Unknown Onset Stroke Research Articles

Haemorrhage after thrombectomy with adjuvant thrombolysis in unknown onset stroke depends on high early lesion water uptake

Background and purposeIn wake-up stroke, CT-based quantitative net water uptake (NWU) might serve as an alternative tool to MRI to guide intravenous thrombolysis with alteplase (IVT). An important complication after...

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Abstract WP21: Intravenous Alteplase for Unknown Onset Stroke on Prior Antiplatelet Therapy: EOS Individual Participant Data

Introduction: Although prior antiplatelet therapy (APT) could potentially contribute to bleeding risk, the influence of prior APT on intravenous thrombolysis outcomes remains controversial. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke in patients receiving prior APT Methods: Patients with an acute stroke of unknown onset were evaluated using an individual patient-level database of randomized controlled trials comparing t-PA with placebo or standard care from the Evaluation of Unknown Onset Stroke Thrombolysis (EOS) trials. A favorable outcome was defined as a modified Rankin Scale of 0 to 1 at 90-days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) at 22 to 36 hours and 90-day mortality. Results: Baseline data on prior APT were available for 780 of 843 patients. Of these, 257 (32.9%) patients were receiving prior APT. Patients with prior APT were older (72 vs. 66 years), and had a higher prevalence of vascular risk factors than those without APT. Overall, there was no interaction between prior APT and treatment effects of alteplase (p interaction=0.23). A favorable outcome was observed in 55 of 125 (45%) patients with prior APT in the alteplase group and in 39 of 132 (30%) patients with prior APT in the control group (adjusted odds ratio [aOR], 2.41 [95% CI, 1.14-5.13]). sICH occurred in 7 patients (5.6%) in the alteplase group but in 1 patient (0.8%) of the controls (aOR, 10.82 [0.63-185.3]). 90-day mortality was observed in 6 patients (6.5%) in the alteplase group compared with 6 patients (6.1%) in the controls (aOR, 1.47 [0.25-8.78]). In patients without prior APT (n=523), favorable outcome was observed in 136 patients (51.3%) in the alteplase group and in 112 patients (45.3%) in the control group (aOR, 1.38 [0.90-2.11]). Additionally, no significant differences were found in terms of safety outcomes between the two groups (sICH: 3 [1.2%] vs. 1 [0.4%]; mortality: 13 [4.9%] vs. 3 [1.1%]). Conclusion: Intravenous alteplase exhibited efficacy for acute stroke without increasing the risks of symptomatic intracranial hemorrhage or mortality in patients with prior antiplatelet therapy.

Study to evaluate the outcome of acute stroke of unknown onset with last well seen less than twenty four hours in Indian population

Study to evaluate the outcome of acute stroke of unknown onset with last well seen less than twenty four hours in Indian population

Characteristics and outcomes of unknown onset stroke: The Japan Stroke Data Bank

BackgroundClinical outcomes of unknown onset stroke (UOS) are influenced by the enlargement of the therapeutic time window for reperfusion therapy. This study aimed to investigate and describe the characteristics and clinical outcomes of patients with UOS. MethodsPatients with acute ischemic stroke (AIS) who were admitted within 24 h of their last known well time, from January 2017 to December 2020, were included. Data were obtained from a long-lasting nationwide hospital-based multicenter prospective registry: the Japan Stroke Data Bank. The co-primary outcomes were the National Institutes of Stroke Scale (NIHSS) scores on admission and unfavorable outcomes at discharge, corresponding to modified Rankin Scale (mRS) scores of 3–6. ResultsOverall, 26,976 patients with AIS were investigated. Patients with UOS (N = 5783, 78 ± 12 years of age) were older than patients with known onset stroke (KOS) (N = 21,193, 75 ± 13 years of age). Age, female sex, higher premorbid mRS scores, atrial fibrillation, and congestive heart failure were associated with UOS in multivariate analysis. UOS was associated with higher NIHSS scores (median = 8 [interquartile range [IQR]: 3–19] vs. 4 [1–10], adjusted incidence rate ratio = 1.37 [95% CI: 1.35–1.38]) and unfavorable outcomes (52.1 vs. 33.6%, adjusted odds ratio = 1.27 [1.14–1.40]). Intergroup differences in unfavorable outcomes were attenuated among females (1.12 [0.95–1.32] vs. males 1.38 [1.21–1.56], P = 0.040) and in the subgroup that received reperfusion therapy (1.10 [0.92–1.33] vs. those who did not receive therapy 1.23 [1.08–1.39], P = 0.012). ConclusionsUOS was associated with unfavorable outcomes but to a lesser degree among females and patients receiving reperfusion therapy.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study

Introduction: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. Methods: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0–1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. Results: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954–1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932–0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989–0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9–96%) of the treatment effect. Conclusion: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Abstract TMP2: Intravenous Thrombolysis For Ischemic Stroke With Unknown Time Of Onset: Differences Between Wake-up Stroke And Non-wake-up Subtypes: EOS

Background: The unknown onset stroke can be categorized into two groups; wake-up stroke (WUS) and non-wake-up unwitnessed stroke with a time of onset unavailable due to aphasia, impaired consciousness, or cognitive impairment (non-wake-up unknown onset stroke, non-WUS). We aimed to assess the differences in efficacy and safety of intravenous thrombolysis (IVT) for these subgroups. Methods: Patients with an unknown onset stroke from the Evaluation of unknown Onset Stroke thrombolysis trials (EOS) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing IVT with placebo/standard treatment. A favorable outcome was defined as a modified Rankin Scale score 0-1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage (sICH) at 22-36 hours and 90-day mortality. The effect of IVT was compared between the treatment groups in the WUS and non-WUS with mixed-effect logistic-regression analysis. Results: A total of 634 patients (233 women [36.8%], median age 70 years [IQR 61-76]) were analyzed. In patients with non-WUS (n=92 [14%]), advanced age, atrial fibrillation, vessel occlusion on MRA and high NIHSS score were more prevalent (P<0.01 for each) than those with WUS (n=542 [86%]). Overall, no significant interaction was noted between the mode of onset and treatment effect (Pinteraction=0.782). In patients with WUS, a favorable outcome was more common in the IVT group than the control (149 [54.8%] vs. 117 [45.5%], adjusted OR: 1.45, 95% CI 1.01-2.11), death occurred in 11 [4.0%] and 5 [1.9%] (p=0.099), and sICH occurred in 5 [1.8%] and 1 [0.3%] (p=0.142). In patients with non-WUS, no significant difference was observed for a favorable outcome (16 [37.2%] vs. 14 [29.2%], aOR 1.73 [0.60-4.98]). One death and one sICH were reported in the IVT group, but none in the controls. Conclusions: The benefit of IVT was significant in patients with WUS. Excellent outcome was also numerically more prevalent in non-WUS but this did not reach significance, probably due to the lack of statistical power.

Basilar artery occlusion treated with mechanical thrombectomy in extended time window using diffusion-weighted imaging/fluid attenuated inversion recovery mismatch - a case report

Introduction. There are individual case reports and case-series in the literature that have applied diffusion-weighted imaging/ fluid attenuated inversion recovery mismatch and intravenous thrombolytic therapy in the treatment of posterior circulation strokes. This case report demonstrates the use of diffusion-weighted imaging/fluid attenuated inversion recovery mismatch in the treatment of basilar artery occlusion with mechanical thrombectomy. Case Report. A 68-year-old male patient presented with a wake-up stroke and a National Institutes of Health Stroke Scale score of 14. Computed tomography angiography showed an occlusion of the basilar artery. Diffusion-weighted imaging/fluid attenuated inversion recovery mismatch was established and mechanical thrombectomy was performed. Complete reperfusion was achieved. Mechanical thrombectomy was performed in the 16th hour from the onset of symptoms. After the intervention, the patient?s National Institutes of Health Stroke Scale score was 9. The patient was discharged without any neurological symptoms and a score of 0 on the modified Rankin Scale. Conclusion. Diffusion- weighted imaging/fluid attenuated inversion recovery mismatch may be a useful criterion for the selection of patients with basilar artery occlusion and unknown-onset strokes who are to be treated with mechanical thrombectomy.

Intravenous thrombolytic therapies in the management of unknown onset and wakeup strokes: A scoping review

Background : The efficacy and safety of thrombolytic therapies for the management of unknown time onset stroke (UTOS) and wake-up stroke (WUS) are in a debate. 
 Objective: The objective of this scoping review is to map the existing research literature to answer the research question: What is the efficacy and safety of intravenous thrombolysis in the management of unknown time onset stroke? 
 Data Sources: The literature search was conducted using the search terms {(Intravenous thrombolysis)} AND {(Unknown time onset stroke)} in pub med and Intravenous thrombolysis *, Unknown time onset stroke *in Cochrane. The review was limited to articles written in the English language. Databases searched included MEDLINE, PubMed and Cochrane electronic databases complemented with a manual search.
 Study Selection and Data Extraction: 45 articles of potential relevance were selected. Out of them 14 were containing relevant information direct to the question. The analysis was conducted by charting descriptive numerical data and by content analysis of the narrative representations
 Results: From 14 relevant papers, 2 Retrospective observational, 2 case control, 1 pilot study, and 5 recent randomized control trials were included for critical appraisal and review writing.
 Conclusions: The penumbral mismatch in UTOS is a cogent method to recognize the patients for thrombolytic therapy without significant risk, but the appropriate imaging criteria to maximize the efficacy and minimize bleeding complications of thrombolytic treatment still has to be fully defined. Results from ongoing trials may be promising with the use of advanced imaging modalities in selected patients.

Ischemic stroke with unknown onset of symptoms: current scenario and perspectives for the future.

Stroke is a major cause of disability worldwide and a neurological emergency. Intravenous thrombolysis and mechanical thrombectomy are effective in the reperfusion of the parenchyma in distress, but the impossibility to determine the exact time of onset was an important cause of exclusion from treatment until a few years ago. To review the clinical and radiological profile of patients with unknown-onset stroke, the imaging methods to guide the reperfusion treatment, and suggest a protocol for the therapeutic approach. The different imaging methods were grouped according to current evidence-based treatments. Most studies found no difference between the clinical and imaging characteristics of patients with wake-up stroke and known-onset stroke, suggesting that the ictus, in the first group, occurs just prior to awakening. Regarding the treatment of patients with unknown-onset stroke, four main phase-three trials stand out: WAKE-UP and EXTEND for intravenous thrombolysis, and DAWN and DEFUSE-3 for mechanical thrombectomy. The length of the therapeutic window is based on the diffusion weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) mismatch, core-penumbra mismatch, and clinical core mismatch paradigms. The challenges to approach unknown-onset stroke involve extending the length of the time window, the reproducibility of real-world imaging modalities, and the discovery of new methods and therapies for this condition. The advance in the possibilities for the treatment of ischemic stroke, while guided by imaging concepts, has become evident. New studies in this field are essential and needed to structure the health care services for this new scenario.

Implementation of a wake-up and unknown symptom onset stroke protocol

Background: Establishing a symptom onset timeline for stroke patients is one of the essential aspects of thrombolytic therapy. Implementing an MRI protocol can potentially increase the rate of thrombolytic therapy and expand treatment to patients who would otherwise be excluded.Objective: This project aimed to increase the rate of thrombolytic therapy by incorporating an additional layer of evaluation within the established acute stroke code process for patients with wake-up stroke (WUS) or unknown symptom onset stroke.Methods: Patients 18 years of age and older who presented as WUS eligible for thrombolytic therapy underwent acute MRI. Patients with a diffusion weighted image and fluid attenuated inversion recovery mismatch (DWI-FLAIR Mismatch) on MRI were treated with thrombolytic therapy.Results: Chi-square test of independence showed patients who underwent the MRI protocol (N = 35) had a higher proportion of alteplase (tissue plasminogen activator,tPA) treatment when compared to a similar sample (N = 44) from 2019 acute stoke logs; ꭓ2 (1, N = 79) = 8.16, p = .006. Six patients received thrombolytic. Safety showed no symptomatic intracerebral hemorrhage (sICH) or deaths.

Detection of acute ischemic stroke and backtracking stroke onset time via machine learning analysis of metabolomics

The time window from stroke onset is critical for the treatment decision. However, in unknown onset stroke, it is often difficult to determine the exact onset time because of the lack of assessment methods, which can result in controversial and random treatment decisions. Previous studies have shown that serum biomarkers, in addition to imaging assessment, are useful for determining the stroke onset time. However, as yet there are no specific biomarkers or corresponding methodologies that are accurate and effective for determining the onset time of unknown onset stroke. Herein, we describe our novel advanced metabolites-based machine learning method (termed extreme gradient boost [XGBoost]) combined with recursive feature elimination, which accurately screened five metabolites from 1124 metabolites detected in serum. These metabolites were capable of both detecting acute ischemic stroke and backtracking the acute ischemic stroke onset time. To further investigate the pathological mechanisms of acute ischemic stroke, we also examined characteristic metabolites in different brain regions, and found two metabolites that could distinguish the core infarct area from the ischemic penumbra. Although this study is based on animal experiments, our machine learning framework and selected metabolites may provide a basis for clinical stroke evaluation and treatment.

Alteplase for Stroke With Unknown Onset Time in Chronic Kidney Disease: A Pooled Analysis of Individual Participant Data.

Although chronic kidney disease (CKD) is associated with worse stroke outcomes, data regarding the influence of CKD on intravenous thrombolysis outcomes are scarce. We sought to assess the efficacy and safety of intravenous thrombolysis for acute ischemic stroke with unknown onset time in patients with CKD. Patients with an acute stroke of unknown onset time from the EOS trials (Evaluation of Unknown Onset Stroke Thrombolysis) collaboration were evaluated using an individual patient-level database of randomized controlled trials comparing intravenous thrombolysis with placebo/standard treatment. CKD was defined as baseline estimated glomerular filtration rate of <60 ml/min/1.73m2 Mixed-effect logistic-regression analysis was performed to evaluate treatment effects. A favorable outcome was defined as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes were symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. Baseline data on renal function were available for 688 of 843 patients. Of these, CKD was present in 146 (21%), including 69 of 351 patients receiving alteplase and 77 of 337 patients receiving placebo/standard treatment. Overall, treatment with alteplase was associated with higher odds of favorable outcome, and CKD did not modify the treatment effect (Pinteraction=0.834). A favorable outcome was observed in 31 of 69 (46%) patients with CKD in the alteplase group and in 28 of 77 (36%) patients with CKD in the control group (adjusted odds ratio, 1.19 [95% CI, 0.55-2.58]). Among patients with CKD, symptomatic intracranial hemorrhage occurred in 2 patients (3%) in the alteplase group but in none of the controls (P=0.133). At 90 days, death was reported in 3 patients (4%) in the alteplase group compared with 2 patients (3%) in the controls (P=0.539). The present analysis indicates that the benefit of alteplase does not differ between stroke patients with unknown onset time with and without CKD, although the statistical power was lacking to confirm the efficacy in subgroups. This study only applies to mild-to-moderate or predialysis CKD.

Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke.

IntroductionHigher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase.MethodsWAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group.ResultsOf 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07).ConclusionHigher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested.Trial RegistrationClinicalTrials.gov Identifier: NCT01525290.

Wake-up stroke and unknown-onset stroke; occurrence and characteristics from the nationwide Norwegian Stroke Register.

Population-based knowledge of the characteristics of wake-up stroke and unknown-onset stroke is limited. We compared occurrence and characteristics of ischaemic and haemorrhagic wake-up stroke, unknown-onset stroke and known-onset stroke in a nationwide register-based study. We included patients registered in the Norwegian Stroke Register from 2012 through 2019. Age, sex, risk factors, clinical characteristics, acute stroke treatment and discharge destination were compared according to stroke type and time of onset. Of the 60,320 patients included, 11,451 (19%) had wake-up stroke, 11,098 (18.4%) had unknown time of onset and 37,771 (62.6%) had known symptom onset. The proportion of haemorrhagic stroke was lower among wake-up stroke patients (1107/11,451, 9.7%, 95% CI: 9.1-10.2) than for known-onset stroke (5230/37,771, 13.8%, 95% CI: 13.5-14.2) and for unknown-onset stroke (1850/11,098, 16.7%, 95% CI: 16.0-17.4). Mild stroke (NIHSS <5) was more frequent in ischaemic wake-up stroke (5364/8308, 64.6%, 95% CI: 63.5-65.5) than in known-onset (16,417/26,746, 61.4%, 95% CI: 60.8-62.0) and unknown-onset stroke (3242/5853, 55.4%, 95% CI: 54.1-56.7), while baseline characteristics were otherwise similar to known-onset stroke. Unknown-onset stroke patients were more often female, lived alone and had more severe strokes compared to wake-up stroke and known-onset stroke patients. Unknown-onset stroke patients were more often in need of community-based health care on discharge and had a higher in-hospital mortality. Ischaemic wake-up strokes shared baseline characteristics with known-onset strokes, but tended to be milder. Ischaemic unknown-onset stroke patients differed significantly from wake-up stroke, emphasising the importance of considering them as separate entities.

Acute Ischemic Stroke With Mild Symptoms-To Thrombolyse or Not to Thrombolyse?

Management of stroke with minor symptoms may represent a therapeutical dilemma as the hemorrhage risk of acute thrombolytic therapy may eventually outweigh the stroke severity. However, around 30% of patients presenting with minor stroke symptoms are ultimately left with disability. The objective of this review is to evaluate the current literature and evidence regarding the management of minor stroke, with a particular emphasis on the role of IV thrombolysis. Definition of minor stroke, pre-hospital recognition of minor stroke and stroke of unknown onset are discussed together with neuroimaging aspects and existing evidence for IV thrombolysis in minor strokes. Though current guidelines advise against the use of thrombolysis in those without clearly disabling symptoms due to a paucity of evidence, advanced imaging techniques may be able to identify those likely to benefit. Further research on this topic is ongoing.

Cerebral microbleeds development after stroke thrombolysis: A secondary analysis of the THAWS randomized clinical trial

Background and aim We determined to investigate the incidence and clinical impact of new cerebral microbleeds after intravenous thrombolysis in patients with acute stroke. Methods The THAWS was a multicenter, randomized trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with wake-up stroke or unknown onset stroke. Prescheduled T2*-weighted imaging assessed cerebral microbleeds at three time points: baseline, 22–36 h, and 7–14 days. Outcomes included new cerebral microbleeds development, modified Rankin Scale (mRS) ≥3 at 90 days, and change in the National Institutes of Health Stroke Scale (NIHSS) score from 24 h to 7 days. Results Of all 131 patients randomized in the THAWS trial, 113 patients (mean 74.3 ± 12.6 years, 50 female, 62 allocated to intravenous thrombolysis) were available for analysis. Overall, 46 (41%) had baseline cerebral microbleeds (15 strictly lobar cerebral microbleeds, 14 mixed cerebral microbleeds, and 17 deep cerebral microbleeds). New cerebral microbleeds only emerged in the intravenous thrombolysis group (seven patients, 11%) within a median of 28.3 h, and did not additionally increase within a median of 7.35 days. In adjusted models, number of cerebral microbleeds (relative risk (RR) 1.30, 95% confidence interval (CI): 1.17–1.44), mixed distribution (RR 19.2, 95% CI: 3.94–93.7), and cerebral microbleeds burden ≥5 (RR 44.9, 95% CI: 5.78–349.8) were associated with new cerebral microbleeds. New cerebral microbleeds were associated with an increase in NIHSS score ( p = 0.023). Treatment with alteplase in patients with baseline ≥5 cerebral microbleeds resulted in a numerical shift toward worse outcomes on ordinal mRS (median [IQR]; 4 [3–4] vs. 0 [0–3]), compared with those with &lt;5 cerebral microbleeds (common odds ratio 17.1, 95% CI: 0.76–382.8). The association of baseline ≥5 cerebral microbleeds with ordinal mRS score differed according to the treatment group ( p interaction = 0.042). Conclusion New cerebral microbleeds developed within 36 h in 11% of the patients after intravenous thrombolysis, and they were significantly associated with mixed-distribution and ≥5 cerebral microbleeds. New cerebral microbleeds development might impede neurological improvement. Furthermore, cerebral microbleeds burden might affect the effect of alteplase.

24-hour blood pressure variability and treatment effect of intravenous alteplase in acute ischaemic stroke.

To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke. In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke. BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76-4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43-2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26-7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34-2.10) in in the highest quintile. There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.ClinicalTrials.gov identifier NCT01525290.

Unknown Onset Stroke: Differences Between Patients with Wake-Up Stroke and Daytime-Unwitnessed Stroke

ObjectivesPatients with unknown onset stroke (UOS) can be categorized as wake-up stroke (WUS) and daytime-unwitnessed stroke (DUS). We sought to determine whether decisions for initial imaging modalities, frequency of mismatch findings, resulting treatment decisions and outcome differ between WUS and DUS patients. Materials and MethodsIn a retrospective analysis, all patients with UOS admitted to our Stroke Unit from January to December 2018 were evaluated and classified as either WUS or DUS. Results180 patients were included (74.4 % WUS, 25.6 % DUS). Compared to WUS patients, DUS patients received more often a non-contrast computed tomography initially (43.5 % vs. 24.6 %, p = 0.016). MR imaging was performed more frequently in WUS patients (53.7 % vs. 34.8 %, p = 0.027). The rate of mismatch findings in patients examined with either multimodal CT or MRI (126 patients, 101 WUS and 26 DUS) did not differ between the groups. Likewise, the rate of intravenous thrombolysis or mechanical thrombectomy was similar in both groups. DUS patients had more often severe neurological deficits at admission as defined by the National Institutes of Stroke Scale score (14.2 vs. 8.6, p < 0.001). ConclusionsPatients with DUS had disadvantages in mismatch-based treatment options due to initial imaging modalities. Current data do not support different treatment concepts in WUS and DUS patients. All UOS patients should initially be evaluated by either multimodal CT or MRI to open a chance to receive reperfusion therapy.

Effect of intravenous alteplase on post‐stroke depression in the WAKE UP trial

The aim was to study the effect of intravenous alteplase on the development of post-stroke depression (PSD) in acute stroke patients, and to identify predictors of PSD. This post hoc analysis included patients with unknown onset stroke randomized to treatment with alteplase or placebo in the WAKE-UP trial (ClinicalTrials.gov number, NCT01525290), in whom a composite end-point of PSD was defined as a Beck Depression Inventory ≥10, medication with an antidepressant, or depression recorded as an adverse event. Multiple logistic regression was used to identify predictors of PSD at 90days. Structural equation modelling was applied to assess the indirect effect of thrombolysis on PSD mediated by the modified Rankin Scale. Information on the composite end-point was available for 438 of 503 randomized patients. PSD was present in 96 of 224 (42.9%) patients in the alteplase group and 115 of 214 (53.7%) in the placebo group (odds ratio 0.63; 95% confidence interval 0.43-0.94; p=0.022; adjusted for age and National Institutes of Health Stroke Scale at baseline). Prognostic factors associated with PSD included baseline medication with antidepressants, higher lesion volume, history of depression and assignment to placebo. While 65% of the effect of thrombolysis on PSD were caused directly, 35% were mediated by an improvement of the mRS. Treatment with alteplase in patients with acute stroke resulted in lower rates of depression at 90days, which were only partially explained by reduced functional disability. Predictors of PSD including history and clinical characteristics may help in identifying patients at risk of PSD.