The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is ...emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglected and standards are missing. This review provides an overview of the current knowledge and expanding research relating to thrombus composition analysis in large vessel occlusions. We first discuss the heterogeneity of thrombogenic factors that underlie the thrombotic formation in stroke and its implications to identify stroke etiology and thrombus age. Further, we show that understanding structural characteristics of thrombus is pivotal for the development of new-targeted lytic therapies as well as to improve, through thrombus modeling, the development of thrombectomy devices. Finally, we discuss the on-going attempts to identify a signature of thrombus composition indirectly through imaging and peripheral blood biomarkers, which might in future assist treatment decision-making as well as secondary prevention. Thrombus analysis might contribute to the advancement and optimization of personalized stroke treatments.
Objective
Impact of different MR perfusion software on selection and outcome of patients with acute ischemic stroke (AIS) and large vessel occlusion (LVO) treated by endovascular thrombectomy (EVT) ...is unclear. We aimed at comparing two commercial MRI software, semi-automated with unadjusted (method A) and adjusted mask (method B), and fully automated (method C) in this setting.
Methods
MRI from 144 consecutive AIS patients with anterior circulation LVO was retrospectively analysed. All diffusion- and perfusion-weighted images (DWI-PWI) were post-processed with the three methods using standard thresholds. Concordance for core and hypoperfusion volumes was assessed with Lin’s test. Clinical outcome was compared between groups in patients who underwent successful EVT in the early and late time window.
Results
Mean core volume was higher and mean hypoperfusion volume was lower in method C than in methods A and B. In the early time window, methods A and B found fewer patients with a mismatch ratio ≤ 1.2 than method C (1/67 1.5% vs. 12/67 17.9%,
p
= 0.0013). In the late time window, methods A and B found fewer patients with a mismatch ratio < 1.8 than method C (3/46 6.5% and 2/46 4.3% vs. 18/46 39.1%,
p
≤ 0.0002). More patients with functional independence at 3 months would not have been treated using method C versus methods A and B in the early (
p
= 0.0063) and late (
p
≤ 0.011) time window.
Conclusions
MRI software for DWI-PWI analysis may influence patients’ selection before EVT and clinical outcome.
Key Points
•
Method C detects fewer patients with favourable mismatch profile.
•
Method C might underselect more patients with functional independence at 3 months.
•
Software used before thrombectomy may influence patients’ outcome.
Background We aimed to assess the prevalence and degree of overlap of potential embolic sources (PES) in patients with embolic stroke of undetermined source (ESUS). Methods and Results In a pooled ...data set derived from 3 prospective stroke registries, patients were categorized in ≥1 groups according to the PES that was/were identified. We categorized PES as follows: atrial cardiopathy, atrial fibrillation diagnosed during follow-up, arterial disease, left ventricular disease, cardiac valvular disease, patent foramen ovale, and cancer. In 800 patients with ESUS (43.1% women; median age, 67.0 years), 3 most prevalent PES were left ventricular disease, arterial disease, and atrial cardiopathy, which were present in 54.4%, 48.5%, and 45.0% of patients, respectively. Most patients (65.5%) had >1 PES, whereas only 29.7% and 4.8% of patients had a single or no PES, respectively. In 31.1% of patients, there were ≥3 PES present. On average, each patient had 2 PES (median, 2). During a median follow-up of 3.7 years, stroke recurrence occurred in 101 (12.6%) of patients (23.3 recurrences per 100 patient-years). In multivariate analysis, the risk of stroke recurrence was higher in the atrial fibrillation group compared with other PES, but not statistically different between patients with 0 to 1, 2, or ≥3 PES. Conclusions There is major overlap of PES in patients with ESUS. This may possibly explain the negative results of the recent large randomized controlled trials of secondary prevention in patients with ESUS and offer a rationale for a randomized controlled trial of combination of anticoagulation and aspirin for the prevention of stroke recurrence in patients with ESUS. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02766205.
Whether endovascular therapy (EVT) added on best medical management (BMM), as compared to BMM alone, is beneficial in acute ischemic stroke with isolated posterior cerebral artery occlusion is ...unknown.
We conducted a multicenter international observational study of consecutive stroke patients admitted within 6 hours from symptoms onset in 26 stroke centers with isolated occlusion of the first (P1) or second (P2) segment of the posterior cerebral artery and treated either with BMM+EVT or BMM alone. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month good functional outcome (modified Rankin Scale mRS score 0-2 or return to baseline modified Rankin Scale). Secondary outcomes were 3-month excellent recovery (modified Rankin Scale score 0-1), symptomatic intracranial hemorrhage, and early neurological deterioration.
Overall, 752 patients were included (167 and 585 patients in the BMM+EVT and BMM alone groups, respectively). Median age was 74 (interquartile range, 63-82) years, 329 (44%) patients were female, median National Institutes of Health Stroke Scale was 6 (interquartile range 4-10), and occlusion site was P1 in 188 (25%) and P2 in 564 (75%) patients. Baseline clinical and radiological data were similar between the 2 groups following propensity score weighting. EVT was associated with a trend towards lower odds of good functional outcome (odds ratio, 0.81 95% CI, 0.66-1.01;
=0.06) and was not associated with excellent functional outcome (odds ratio, 1.17 95% CI, 0.95-1.43;
=0.15). EVT was associated with a higher risk of symptomatic intracranial hemorrhage (odds ratio, 2.51 95% CI, 1.35-4.67;
=0.004) and early neurological deterioration (odds ratio, 2.51 95% CI, 1.64-3.84;
<0.0001).
In this observational study of patients with proximal posterior cerebral artery occlusion, EVT was not associated with good or excellent functional outcome as compared to BMM alone. However, EVT was associated with higher rates of symptomatic intracranial hemorrhage and early neurological deterioration. EVT should not be routinely recommended in this population, but randomization into a clinical trial is highly warranted.
Ischemic stroke patients show alterations in peripheral leukocyte counts that may result from the sterile inflammation response as well as the occurrence of early infections. We here aimed to ...determine whether alterations of circulating leukocytes in acute ischemic stroke are associated with long-term functional outcome and hemorrhagic complications, independently of the occurrence of infections.
Blood laboratory values of patients with acute ischemic stroke, presenting within 4.5 h from symptom onset, were collected. Leukocyte subsets were analyzed in relation to 3-month functional outcome, mortality, and parenchymal hemorrhagic transformation (PH). A multivariable logistic regression analysis, considering the occurrence of early post-stroke infections, was performed for each outcome measure.
Five-hundred-ten patients were included in the study. Independently of infections, good functional outcome was associated with a lower neutrophil to lymphocyte ratio (NL-R, OR 0.906 95% CI 0.822-0.998), a higher lymphocyte count (OR 1.547 95% CI 1.051-2.277), a higher eosinophil count (OR 1.027 95% CI 1.007-1.048), and a higher eosinophil to leukocyte ratio (EoLeu-R, OR 1.240 95% CI 1.071-1.436) at admission. Death within 3 months was associated with higher NL-R (OR 1.103 95% CI 1.032-1.179) as well as with lower eosinophil counts (OR 0.909 95% CI 0.827-0.999). Patients developing parenchymal hemorrhagic transformation had higher neutrophil counts (OR 1.420 95% CI 1.197-1.684) as well as a higher NL-R (OR 1.192 95% IC 1.088-1.305).
Leukocyte subtype profiles in the acute phase of ischemic stroke represent a predictor of outcome independently of infections. Stroke-evoked sterile inflammation is a pathophysiological relevant mechanism that deserves further investigation.
BACKGROUND AND PURPOSE—Early arterial recanalization in acute ischemic stroke is strongly associated with better outcomes. However, early worsening of arterial patency was seldom studied. We ...investigated potential predictors and long-term prognosis of worsening of arterial patency at 24 hours after stroke onset.
METHODS—Patients from the Acute Stroke Registry and Analysis of Lausanne registry including admission and 24-hour vascular imaging (computed tomography or magnetic resonance angiography) were included. Worsening of arterial patency was defined as a new occlusion and significant stenosis in any extracranial or intracranial artery, comparing 24 hours with admission imaging. Variables associated with worsening of arterial patency were assessed by stepwise multiple logistic regression. The impact of arterial worsening on 3-month outcome was investigated with an adjusted modified Rankin Scale shift analysis.
RESULTS—Among 2152 included patients, 1387 (64.5%) received intravenous thrombolysis and endovascular treatment, and 65 (3.0%) experienced 24-hour worsening of arterial patency. In multivariable analysis, history of hypertension seemed protective (adjusted odds ratio aOR, 0.45; 95% CI, 0.27–0.75) while higher admission National Institutes of Health Stroke Scale (aOR, 1.06; 95% CI, 1.02–1.10), intracranial (aOR, 4.78; 95% CI, 2.03–11.25) and extracranial stenosis (aOR, 3.67; 95% CI, 1.95–6.93), and good collaterals (aOR, 3.71; 95% CI, 1.54–8.95) were independent predictors of worsening of arterial patency. Its occurrence was associated with a major unfavorable shift in the distribution of the modified Rankin Scale at 3 months (aOR, 5.97; 95% CI, 3.64–9.79).
CONCLUSIONS—Stroke severity and admission vascular imaging findings may help to identify patients at a higher risk of developing worsening of arterial patency at 24 hours. The impact of worsening of arterial patency on long-term outcome warrants better methods to detect and prevent this early complication.
Background and purposeThe real-life application of DAWN and DEFUSE-3 trials has been poorly investigated. We aimed to identify the proportion of patients with acute ischemic stroke (AIS) eligible for ...late endovascular treatment (EVT) in our stroke center based on trial and more liberal selection criteria.MethodsAll consecutive patients in our stroke registry (2003–2017) admitted within 5–23 hours of last proof of good health were selected if they had complete clinical and radiological datasets. We calculated the proportion of patients eligible for late EVT according to trial (DAWN and/or DEFUSE-3) and more liberal clinical/imaging mismatch criteria (including lower admission National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score for core estimation).ResultsOf 1705 patients with AIS admitted to our comprehensive stroke center in the late time window, we identified 925 patients with complete clinical and radiological data. Among them, the proportions of late EVT eligibility were 2.5% (n=23) with DAWN, 5.1% (n=47) with DEFUSE-3, and 11.1% (n=103) with more liberal criteria. Considering late-arriving patients with large vessel occlusion (n=221), the percentages of eligible patients were 10.4%, 21.3%, and 46.6%, respectively. A favorable outcome was observed at comparable rates in treated patients selected by trial or liberal criteria (67% vs 58%, p=0.49).ConclusionsIn a long-term stroke registry, the proportion of late EVT eligibility varied greatly according to selection criteria and referral pattern. Among late-arriving patients referred to our comprehensive stroke center, we found 5.6% eligible according to trial (DAWN/DEFUSE-3) and 11.1% according to liberal criteria. These data indicate that late EVT could be offered to a larger population of patients if more liberal criteria are applied.
Efficacy and safety of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) due to intracranial artery dissection (IAD) are currently not established. We aimed to present a single-center ...experience on IAD-related AIS treated by IVT. We selected all consecutive patients with IAD-related AIS treated by IVT from a prospectively constructed single-center acute stroke registry from 2003 to 2017. We reviewed demographical, clinical and neuroimaging data and recorded hemorrhagic complications, mortality within 7 days and modified Rankin Scale at 3-months. Out of 181 AISs related to cervicocephalic dissections, 10 (5.5%) were due to IAD and five of these patients received IVT. Among these five patients, median age was 62 years; hypertension and dyslipidemia were the most frequent vascular risk factors. IAD locations were distal internal carotid artery, middle cerebral artery (M1), anterior cerebral artery (A2), and, in two cases, the basilar artery. All anterior circulation IADs were occlusive or subocclusive, while the two basilar artery IADs caused arterial stenosis. After IVT, there were no subarachnoid or symptomatic intracranial hemorrhages. One patient had an asymptomatic hemorrhagic infarct type 1. Two patients died within 7 days from ischemic mass effect. The other three patients had favorable clinical outcomes at 3-months. In this small single-center case series of IAD-related AIS, thrombolysis seemed relatively safe. However, IVT efficacy and the likelihood of arterial recanalization are still uncertain in this context. Further studies are needed to assess the safety and efficacy of IVT in these patients.
Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze ...cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO
cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.
Biotinidase deficiency is an autosomal recessive disorder in which affected individuals are unable to recycle biotin. Untreated, children usually exhibit hypotonia, seizures, ataxia, developmental ...delay, and/or hearing loss. Individuals diagnosed by newborn screening have an excellent prognosis with life-long biotin supplementation. We report a young adult diagnosed with profound biotinidase deficiency by newborn screening who was asymptomatic while on therapy. At 18 years of age, 6 months after voluntarily discontinuation of biotin, he developed a progressive distal muscle weakness. Molecular analysis of the
BTD
gene showed a pathogenic homozygous duplication c.1372_1373dupT p.(Cys458Leu
fs
Ter26) (
1
). Despite 16 months since reintroduction of biotin, muscle strength only partially recovered. Transition to adulthood in chronic metabolic diseases is known to be associated with an increased risk for non-compliance. Neurological findings in this adult are similar to those described in others with adult-onset biotinidase deficiency. Long-term prognosis in non-compliant symptomatic adult with biotinidase deficiency likely depends on the delay and/or severity of intervening symptoms until reintroduction of biotin.
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