BACKGROUND AND PURPOSE: A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. MATERIALS AND METHODS: Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 +/- 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. RESULTS: Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 +/- 0.07 and 0.066 +/- 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). CONCLUSIONS: Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.
BACKGROUND: Current studies that analyze the usefulness of amino acid and FDG-PET in distinguishing brain metastasis recurrence and radionecrosis after radiation therapy are limited by small cohort size. PURPOSE: Our aim was to assess the diagnostic accuracy of amino acid and FDG-PET in differentiating brain metastasis recurrence from radionecrosis after radiation therapy. DATA SOURCES: Studies were retrieved from PubMed, Embase, and the Cochrane Library. STUDY SELECTION: Fifteen studies were included from the literature. Each study used PET to differentiate radiation necrosis from tumor recurrence in contrast-enhancing lesions on follow-up brain MR imaging after treating brain metastasis with radiation therapy. DATA ANALYSIS: Data were analyzed with a bivariate random-effects model. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were pooled, and a summary receiver operating characteristic curve was fit to the data. DATA SYNTHESIS: The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of PET were 0.85, 0.88, 7.0, 0.17, and 40, respectively. The area under the receiver operating characteristic curve was 0.93. On subgroup analysis of different tracers, amino acid and FDG-PET had similar diagnostic accuracy. Meta-regression analysis demonstrated that the method of quantification based on patient, lesion, or PET scan (based on lesion versus not, P = .07) contributed to the heterogeneity. LIMITATIONS: Our study was limited by small sample size, and 60% of the included studies were of retrospective design. CONCLUSIONS: Amino acid and FDG-PET had good diagnostic accuracy in differentiating brain metastasis recurrence from radionecrosis after radiation therapy.
BACKGROUND AND PURPOSE: The neonatal brain has active energy metabolism, and glucose oxidation is the major energy source of brain tissue. Lactate is produced by astrocytes and released to neurons. In the central nervous system, lactate is transported between neurons and astrocytes via the astrocyte-neuron lactate shuttle. The aim of this study was to investigate the regulatory mechanisms of energy metabolism in neurons and astrocytes in the basal ganglia of a neonatal hypoxic-ischemic brain injury piglet model. MATERIALS AND METHODS: A total of 35 healthy piglets (3-5 days of age; 1.0-1.5 kg) were assigned to a control group (n = 5) or a hypoxic-ischemic model group (n = 30). The hypoxic-ischemic model group was further divided into 6 groups according to the H-1-MR spectroscopy and PET/CT scan times after hypoxia-ischemia (0-2, 2-6, 6-12, 12-24, 24-48, and 48-72 hours; n = 5/group). H-1-MR spectroscopy data were processed with LCModel software. Maximum standard uptake values refer to the maximum standard uptake values for glucose (or FDG). The maximum standard uptake values of the basal ganglia-to-occipital cortex ratio were analyzed. The expression levels of glucose transporters and monocarboxylate transporters were detected by immunohistochemical analysis. RESULTS: Lactate levels decreased after an initial increase, with the maximal level occurring around 2-6 hours following hypoxia-ischemia. After hypoxia-ischemia, the maximum standard uptake values of the basal ganglia and basal ganglia/occipital cortex initially increased then decreased, with the maximum occurring at approximately 6-12 hours. The lactate and glucose uptake (basal ganglia/occipital cortex maximum standard uptake values) levels were positively correlated. The expression levels of glucose transporter-1 and glucose transporter-3 were positively correlated with the basal ganglia/occipital cortex. The expression levels of monocarboxylic acid transporter-2 and monocarboxylic acid transporter-4 were positively correlated with lactate content. CONCLUSIONS: The results indicate that lactate and glucose transporters have a synergistic effect on the energy metabolism of neurons and astrocytes following hypoxic-ischemic reperfusion brain injury.
One hundred thirty-one patients with histologically proved solid sinonasal lesions (56 benign and 75 malignant) who underwent conventional DWI and intravoxel incoherent motion were evaluated. The diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) values derived from intravoxel incoherent motion and ADC values derived from conventional DWI were measured and compared. The mean ADC and D values were significantly lower in malignant sinonasal lesions than in benign sinonasal lesions and the mean f value was higher in malignant than in benign lesions. Multiparametric models can significantly improve the cross-validated areas under the curve for the differentiation of sinonasal lesions compared with single-parametric models. The authors conclude that intravoxel incoherent motion appears to be a more effective MR imaging technique than conventional DWI in the differentiation of benign and malignant sinonasal lesions. BACKGROUND AND PURPOSE: Intravoxel incoherent motion is a promising method for the differentiation of sinonasal lesions. This study aimed to evaluate the value of intravoxel incoherent motion in the differentiation of benign and malignant sinonasal lesions and to compare the diagnostic performance of intravoxel incoherent motion with that of conventional DWI. MATERIALS AND METHODS: One hundred thirty-one patients with histologically proved solid sinonasal lesions (56 benign and 75 malignant) who underwent conventional DWI and intravoxel incoherent motion were recruited in this study. The diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) values derived from intravoxel incoherent motion and ADC values derived from conventional DWI were measured and compared between the 2 groups using the Student t test. Receiver operating characteristic curve analysis, logistic regression analysis, and 10-fold cross-validation were performed to evaluate the diagnostic performance of single-parametric and multiparametric models. RESULTS: The mean ADC and D values were significantly lower in malignant sinonasal lesions than in benign sinonasal lesions (both P < .001). The mean f value was higher in malignant lesions than in benign lesions (P = .003). Multiparametric models can significantly improve the cross-validated areas under the curve for the differentiation of sinonasal lesions compared with single-parametric models (all corrected P < .05 except the D value). The model of D+f provided a better diagnostic performance than the ADC value (corrected P < .001). CONCLUSIONS: Intravoxel incoherent motion appears to be a more effective MR imaging technique than conventional DWI in the differentiation of benign and malignant sinonasal lesions.
BACKGROUND AND PURPOSE: MR imaging can detect nasopharyngeal carcinoma that is hidden from endoscopic view, but for accurate detection carcinoma confined within the nasopharynx (stage T1) must be distinguished from benign hyperplasia of the nasopharynx. This study aimed to document the MR imaging features of stage T1 nasopharyngeal carcinoma and to attempt to identify features distinguishing it from benign hyperplasia. MATERIALS AND METHODS: MR images of 189 patients with nasopharyngeal carcinoma confined to the nasopharynx and those of 144 patients with benign hyperplasia were reviewed and compared in this retrospective study. The center, volume, size asymmetry (maximum percentage difference in area between the right and left nasopharyngeal halves), signal intensity asymmetry, deep mucosal white line (greater contrast enhancement along the deep tumor margin), and absence/distortion of the adenoidal septa were evaluated. Differences were assessed with logistic regression and the (2) test. RESULTS: The nasopharyngeal carcinoma center was lateral, central, or diffuse in 134/189 (70.9%), 25/189 (13.2%), and 30/189 (15.9%) cases, respectively. Nasopharyngeal carcinomas involving the walls showed that a deep mucosal white line was present in 180/183 (98.4%), with a focal loss of this line in 153/180 (85%) cases. Adenoidal septa were absent or distorted in 111/111 (100%) nasopharyngeal carcinomas involving the adenoid. Compared with benign hyperplasia, nasopharyngeal carcinoma had a significantly greater volume, size asymmetry, signal asymmetry, focal loss of the deep mucosal white line, and absence/distortion of the adenoidal septa (P < .001). Although size asymmetry was the most accurate criterion (89.5%) for nasopharyngeal carcinoma detection, use of this parameter alone would have missed 11.9% of early-stage T1 nasopharyngeal carcinomas. CONCLUSIONS: MR imaging features can help distinguish stage T1 nasopharyngeal carcinoma from benign hyperplasia in most cases.
BACKGROUND AND PURPOSE: Many studies have shown that insomnia is an independent factor in cognitive impairment, but the involved neurobiological mechanisms remain unclear. We used regional homogeneity to explore the specific neurobiologic indicators of chronic insomnia disorder with mild cognitive impairment. MATERIALS AND METHODS: Thirty-nine patients with insomnia were divided into a group with and without cognitive impairment; we also included a control group (n = 28). Abnormalities in brain functional activity were identified by comparing the regional homogeneity values for each brain region among the groups. RESULTS: Subjective insomnia scores were negatively correlated with cognitive impairment after controlling for age, sex, and educational effects. Regions with significant differences in regional homogeneity values in the 3 groups were concentrated in the right medial prefrontal cortex, the right superior frontal gyrus, and the left superior occipital gyrus. Meanwhile, subjective insomnia scores were negatively correlated with the strength of the decreased regional homogeneity in the right medial prefrontal cortex. The increased regional homogeneity value in the right superior frontal gyrus was positively correlated with the Montreal Cognitive Assessment score in patients. CONCLUSIONS: Our results indicate that decreased regional homogeneity values in the medial prefrontal cortex and increased regional homogeneity values in the cuneus may be important neurobiologic indicators of chronic insomnia disorder and accompanying cognitive impairment. Overall, our study described the regional homogeneity of the whole brain in chronic insomnia disorder with mild cognitive impairment and could be the basis for future studies.
BACKGROUND AND PURPOSE: The multisegment clot sign has been observed at the site of large-artery occlusion in patients with acute ischemic stroke. This study aimed to assess its occurrence rate and relationship with stroke etiologies in patients with acute intracranial large-artery occlusion. MATERIALS AND METHODS: We included consecutive patients with acute ischemic stroke who had acute intracranial large-artery occlusion and underwent perfusion CT within 8 hours after stroke onset. The multisegment clot sign was assessed on dynamic CT angiography derived from perfusion CT. The stroke etiologies were defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria. Poisson regression analyses and diagnostic testing were used to investigate the relationship between the multisegment clot sign and stroke etiologies. RESULTS: Finally, 194 patients with intracranial large-artery occlusion were enrolled. According to the Trial of Org 10172 in Acute Stroke Treatment criteria, 110 (56.7%) patients were diagnosed with cardioembolism; 43 (22.2%), with large-artery atherosclerosis; and 41 (21.1%), with undetermined etiology. The multisegment clot sign was found in 74 (38%) patients. Poisson regression analysis showed that the presence of the multisegment clot sign was significantly higher in patients with cardioembolism than in those with large-artery atherosclerosis (52.7% versus 9.3%; prevalence ratio, 1.53; 95% confidence interval, 1.03-2.90; P = .037). For determined etiologies, the sensitivity, specificity, and positive and negative predictive values of the multisegment clot sign for predicting cardioembolism were 52.7%, 90.7%, 93.5%, and 42.9%, respectively. CONCLUSIONS: The presence of the multisegment clot sign on dynamic CTA specifically indicates intracranial large-artery occlusion caused by an embolism from a cardiac source, which may be useful for acute management and secondary prevention of stroke.
BACKGROUND AND PURPOSE: Some retrospective studies have found that the aneurysm wall enhancement on high-resolution MR vessel wall postgadolinium T1WI has the potential to distinguish unstable aneurysms. This study aimed to identify hemodynamic characteristics that differ between the enhanced and nonenhanced areas of the aneurysm wall on high-resolution MR vessel wall postgadolinium T1WI. MATERIALS AND METHODS: TOF-MRA and high-resolution MR vessel wall T1WI of 25 patients were fused to localize the enhanced area of the aneurysm wall. Using computational fluid dynamics, we studied the aneurysm models. Mean static pressure, mean wall shear stress, and oscillatory shear index were compared between the enhanced and nonenhanced areas. RESULTS: The aneurysmal enhanced area had lower wall shear stress (P < .05) and a lower oscillatory shear index (P = .021) than the nonenhanced area. In addition, the whole aneurysm had lower wall shear stress (P < .05) and a higher oscillatory shear index (P = .007) than the parent artery. CONCLUSIONS: This study suggests that there are hemodynamic differences between the enhanced and nonenhanced areas of the aneurysm wall on high-resolution MR vessel wall postgadolinium T1WI.
BACKGROUND: There is ongoing debate regarding the optimal first-line thrombectomy technique for large-vessel occlusion. PURPOSE: We performed a systematic review and meta-analysis of comparative studies on stent retriever-first and aspiration-first thrombectomy. DATA SOURCES: We searched Ovid MEDLINE, PubMed, and EMBASE from 2009 to February 2018. STUDY SELECTION: Two reviewers independently selected the studies. The primary end point was successful reperfusion (TICI 2b/3). DATA ANALYSIS: Random-effects meta-analysis was used for analysis. DATA SYNTHESIS: Eighteen studies including 2893 patients were included. There was no significant difference in the rate of final successful reperfusion (83.9% versus 83.3%; OR = 0.87; 95% CI, 0.62%-1.27%) or good functional outcome (mRS 0-2) at 90 days (OR = 1.07; 95% CI, 0.80-1.44) between the stent-retriever thrombectomy and aspiration groups. The stent-retriever thrombectomy-first group achieved a statistically significant higher TICI 2b/3 rate after the first-line device than the aspiration-first group (74.9% versus 66.4%; OR = 1.53; 95% CI, 1.14%-2.05%) and resulted in lower use of a rescue device (19.9% versus 32.5%; OR = 0.36; 95% CI, 0.14%-0.90%). The aspiration-first approach resulted in a statistically shorter groin-to-reperfusion time (weighted mean difference, 7.15 minutes; 95% CI, 1.63-12.67 minutes). There was no difference in the number of passes, symptomatic intracerebral hemorrhage, vessel dissection or perforation, and mortality between groups. LIMITATIONS: Most of the included studies were nonrandomized. There was significant heterogeneity in some of the outcome variables. CONCLUSIONS: Stent-retriever thrombectomy-first and aspiration-first thrombectomy were associated with comparable final reperfusion rates and functional outcome. Stent-retriever thrombectomy was superior in achieving reperfusion as a stand-alone first-line technique, with lower use of rescue devices but a longer groin-to-reperfusion time.
BACKGROUND AND PURPOSE: Anti-N-methyl-D-aspertate receptor encephalitis is an autoimmune-mediated disease without specific brain MRI features. Our aim was to investigate the brain MR imaging characteristics of anti-N-methyl-D-aspartate receptor encephalitis and their associations with clinical outcome at a 2-year follow-up. MATERIALS AND METHODS: We enrolled 53 patients with anti-N-methyl-D-aspartate receptor encephalitis and performed 2-year follow-up. Brain MRIs were acquired for all patients at the onset phase. The brain MR imaging manifestations were classified into 4 types: type 1: normal MR imaging findings; type 2: only hippocampal lesions; type 3: lesions not involving the hippocampus; and type 4: lesions in both the hippocampus and other brain areas. The modified Rankin Scale score at 2-year follow-up was assessed, and the association between the mRS and onset brain MR imaging characteristics was evaluated. RESULTS: Twenty-eight (28/53, 53%) patients had normal MR imaging findings (type 1), and the others (25/53, 47%) had abnormal MRI findings: type 2: 7 patients (13%); type 3: seven patients (13%); and type 4: eleven patients (21%). Normal brain MRI findings were more common in female patients (P = .02). Psychiatric and behavioral abnormalities were more common in adults (P = .015), and autonomic symptoms (P = .025) were more common in pediatric patients. The presence of hippocampal lesions (P = .008, OR = 9.584; 95% CI, 1.803-50.931) and relapse (P = .043, OR = 0.111; 95% CI, 0.013-0.930) was associated with poor outcome. CONCLUSIONS: Normal brain MRI findings were observed in half of the patients. Lesions in the hippocampus were the most common MR imaging abnormal finding. The presence of hippocampal lesions is the main MR imaging predictor for poor prognosis in patients with anti-N-methyl-D-aspartate receptor encephalitis.
BACKGROUND AND PURPOSE: Although flow diverters have been reported with favorable clinical and angiographic outcomes in various literatures, randomized trials determining their true effectiveness and safety are still in lack. The Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms Using the Tubridge Flow Diverter (PARAT) trial was designed to evaluate the safety and efficacy of the Tubridge flow diverter in the treatment of large or giant aneurysms in comparison with Enterprise stent-assisted coiling. MATERIALS AND METHODS: This prospective, multicenter, randomized trial was conducted at 12 hospitals throughout China. Enrolled adults with unruptured large/giant intracranial aneurysms were randomly assigned (1:1) to receive either Enterprise stent-assisted coiling or Tubridge flow diverter implantation. The primary end point was complete occlusion at 6-month follow-up, while secondary end points included technical success, mortality, target vessel-related stroke, aneurysm bleeding, in-stent stenosis, parent artery occlusion, and the frequency of all adverse events. RESULTS: Among 185 enrolled subjects, 41 withdrew before procedure initiation. Overall, 82 subjects underwent Tubridge implantation, and 62 subjects were primarily treated with stent-assisted coiling. The results of 6-month follow-up imaging included complete occlusion rates of 75.34% versus 24.53% for the Tubridge and stent-assisted coiling groups, respectively, with a calculated common odds ratio of 9.4 (95% confidence interval, 4.14-21.38; P < .001). There was a higher, nonsignificant frequency of complications for Tubridge subjects. Multivariate analysis showed a decreased stroke rate at the primary investigational site, with a marginal P value (P = .051). CONCLUSIONS: This trial showed an obviously higher rate of large and giant aneurysm obliteration with the Tubridge FD over Enterprise stent-assisted coiling. However, this higher obliteration rate came at the cost of a nonsignificantly higher rate of complications. Investigational site comparisons suggested that a learning curve for flow-diverter implantation should be recognized and factored into trial designs.
BACKGROUND AND PURPOSE: Neural system was one of the important contributors to the etiopathogenesis of adolescent idiopathic scoliosis; additionally, the morphology of corpus callosum interconnecting both hemispheres of the brain was found to be altered morphologically. Our aim was to evaluate and compare the microstructural changes of the corpus callosum and its interhemispheric white matter fiber tracts interconnecting both cerebral hemispheres in patients with adolescent idiopathic scoliosis and matched controls using diffusion tensor imaging. MATERIALS AND METHODS: Brain DTI was performed in 69 patients with adolescent idiopathic scoliosis (female, right thoracic/thoracolumbar curve) and 40 age-matched controls without adolescent idiopathic scoliosis (female). 2D and 3D segmentation of the corpus callosum were performed using a region-growing method, and the corpus callosum was further divided into 6 regions, including the rostrum, genu, anterior and posterior midbodies, isthmus, and splenium. The laterality index was calculated to quantify the asymmetry of the corpus callosum. Interhemispheric fiber tractography were performed using the Brodmann atlas. RESULTS: 2D ROI analysis revealed reduced fractional anisotropy in the genu and splenium (P = .075 and P = .024, respectively). Consistently reduced fractional anisotropy on the left sides of the genu and splenium was also found in 3D ROI analysis (P = .03 and P = .012, respectively). The laterality index analysis revealed a pseudo-right lateralization of the corpus callosum in adolescent idiopathic scoliosis. Interhemispheric fibers via the splenium interconnecting Brodmann 3, 1, and 2; Brodmann 17; and Brodmann 18 (corresponding to the primary somatosensory cortex and primary and secondary visual cortices) were also found to have reduced fractional anisotropy (P .05). CONCLUSIONS: Reduced fractional anisotropy was found in the genu and splenium of the corpus callosum and corresponding interhemispheric fiber tracts interconnecting the somatosensory and visual cortices via the splenium. Our results are suggestive of altered white matter microstructure within the brain of those with adolescent idiopathic scoliosis, which could be related to abnormal brain maturation during adolescence in adolescent idiopathic scoliosis and could possibly explain the previously documented somatosensory function impairment and visuo-oculomotor dysfunction in this condition.
BACKGROUND AND PURPOSE: It is still poorly understood about the dynamic changes of the thrombus after intravenous thrombolysis and how the remaining thrombus affects clinical outcome in human stroke. Collateral flow was assumed to help to deliver endo/exogenous tissue-type plasminogen activator to the clot. We aimed to analyze the impact of collateral flow on the dynamic changes of the thrombus in patients with acute large-artery occlusion who received intravenous thrombolysis. MATERIALS AND METHODS: We reviewed consecutive patients with acute ischemic stroke with M1 segment or distal internal carotid artery occlusion who underwent multimodal MR imaging or CT perfusion before and 24 hours after intravenous thrombolysis without recanalization. Patients were divided into 3 groups (thrombus extension, shortening, and no change) according to thrombus-length change between baseline and 24 hours. Collateral flow was measured with arrival time delay and the collateral scoring system. Poor outcome was defined as a 3-month modified Rankin Scale score of 3. RESULTS: Among 51 patients, 18 (35.3%) had thrombus extension, 14 (27%) had thrombus shortening, and 19 (37.3%) had thrombus without change. Arrival time delay was independently associated with thrombus extension (OR = 1.499; 95% CI, 1.053-2.135; P = .025). Similarly, the collateral score on the peak artery phase was independently associated with thrombus extension (OR = 0.456; 95% CI, 0.211-0.984; P = .045), whereas baseline National Institutes of Health Stroke Scale score (OR = 0.768; 95% CI, 0.614-0.961; P = .021) and baseline thrombus length (OR = 1.193; 95% CI, 1.021-1.394; P = .026) were associated with thrombus shortening. All patients with thrombus extension had poor outcomes. CONCLUSIONS: Slow collateral flow was related to thrombus extension in patients with large-artery occlusion without recanalization after intravenous thrombolysis.
BACKGROUND AND PURPOSE: Endovascular thrombectomy has been accepted as the standard of care for patients with acute ischemic stroke. Our aim was to investigate the clinical outcomes of patients with mild ischemic stroke with acute proximal large-vessel occlusion after endovascular treatment within 24 hours of symptom onset. MATERIALS AND METHODS: Between January 2014 and August 2017, ninety-three Chinese patients with mild ischemic stroke (NIHSS scores, 0-8) and large-vessel occlusion with endovascular treatment were retrospectively enrolled from 7 comprehensive stroke centers. They were divided into 2 groups: 6 hours and 6-24 hours from symptom onset to groin puncture. We analyzed their modified Rankin Scale scores at 90 days, symptomatic intracranial hemorrhage at 48 hours, and mortality during 90 days. Multivariable linear regression analysis was used to identify predictors for NIHSS shift after discharge. RESULTS: Twenty-nine patients received endovascular treatment within 6-24 hours after symptom onset and had an imaging mismatch based on perfusion CT or diffusion-weighted MR imaging. There were no substantial differences between the 2 groups in 90-day functional independence (P = .54) and the risks of the combination of symptomatic intracranial hemorrhage and death (P = .72). Two significant indicators of NIHSS shift were 48-hour symptomatic intracranial hemorrhage (unstandardized = 7.28; 95% CI, 3.48-11.1; P < .001) and baseline systolic blood pressure (unstandardized = 0.08; 95% CI, 0.03-0.14; P = .005). CONCLUSIONS: Patients with mild ischemic stroke and large-vessel occlusion in the anterior circulation, an imaging mismatch, and endovascular treatment within 6-24 hours of initial symptoms showed no heterogeneity in the efficacy and safety outcome compared with those treated 6 hours from symptom onset.