Asymptomatic parenchymal haemorrhage following endovascular treatment: Impact on functional outcome in patients with acute ischaemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischaemic stroke (AIS), haemorrhagic transformation (HT) following endovascular treatment (EVT) is associated with poor functional outcome. However, the impact of asymptomatic HT, not linked to neurological deterioration in the acute phase, is unknown. We aimed to investigate the impact of asymptomatic PH1 (aPH1) and PH2 (aPH2) subtypes of HT on the functional outcome of patients treated with EVT. METHODS: We conducted a retrospective study of patients with AIS who were consecutively admitted to our comprehensive stroke centre between January 2019 and December 2022, and who underwent EVT. We collected clinical, radiological, and procedural data. HTs were categorized according to the Heidelberg classification. The primary outcome was the shift on the modified Rankin Scale (mRS) at 3 months of follow-up. We performed bivariate and multivariable ordinal regression analyses to test the association between aPH1/aPH2 and the primary outcome. RESULTS: We included 314 patients (mean age = 72.5 years [SD = 13.6], 171 [54.5%] women). We detected 54 (17.2%) patients with HT; 23 (7.3%) were classified as PH2 (11 asymptomatic) and 17 (5.4%) as PH1 (16 asymptomatic). The adjusted common odds ratio for aPH2 of worsening 1 point on the 3-month mRS was 3.32 (95% confidence interval = 1.16-9.57, p = 0.026). No association was observed for aPH1. aPH2 was also independently associated with lower odds of achieving a favourable outcome (mRS = 0-2). Neither aPH1 nor aPH2 was associated with mortality. CONCLUSIONS: In patients with AIS treated with EVT, aPH2 is independently associated with unfavourable functional outcome.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Left atrial appendage occlusion in patients with spontaneous intracerebral hemorrhage: An observational study.

BACKGROUND: Patients with atrial fibrillation (AF) and intracerebral hemorrhage (ICH) are at high risk of ischemic and recurrent bleeding events. Therefore, the decision of restarting or avoiding anticoagulation is challenging. Left atrial appendage occlusion (LAAO) is an alternative for these patients. However, few data are available about safety of early LAAO and factors associated with ischemic stroke and ICH recurrence. METHODS: A unicentric, observational, retrospective study including all patients with AF and a previous ICH who underwent LAAO. We analyzed baseline clinical and neuroimaging characteristics, procedural outcomes, post-procedural therapies and long-term follow-up. RESULTS: Forty patients were included, whose mean age was 76.6 ±7.6 years and 73 % were men. In patients in whom a Magnetic Resonance (MR) was performed (n=22, 55 %), cortical microbleeds were detected in 15 (68 %) and cortical superficial siderosis in one patient. The procedure was successful and safe in 100 % of the patients and it was performed within 30 days of the ICH in 37 % of them. After a median follow up of 46.2 months [26-69], intracranial hemorrhage (ICrH) recurrence occurred in 6 patients (5 ICH and 1 subdural hematoma -SDH-) and the index ICH was lobar in all of them. Ischemic events were significantly lower than expected according to the CHA2DS2-VASc score (7.5 % vs. 16.6 %, p=0.048) and bleeding events were similar to expected by the HAS-BLED score (20 % vs 23.4 %, p=0.63). CONCLUSIONS: In patients with ICH and AF, early LAAO was found to be safe and associated with a reduction in ischemic stroke. However, recurrent ICH risk remains high, and it appears to be mainly driven by cerebral amyloid angiopathy.

Soluble low-density lipoprotein receptor-related protein 1 as a surrogate marker of carotid plaque inflammation assessed by 18F-FDG PET in patients with a recent ischemic stroke.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) identifies carotid plaque inflammation and predicts stroke recurrence. AIM: Our aim was to evaluate the performance of soluble low-density lipoprotein receptor-related protein 1 (sLRP1) as an indicator of carotid plaque inflammation. METHODS: A prospective study was conducted among adult patients with recent (< 7 days) anterior circulation ischemic stroke and at least one atherosclerotic plaque in the ipsilateral internal carotid artery. Patients underwent an early (< 15 days from inclusion) 18F-FDG PET, and the maximum standardized uptake value (SUVmax) within the plaque was measured. sLRP1 levels were measured in plasma samples by ELISA. The association of sLRP1 with SUVmax was assessed using bivariate and multivariable linear regression analyses. Hazard ratios (HR) were estimated with Cox regression to evaluate the association between circulating sLRP1 and stroke recurrence. RESULTS: The study was conducted with 64 participants, of which 57.8% had ≥ 50% carotid stenosis. The multivariable linear and logistic regression analyses showed that sLRP1 was independently associated with (i) SUVmax within the plaque (ß = 0.159, 95% CI 0.062-0.257, p = 0.002) and (ii) a probability of presenting SUVmax ≥ 2.85 g/mL (OR = 1.31, 95% CI 1.00-1.01, p = 0.046), respectively. Participants with stroke recurrence showed higher sLRP1 levels at baseline [6447 ng/mL (4897-11163) vs. 3713 ng/mL (2793-4730); p = 0.018]. CONCLUSIONS: sLRP1 was independently associated with carotid plaque inflammation as measured by 18F-FDG PET in patients with recent ischemic stroke and carotid atherosclerosis.

Ischaemic stroke patients present sex differences in gut microbiota.

BACKGROUND: Gut microbiota plays a role in the pathophysiology of ischaemic stroke (IS) through the bidirectional gut-brain axis. Nevertheless, little is known about sex-specific microbiota signatures in IS occurrence. METHODS: A total of 89 IS patients and 12 healthy controls were enrolled. We studied the taxonomic differences of the gut microbiota between men and women with IS by shotgun metagenomic sequencing. To evaluate the causal effect of several bacteria on IS risk, we performed a two-sample Mendelian randomisation (MR) with inverse-variance weighting (IVW) using genome-wide association analysis (GWAS) summary statistics from two cohorts of 5959 subjects with genetic and microbiota data and 1,296,908 subjects with genetic and IS data, respectively. RESULTS: α-Diversity analysis measured using Observed Species (p = 0.017), Chao1 (p = 0.009) and Abundance-based Coverage Estimator (p = 0.012) indexes revealed that IS men have a higher species richness compared with IS women. Moreover, we found sex-differences in IS patients in relation to the phylum Fusobacteria, class Fusobacteriia, order Fusobacteriales and family Fusobacteriaceae (all Bonferroni-corrected p < 0.001). MR confirmed that increased Fusobacteriaceae levels in the gut are causally associated with an increased risk of IS (IVW p = 0.02, ß = 0.32). CONCLUSIONS: Our study is the first to indicate that there are gut microbiome differences between men and women with IS, identifying high levels of Fusobacteriaceae in women as a specific risk factor for IS. Incorporating sex stratification analysis is important in the design, analysis and interpretation of studies on stroke and the gut microbiota.

Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke.

During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke.

Clinical characteristics and outcome of amaurosis fugax due to transient retinal ischemia: Results from a contemporary cohort.

BACKGROUND: Whether presenting an episode of amaurosis fugax (AFx) increases the risk of ischemic stroke is controversial and there is a lack of consensus in the following management. We aimed to describe the clinical characteristics and prognosis of patients with AFx due to suspected transient retinal ischemia. METHODS: Observational, retrospective study of patients admitted in a Comprehensive Stroke Center with diagnosis of AFx due to suspected transient retinal ischemia between 2015 and 2020. Clinical characteristics and diagnostic-therapeutic data were collected, as well as recurrences (new episodes of amaurosis and/or ischemic strokes). Multivariable Cox regression analyses were performed to study factors associated with the risk of recurrence. RESULTS: We included 91 patients with a mean age of 67.9±14.8 years, 43(47.3%) were women. After the diagnostic workup 14(15.4%) AFx were attributed to an atherothrombotic etiology, 4(4.4%) cardioembolic source, 10(11%) other determined cause (TOAST-OC) and 63(69,2%) indeterminate etiology. 71(78%) patients started antiplatelet therapy and 2(2.2%) anticoagulant therapy. After a median follow-up of 3.5 years (IQR 1.8-5.2), at least one recurrence was recorded in eight (8.8%) patients (four new AFx and four cerebral infarctions). TOAST-OC (HR=9.66, 95% CI 2.41-38.70; p=0.001) and prior history of ischemic stroke (HR=4.21. 95% CI 1.01-17.66; p=0.049) were both independently associated with the risk of recurrence. CONCLUSIONS: In two out of three patients, AFx due to transient retinal ischemia was of undetermined cause. The risk of stroke recurrence after a first episode of AFx in our cohort was 8.8%. Patients with TOAST-OC etiology identified were at highest risk of recurrence.

Genetic Architecture of Ischaemic Strokes after COVID-19 Shows Similarities with Large Vessel Strokes.

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated (p-value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p-value = 2.3 × 10-2, se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p-value = 1.3 × 10-3, se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p-value = 3.6 × 10-4, se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p-value = 1.0 × 10-2, se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Biological Age Acceleration Is Lower in Women With Ischemic Stroke Compared to Men.

BACKGROUND: Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA. METHODS: We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins. RESULTS: Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, P=1.34×10-2); the same tendency was observed in the second cohort (women=-0.57, men=0.79, P=0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (P<0.05), belonging to the immune effector process (P=1.54×10-6) and platelet degranulation (P<8.74×10-6) pathways. CONCLUSIONS: This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.

Lesions causing hallucinations localize to one common brain network.

The brain regions responsible for hallucinations remain unclear. We studied 89 brain lesions causing hallucinations using a recently validated technique termed lesion network mapping. We found that hallucinations occurred following lesions to a variety of different brain regions, but these lesion locations fell within a single functionally connected brain network. This network was defined by connectivity to the cerebellar vermis, inferior cerebellum (bilateral lobule X), and the right superior temporal sulcus. Within this single hallucination network, additional connections with the lesion location dictated the sensory modality of the hallucination: lesions causing visual hallucinations were connected to the lateral geniculate nucleus in the thalamus while lesions causing auditory hallucinations were connected to the dentate nucleus in the cerebellum. Our results suggest that lesions causing hallucinations localize to a single common brain network, but additional connections within this network dictate the sensory modality, lending insight into the causal neuroanatomical substrate of hallucinations.

Risk factors analysis according to regional distribution of white matter hyperintensities in a stroke cohort.

OBJECTIVES: The spectrum of distribution of white matter hyperintensities (WMH) may reflect different functional, histopathological, and etiological features. We examined the relationships between cerebrovascular risk factors (CVRF) and different patterns of WMH in MRI using a qualitative visual scale in ischemic stroke (IS) patients. METHODS: We assembled clinical data and imaging findings from patients of two independent cohorts with recent IS. MRI scans were evaluated using a modified visual scale from Fazekas, Wahlund, and Van Swieten. WMH distributions were analyzed separately in periventricular (PV-WMH) and deep (D-WMH) white matter, basal ganglia (BG-WMH), and brainstem (B-WMH). Presence of confluence of PV-WMH and D-WMH and anterior-versus-posterior WMH predominance were also evaluated. Statistical analysis was performed with SPSS software. RESULTS: We included 618 patients, with a mean age of 72 years (standard deviation [SD] 11 years). The most frequent WMH pattern was D-WMH (73%). In a multivariable analysis, hypertension was associated with PV-WMH (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.29-2.50, p = 0.001) and BG-WMH (OR 2.13, 95% CI 1.19-3.83, p = 0.012). Diabetes mellitus was significantly related to PV-WMH (OR 1.69, 95% CI 1.24-2.30, p = 0.001), D-WMH (OR 1.46, 95% CI 1.07-1.49, p = 0.017), and confluence patterns of D-WMH and PV-WMH (OR 1.62, 95% CI 1.07-2.47, p = 0.024). Hyperlipidemia was found to be independently related to brainstem distribution (OR 1.70, 95% CI 1.08-2.69, p = 0.022). CONCLUSIONS: Different CVRF profiles were significantly related to specific WMH spatial distribution patterns in a large IS cohort. KEY POINTS: • An observational study of WMH in a large IS cohort was assessed by a modified visual evaluation. • Different CVRF profiles were significantly related to specific WMH spatial distribution patterns. • Distinct WMH anatomical patterns could be related to different pathophysiological mechanisms.

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.

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Frequency, Predictors, Etiology, and Outcomes for Deep Intracerebral Hemorrhage without Hypertension.

OBJECTIVES: Some patients with deep intracerebral hemorrhage (ICH) have a transient hypertensive response and they may be erroneously classified as secondary to hypertension. We investigated frequency, risk factors, and outcomes for patients with deep ICH without hypertension. MATERIALS AND METHODS: We consecutively recruited patients with spontaneous ICH attending two Spanish stroke centers (January 2015-June 2019). Excluded were patients with lobar/infratentorial ICH and patients who died during hospitalization. We defined deep ICH without hypertension when the bleeding was in a deep structure, no requirement for antihypertensive agents during follow-up and no evident chronic hypertension markers evaluated by transthoracic echocardiography, 24 h ambulatory blood pressure monitoring and/or electrocardiography. We compared clinical, radiological, and 3-month functional outcome data for deep-ICH patients with hypertension versus those without hypertension. RESULTS: Of 759 patients with ICH, 219 (mean age 69.6 ± 15.4 years, 54.8% men) met the inclusion criteria and 36 (16.4%) did not have hypertension. Of these 36 patients, 19 (52.7%) had a transient hypertensive response. Independent predictors of deep ICH without hypertension were age (adjusted OR:0.94;95%CI:0.91-0.96) and dyslipidemia (adjusted OR:0.27;95% CI:0.08-0.85). One third of deep ICH without hypertension were secondary to vascular malformations. Favorable outcomes (modified Rankin Scale 0-2) were more frequent in patients with deep ICH without hypertension compared to those with hypertension (70.9% vs 33.8%; p < 0.001). CONCLUSION: Of patients with deep ICH, 16.4% were unrelated with hypertension, around half showed hypertensive response, and around a third had vascular malformations. We suggest studying hypertension markers and performing a follow-up brain MRI in those patients with deep ICH without prior hypertension.

The Role of Vascular Imaging atReferral Centers in the Drip and Ship Paradigm.

BACKGROUND: In drip-and-ship protocols, non-invasive vascular imaging (NIVI) at Referral Centers (RC), although recommended, is not consistently performed and its value is uncertain. We evaluated the role of NIVI at RC, comparing patients with (VI+) and without (VI-) vascular imaging in several outcomes. METHODS: Observational, multicenter study from a prospective government-mandated population-based registry of code stroke patients. We selected acute ischemic stroke patients, initially assessed at RC from January-2016 to June-2020. We compared and analyzed the rates of patients transferred to a Comprehensive Stroke Center (CSC) for Endovascular Treatment (EVT), rates of EVT and workflow times between VI+ and VI- patients. RESULTS: From 5128 ischemic code stroke patients admitted at RC; 3067 (59.8%) were VI+, 1822 (35.5%) were secondarily transferred to a CSC and 600 (11.7%) received EVT. Among all patients with severe stroke (NIHSS ≥16) at RC, a multivariate analysis showed that lower age, thrombolytic treatment, and VI+ (OR:1.479, CI95%: 1.117-1.960, p=0.006) were independent factors associated to EVT. The rate of secondary transfer to a CSC was lower in VI+ group (24.6% vs. 51.6%, p<0.001). Among transferred patients, EVT was more frequent in VI+ than VI- (48.6% vs. 21.7%, p<0.001). Interval times as door-in door-out (median-minutes 83.5 vs. 82, p= 0.13) and RC-Door to puncture (median-minutes 189 vs. 178, p= 0.47) did not show differences between both groups. CONCLUSION: In the present study, NIVI at RC improves selection for EVT, and is associated with receiving EVT in severe stroke patients. Time-metrics related to drip-and-ship model were not affected by NIVI.

Reasons for Not Performing Mechanical Thrombectomy: A Population-Based Study of Stroke Codes.

Background and Purpose: Mechanical thrombectomy (MT) is effective for acute ischemic stroke (AIS) in selected patients with large intracranial vessel occlusion. A minority of patients with AIS receive MT. We aimed to describe the reasons for excluding patients with AIS for MT. Methods: We evaluated patients with AIS in a prospective population-based multicenter registry (Codi Ictus Catalunya registry) that includes all stroke code activations from January to June 2018 in Catalonia, Spain. We analyzed the major reasons for not treating with MT. Results: Stroke code was activated in 3060 patients. Excluding 355 intracranial hemorrhages and 502 stroke mimics, resulted in 2203 patients with AIS (mean age 72.8±13.8 years; 44.6% were women). Of the patients with AIS, 405 (18.4%) were treated with MT. We analyzed the reasons for not treating with MT. The following reasons were considered not modifiable: absence of large intracranial vessel occlusion (922, 41.9%), transient ischemic attack (206, 9.4%), and more than one cause (124, 5.6%). The potentially modifiable reasons for not performing MT by changing selection criteria were as follows: an intracranial artery occlusion that was considered inaccessible or not indicated (48, 2.2%); clinical presentation that was considered too mild to be treated (222, 10.1%); neuroimaging criteria (129, 5.9%), age/prior modified Rankin Scale score/medical comorbidities (129, 5.9%), and therapeutic time window >8 hours (16, 0.7%). Conclusions: In our area, considering all potentially modifiable causes for not performing MT, the percentage of patients with AIS eligible for MT could increase from 18.4% to a maximum of 43.1%. The clinical benefit of this increase is still uncertain and should be confirmed in future trials. Criteria for stroke code activation must be considered for the generalizability of these results.

Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke: A Mendelian Randomization Study.

Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86­0.94]; q value=7.43×10−5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92­0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65­0.77]; q value=5.11×10−14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06­1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome.

BACKGROUND AND PURPOSE: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = ΔNIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. METHODS: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS6-24h was examined. Finally, the association of ΔNIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). RESULTS: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median ΔNIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS6-24h (R2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R2=0.27), but much of the variance remained unexplained. ΔNIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS3-24h was similarly associated with 90-day outcomes. CONCLUSIONS: The dynamic phenotype, ΔNIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

Impact of COVID-19 Infection on the Outcome of Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: We evaluated whether stroke severity, functional outcome, and mortality are different in patients with ischemic stroke with or without coronavirus disease 2019 (COVID-19) infection. METHODS: A prospective, observational, multicentre cohort study in Catalonia, Spain. Recruitment was consecutive from mid-March to mid-May 2020. Patients had an acute ischemic stroke within 48 hours and a previous modified Rankin Scale (mRS) score of 0 to 3. We collected demographic data, vascular risk factors, prior mRS score, National Institutes of Health Stroke Scale score, rate of reperfusion therapies, logistics, and metrics. Primary end point was functional outcome at 3 months. Favourable outcome was defined depending on the previous mRS score. Secondary outcome was mortality at 3 months. We performed mRS shift and multivariable analyses. RESULTS: We evaluated 701 patients (mean age 72.3±13.3 years, 60.5% men) and 91 (13%) had COVID-19 infection. Median baseline National Institutes of Health Stroke Scale score was higher in patients with COVID-19 compared with patients without COVID-19 (8 [3-18] versus 6 [2-14], P=0.049). Proportion of patients with a favourable functional outcome was 33.7% in the COVID-19 and 47% in the non-COVID-19 group. However, after a multivariable logistic regression analysis, COVID-19 infection did not increase the probability of unfavourable functional outcome. Mortality rate was 39.3% among patients with COVID-19 and 16.1% in the non-COVID-19 group. In the multivariable logistic regression analysis, COVID-19 infection was a risk factor for mortality (hazard ratio, 3.14 [95% CI, 2.10-4.71]; P<0.001). CONCLUSIONS: Patients with ischemic stroke and COVID-19 infection have more severe strokes and a higher mortality than patients with stroke without COVID-19 infection. However, functional outcome is comparable in both groups.

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.