Neurological Prognostic Factors in Hospitalized Patients with COVID-19.

We aimed to search whether neurological symptoms or signs (NSS) and the MEWS (Modified Early Warning Score) score were associated with in-hospital mortality or oxygen requirement during the first 14 days of hospitalization in COVID-19 patients recruited at the University Hospital in Krakow, Poland. The detailed clinical questionnaires on twenty NSS were either filled out by patients prospectively or retrospectively assessed by neurologists based on daily medical records. NSS were considered high or low-risk if they were associated with increased or decreased mortality in the univariable analysis. This cohort study included 349 patients with COVID-19 (median age 64, interquartile range (51-77), women 54.72%). The presence of high-risk NSS (decreased level of consciousness, delirium, seizures, and symptoms of stroke or transient ischemic attack) or its combination with the absence of low-risk NSS (headache, dizziness, decreased mood, and fatigue) increased the risk of in-hospital mortality in SARS-CoV-2 infection 3.13 and 7.67-fold, respectively. The presence of low-risk NSS decreased the risk of in-hospital mortality in COVID-19 patients more than 6-fold. Death in patients with SARS-CoV-2 infection, apart from NSS, was predicted by older age, neoplasm, and higher MEWS scores on admission. High-risk NSS or their combination with the absence of low-risk NSS increased the risk of oxygen requirement during hospitalization in COVID-19 patients 4.48 and 1.86-fold, respectively. Independent predictors of oxygen therapy during hospitalization in patients with SARS-CoV-2 infection were also older age, male sex, neoplasm, and higher MEWS score on admission.

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.

Prognostic significance of age in patients with acute ischaemic stroke treated with intravenous thrombolysis.

AIM OF THE STUDY: To assess the influence of age on long-term functional outcome in patients with acute ischaemic stroke (AIS) treated with intravenous thrombolysis (IVT). MATERIAL AND METHODS: We performed retrospective analysis of 362 AIS patients treated with IVT or IVT and subsequent mechanical thrombectomy in the University Hospital in Krakow, Poland. Patients were categorised into four subgroups by age: (I) below the age of 60, (II) 60 to 69, (III) 70 to 79, and (IV) 80 or more. The outcomes were assessed with modified Rankin scale (mRS) 90 days after stroke onset, and defined as favourable (mRS 0-2), poor (mRS 3-5), or death (mRS = 6). RESULTS: Patients aged 80 or more compared to those below 60 were more often women (72.64% vs. 26.76%, < 0.001), more often suffered from hypertension (94.34% vs. 60.56%, p < 0.001), ischaemic heart disease (27.36% vs. 8.45%, p = 0.002), atrial fibrillation (49.06% vs. 5.63%, p < 0.001), and premorbid disability (pre-stroke mRS ≥ 1: 17.92% vs. 1.41%, p < 0.001), less often were active smokers (0% vs. 27.14%, p < 0.001), more often had cardioembolic aetiology (50.00% vs. 16.90%, p < 0.001), and less often other stroke aetiology (1.89% vs. 15.49%, < 0.008), had shorter time from stroke onset to IVT (125 [93-180] vs. 140 [110-186] min, p < 0.008), less often underwent mechanical thrombectomy (18.87% vs. 46.48%, p < 0.001), had higher CRP levels (10.3 [3.2-39.8] vs. 4.3 [2.1-9.6] mg/L, p = 0.003), higher maximal systolic blood pressure within 24 hours after IVT (153 [140-170] vs. 138 [120-145] mmHg, p < 0.001), and higher creatinine concentration (88 [68-108] vs. 77 [67-87] µmol/l, p = 0.004), less often had a favourable outcome (48.04% vs. 85.51%, odds ratio [OR] 0.16, 95%CI: 0.07-0.34, p < 0.001), and had a greater risk of death (26.47% vs. 5.80%, OR 5.85, 95%CI: 1.95-17.59, p < 0.001) within three months of stroke onset. Multivariable logistic regression analysis showed that the independent predictors of worse outcome in patients aged 80 or more were NIHSS score after IVT (OR 0.64, 95%CI: 0.53-0.78, p < 0.001), pre-stroke mRS score ≥ 1 (OR 0.10, 95%CI: 0.02-0.61, p = 0.012), and CRP levels (OR 0.96, 95%CI: 0.93-0.99, p = 0.007). CONCLUSIONS: AIS patients treated with reperfusion therapy and aged 80 or more have around a six times higher risk of an unfavourable outcome or death within three months of stroke onset compared to those aged below 60. Higher NIHSS score after IVT, any signs of disability before stroke as measured with mRS, and higher CRP levels are independent risk factors for worse prognosis in the elderly.

The prognostic significance of large vessel occlusion in stroke patients treated by intravenous thrombolysis.

PURPOSE: According to guidelines, to shorten the treatment window, acute ischaemic stroke (AIS) treatment by intravenous thrombolysis (IVT) can be done based on the results of head computed tomography (CT) without contrast. The impact of large vessel occlusion (LVO) on computed tomography angiography (CTA) in stroke prognosis in patients treated IVT or IVT and mechanical thrombectomy (MT), where indicated, has not yet been studied systematically. We investigated the influence of LVO in consecutive AIS patients on haemorrhagic transformation (HT) on CT 24 h after treatment, mRS < 2 on discharge (unfavourable outcome), and in-hospital mortality. MATERIAL AND METHODS: We analysed several parameters within 24 h after AIS: demographics, risk factors, mRS score pre-stroke, NIHSS upon admission and 24 h later, several clinical and biochemical parameters, and chronic treatment. RESULTS: We registered 1209 patients, of whom 362 (29.9%) received IVT and 108 had MT, where indicated. Admission CTA showed LVO in 197 patients (54.4%). Multivariate regression analysis showed that the presence of LVO and lower delta NIHSS (NIHSS on admission minus NIHSS 24 hours later) were independent parameters affecting HT risk. Multivariate analysis showed that the presence LVO and also older age, female sex, lower delta NIHSS, HT, stroke-associated infection, CRP levels ≥ 10 mg/L, and higher WBC count affected unfavourable outcome on discharge. LVO did not affect in-hospital mortality. CONCLUSIONS: LVO in AIS patients treated by IVT or IVT and MT affects the risk of HT and unfavourable short-term outcome but not in-hospital mortality.

Fasting Normoglycemia after Intravenous Thrombolysis Predicts Favorable Long-Term Outcome in Non-Diabetic Patients with Acute Ischemic Stroke.

BACKGROUND: Only a few studies evaluated the role of fasting glucose levels after intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS). Importantly, formal analysis concerning the prognostic role of fasting glucose levels in these patients with and without diabetes mellitus (DM) was not performed. Therefore, we assessed whether fasting normoglycemia (FNG) next morning after AIS treated with IVT was associated with 90-day functional outcome in diabetic and non-diabetic patients. METHODS: We retrospectively analyzed 362 AIS patients treated with IVT at The University Hospital in Krakow. FNG was defined as glucose below 5.5 mmol/L. A favorable outcome was defined as modified Rankin score (mRS) of 0-2 at day 90 after AIS onset. RESULTS: At 3-month follow-up, FNG was associated with favorable outcome (87.5% vs. 60.8%, p < 0.001) and decreased risk of death (3.1% vs. 18.1%, p = 0.002). Independent predictors of a favorable outcome for the whole group were: younger age (HR 0.92, 95%CI 0.89-0.95), lower NIHSS score after IVT (HR 0.70, 95%CI 0.65-0.76), lower maximal systolic blood pressure within 24 h after IVT (HR 0.92, 95%CI 0.89-0.95) and FNG (HR 4.12, 95%CI 1.38-12.35). Association between FNG and mortality was found in univariable (HR 1.47, 95%CI 0.04-0.62) but not in multivariable analysis (HR 0.23, 95%CI 0.03-1.81). In subgroup analyses, FNG was an independent predictor of favorable outcome (HR 5.96, 95%CI 1.42-25.1) only in patients without DM. CONCLUSIONS: FNG next morning after IVT is an independent protective factor for a favorable long-term outcome in non-diabetic AIS patients.

C-Reactive Protein and White Blood Cell Count in Non-Infective Acute Ischemic Stroke Patients Treated with Intravenous Thrombolysis.

Background: Previous studies on inflammatory biomarkers in acute ischemic stroke (AIS) produced divergent results. We evaluated whether C-reactive protein (CRP) and white blood cell count (WBC) measured fasting 12-24 h after intravenous thrombolysis (IVT) were associated with outcome in AIS patients without concomitant infection. Methods: The study included 352 AIS patients treated with IVT. Excluded were patients with community-acquired or nosocomial infection. Outcome was measured on discharge and 90 days after stroke onset with the modified Rankin scale (mRS) and defined as poor outcome (mRS 3-6) or death (mRS = 6). Results: Final analysis included 158 patients (median age 72 years (interquartile range 63-82), 53.2% (n = 84) women). Poor outcome on discharge and at day 90 was 3.8-fold and 5.8-fold higher for patients with CRP ≥ 8.65 mg/L (fifth quintile of CRP), respectively, compared with first quintile (<1.71 mg/L). These results remained significant after adjustment for potential confounders (odds ratio (OR) on discharge = 10.68, 95% CI: 2.54-44.83, OR at day 90 after stroke = 7.21, 95% CI: 1.44-36.00). In-hospital death was 6.3-fold higher for patients with fifth quintile of CRP as compared with first quintile and remained independent from other variables (OR = 4.79, 95% CI: 1.29-17.88). Independent predictors of 90-day mortality were WBC < 6.4 × 109 /L (OR = 5.00, 95% CI: 1.49-16.78), baseline National Institute of Health Stroke Scale (NIHSS) score (OR = 1.13 per point, 95% CI: 1.01-1.25) and bleeding brain complications (OR = 5.53, 95% CI: 1.59-19.25) but not CRP ≥ 8.65 mg/L. Conclusions: Non-infective CRP levels are an independent risk factor for poor short- and long-term outcomes and in-hospital mortality in AIS patients treated with IVT. Decreased WBC but not CRP is a predictor for 90-day mortality.

Prognostic Significance of Stroke-Associated Infection and other Readily Available Parameters in Acute Ischemic Stroke Treated by Intravenous Thrombolysis.

OBJECTIVES: The impact of contracting stroke-associate infection (SAI) that requires antibiotic treatment after an acute ischemic stroke (AIS) treated with alteplase remains unclear. We studied the profiles of SAI in patients with AIS treated with alteplase toward identifying predictive factors and prognostic implications at 90 days post-stroke. METHODS: We analyzed 33 parameters readily available within 24 hours after AIS: demographics, risk factors, and several clinical and biochemical parameters. Outcome measures were mRS ≤ 2 and mortality 90 days post-stroke. RESULTS: 83 (23.6%) of 352 patients developed SAI. Multivariate logistic regression analysis showed that atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS (the difference between NIHSS score measured upon admission and 24 hours after later), CRP≥10 mg/L, and elevated WBC count affected SAI risk (model including CRP levels and WBC count) and atrial fibrillation, mRS above 0 pre-stroke, lower delta NIHSS, HT, and elevated fibrinogen levels affected SAI risk (model excluding CRP levels and WBC count). 231 patients (74.1%) had mRS ≤ 2 at day 90. Multivariate logistic regression analysis showed that younger age, no hypertension, mRS=0 pre-stroke, higher delta NIHSS, no HT, no SAI, and CRP<10 mg/L, were associated with mRS≤2 at day 90. 54 (15.3%) patients died within 90 days. Multivariate logistic regression analysis showed that pre-stroke mRS>0, lower delta NIHSS, HT, CRP≥10 mg/L, lower triglyceride levels affected the risk of death within 90 days. CONCLUSIONS: Several markers available within 24 hours post-stroke were predictive of SAI that requires antibiotic treatment. SAI affects long-term outcome but not mortality.

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.

Multi-ancestry genetic study in 5,876 patients identifies an association between excitotoxic genes and early outcomes after acute ischemic 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 NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% 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 loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23 , a pre-synaptic protein, and GRIA1 , a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke. RESEARCH INTO CONTEXT: Evidence before this study: No previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this study: This is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidence: The findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.

Time from stroke onset to groin puncture affects rate of recanalisation after mechanical thrombectomy: a real-life single centre experience.

AIM OF THE STUDY: We investigated whether the time elapsed between stroke onset and groin puncture (SO-GP) affects the rate of recanalisation as measured by the Thrombolysis in Cerebral Infarction (TICI) scale. CLINICAL RATIONALE FOR THE STUDY: There is no doubt that the effectiveness of thrombolysis in acute ischaemic stroke (AIS) is time-dependent. There is growing evidence that there is a correlation between SO-GP time and rate of recanalisation in patients treated by mechanical thrombectomy (MT). MATERIALS AND METHODS: This study was performed in patients treated in the Comprehensive Stroke Centre in Krakow that covers 3.5 million inhabitants. The following data was collected for this study: demographics, stroke risk factors, transportation (directly from home or via another hospital), admission NIHSS, IV rt-PA administration prior to MT, the number of passes used during MT, and SO-GP time. The favourable outcome measure was TICI 2b or 3. RESULTS: 223 patients (48.4% females; mean age: 66.0 ± 16.6 years) with anterior circulation strokes were treated by MT; 64.6% arrived directly from home. Mean admission NIHSS was 15.6 ± 5.3. IV rtPA was administered in 68.6% of patients. At least two thrombectomy passes were required in 20.6% of cases. Median SO-GP time was 240 minutes (IQR range: 180-305 minutes). Grade 3 or 2b TICI scores were obtained in 70.4% of patients. Univariate logistic regression showed that among all studied parameters, only NIHSS affected the rate of recanalisation, but in a multivariate logistic regression model, the only parameter that affected the rate of recanalisation was the SO-GP time (OR = 0.76; 95% CI: 0.60-0.98, p = 0.03). CONCLUSIONS AND CLINICAL IMPLICATIONS: We suggest that SO-GP time affects the rate of recanalisation in patients with MT.

Post-stroke infection in acute ischemic stroke patients treated with mechanical thrombectomy does not affect long-term outcome.

INTRODUCTION: The impact of an infection that requires antibiotic treatment (IRAT) after an acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT) remains unclear. AIM: Here, we studied the prevalence and the profile of IRAT in patients with AIS treated with MT, aiming to identify predictive factors and prognostic implications at 90 days after stroke. MATERIAL AND METHODS: We analyzed parameters available within 24 h after AIS including demographics, risk factors, National Institutes of Health Stroke Scale (NIHSS) upon admission and 24 h later, hemorrhagic transformation (HT) on computed tomography, and several clinical and biochemical markers. The outcome measures were the modified Rankin Scale (mRS) 0-2 and 90 days post-stroke mortality. RESULTS: We included 291 patients; in 184 (63.2%) patients MT was preceded by intravenous thrombolysis (IVT), and 83 (28.5%) patients developed IRAT. Multivariate analysis showed that male sex and hemorrhagic transformation on CT taken 24 h after stroke increased the risk of IRAT. We found that younger age, male sex, lower delta NIHSS, shorter time from stroke onset to groin puncture, better recanalization and a lack of hemorrhagic transformation on CT taken 24 h after stroke favorably affected outcome at day 90. Multivariate analysis showed that older age, higher delta NIHSS, unknown stroke etiology and lack of treatment with IVT were independent predictors of death up to day 90. Infection that required antibiotic treatment did not enter in the models for the studied outcome measures. CONCLUSIONS: In AIS patients treated with MT, IRAT is not an independent factor that affects favorable outcome or mortality 90 days after stroke.