treatment (EVT) in distal medium vessel occlusion (DMVO) stroke is beneficial even beyond middle cerebral artery (MCA) - M2 segment. However, data about aspiration thrombectomy of DMVOs is scarce since common state-of-the-art aspiration catheters are usually too large for small distal intracranial arteries. We report our initial experiences using the microcatheter aspiration thrombectomy (MAT) technique as frontline therapy for acute DMVOs in the MCA territory. METHODS: We retrospectively analyzed all acute ischemic stroke (AIS) patients that underwent MAT of a primary or secondary DMVO in the M3 or M4 segment between January 2019 and October 2021. Recanalization rates, procedural safety and outcome data were recorded. RESULTS: MAT of acute M3 and M4 occlusions was performed in 19 patients with AIS. Six had isolated DMVO strokes, 13 had secondary DMVOs during EVT of a proximal large vessel occlusion. Successful revascularization to DMVO TICI ≥ 2b was achieved in 58% (11/19) with a single pass in all of them. The median National Institutes of Health Strokes Scale (NIHSS) score at admission and discharge was 12 and 3, respectively. 68% (13/19) of the patients had a good clinical outcome at discharge (modified Rankin Scale 0-2). No symptomatic complications related to MAT occurred. CONCLUSIONS: MAT of DMVOs in the MCA territory is technically feasible and effective. Compared to stent retriever-based thrombectomy in DMVOs the hemorrhagic complication rate appears notably lower. Further studies are needed to validate the benefit of mechanical thrombectomy in the distal intracranial vasculature.

Advancement of door-to-needle times in acute stroke treatment after repetitive process analysis: never give up!

Background: In acute ischemic stroke, timely treatment is of utmost relevance. Identification of delaying factors and knowledge about challenges concerning hospital structures are crucial for continuous improvement of process times in stroke care. Objective: In this study, we report on our experience in optimizing the door-to-needle time (DNT) at our tertiary care center by continuous quality improvement. Methods: Five hundred forty patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) at Hannover Medical School were consecutively analyzed in two phases. In study phase I, including 292 patients, process times and delaying factors were collected prospectively from May 2015 until September 2017. In study phase II, process times of 248 patients were obtained from January 2019 until February 2021. In each study phase, a new clinical standard operation procedure (SOP) was implemented, considering previously identified delaying factors. Pre- and post-SOP treatment times and delaying factors were analyzed to evaluate the new protocols. Results: In study phase I, SOP I reduced the median DNT by 15 min. The probability to receive treatment within 30 min after admission increased by factor 5.35 [95% confidence interval (CI): 2.46-11.66]. Further development of the SOP with implementation of a mobile thrombolysis kit led to a further decrease of DNT by 5 min in median in study phase II. The median DNT was 29 (25th-75th percentiles: 18-44) min, and the probability to undergo IVT within 15 min after admission increased by factor 4.2 (95% CI: 1.63-10.83) compared with study phase I. Conclusion: Continuous process analysis and subsequent development of targeted workflow adjustments led to a substantial improvement of DNT. These results illustrate that with appropriate vigilance, there is constantly an opportunity for improvement in stroke care.

Endogenous Deoxyribonuclease Activity and Cell-Free Deoxyribonucleic Acid in Acute Ischemic Stroke: A Cohort Study.

BACKGROUND: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. METHODS: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. RESULTS: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001-12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006-45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237-0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. CONCLUSIONS: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.

Circulating Cytokines and Growth Factors in Acute Cerebral Large Vessel Occlusion-Association with Success of Endovascular Treatment.

Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199-0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke.

Endovascular Treatment of Acute Ischemic Stroke in Clinical Practice: Analysis of Workflow and Outcome in a Tertiary Care Center.

Background and Purpose: Pre- and intra-hospital workflow in mechanical recanalization of large cervicocephalic arteries in patients with acute ischemic stroke still needs optimization. In this study, we analyze workflow and outcome in our routine care of stroke patients undergoing mechanical thrombectomy as a precondition for such optimization. Methods: Processes of pre- and intra-hospital management, causes of treatment delay, imaging results (Alberta Stroke Program Early Computed Tomography Score, localization of vessel occlusion), recanalization (modified thrombolysis in cerebral infarction score), and patient outcome (modified Rankin scale at discharge and at the end of inpatient rehabilitation) were analyzed for all patients who underwent mechanical thrombectomy between April 1, 2016, and September 30, 2018, at our site. Results: Finally, data of 282 patients were considered, of whom 150 (53%) had been referred from external hospitals. Recanalization success and patient outcome were similar to randomized controlled thrombectomy studies and registries. Delay in treatment occurred when medical treatment of a hypertensive crisis, epileptic fits, vomiting, or agitation was mandatory but also due to missing prenotification of the hospital emergency staff by the rescue service, multiple mode or repeated brain imaging, and transfer from another hospital. Even transfer from external hospitals located within a 10-km radius of our endovascular treatment center led to a median increase of the onset-to-groin time of ~60 min. Conclusion: The analysis revealed several starting points for an improvement in the workflow of thrombectomy in our center. Analyses of workflow and treatment results should be carried out regularly to identify the potential for optimization of operational procedures and selection criteria for patients who could benefit from endovascular treatment.

Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients.

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.