scholarly journals Genome-wide association meta-analysis of functional outcome after ischemic stroke

Neurology ◽  
2019 ◽  
Vol 92 (12) ◽  
pp. e1271-e1283 ◽  
Author(s):  
Martin Söderholm ◽  
Annie Pedersen ◽  
Erik Lorentzen ◽  
Tara M. Stanne ◽  
Steve Bevan ◽  
...  

ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0–2 vs 3–6 and 0–1 vs 2–6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10−8.ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0–2 vs 3–6, p = 5.3 × 10−9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10−5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

Stroke ◽  
2021 ◽  
Author(s):  
Mouhammad A. Jumaa ◽  
Alicia C. Castonguay ◽  
Hisham Salahuddin ◽  
Ashutosh P. Jadhav ◽  
Kaustubh Limaye ◽  
...  

Background and Purpose: The safety and benefit of mechanical thrombectomy in the treatment of acute ischemic stroke patients with M2 segment middle cerebral artery occlusions remain uncertain. Here, we compare clinical and angiographic outcomes in M2 versus M1 occlusions in the STRATIS (Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke) Registry. Methods: The STRATIS Registry was a prospective, multicenter, nonrandomized, observational study of acute ischemic stroke large vessel occlusion patients treated with the Solitaire stent-retriever as the first-choice therapy within 8 hours from symptoms onset. Primary outcome was defined as functional disability at 3 months measured by dichotomized modified Rankin Scale. Secondary outcomes included reperfusion rates and rates of symptomatic intracranial hemorrhage. Results: A total of 984 patients were included, of which 538 (54.7%) had M1 and 170 (17.3%) had M2 occlusions. Baseline demographics were well balanced within the groups, with the exception of mean baseline National Institutes of Health Stroke Scale score which was significantly higher in the M1 population (17.3±5.5 versus 15.7±5.0, P ≤0.001). No difference was seen in mean puncture to revascularization times between the cohorts (46.0±27.8 versus 45.1±29.5 minutes, P =0.75). Rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction≥2b) were similar between the groups (91% versus 95%, P =0.09). M2 patients had significantly increased rates of symptomatic ICH at 24 hours (4% versus 1%, P =0.01). Rates of good functional outcome (modified Rankin Scale score of 0–2; 58% versus 59%, P =0.83) and mortality (15% versus 14%, P =0.75) were similar between the 2 groups. There was no difference in the association of outcome and onset to groin puncture or onset to successful reperfusion in M1 and M2 occlusions. Conclusions: In the STRATIS Registry, M2 occlusions achieved similar rates of successful reperfusion, good functional outcome, and mortality, although increased rates of symptomatic ICH were demonstrated when compared with M1 occlusions. The time dependence of benefit was also similar between the 2 groups. Further studies are needed to understand the benefit of mechanical thrombectomy for M2 occlusions. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02239640.


2021 ◽  
Vol 118 (47) ◽  
pp. e2107830118
Author(s):  
Andrey K. Shevchenko ◽  
Daria V. Zhernakova ◽  
Sergey V. Malov ◽  
Alexey Komissarov ◽  
Sofia M. Kolchanova ◽  
...  

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States–African American or United States–European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.


Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 357-364 ◽  
Author(s):  
Ravinder-Jeet Singh ◽  
Debabrata Chakraborty ◽  
Sadanand Dey ◽  
Aravind Ganesh ◽  
Abdulaziz Sulaiman Al Sultan ◽  
...  

Background and Purpose— Intraluminal thrombus (ILT) is an uncommon finding among patients with ischemic stroke. We report clinical-imaging manifestations, treatment offered, and outcome among patients with ischemic stroke/transient ischemic attack and ILT in their cervico-cephalic arteries. Methods— Sixty-one of 3750 consecutive patients with acute ischemic stroke/transient ischemic attack (within 24 hours of onset) and ILT on initial arch-to-vertex computed tomography angiography from April 2015 through September 2017 constituted the prospective study cohort. Functional outcome was assessed using the modified Rankin Scale score with functional independence at discharge defined as modified Rankin Scale score ≤2. Results— Prevalence of ILT on computed tomography angiography was 1.6% (95% CI, 1.2%–2.1%). Median age was 67 years (interquartile range, 56–73), and 40 subjects (65%) were male. The initial clinical presentation included transient ischemic attack in 12 (20%) and stroke in 49 patients (80%); most strokes (76%) were mild (National Institutes of Health Stroke Scale ≤5). The most common ILT location was cervical carotid or vertebral artery (n=48 [79%]) followed by intracranial (n=11 [18%]) and tandem lesions (n=2 [3%]). The most common initial treatment strategy was combination antithrombotics (heparin with single antiplatelet agent) among 57 patients (93%). Follow-up computed tomography angiography (n=59), after a median 6 days (interquartile range 4–10 days), revealed thrombus resolution in 44 patients (75% [completely in 27%]). Twenty four of 30 patients (80%) with >50% residual carotid stenosis underwent carotid revascularization (endarterectomy in 15 and stenting in 9 patients) without peri-procedural complications a median of 9 days after symptom onset. In-hospital stroke recurrence occurred in 4 patients (6.6%). Functional independence was achieved in 46 patients (75%) at discharge. Conclusions— Patients presenting with acute stroke/transient ischemic attack with ILT on baseline imaging have a favorable clinical course in hospital with low stroke recurrence, high rate of thrombus resolution, and good functional outcome when treated with combination antithrombotic therapy.


Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 498-500 ◽  
Author(s):  
Ole Morten Rønning ◽  
Nicola Logallo ◽  
Bente Thommessen ◽  
Håkon Tobro ◽  
Vojtech Novotny ◽  
...  

Background and Purpose— Thrombolysis with alteplase has beneficial effect on outcome and is safe within 4.5 hours. The present study compares the efficacy and safety of tenecteplase and alteplase in patients treated 3 to 4.5 hours after ischemic stroke. Methods— The data are from a prespecified substudy of patients included in The NOR-TEST (Norwegian Tenecteplase Stroke Trial), a randomized control trial comparing tenecteplase with alteplase. Results— The median admission National Institutes of Health Stroke Scale for this study population was 3 (interquartile range, 2–6). In the intention-to-treat analysis, 57% of patients that received tenecteplase and 53% of patients that received alteplase reached good functional outcome (modified Rankin Scale score of 0–1) at 3 months (odds ratio, 1.19; 95% CI, 0.68–2.10). The rates of intracranial hemorrhage in the first 48 hours were 5.7% in the tenecteplase group and 6.7% in the alteplase group (odds ratio, 0.84; 95% CI, 0.26–2.70). At 3 months, mortality was 5.7% and 4.5%, respectively. After excluding stroke mimics and patients with modified Rankin Scale score of >1 before stroke, the proportion of patients with good functional outcome was 61% in the tenecteplase group and 57% in the alteplase group (odds ratio, 1.24; 95% CI, 0.65–2.37). Conclusions— Tenecteplase is at least as effective as alteplase to achieve a good clinical outcome in patients with mild stroke treated between 3 and 4.5 hours after ischemic stroke. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01949948.


Neurology ◽  
2019 ◽  
Vol 94 (1) ◽  
pp. e97-e106 ◽  
Author(s):  
Robert-Jan B. Goldhoorn ◽  
Marie Louise E. Bernsen ◽  
Jeannette Hofmeijer ◽  
Jasper M. Martens ◽  
Hester F. Lingsma ◽  
...  

ObjectiveTo compare outcomes after endovascular treatment (EVT) for acute ischemic stroke with 3 different types of anesthetic management in clinical practice, as anesthetic management may influence functional outcome.MethodsData of patients with an anterior circulation occlusion, included in the Dutch nationwide, prospective Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry between March 2014 and June 2016, were analyzed. Patients were divided into 3 groups defined by anesthetic technique performed during EVT: local anesthesia only (LA), general anesthesia (GA), or conscious sedation (CS). Primary outcome was the modified Rankin Scale score at 90 days. To compare functional outcome between groups, we estimated a common odds ratio (OR) with ordinal logistic regression, adjusted for age, sex, prestroke modified Rankin Scale score, baseline NIH Stroke Scale score, collaterals, and time from onset to arrival at intervention center.ResultsA total of 1,376 patients were included. Performed anesthetic technique was LA in 821 (60%), GA in 381 (28%), and CS in 174 (13%) patients. Compared to LA, both GA and CS were associated with worse functional outcome on the modified Rankin Scale score at 90 days (GA cORadj 0.75; 95% confidence interval [CI] 0.58–0.97; CS cORadj 0.45; 95% CI 0.33–0.62). CS was associated with worse functional outcome than GA (cORadj 0.60; 95% CI 0.42–0.87).ConclusionsLA is associated with better functional outcome than systemic sedation in patients undergoing EVT for acute ischemic stroke. Whereas LA had a clear advantage over CS, this was less prominent compared to GA.Classification of evidenceThis study provides Class III evidence that for patients with acute ischemic stroke undergoing EVT, LA improves functional outcome compared to GA or CS.


Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3232-3240 ◽  
Author(s):  
Johanna M. Ospel ◽  
Bijoy K. Menon ◽  
Andrew M. Demchuk ◽  
Mohammed A. Almekhlafi ◽  
Nima Kashani ◽  
...  

Background and Purpose: Available data on the clinical course of patients with acute ischemic stroke due to medium vessel occlusion (MeVO) are mostly limited to those with M2 segment occlusions. Outcomes are generally better compared with more proximal occlusions, but many patients will still suffer from severe morbidity. We aimed to determine the clinical course of acute ischemic stroke due to MeVO with and without intravenous alteplase treatment. Methods: Patients with MeVO (M2/M3/A2/A3/P2/P3 occlusion) from the INTERRSeCT (The Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) and PRoveIT (Precise and Rapid Assessment of Collaterals Using Multi-Phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy) studies were included. Baseline characteristics and clinical outcomes were summarized using descriptive statistics. The primary outcome was a modified Rankin Scale score of 0 to 1 at 90 days, describing excellent functional outcome. Secondary outcomes were the common odds ratio for a 1-point shift across the modified Rankin Scale and functional independence, defined as modified Rankin Scale score of 0 to 2. We compared outcomes between patients with versus without intravenous alteplase treatment and between patients who did and did not show recanalization on follow-up computed tomography angiography. Logistic regression was used to provide adjusted effect-size estimates. Results: Among 258 patients with MeVO, the median baseline National Institutes of Health Stroke Scale score was 7 (interquartile range: 5–12). A total of 72.1% (186/258) patients were treated with intravenous alteplase and in 41.8% (84/201), recanalization of the occlusion (revised arterial occlusive lesion score 2b/3) was seen on follow-up computed tomography angiography. Excellent functional outcome was achieved by 50.0% (129/258), and 67.4% (174/258) patients gained functional independence, while 8.9% (23/258) patients died within 90 days. Recanalization was observed in 21.4% (9/42) patients who were not treated with alteplase and 47.2% (75/159) patients treated with alteplase ( P =0.003). Early recanalization (adjusted odds ratio, 2.29 [95% CI, 1.23–4.28]) was significantly associated with excellent functional outcome, while intravenous alteplase was not (adjusted odds ratio, 1.70 [95% CI, 0.88–3.25]). Conclusions: One of every 2 patients with MeVO did not achieve excellent clinical outcome at 90 days with best medical management. Early recanalization was strongly associated with excellent outcome but occurred in <50% of patients despite intravenous alteplase treatment.


2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Yamase ◽  
H Horibe ◽  
K Kato ◽  
M Oguri ◽  
T Fujimaki ◽  
...  

Abstract Background Given that substantial genetic components have been shown in ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), a heritability may be higher in early-onset than late-onset individuals with these conditions. Although genome-wide association studies have identified various genes and loci significantly associated with ischemic stroke, ICH, or intracranial aneurysm mainly in European ancestry populations, genetic variants that contribute to susceptibility to these disorders in Japanese individuals remain to be identified definitively. Purpose The purpose of the study was to identify genetic variants that confer susceptibility to ischemic stroke, ICH, or SAH in Japanese. We have now performed exome-wide association studies (EWASs) in early-onset subjects with these conditions and corresponding controls. Methods A total of 6649 individuals aged ≤65 years were examined. For the EWAS of ischemic or hemorrhagic stroke, 6224 individuals (450 subjects with ischemic stroke, 5774 controls) or 6179 individuals (261 subjects with ICH, 176 subjects with SAH, 5742 controls), respectively, were examined. EWASs were performed with the use of Illumina Human Exome-12 v1.2 DNA Analysis BeadChip or Infinium Exome-24 v1.0 BeadChip. To compensate for multiple comparisons of allele frequencies with ischemic stroke, ICH, or SAH, we applied a false discovery rate (FDR) of <0.05 for statistical significance of association. Results The relation of allele frequencies of 31,245 single nucleotide polymorphisms (SNPs) that passed quality control to ischemic stroke was examined with Fisher's exact test, and 31 SNPs were significantly (FDR <0.05) associated with ischemic stroke. The relation of allele frequencies of 31,253 or 30,970 SNPs to ICH or SAH, respectively, was examined with Fisher's exact test, and six or two SNPs were significantly (FDR <0.05) associated with ICH or SAH, respectively. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension and diabetes mellitus revealed that 12 SNPs were significantly [P <0.0004 (Bonferroni's correction, 0.05/124)] related to ischemic stroke. Similar analysis with adjustment for age, sex, and the prevalence of hypertension revealed that six or two SNPs were significantly [P <0.0016 (0.05/32)] related to ICH or SAH, respectively. After examination of linkage disequilibrium of identified SNPs and results of previous genome-wide association studies, we have newly identified HHIPL2, CTNNA3, LOC643770, UTP20, and TRIB3 as susceptibility loci for ischemic stroke, DNTTIP2 and FAM205A as susceptibility loci for ICH, and FAM160A1 and OR52E4 as such loci for SAH. Conclusion We have thus newly identified nine genes that confer susceptibility to early-onset ischemic stroke, ICH, or SAH. Determination of genotypes for the SNPs in these genes may prove informative for assessment of the genetic risk for ischemic stroke, ICH, or SAH in Japanese.


2020 ◽  
Vol 26 (4) ◽  
pp. 396-404
Author(s):  
Joseph T Marion ◽  
Seyed Mohammad Seyedsaadat ◽  
Jeffery J Pasternak ◽  
Alejandro A Rabinstein ◽  
David F Kallmes ◽  
...  

Purpose Compare functional outcomes of acute ischemic stroke patients undergoing embolectomy with either local anesthesia or conscious sedation. Secondarily, identify differences in hemodynamic parameters and complication rates between groups. Materials and methods Single institution, retrospective review of all acute ischemic stroke patients undergoing embolectomy between January 2014 and July 2018 ( n = 185). Patients receiving general anesthesia ( n = 27) were excluded. One-hundred and eleven of 158 (70.3%) composed the local anesthesia group, and 47 (29.7%) composed the conscious sedation group. Median age was 71 years (interquartile range 59–79). Seventy-eight (49.4%) were male. The median National Institute of Health stroke scale score was 17.5 (interquartile range 11–21). Hemodynamic, medication, complication, and functional outcome data were collected from the anesthesia protocol and medical records. Good functional outcome was defined as a three-month modified Rankin Scale < 2. A multivariate analysis was performed to estimate the association of anesthesia type on three-month modified Rankin Scale score. Results Three-month modified Rankin Scale score <2 was similar between groups ( p = 0.5). Patients receiving conscious sedation were on average younger than patients receiving local anesthesia ( p = 0.01). Conscious sedation patients were more likely to receive intravenous thrombolytic prior to embolectomy ( p = 0.025). The complication rate and hemodynamic parameters were similar between groups. Conclusion Functional outcome of acute ischemic stroke patients undergoing embolectomy appears to be similar for patients receiving local anesthesia and conscious sedation. This similarity may be beneficial to a future study comparing general anesthesia to local anesthesia and conscious sedation. The use of local anesthesia or conscious sedation does not significantly impact hemodynamic status.


Author(s):  
Adam A. Dmytriw ◽  
Mahmoud Dibas ◽  
Clemens M. Schirmer ◽  
Fabio Settecase ◽  
Manraj K. S. Heran ◽  
...  

Background Acute ischemic stroke (AIS) in the context of COVID‐19 has received considerable attention for its propensity to affect patients of all ages. We aimed to evaluate the effect of age on functional outcome and mortality following an acute ischemic event. Methods and Results A prospectively maintained database from comprehensive stroke centers in Canada and the United States was analyzed for patients with AIS from March 14 to September 30, 2020 who tested positive for SARS‐CoV‐2. The primary outcome was Modified Rankin Scale score at discharge, and the secondary outcome was mortality. Baseline characteristics, laboratory values, imaging, and thrombectomy workflow process times were assessed. Among all 126 patients with COVID‐19 who were diagnosed with AIS, the median age was 63 years (range, 27–94). There were 35 (27.8%) patients with AIS in the aged ≤55 years group, 47 (37.3%) in the aged 56 to 70 group, and 44 (34.9%) in the aged >70 group. Intravenous tissue plasminogen activator and thrombectomy rates were comparable across these groups, ( P =0.331 and 0.212, respectively). There was a significantly lower rate of mortality between each group favoring younger age (21.9% versus 45.0% versus 48.8%, P =0.047). After multivariable adjustment for possible confounders, a 1‐year increase in age was significantly associated with fewer instances of a favorable outcome of Modified Rankin Scale 0 to 2 (odds ratio [OR], 0.95; 95 CI%, 0.90–0.99; P =0.048) and higher mortality (OR, 1.06; 95 CI%, 1.02–1.10; P =0.007). Conclusions AIS in the context of COVID‐19 affects young patients at much greater rates than pre‐pandemic controls. Nevertheless, instances of poor functional outcome and mortality are closely tied to increasing age.


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