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.

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.

Microbleeds, Cerebral Hemorrhage, and Functional Outcome After Stroke Thrombolysis.

Background and Purpose- We assessed whether the presence, number, and distribution of cerebral microbleeds (CMBs) on pre-intravenous thrombolysis MRI scans of acute ischemic stroke patients are associated with an increased risk of intracerebral hemorrhage (ICH) or poor functional outcome. Methods- We performed an individual patient data meta-analysis, including prospective and retrospective studies of acute ischemic stroke treated with intravenous tissue-type plasminogen activator. Using multilevel mixed-effects logistic regression, we investigated associations of pre-treatment CMB presence, burden (1, 2-4, ≥5, and >10), and presumed pathogenesis (cerebral amyloid angiopathy defined as strictly lobar CMBs and noncerebral amyloid angiopathy) with symptomatic ICH, parenchymal hematoma (within [parenchymal hemorrhage, PH] and remote from the ischemic area [remote parenchymal hemorrhage, PHr]), and poor 3- to 6-month functional outcome (modified Rankin score >2). Results- In 1973 patients from 8 centers, the crude prevalence of CMBs was 526 of 1973 (26.7%). A total of 77 of 1973 (3.9%) patients experienced symptomatic ICH, 210 of 1806 (11.6%) experienced PH, and 56 of 1720 (3.3%) experienced PHr. In adjusted analyses, patients with CMBs (compared with those without CMBs) had increased risk of PH (odds ratio: 1.50; 95% confidence interval: 1.09-2.07; P=0.013) and PHr (odds ratio: 3.04; 95% confidence interval: 1.73-5.35; P<0.001) but not symptomatic ICH. Both cerebral amyloid angiopathy and noncerebral amyloid angiopathy patterns of CMBs were associated with PH and PHr. Increasing CMB burden category was associated with the risk of symptomatic ICH ( P=0.014), PH ( P=0.013), and PHr ( P<0.00001). Five or more and >10 CMBs independently predicted poor 3- to 6-month outcome (odds ratio: 1.85; 95% confidence interval: 1.10-3.12; P=0.020; and odds ratio: 3.99; 95% confidence interval: 1.55-10.22; P=0.004, respectively). Conclusions- Increasing CMB burden is associated with increased risk of ICH (including PHr) and poor 3- to 6-month functional outcome after intravenous thrombolysis for acute ischemic stroke.

Predictors of infarct growth after endovascular therapy for acute ischemic stroke.

BACKGROUND: Intra-arterial (IA) thrombectomy for acute ischemic stroke has an excellent recanalization rate but variable outcomes. The core infarct also grows at a variable rate despite recanalization. We aim to study the factors that are associated with infarct growth after IA therapy. METHODS: We reviewed the hyperacute ischemic stroke imaging database at Cleveland Clinic for those undergoing endovascular thrombectomy of anterior circulation from 2009 to 2012. Patients with both pretreatment and follow-up magnetic resonance imaging were included. Seventy-six patients were stratified into quartiles by infarct volume growth from initial to follow-up diffusion-weighted imaging (DWI) measure by a region of interest demarcation. RESULTS: The median infarct growth of each quartile was .6 cm(3) (no-growth group), 13.8, 37, and 160.2 cm(3) (large-growth group). Pretreatment stroke severity was comparable among groups. Compared with the no-growth group, the large-growth group had larger initial infarct defined by computed tomography (CT) Alberta Stroke Program Early CT score (median 10 versus 8, P = .032) and DWI volume (mean 13.8 versus 29.2 cm(3), P = .034), lack of full collateral vessels on CT angiography (36.8% versus 0%, P = .003), and a lower recanalization rate (thrombolysis in cerebral infarction ≥2b, P = .044). The increase in infarct growth is associated with decrease in favorable outcomes defined by a modified Rankin Scale score of 0-2 at 30 days: 57.9%, 42.1%, 21.1%, and 5.3%, respectively (P < .001). DWI reversal was observed in 11 of 76 patients, translating to 82% favorable outcome. CONCLUSIONS: Infarct evolution after endovascular thrombectomy is associated with an outcome. DWI reversal or no growth translated to a favorable outcome. Small initial ischemic core, good collateral support, and better recanalization grades predict the smaller infarct growth and favorable outcome after endovascular thrombectomy.

Cilostazol addition to aspirin may worsen the short-term outcome in patients with large artery disease: ADS subanalysis.

BACKGROUND: Our previous acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of neurological deterioration in non-cardioembolic stroke patients. In this post-hoc analysis, we investigated whether the impact of dual antiplatelet therapy (DAPT) may depend on neurological severity, as represented by large artery disease. METHODS: Neurological deterioration was defined as neurological progression with an increment of the National Institutes of Health Stroke Scale (NIHSS) score of ≥2. NIHSS score subgroups were divided into that of 0-1, 2-4, 5-10, and >10. RESULTS: Among 1014 patients, 203 (20%) had the large artery disease, and 811 (80%) did not. In the total cohort, the rate of neurological deterioration was 10.8% in the DAPT group and 8.3% in the aspirin group (P = 0.197). When we focused on the large artery disease group, DAPT group had a higher rate of neurological deterioration as 18.3% compared to 8.2% in the aspirin group (P = 0.036). Among patients with NIHSS score of 0-1 and 2-4, the rates of neurological deterioration were not different between the two group (both, P = 1.000). However, when NIHSS score elevated to 5-10, 45% in the DAPT group and 9.1% in the aspirin group deteriorated (P = 0.013). Among the patients with NIHSS score of >10, 60% in the DAPT group and none (0%) in the aspirin group had the neurological deterioration (P = 0.045). CONCLUSION: DAPT with aspirin and cilostazol was associated with higher rate of neurological deterioration when patients have large artery disease and not mild neurological deficits.

Intravenous Alteplase at 0.6 mg/kg for Unknown Onset Stroke with Prior Antithrombotic Medication: THAWS Randomized Clinical Trial.

AIM: This study aimed to assess the potential effect of prior antithrombotic medication for thrombolysis in an unknown onset stroke. METHODS: This was a predefined sub-analysis of the THAWS trial. Stroke patients with a time last known well ＞4.5 h who had a DWI-fluid-attenuated inversion recovery mismatch were randomly assigned (1:1) to receive alteplase at 0.6 mg/kg (alteplase group) or standard medical treatment (control group). Patients were dichotomized by prior antithrombotic medication. RESULTS: Of 126 patients (intention-to-treat population), 40 took antithrombotic medication (24 with antiplatelets alone, 13 with anticoagulants alone, and 3 with both), and the remaining 86 did not before stroke onset. Of these, 17 and 52 patients, respectively, received alteplase, and 23 and 34, respectively, had standard medical treatment. Antithrombotic therapy was initiated within 24 h after randomization less frequently in the alteplase group (12% vs. 86%, p＜0.01). Both any intracranial hemorrhage within 22-36 h (26% vs. 14%) and a modified Rankin Scale score of 0-1 at 90 days (good outcome) (47% vs. 48%) were comparable between the two groups. A good outcome was more common in the alteplase group than in the control group in patients with prior antithrombotic medication [relative risk (RR) 2.25, 95% confidence interval (CI) 1.02-4.99], but it tended to be less common in the alteplase group in those without (RR 0.69, 95% CI 0.46-1.03) (p＜0.01 for interaction). The frequency of any intracranial hemorrhage did not significantly differ between the two groups in any patients dichotomized by prior antithrombotic medication. CONCLUSION: Alteplase appears more beneficial in patients with prior antithrombotic medication.

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 <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.

[A case of neurogenic pulmonary edema due to left internal carotid artery occlusion].

A 79-year-old woman developed consciousness disturbance, left eye deviation, right hemiplegia and aphasia with hypoxemia. Chest X-ray showed bilateral pulmonary edema. MRI revealed the left internal carotid artery occlusion and entire left middle cerebral artery infarct including insular cortex. We performed mechanical thrombectomy therapy and TICI3 recanalization was obtained. During operation, the respiratory condition deteriorated and the ventilator was started after mechanical thrombectomy therapy. Chest X-ray showed butterfly shadow, which indicated pulmonary edema. Pulmonary edema improved on the 2nd day of onset, and disappeared on the 3rd day. There was no heart diseases such as Takotsubo myocardiopathy, acute cardiac failure and cardiomyopathy on echocardiography and electrocardiography. Therefore, we diagnosed her as having neurogenic pulmonary edema due to cerebral infarction including insular cortex. We consider that left insular cortex infarction was a trigger of neurogenic pulmonary edema. If hypoxemia associated with infarction including the insular cortex, neurogenic pulmonary edema should be considered for medical treatment.

A Case of Brain Abscess Caused by Actinomyces Cardiffensis and Parvimonas Micra.

Brain abscesses occur in 0.3-1.3 per 100,000 worldwide each year with 0.4-0.9 in Japan alone. Most of the causes are direct infection from a nearby infectious lesion and are rarely caused by an odontogenic infection. Here, we reported a case of brain abscess suspected to be associated with odontogenic infection. The patient was a 55-year-old woman. Blurred eyes and pain in the left eye noted, for which she consulted an ophthalmologist, but her eyes were normal. She was conscious and was able to converse clearly, but she could not read the letters and had difficulty in writing at the time of admission. A brain abscess was diagnosed based on the head magnetic resonance imaging (MRI) and clinical course, and a small craniotomy abscess drainage was performed. A. cardiffensis and P. micra were detected in the abscess, suggesting the involvement of periodontal disease bacteria. After the surgery, antimicrobial treatment was performed for about 2 months. At the same time, perioperative treatment was performed. On the 70th day after the surgery, tooth extraction, which was considered as the source of infection, was performed. The patient was discharged 74 days after surgery. A good turning point was obtained without relapse of symptoms.

Computational fluid dynamics analysis for the preoperative prediction of airway changes after maxillomandibular advancement surgery.

Maxillomandibular advancement surgery is useful for treatment of sleep apnea. However, preoperative analysis and evaluation to facilitate decision-making regarding the direction and distance of maxillomandibular movement has primarily consisted of morphological analysis; physiological function is not evaluated. To improve preoperative prediction, this study used fluid simulation to investigate the characteristics and effects of airway changes associated with maxillomandibular movement. A one-dimensional model with general applicability was thus developed. Actual measurements of flow in patients were used in this fluid simulation, thus achieving an analysis closer to clinical conditions. The simulation results were qualitatively consistent with the actual measurements, which confirmed the usefulness of the simulation. In addition, the results of the one-dimensional model were within the error ranges of the actual measurements. The present results establish a foundation for using accumulating preoperative measurement data for more-precise prediction of postoperative outcomes.

Dramatic changes of a DWI lesion in a patient with acute ischemic stroke treated with IV t-PA.

A diffusion-weighted imaging (DWI) lesion changed dramatically in a hyperacute stroke case treated with intravenous tissue-plasminogen activator (IV t-PA). The initial hyperintense lesion on DWI disappeared completely immediately after IV t-PA treatment without improvement of neurological symptoms. However, the lesion reappeared 24 hours later. Successful thrombolysis can resolve DWI lesions but does not always improve the neurological symptoms.