Cerebral Small Vessel Disease Burden for Bleeding Risk during Antithrombotic Therapy: Bleeding with Antithrombotic Therapy 2 Study.

OBJECTIVE: This study was undertaken to determine the excess risk of antithrombotic-related bleeding due to cerebral small vessel disease (SVD) burden. METHODS: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. RESULTS: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient-years of follow-up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1-3). Incidence rate of major bleeding was 0.39 (per 100 patinet-years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26-13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99-43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08-2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13-10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02-6.35) significantly increased in SVD score 4 compared to score 0. INTERPRETATION: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774-787.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation.

BACKGROUND: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. METHODS: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. RESULTS: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. CONCLUSION: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.

Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes with Alteplase at 0.6 mg/kg in Clinical Practice: THAWS2 Study.

INTRODUCTION: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice. METHODS: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time >4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0-1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0-1 at 90 days, and change in NIHSS at 24 h from baseline. RESULTS: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75-16.25) at baseline to 5 (3-12.25) at 24 h after alteplase initiation (change, -4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of -8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge. CONCLUSIONS: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them.

Magnetic Resonance Imaging-Guided Intravenous Thrombolysis in Cardioembolic Stroke Patients With Unknown Time of Onset　- Subanalysis of the THAWS Randomized Control Trial.

BACKGROUND: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset.Methods and Results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis. CONCLUSIONS: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Sequential detection rates of intramural hematoma for diagnosing spontaneous intracranial artery dissection.

BACKGROUND AND PURPOSE: Spontaneous intracranial artery dissection (IAD) can be definitively diagnosed by detecting intramural hematoma (IMH) on arterial wall imaging. However, evidence of a time-dependent natural history for the development of radiological findings is lacking. Therefore, this study aimed to determine when imaging detects IAD. METHODS: We obtained data from our cohort databases between March 2011 and August 2018 on consecutive patients who had definite, probable, or possible IAD based on the multidisciplinary expert consensus criteria. We assessed IMH on initial and follow-up high-resolution three-dimensional T1-weighted imaging (HR-3D-T1WI). We retrospectively investigated the association between IMH detection and days from symptom onset to initial HR-3D-T1WI and compared the IMH detection rate with other definitive diagnostic arterial dissection findings. RESULTS: We analyzed 106 patients (mean age = 51 ± 13 years, 31 women) with at least initial HR-3D-T1WI data. The final diagnoses were definite, probable, and possible IAD in 83, 18, and 5 patients, respectively. IMHs were observed in 63 patients (59%, 95% confidence interval [CI] = 49%-69%). Overall IMH detection rate was 55% (95% CI = 45%-64%), 20% (95% CI = 3%-60%), 40% (95% CI = 21%-64%), and 50% (95% CI = 37%-63%) on the initial HR-3D-T1WI and Days 3, 7, and 13, respectively. Among 68 patients evaluated with digital subtraction angiography and HR-3D-T1WI, IMH was confirmed more frequently than other definitive diagnostic arterial dissection findings. CONCLUSIONS: The overall IMH detection rate on HR-3D-T1WI was >50% and peaked in 1-2 weeks. IMH was a frequently detectable finding for the diagnosis of IAD compared to other radiological findings.

Temporal Trajectory of Systolic Blood Pressure and Outcomes in Acute Intracerebral Hemorrhage: ATACH-2 Trial Cohort.

BACKGROUND: To highlight the heterogeneity of acute temporal blood pressure (BP) changes in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) and associations with the outcomes of intracerebral hemorrhage. METHODS: One thousand patients with acute intracerebral hemorrhage, who had been randomized to intensive (110-139 mm Hg) or standard (140-179 mm Hg) systolic BP (SBP) lowering with intravenous nicardipine in ATACH-2 from 2011 to 2015, were analyzed about temporal changes in hourly maximum SBP up to 24 hours after randomization using group-based trajectory modeling. Outcomes included death or disability (modified Rankin Scale score 4-6) at 3 months, neurological deterioration within 24 hours (≥2-point decrease in Glasgow Coma Scale score or ≥4-point increase in National Institutes of Health Stroke Scale score), and acute kidney injury (≥0.3 mg/dL within 48 hours or ≥1.5-fold increase in serum creatinine) within 7 days after onset. RESULTS: Group-based trajectory modeling revealed 4 SBP trajectory groups: moderate SBP (from ≈190 mm Hg at hospital arrival to 150-160 mm Hg after randomization; n=298), moderate-to-low SBP (from ≈190 mm Hg to <140 mm Hg; n=395), high-to-low SBP (from >210 mm Hg to <140 mm Hg; n=134), and high SBP (from >210 mm Hg to 160-170 mm Hg; n=173). Patients with intensive treatment accounted for 11.1%, 88.6%, 85.1%, and 1.7% of each group, respectively. Compared with the moderate-to-low SBP group, the high-to-low SBP group showed increased risks of death or disability at 3 months (adjusted odds ratio, 2.29 [95% CI, 1.24-4.26]) and acute kidney injury (adjusted odds ratio, 3.50 [95% CI, 1.83-6.69]), while no increase in neurological deterioration was seen in this group (adjusted odds ratio, 0.48 [95% CI, 0.20-1.13]). The moderate SBP and high SBP groups showed no significant risk differences for such outcomes. CONCLUSIONS: Data-driven observation using a group-based trajectory modeling approach may be useful to clarify the relationship between antihypertensive treatment, temporal SBP changes, and outcomes in acute intracerebral hemorrhage. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01176565.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Magnetic Resonance Imaging-Guided Thrombolysis (0.6 mg/kg) Was Beneficial for Unknown Onset Stroke Above a Certain Core Size: THAWS RCT Substudy.

BACKGROUND AND PURPOSE: We determined to identify patients with unknown onset stroke who could have favorable 90-day outcomes after low-dose thrombolysis from the THAWS (Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg) database. METHODS: This was a subanalysis of an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients with stroke with a time last-known-well >4.5 hours who showed a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg intravenously or standard medical treatment. The patients were dichotomized by ischemic core size or National Institutes of Health Stroke Scale score, and the effects of assigned treatments were compared in each group. The efficacy outcome was favorable outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. RESULTS: The median DWI-Alberta Stroke Program Early CT Score (ASPECTS) was 9, and the median ischemic core volume was 2.5 mL. Both favorable outcome (47.1% versus 48.3%) and any intracranial hemorrhage (26% versus 14%) at 22 to 36 hours were comparable between the 68 thrombolyzed patients and the 58 control patients. There was a significant treatment-by-cohort interaction for favorable outcome between dichotomized patients by ASPECTS on DWI (P=0.026) and core volume (P=0.035). Favorable outcome was more common in the alteplase group than in the control group in patients with DWI-ASPECTS 5 to 8 (RR, 4.75 [95% CI, 1.33-30.2]), although not in patients with DWI-ASPECTS 9 to 10. Favorable outcome tended to be more common in the alteplase group than in the control group in patients with core volume >6.4 mL (RR, 6.15 [95% CI, 0.87-43.64]), although not in patients with volume ≤6.4 mL. The frequency of any intracranial hemorrhage did not differ significantly between the 2 treatment groups in any dichotomized patients. CONCLUSIONS: Patients developing unknown onset stroke with DWI-ASPECTS 5 to 8 showed favorable outcomes more commonly after low-dose thrombolysis than after standard treatment. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02002325. URL: https://www.umin.ac.jp/ctr; Unique Identifier: UMIN000011630.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Oral Carriage of Streptococcus mutans Harboring the cnm Gene Relates to an Increased Incidence of Cerebral Microbleeds.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMB) are associated with stroke and cognitive impairment. We previously reported a high prevalence of CMB in people with Streptococcus mutans expressing Cnm, a collagen-binding protein in the oral cavity. S.mutans is a major pathogen responsible for dental caries. Repeated challenge with S.mutans harboring the cnm gene encoding Cnm induced cerebral bleeding in stroke-prone spontaneously hypertensive rats. The purpose of this longitudinal study is to examine the relationship of cnm-positive S.mutans to the development of CMB. METHODS: We retrospectively investigated patients with stroke receiving oral microbiological examination and head 3T magnetic resonance imaging evaluations twice in the period 2014 to 2019, allowing >180-day interval. Patients with cnm-positive S.mutans were compared with those without. Quasi-Poisson regression models were used to explore associations between cnm-positive S.mutans and the increase in number of CMB between the 2 magnetic resonance imaging scans. RESULTS: A total of 111 patients were identified; 21 (19%) with cnm-positive S.mutans and 90 (81%) without. Clinical history, including blood pressure and the use of antithrombotic agents, were comparable between the 2 groups. New CMB were more commonly observed in patients with cnm-positive S.mutans (52% versus 23%; P=0.008). The incidence of CMB was significantly higher in the group with cnm-positive S.mutans, especially in deep areas, (incidence rate ratios [95% CI], 5.1 [1.9-13.6] for CMB in any brain region; 15.0 [5.4-42.0] for deep CMB), which persisted after adjusting for age, sex, hypertension, and renal impairment (4.7 [1.8-11.9] for CMB in any brain region; 13.9 [4.3-44.5] for deep CMB). CONCLUSIONS: This study demonstrates that cnm-positive S.mutans is associated with an increased incidence of CMB. Treatment for cnm-positive S.mutans infection may be a novel microbiota-based therapeutic approach for stroke and cognitive impairment.

Sex Differences in Blood Pressure-Lowering Therapy and Outcomes Following Intracerebral Hemorrhage: Results From ATACH-2.

BACKGROUND AND PURPOSE: Evidence regarding sex differences in clinical outcomes and treatment effect following intracerebral hemorrhage is limited. Using the ATACH-2 trial (Antihypertensive Treatment in Intracerebral Hemorrhage-2) data, we explored whether sex disparities exist in outcomes and response to intensive blood pressure (BP)-lowering therapy. METHODS: Eligible intracerebral hemorrhage subjects were randomly assigned to intensive (target systolic BP, 110-139 mm Hg) or standard (140-179 mm Hg) BP-lowering therapy within 4.5 hours after onset. Relative risk of death or disability corresponding to the modified Rankin Scale score of 4 to 6 was calculated, and interaction between sex and treatment was explored. RESULTS: In total, 380 women and 620 men were included. Women were older, more prescribed antihypertensive drugs before onset, and had more lobar intracerebral hemorrhage than men. Hematoma expansion was observed less in women. After multivariable adjustment, the relative risk of death or disability in women was 1.19 (95% CI, 1.02-1.37, P=0.023). The relative risk of death or disability between intensive versus standard BP-lowering therapy was 0.91 (95% CI, 0.74-1.13) in women versus 1.13 (95% CI, 0.92-1.39) in men (P for interaction=0.11), with inconclusive Gail-Simmon test (P=0.16). CONCLUSIONS: Women had a higher risk of death or disability following intracerebral hemorrhage. The benefit of intensive BP-lowering therapy in women is inconclusive, consistent with the overall results of ATACH-2. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.

Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial.

Background and Purpose- We assessed whether lower-dose alteplase at 0.6 mg/kg is efficacious and safe for acute fluid-attenuated inversion recovery-negative stroke with unknown time of onset. Methods- This was an investigator-initiated, multicenter, randomized, open-label, blinded-end point trial. Patients met the standard indication criteria for intravenous thrombolysis other than a time last-known-well >4.5 hours (eg, wake-up stroke). Patients were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg or standard medical treatment if magnetic resonance imaging showed acute ischemic lesion on diffusion-weighted imaging and no marked corresponding hyperintensity on fluid-attenuated inversion recovery. The primary outcome was a favorable outcome (90-day modified Rankin Scale score of 0-1). Results- Following the early stop and positive results of the WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke), this trial was prematurely terminated with 131 of the anticipated 300 patients (55 women; mean age, 74.4±12.2 years). Favorable outcome was comparable between the alteplase group (32/68, 47.1%) and the control group (28/58, 48.3%; relative risk [RR], 0.97 [95% CI, 0.68-1.41]; P=0.892). Symptomatic intracranial hemorrhage within 22 to 36 hours occurred in 1/71 and 0/60 (RR, infinity [95% CI, 0.06 to infinity]; P>0.999), respectively. Death at 90 days occurred in 2/71 and 2/60 (RR, 0.85 [95% CI, 0.06-12.58]; P>0.999), respectively. Conclusions- No difference in favorable outcome was seen between alteplase and control groups among patients with ischemic stroke with unknown time of onset. The safety of alteplase at 0.6 mg/kg was comparable to that of standard treatment. Early study termination precludes any definitive conclusions. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02002325.

Left Atrial Size and Ischemic Events after Ischemic Stroke or Transient Ischemic Attack in Patients with Nonvalvular Atrial Fibrillation.

BACKGROUND: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism. RESULTS: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9-2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02-3.00). CONCLUSION: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.

Total small vessel disease score and functional outcomes following acute intracerebral hemorrhage.

BACKGROUND: Individual cerebral small vessel disease (SVD) markers are independent predictors for poor prognosis following intracerebral hemorrhage (ICH), however, the impact of the cumulative SVD burden on outcomes remains unclear. We aimed to investigate the association between the global SVD burden and functional outcomes following ICH. METHODS: We retrospectively evaluated a consecutive cohort of patients with ICH who underwent brain magnetic resonance imaging and magnetic resonance angiography, from a prospective registry. We identified the presence and severity of the SVD markers (cerebral microbleeds, lacunar infarctions, periventricular hyperintensities, and deep white matter hyperintensities) and summed them to obtain the modified total SVD score (0-4). Poor functional outcomes were defined as a modified Rankin Scale score at discharge ≥ 3. A multivariate logistic regression model was used to assess the association between patient outcomes and the SVD score. RESULTS: A total of 144 patients were included (65.0 ± 12.2 years, 67.4% male). The modified total SVD score was potentially associated with poor functional outcomes (odds ratio [OR] 1.72, 95% confidence interval [CI] 0.97-3.03) after adjustment for age, sex, history of stroke, chronic kidney disease, prior use of antithrombotic agents, the National Institutes of Health Stroke Scale score on admission, the non-lobar location of ICH, and hematoma volume on admission. Moreover, among older patients (≥ 65 years), the SVD score was associated with poor outcomes (OR 3.11, 95% CI 1.01-9.55). Among those with supratentorial ICH, the score remained significant (OR 2.06, 95% CI 1.11-3.83). CONCLUSIONS: The modified total SVD score may have predictive value for poor functional outcomes following ICH.

Effect of Enzyme Replacement Therapy on Basilar Artery Diameter in Male Patients With Fabry Disease.

Background and Purpose- The effect of enzyme replacement therapy (ERT) on cerebrovascular complications remains largely unexplored. We aimed to investigate the relationship between basilar artery (BA) diameter and long-term ERT in patients with Fabry disease. Methods- We obtained baseline magnetic resonance imaging data from 30 patients (40.5±16.3 years, male: 14) in the single institution; among them, 21 patients prospectively had follow-up magnetic resonance imaging assessments. The short axis of BA diameter was measured at the midpons level on axial T2-weighted images. Brain magnetic resonance imaging measurements included markers of cerebral small vessel disease (lacunas, white matter hyperintensities, and cerebral microbleeds). We assessed variables associated with baseline BA diameter and annual BA diameter change using linear regression analyses. Results- Hypertension, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities correlated with the initial BA diameter. After a mean interval of 7.2±4.6 years, the annual BA diameter change correlated positively with severe white matter hyperintensities and inversely with the duration of ERT (ß=-0.48, P=0.033). After stratifying patients by sex, a significant correlation between the duration of ERT and BA diameter was found only in men (ß=-0.72, P=0.019). Conclusions- Our results show a possible relationship between ERT and changes in BA diameter. Future studies to elucidate the clinical impact of BA changes as a potential surrogate marker are needed.

Magnetic Resonance Imaging Findings Related to Stroke Risk in Japanese Patients With Fabry Disease.

Background and Purpose- Stroke is the most frequent severe clinical event in patients with Fabry disease. We aimed to evaluate the cerebral magnetic resonance imaging findings of patients with Fabry disease and assess their association with future stroke risk after enzyme replacement therapy (ERT) induction. Methods- We retrospectively reviewed the magnetic resonance imaging findings of 25 patients with Fabry disease. Of these, 12 adult patients without prior stroke or ERT were enrolled to evaluate the association between baseline magnetic resonance imaging findings and stroke occurrence after ERT initiation. We assessed white matter hyperintensities, periventricular hyperintensities, and basilar artery diameter as neuroimaging markers. Results- The mean age of participants was 38.8±16.8 years. Fourteen patients (56.0%) were women. White matter hyperintensities and periventricular hyperintensities were observed in 15 and 13 cases, respectively. The mean basilar artery diameter was 3.2±0.55 mm. Two patients demonstrated old infarct lesions. Three of 12 patients in whom ERT was initiated had symptomatic stroke after baseline magnetic resonance imaging. Of these, 2 developed stroke within 6-month post-ERT initiation. The baseline basilar artery diameter was larger in patients who developed stroke than in those who did not (4.0±0.40 versus 2.9±0.49 mm, P=0.02). Conclusions- Basilar artery diameter may be associated with stroke risk after ERT initiation among Japanese patients with Fabry disease.

Cortical Cerebral Microinfarcts on 3T Magnetic Resonance Imaging in Patients With Carotid Artery Stenosis.

Background and Purpose- Carotid artery stenosis is common in the elderly and contributes to cognitive impairment and dementia. Cortical cerebral microinfarcts (CMIs) play an important role in vascular cognitive impairment and dementia. We aimed to investigate the association between CMIs on 3T magnetic resonance imaging and clinical and radiological features, including plaque morphology, and cognitive function in patients with carotid stenosis. Methods- Eighty-nine patients with >30% carotid stenosis on ultrasound were prospectively enrolled, and underwent brain and carotid artery magnetic resonance imaging. CMIs were rated according to predetermined criteria based on 3D-double inversion recovery and fluid-attenuated inversion recovery images. Results- CMIs were identified in 26 patients (29%; median number 0, range 0-9). Poisson regression models adjusted for age and sex revealed that CMIs were associated with intraplaque hemorrhage (rate ratio, 1.95; 95% CI, 1.26-3.18), lacunar infarcts (rate ratio, 1.54; 95% CI, 1.00-2.44), and cortical infarcts (rate ratio, 3.22; 95% CI, 2.20-5.00). These associations were also observed in asymptomatic patients (n=64). Of 81 patients with unilateral carotid stenosis, the prevalence and number of CMIs were significantly higher in the hemisphere ipsilateral to the carotid stenosis than in the contralateral hemisphere ( P=0.005 and P<0.001, respectively). The presence of CMIs was associated with poor cognitive function. Conclusions- Our results indicate that vulnerable carotid plaque increases the risk of CMIs and subsequent cognitive impairment. Carotid atherosclerosis could be a potential therapeutic target for cognitive impairment.

Clinical and Radiological Characteristics of Intracranial Artery Dissection Using Recently Proposed Diagnostic Criteria.

BACKGROUND: Data on the clinical and radiological characteristics of intracranial artery dissection (IAD) have remained limited. Our purpose was to reveal the clinical and radiological characteristics of IAD according to diagnostic criteria for IAD as recently reported by a group of international experts. METHODS: Patients were retrospectively enrolled using a prospective single-center stroke registry between 2011 and 2016. Baseline characteristics and radiological findings including conventional magnetic resonance imaging (MRI) sequences, magnetic resonance angiography (MRA), high-resolution 3-dimensional T1-weighted imaging (HR-3D-T1WI), and digital subtraction angiography were reviewed. We performed statistical comparisons to determine which findings from which modalities are useful. RESULTS: We identified 118 patients with suspected artery dissection, with 64 patients (median age, 51 [interquartile range, 45-56) years; 16 women) finally meeting the criteria for definite (n = 47), probable (n = 15), or possible (n = 2) idiopathic IAD. Ischemic stroke alone was found in 31 patients (48%) on admission. There were 36 patients (56%) suffering from hypertension and 39 (61%) with smoking history. The vertebral artery alone was the most affected in 42 patients (66%). Intramural hematoma (IMH) was more frequently detected on HR-3D-T1WI than on conventional MRI/MRA (odds ratio, 4.72; 95% confidence interval, 1.71-13.00). In 54 patients (84%), the modified Rankin Scale score after 3 months was 0-1. CONCLUSIONS: Male dominance and age at IAD onset were similar to previous studies, and more than half had hypertension and smoking history. We confirmed that HR-3D-T1WI is useful for detecting IMH in the diagnostic criteria.

Detection of Stenosis Progression in Intracranial Vertebral Artery Dissection Using Carotid Ultrasonography.

BACKGROUND: The purpose of this study was to assess whether carotid ultrasonography indices detect arterial stenosis progression in patients with vertebral artery (VA) dissection. METHODS: This was a retrospective, single-center, observational study that enrolled patients with intracranial VA dissection who were admitted from January 2011 to June 2017. Magnetic resonance angiography (MRA) was done on admission and followed up at a median 20 days after onset (interquartile range [IQR] 9-58 days), and ultrasonography was performed at a median of 22 (interquartile range 7-56) days. Peak systolic velocity (PSV), end-diastolic velocity (EDV), mean velocity (MV), and pulsatility index (PI) were measured by ultrasonography, and the ratio of each follow-up value to the baseline (follow-up/baseline) value was calculated. Two stroke neurologists categorized into 3 groups by morphological changes of the dissected vessel: patients with stenosis progression (progression group: P-group); those with no remarkable change or dilatation improved (stable group: S-group); and those with stenosis regression or dilatation enlargement (enlargement group: E-group). Ultrasonography indices were compared among the groups. RESULTS: Of the 42 patients who were enrolled to this study, 39 patients underwent ultrasonography and MRA on both admission and follow-up. The PI ratio was significantly higher in the P-group than in the S-group (1.96 ± .80 versus .98 ± .44, P = .02) and in the E-group (versus .65 ± .35, P < .01). There were no significant differences in the PSV ratio, EDV ratio, and MV ratio. CONCLUSIONS: In patients with VA dissection, the PI ratio on ultrasonography is a promising index to detect stenosis progression.