Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.

[Thrombosis with Thrombocytopenia Syndrome following adenovirus vector-based vaccines to prevent COVID-19: epidemiology and clinical presentation in Spain]. / Síndrome de Trombosis con Trombocitopenia asociado a vacunas de adenovirus frente a la COVID-19: epidemiología y presentación clínica de la serie española.

BACKGROUND: We describe the epidemiological and clinical characteristics of thrombosis with thrombocytopenia syndrome (TTS) cases reported in Spain. METHODS: We included all venous or arterial thrombosis with thrombocytopenia following adenovirus vector-based vaccines (AstraZeneca or Janssen) to prevent COVID-19 disease between February 1st and September 26th, 2021. We describe the crude rate and the standardized morbidity ratio. We assessed the predictors of mortality. RESULTS: Sixty-one cases were reported and 45 fulfilled eligibility criteria, 82% women. The crude TTS rate was 4/1,000,000 doses and 14-15/1,000,000 doses between 30-49 years. The number of observed cases of cerebral venous thrombosis was 6-18 higher than the expected in patients younger than 49 years. Symptoms started 10 (interquartile range (IQR): 7-14) days after vaccination. Eighty percent (95% confidence interval (CI): 65-90%) had thrombocytopenia at the time of the emergency department visit, and 65% (95% CI: 49-78%) had D-dimer >2000 ng/mL. Patients had multiple location thrombosis in 36% and fatal outcome in 24% cases. A platelet nadir <50,000 /µL (odds ratio (OR): 7.4; CI 95%: 1.2-47.5) and intracranial hemorrhage (OR: 7.9; IC95%: 1.3-47.0) were associated with fatal outcome. CONCLUSION: TTS must be suspected in patients with symptoms 10 days after vaccination and thrombocytopenia and/or D-dimer increase.

Delayed Neurological Improvement After Full Endovascular Reperfusion in Acute Anterior Circulation Ischemic Stroke.

Background and Purpose: We aimed to determine the prevalence and predictors of delayed neurological improvement (DNI) after complete endovascular reperfusion in anterior circulation acute ischemic stroke (AIS). Methods: Retrospective analysis of an online multicenter prospective reperfusion registry of patients with consecutive anterior circulation AIS treated with endovascular thrombectomy (EVT) from January 2018 to June 2019 in tertiary stroke centers of the NORDICTUS (NORD-Spain Network for Research and Innovation in ICTUS) network. We included patients with AIS with a proximal occlusion in whom a modified Thrombolysis in Cerebral Infarction 3 reperfusion pattern was obtained. DNI was defined if, despite absence of early neurological improvement during the first 24 hours, patients achieved functional independence on day 90. Clinical and radiological variables obtained before EVT were analyzed as potential predictors of DNI. Results: Of 1565 patients with consecutive AIS treated with EVT, 1381 had proximal anterior circulation occlusions, 803 (58%) of whom achieved a modified Thrombolysis in Cerebral Infarction 3. Of these, 628 patients fulfilled all selection criteria and were included in the study. Mean age was 73.8 years, 323 (51.4%) were female, and median baseline National Institutes of Health Stroke Scale was 16. Absence of early neurological improvement was observed in 142 (22.6%) patients; 32 of these (22.5%) achieved good long-term outcome and constitute the DNI group. Predictors of DNI in multivariable-adjusted logistic regression were male sex (odds ratio, 6.4 [95% CI, 2.1­22.3] P=0.002), lower pre-EVT National Institutes of Health Stroke Scale score (odds ratio, 1.4 [95% CI, 1.2­1.5], P<0.001), and intravenous thrombolysis (odds ratio, 9.1 [95% CI, 2.7­30.90], P<0.001). Conclusions: One-quarter of patients with anterior circulation AIS who do not clinically improve within the first 24 hours after complete cerebral endovascular recanalization will achieve long-term functional independence, regardless of the poor early clinical course. Male sex, lower initial clinical severity, and use of intravenous thrombolysis before EVT predicted this clinical pattern.

PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, ß=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Impact of Mediterranean Diet prior to Stroke on the Prognosis of Patients Undergoing Endovascular Treatment.

INTRODUCTION: Mediterranean diet (MeDiet) has been associated with lower risk of stroke. Additionally, animal models suggested that some components of MeDiet are associated with better outcomes after ischemic stroke (IS). We aimed to evaluate the association between global adherence to the MeDiet and the consumption of particular components of the MeDiet with stroke outcomes. MATERIAL AND METHODS: Multicenter observational study of consecutive IS patients treated with endovascular therapy. Inclusion criteria were large anterior circulation vessel occlusion and pre-stroke modified Rankin scale (mRS) <2. Adherence to MeDiet prior to stroke was evaluated using MEDAS 14-item scale. We evaluated the total score and also individual components of the scale. Clinical, radiological, and prognostic variables were collected. Good functional prognosis was considered as mRS ≤2 and complete recanalization as thrombolysis in cerebral infarction 3. RESULTS: From January 1 to October 30, 2018, 239 patients were included (mean age 71 years, 48% women, median baseline NIHSS 16). Median MEDAS scale was 8 points (7-10). Patients with a higher adherence to MeDiet had significantly lower total and LDL-cholesterol levels. Total adherence score was not associated with stroke outcomes. In multivariate analyses, consumption of olive oil as the principal source of fat was independently associated with good functional outcome at 3 months, OR 3.2 (1.1-10.1) and daily consumption of wine was independently associated with complete recanalization, OR 2.0 (1.1-3.8). CONCLUSIONS: Our study suggests that some components of MeDiet, such as olive oil and wine consumption, are related to better prognosis after stroke. More studies are needed to confirm these findings.

Blood biomarkers predictive of epilepsy after an acute stroke event.

OBJECTIVE: Blood biomarkers have not been widely investigated in poststroke epilepsy. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and analyze their association with the development of epilepsy at long term. METHODS: A panel of 14 blood biomarkers was evaluated in patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z-scores. Stroke and epilepsy-related variables were also assessed: stroke severity, determined by National Institutes of Health Stroke Scale (NIHSS) score, stroke type and cause, time from stroke to onset of late seizures, and type of seizure. Multiple Cox regression models were used to identify clinical variables and biomarkers independently associated with epilepsy. RESULTS: From a cohort of 1115 patients, 895 patients were included. Mean ± standard deviation (SD) age was 72.0 ± 13.1 years, and 57.8% of patients were men. Fifty-one patients (5.7%) developed late seizures, with a median time to onset of 232 days (interquartile range [IQR] 86-491). NIHSS score ≥8 (P < .001, hazard ratio [HR] 4.013, 95% confidence interval [CI] 2.123-7.586) and a history of early onset seizures (P < .001, HR 4.038, 95% CI 1.802-9.045) were factors independently associated with a risk of developing epilepsy. Independent blood biomarkers predictive of epilepsy were high endostatin levels >1.203 (P = .046, HR 4.300, 95% CI 1.028-17.996) and low levels of heat shock 70 kDa protein-8 (Hsc70) <2.496 (P = .006, HR 3.795, 95% CI 1.476-9.760) and S100B <1.364 (P = .001, HR 2.955, 95% CI 1.534-5.491). The risk of epilepsy when these biomarkers were combined increased to 17%. The area under the receiver-operating characteristic (ROC) curve of the predictive model was stronger when clinical variables were combined with blood biomarkers (74.3%, 95% CI 65.2%-83.3%) than when they were used alone (68.9%, 95% CI 60.3%-77.6%). SIGNIFICANCE: Downregulated S100B and Hsc70 and upregulated endostatin may assist in prediction of poststroke epilepsy and may provide additional information to clinical risk factors. In addition, these data are hypothesis-generating for the epileptogenic process.

Correlation of blood biomarkers with early-onset seizures after an acute stroke event.

INTRODUCTION: Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures. METHODS: We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures. RESULTS: Mean ±â€¯standard deviation (SD) age was 72.3 ±â€¯13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%). CONCLUSION: Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. This article is part of the Special Issue "Seizures & Stroke".

Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial.

BACKGROUND: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo. METHODS: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days). RESULTS: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23-68.6; p = 0.03). CONCLUSIONS: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials.

2,5-Dimethylfuran as a Validated Biomarker of Smoking Status.

INTRODUCTION: Exposure biomarkers are required in tobacco use studies to accurately assess smoking status since self-reporting usually results in misclassification estimates. This study uses breath analysis and assesses some volatile organic compounds (VOCs) as potential biomarkers of tobacco smoke exposure. METHODS: Forced-expiratory breath samples were obtained from 377 volunteers (174 smokers and 203 nonsmokers). Exhaled breath levels of different VOCs previously related to tobacco smoke were evaluated. The toluene-to-benzene ratio was evaluated as this ratio has been found to be different in atmospheric samples and tobacco smoke emissions. Finally, breath analyses from 64 patients attending a clinical practice were evaluated and the results were compared to their self-reporting status. RESULTS: Univariate analysis shows that all compounds evaluated gave significant differences (p < .001). Receiver operating characteristic (ROC) curves suggest that xylenes and toluene are not able to accurately determine smoking status, and benzene and the T/B ratio present potential utility in certain conditions. The highest discriminant capacity was obtained for 2,5-dimethylfuran (AUC = 0.982, 95% confidence interval [CI]: 0.969-0.995), with a cut-off value of 0.016 ppbv (sensibility = 0.965, specificity = 0.896). Drinking coffee was the only confounding parameter that can give low breath levels for this compound. The evaluation of the results obtained from the patients attending a clinical practice showed that 8% of people who claim to be nonsmokers hid their real smoking status. CONCLUSIONS: The results obtained confirm that the determination of 2,5-dimethylfuran in breath samples is a good and simpler alternative to conventional blood or urine tests for assessing smoking status. IMPLICATIONS: Analysis of 2,5-dimethylfuran in breath samples results in a simple and fast method for the determination of the smoking status of a person. This methodology presents multiple advantages as it is neither invasive nor embarrassing for patients attending clinical practices. Moreover, analysis of biomarkers in breath samples is simpler and faster than using conventional methods based on urine or blood analysis.

Pre-Existing Cerebral Small Vessel Disease Limits Early Recovery in Patients with Acute Lacunar Infarct.

BACKGROUND AND PURPOSE: To assess whether neuroimaging markers of chronic cerebral small vessel disease (cSVDm) influence early recovery after acute ischemic stroke (AIS). METHODS: Retrospective analysis of patients diagnosed with AIS and included in the Spanish Neurological Society Stroke Database. INCLUSION CRITERIA: (1) Brain MRI performed after acute stroke and (2) Premorbid modified Rankin scale (mRS) = 0. EXCLUSION CRITERIA: (1) Uncommon stroke etiologies, (2) AIS not confirmed on neuroimaging, or (3) Old territorial infarcts on neuroimaging. Patients scored from 0 to 2 according to the amount of cSVDm. Patients were divided into lacunar ischemic stroke (LIS) and nonlacunar ischemic stroke (NLIS) groups according to TOAST classification. PRIMARY OUTCOME: Distribution of mRS at discharge. SECONDARY OUTCOMES: NIHSS improvement more than or equal to 3 at 24 hours and at discharge, NIHSS worsening more than or equal to 3 points at 24 hours. RESULTS: We studied 4424 patients (3457 NLIS, 967 LIS). The presence of cSVDm increased the risk of worsening 1 category on the mRS at discharge in the LIS group ([1] cSVDm: OR 1.89 CI 95% 1.29-2.75, P = .001. [2] cSVDm: OR 1.87, CI 95% 1.37-2.56 P = .001) and was an independent factor for not achieving an improvement more than or equal to 3 points on the NIHSS at discharge for all the patients and the LIS group (all stroke patients: [1] cSVDm: OR 0.81 CI 95% .68-.97 P = .022. [2] cSVD: OR 0.58 CI95% .45-.77, P = .001./LIS: [1] cSVDm: OR 0.64, CI 95% .41-.98, P = .038. [2] cSVDm: OR 0.43, CI 95% .24-.75 P = .003). CONCLUSIONS: Pre-existing SVD limits early functional and neurological recovery after AIS, especially in LIS patients.

Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice.

Background and Purpose- Recanalization with tPA (tissue-type plasminogen activator) is the only pharmacological therapy available for patients with ischemic stroke. However, the percentage of patients who may receive this therapy is limited by the risk of hemorrhagic transformation (HT)-the main complication of ischemic stroke. Our aim is to establish whether iron overload affects HT risk, to identify mechanisms that could help to select patients and to prevent this devastating complication. Methods- Mice fed with control or high-iron diet were subjected to thromboembolic stroke, with or without tPA therapy at different times after occlusion. Blood samples were collected for determination of malondialdehyde, matrix metalloproteinases, and fibronectin. Brain samples were collected 24 hours after occlusion to determine brain infarct and edema size, hemorrhage extension, IgG extravasation, and inflammatory and oxidative markers (neutrophil infiltration, 4-hydroxynonenal, and matrix metalloproteinase-9 staining). Results- Despite an increased rate of recanalization, iron-overload mice showed less neuroprotection after tPA administration. Importantly, iron overload exacerbated the risk of HT after early tPA administration, accelerated ischemia-induced serum matrix metalloproteinase-9 increase, and enhanced basal serum lipid peroxidation. High iron increased brain lipid peroxidation at most times and neutrophil infiltration at the latest time studied. Conclusions- Our data showing that iron overload increases the death of the compromised tissues, accelerates the time of tPA-induced reperfusion, and exacerbates the risk of HT may have relevant clinical implications for a safer thrombolysis. Patients with stroke with iron overload might be at high risk of HT after fibrinolysis, and, therefore, clinical studies must be performed to confirm our results.

Low Levels of Caveolin-1 Predict Symptomatic Bleeding After Thrombolytic Therapy in Patients With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Experimental models of cerebral ischemia demonstrate that the decrease in the caveolin-1 membrane protein results in an increase in endothelial permeability. Because this phenomenon is responsible for hemorrhagic transformation (HT) after cerebral ischemia, we aimed to determine whether caveolin-1 levels may predict bleeding after recombinant tissue-type plasminogen activator (r-tPA) administration in patients with acute stroke. METHODS: We studied 133 patients with a first hemispheric stroke treated with r-tPA within 4.5 hours of symptom onset. HT was evaluated and classified on cranial computed tomography at 24 hours and was considered as symptomatic HT (sHT) if associated with neurological deterioration. Serum caveolin-1 levels were analyzed before and at 2, 24, and 72 hours post-r-tPA administration in patients and in 40 healthy controls. RESULTS: Baseline caveolin-1 levels were higher in patients than controls (0.24 [0.17-0.40] versus 0.07 [0.0-0.20] ng/mL; P<0.000). Twenty six (19.5%) patients had HT, which was symptomatic in 7 (5.3%). Patients with parenchymal hemorrhage-2 and sHT had lower baseline caveolin-1 levels than the rest of patients (0.08 [0.04-0.19] versus 0.26 [0.14-0.40]; P=0.019 and 0.08 [0.02-0.17] versus 0.26 [0.13-0.41]; P=0.019, respectively). The levels remained stable in the first 72 hours in patients with parenchymal hemorrhage-2 and sHT, whereas in the rest of patients levels decreased in this time. Caveolin-1 levels ≤0.17 ng/mL had the highest predictive capacity of sHT (86% sensitivity, 65% specificity, 99% negative predictive value, 12% positive predictive value). After adjustment for confounders, caveolin-1 levels ≤0.17 ng/mL independently predicted sHT (odds ratio, 11.6; 95% confidence interval, 11.3-102.8; P=0.027). CONCLUSIONS: Low serum levels of caveolin-1 are an independent predictor of sHT after r-tPA administration. Because of the small sample size, further research is needed to validate these data.

Association of Clinical, Imaging, and Thrombus Characteristics With Recanalization of Visible Intracranial Occlusion in Patients With Acute Ischemic Stroke.

Importance: Recanalization of intracranial thrombus is associated with improved clinical outcome in patients with acute ischemic stroke. The association of intravenous alteplase treatment and thrombus characteristics with recanalization over time is important for stroke triage and future trial design. Objective: To examine recanalization over time across a range of intracranial thrombus occlusion sites and clinical and imaging characteristics in patients with ischemic stroke treated with intravenous alteplase or not treated with alteplase. Design, Setting, and Participants: Multicenter prospective cohort study of 575 patients from 12 centers (in Canada, Spain, South Korea, the Czech Republic, and Turkey) with acute ischemic stroke and intracranial arterial occlusion demonstrated on computed tomographic angiography (CTA). Exposures: Demographics, clinical characteristics, time from alteplase to recanalization, and intracranial thrombus characteristics (location and permeability) defined on CTA. Main Outcomes and Measures: Recanalization on repeat CTA or on first angiographic acquisition of affected intracranial circulation obtained within 6 hours of baseline CTA, defined using the revised arterial occlusion scale (rAOL) (scores from 0 [primary occlusive lesion remains the same] to 3 [complete revascularization of primary occlusion]). Results: Among 575 patients (median age, 72 years [IQR, 63-80]; 51.5% men; median time from patient last known well to baseline CTA of 114 minutes [IQR, 74-180]), 275 patients (47.8%) received intravenous alteplase only, 195 (33.9%) received intravenous alteplase plus endovascular thrombectomy, 48 (8.3%) received endovascular thrombectomy alone, and 57 (9.9%) received conservative treatment. Median time from baseline CTA to recanalization assessment was 158 minutes (IQR, 79-268); median time from intravenous alteplase start to recanalization assessment was 132.5 minutes (IQR, 62-238). Successful recanalization occurred at an unadjusted rate of 27.3% (157/575) overall, including in 30.4% (143/470) of patients who received intravenous alteplase and 13.3% (14/105) who did not (difference, 17.1% [95% CI, 10.2%-25.8%]). Among patients receiving alteplase, the following factors were associated with recanalization: time from treatment start to recanalization assessment (OR, 1.28 for every 30-minute increase in time [95% CI, 1.18-1.38]), more distal thrombus location, eg, distal M1 middle cerebral artery (39/84 [46.4%]) vs internal carotid artery (10/92 [10.9%]) (OR, 5.61 [95% CI, 2.38-13.26]), and higher residual flow (thrombus permeability) grade, eg, hairline streak (30/45 [66.7%]) vs none (91/377 [24.1%]) (OR, 7.03 [95% CI, 3.32-14.87]). Conclusions and Relevance: In patients with acute ischemic stroke, more distal thrombus location, greater thrombus permeability, and longer time to recanalization assessment were associated with recanalization of arterial occlusion after administration of intravenous alteplase; among patients who did not receive alteplase, rates of arterial recanalization were low. These findings may help inform treatment and triage decisions in patients with acute ischemic stroke.

Blood Biomarkers for the Early Diagnosis of Stroke: The Stroke-Chip Study.

BACKGROUND AND PURPOSE: Stroke diagnosis could be challenging in the acute phase. We aimed to develop a blood-based diagnostic tool to differentiate between real strokes and stroke mimics and between ischemic and hemorrhagic strokes in the hyperacute phase. METHODS: The Stroke-Chip was a prospective, observational, multicenter study, conducted at 6 Stroke Centers in Catalonia. Consecutive patients with suspected stroke were enrolled within the first 6 hours after symptom onset, and blood samples were drawn immediately after admission. A 21-biomarker panel selected among previous results and from the literature was measured by immunoassays. Outcomes were differentiation between real strokes and stroke mimics and between ischemic and hemorrhagic strokes. Predictive models were developed by combining biomarkers and clinical variables in logistic regression models. Accuracy was evaluated with receiver operating characteristic curves. RESULTS: From August 2012 to December 2013, 1308 patients were included (71.9% ischemic, 14.8% stroke mimics, and 13.3% hemorrhagic). For stroke versus stroke mimics comparison, no biomarker resulted included in the logistic regression model, but it was only integrated by clinical variables, with a predictive accuracy of 80.8%. For ischemic versus hemorrhagic strokes comparison, NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) >4.9 (odds ratio, 2.40; 95% confidence interval, 1.55-3.71; P<0.0001) and endostatin >4.7 (odds ratio, 2.02; 95% confidence interval, 1.19-3.45; P=0.010), together with age, sex, blood pressure, stroke severity, atrial fibrillation, and hypertension, were included in the model. Predictive accuracy was 80.6%. CONCLUSIONS: The studied biomarkers were not sufficient for an accurate differential diagnosis of stroke in the hyperacute setting. Additional discovery of new biomarkers and improvement on laboratory techniques seem necessary for achieving a molecular diagnosis of stroke.

GRECOS Project (Genotyping Recurrence Risk of Stroke): The Use of Genetics to Predict the Vascular Recurrence After Stroke.

BACKGROUND AND PURPOSE: Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. METHODS: We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. RESULTS: The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10-03), a gene related to artery calcification, was associated with new IS during the first year of follow-up. This polymorphism was replicated in a Spanish cohort (n=1.305); however, it was not significantly associated in a North American cohort (n=1.683). The GRECOS score predicted new IS (P=3.2×10-09) and could classify patients, from low risk of stroke recurrence (1.9%) to high risk (12.6%). Moreover, the addition of genetic risk factors to the GRECOS score improves the prediction compared with previous Stroke Prognosis Instrument-II score (P=0.03). CONCLUSIONS: The use of genetics could be useful to estimate vascular recurrence risk after IS. Genetic variability in the MGP gene was associated with vascular recurrence in the Spanish population.

Diffusion tensor imaging as a prognostic biomarker for motor recovery and rehabilitation after stroke.

PURPOSE: Despite improved acute treatment and new tools to facilitate recovery, most patients have motor deficits after stroke, often causing disability. However, motor impairment varies considerably among patients, and recovery in the acute/subacute phase is difficult to predict using clinical measures alone, particularly in severely impaired patients. Accurate early prediction of recovery would help rationalize rehabilitation goals and improve the design of trials testing strategies to facilitate recovery. METHODS: We review the role of diffusion tensor imaging (DTI) in predicting motor recovery after stroke, in monitoring treatment response, and in evaluating white matter remodeling. We critically appraise DTI studies and discuss their limitations, and we explore directions for future study. RESULTS: Growing evidence suggests that combining clinical scores with information about corticospinal tract (CST) integrity can improve predictions about motor outcome. The extent of CST damage on DTI and/or the overlap between the CST and a lesion are key prognostic factor that determines motor performance and outcome. Three main strategies to quantify stroke-related CST damage have been proposed: (i) measuring FA distal to the stroke area, (ii) measuring the number of fibers that go through the stroke with tractography, and (iii) measuring the overlap between the stroke and a CST map derived from healthy age- and gender-matched controls. CONCLUSION: Recovery of motor function probably involves remodeling of the CST proper and/or a greater reliance on alternative motor tracts through spontaneous and treatment-induced plasticity. DTI-metrics represent promising clinical biomarkers to predict motor recovery and to monitor and predict the response to neurorehabilitative interventions.

Changes in Activated Thrombin-Activatable Fibrinolysis Inhibitor Levels Following Thrombolytic Therapy in Ischemic Stroke Patients Correlate with Clinical Outcome.

BACKGROUND AND PURPOSE: Thrombin-activatable fibrinolysis inhibitor (TAFI) activation following thrombolysis may affect thrombolysis effectiveness in acute ischemic stroke (AIS). To support this hypothesis, we propose to study the relationship between TAFI consumption, activated/inactivated TAFI (TAFIa/ai) and stroke severity and outcome in 2 groups of AIS patients, one treated and one untreated with intravenous recombinant tissue type plasminogen activator (rt-PA). METHODS: In this prospective, longitudinal, multicenter, observational study, we aimed to study the association between TAFIa/ai and stroke outcome. TAFI levels were sequentially measured in patients treated with intravenous rt-PA thrombolysis (T), and in patients not given any thrombolytic therapy (NT). Baseline reference values were established in healthy subjects matched for age and gender. The National Institutes of Health Stroke Scale (NIHSS) score assessed at baseline and on day 2 was dichotomized into 2 severity groups (0-7 vs. >7). The modified Rankin Scale (mRS) score at day 90 was dichotomized for favorable (0-1) and unfavorable (2-6) outcomes. RESULTS: A total of 109 patients were included, with 41 receiving rt-PA. At admission, patients had higher TAFIa/ai levels than reference. A significant increase in TAFIa/ai levels was observed at the end of thrombolysis (mean change from baseline of 963%) and lasted up to 4 h (191%). Higher TAFIa/ai levels were associated with a more severe day 2 NIHSS score (p = 0.0098 at T2h post thrombolysis) and an unfavorable mRS score from T48h (p = 0.0417) to day 90 (p = 0.0046). In NT patients, higher TAFIa/ai levels at admission were associated with a more severe stroke, as assessed by day 2 NIHSS score (p = 0.0026) and mRS score (p = 0.0003). CONCLUSION: These data demonstrate a consistent relationship between TAFI levels and early clinical severity during rt-PA treatment.

Functional outcome after primary endovascular therapy or IV thrombolysis alone for stroke. An observational, comparative effectiveness study.

BACKGROUND: Among the acute ischemic stroke patients with large vessel occlusions and contraindications for the use of IV thrombolysis, mainly on oral anticoagulation or presenting too late, primary endovascular therapy is often performed as an alternative to the standard therapy even though evidence supporting the use of endovascular reperfusion therapies is not yet established. Using different statistical approaches, we compared the functional independence rates at 3 months among patients undergoing primary endovascular therapy and patients treated only with IV thrombolysis. METHODS: We used data from a prospective, government-mandated and externally audited registry of reperfusion therapies for ischemic stroke (January 2011 to November 2012). Patients were selected if treated with either IV thrombolysis alone (n = 1,582) or primary endovascular thrombectomy (n = 250). A series of exclusions were made to homogenize the clinical characteristics among the two groups. We then carried out multivariate logistic regression and propensity score matching analyses on the final study sample (n = 1,179) to compare functional independence at 3 months, as measured by the modified Rankin scale scores 0-2, between the two groups. RESULTS: The unadjusted likelihood of good outcome was poorer among the endovascular group (OR: 0.69; 95% CI: 0.47-1.0). After adjustment, no differences by treatment modality were seen (OR: 1.51; 95% CI: 0.93-2.43 for primary endovascular therapy). Patients undergoing endovascular thrombectomy within 180-270 min (OR: 2.89; 95% CI: 1.17-7.15) and patients with severe strokes (OR: 1.84; 95% CI: 1.02-3.35) did better than their intravenous thrombolysis counterparts. The propensity score-matched analyses with and without adjustment by additional covariates showed that endovascular thrombectomy was as effective as intravenous thrombolysis alone in achieving functional independence (OR for unadjusted propensity score matched: 1.35; 95% CI: 0.9-2.02, OR for adjusted propensity score matched: 1.45; 95% CI: 0.91-2.32). CONCLUSION: This comparative effectiveness study shows that in ischemic stroke patients with contraindications for IV thrombolysis, primary endovascular treatment might be an alternative therapy at least as effective as IV thrombolysis alone. Randomized controlled trials are urgently needed.

Post-event follow-up costs in patients with atherosclerotic cardiovascular disease in Spain.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is one of the main causes of morbidity and mortality in developed countries and entails high resources use and costs for health systems. The risk of suffering future cardiovascular (CV) events and the consequent resources use is higher in those patients who have already had a previous cardiovascular event. The objective of the study was to determine the average annual cost of patients with a new or recurrent atherosclerotic CV event during the 2 years after the event. Methodology: Retrospective observational study of electronic medical records of patients from the BIG-PAC® database (7 integrated health areas of 7 Autonomous Communities; n = 1.8 million). Patients with a new or recurrent episode of ASCVD (angina, acute myocardial infarction, transient ischemic attack, stroke, or peripheral arterial disease) between 1-Jan-2017 and 31-Dec-2018 were included. The resources use within two years of the diagnosis was estimated in order to estimate the average cost of patient follow-up. Results: A total of 26,976 patients with an ASCVD episode were identified during the recruitment period; Out of them, 6,798 had a recurrent event during the follow-up period and 2,414 died. The average costs per patient were €11,171 during the first year and €9,944 during the second year. Discussion: Patients with ASCVD represent a significant economic burden for the health system and for society. Despite the perception that drug costs in the follow-up of chronic patients imply a high percentage of the costs, these accounted for only one tenth of the total amount. Implementing preventive programs and increasing the control of cardiovascular risk factors may have a significant social and health impact by helping to reduce mortality and costs for the Spanish National Health System. The costs derived from pharmacological treatments were obtained from the NHS pricing nomenclator database (https://www.sanidad.gob.es/profesionales/nomenclator.do).