Publications by authors named "Anna Kufner"

13 Publications

  • Page 1 of 1

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

J Cereb Blood Flow Metab 2021 Apr 17:271678X211010071. Epub 2021 Apr 17.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Stroke Research Berlin, Berlin, Germany.

MRI-based vessel size imaging (VSI) allows for assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort ('Biomarkers And Perfusion--Training-Induced changes after Stroke') nested within a randomized controlled trial (intervention: 4-week training relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (β 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (β 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.
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April 2021

Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Analysis of the WAKE-UP Trial.

Front Neurol 2020 4;11:623881. Epub 2021 Feb 4.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Here, 85% of all patients ( = 140) and 95% of middle cerebral artery (MCA) occlusion patients ( = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth ( = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (β = 2.161; 95% CI 0.96-3.36; = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), -value for interaction was 0.11. While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Main trial (WAKE-UP):, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.
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February 2021

Association Between Thrombus Perviousness Assessed on Computed Tomography and Stroke Cause.

Stroke 2020 12 1;51(12):3613-3622. Epub 2020 Oct 1.

Klinik und Hochschulambulanz für Neurologie (A.K., H.E., M.E., C.H.N., L.S.).

Background And Purpose: A recent study proposed that thrombus perviousness (TP)-the degree to which contrast agents penetrate the thrombus in an occluded vessel measured on noncontrast computed tomography (NCCT) and CT angiography-may be associated with cardioembolic stroke cause with high specificity. Our aim was to investigate which clinical and laboratory parameters affect measures of TP and to validate its diagnostic accuracy in an independent cohort of patients with acute ischemic stroke.

Methods: Seventy-five patients from a prospectively maintained database with proximal occlusions of the middle cerebral artery (M1) were retrospectively analyzed. Thrombi were segmented on coregistered noncontrast computed tomography and CT angiography to determine the thrombus attenuation increase and void fraction (attenuation increase relative to contralateral side).

Results: TP measures were significantly higher in patients with cardioembolic stroke compared to patients with stroke attributed to large artery atherosclerosis (median thrombus attenuation increase [interquartile range], 2.79 [-3.54 to 8.85] versus -5.11 [-11.23 to -1.47]; =0.001). In linear regression analysis for TP including age, time to scan, prior medication with antiplatelets or anticoagulants, and selected laboratory parameters, only stroke cause was significantly associated with TP. In multivariable binary logistic regression analysis for dichotomized stroke cause (ie, cardioembolic versus noncardioembolic stroke), only thrombus attenuation increase was independently associated with cardioembolic stroke (odds ratio of 1.12 [95% CI, 1.04-1.22]; =0.004). Receiver operating characteristic analysis indicated that TP can identify cardioembolic stroke with an area under the curve of 0.75 (95% CI, 0.63-0.87) for thrombus attenuation increase. With a cutoff value of 6.23 Hounsfield units, cardioembolic strokes were identified with 100% specificity. Results for void fraction were similar.

Conclusions: The assessment of TP on baseline noncontrast computed tomography/CT angiography in patients with M1 occlusion may aid in determining cardioembolic stroke cause and guide secondary prevention. Selected clinical and laboratory parameters other than stroke cause did not affect TP measures.
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December 2020

Two simple and rapid methods based on maximum diameter accurately estimate large lesion volumes in acute stroke.

Brain Behav 2020 11 9;10(11):e01828. Epub 2020 Sep 9.

Department of Neurology, Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin, Berlin, Germany.

Background: We compared two simple and rapid diameter-based methods (ABC/2, od-value) in terms of their accuracy in predicting lesion volume >70 ml and >100 ml.

Methods: In 238 DWI images of ischemic stroke patients from the AXIS2 trial, maximum lesion diameter and corresponding maximum orthogonal diameter were measured. Estimation of infarct volume based on od-value and ABC/2 calculation was compared to volumetric assessments.

Results: Accuracy of od-value and ABC/2 was similar for >70 ml (92.0 vs. 87.4) and >100 ml (92.9 vs. 93.3). ABC/2 overestimated lesion volume by 29.9%, resulting in a lower specificity.

Conclusions: Od-value is a robust tool for patient selection in trials.
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November 2020

Smoking Does Not Alter Treatment Effect of Intravenous Thrombolysis in Mild to Moderate Acute Ischemic Stroke-A Dutch String-of-Pearls Institute (PSI) Stroke Study.

Front Neurol 2020 31;11:786. Epub 2020 Jul 31.

Center for Stroke Research Berlin (CSB), Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.

The smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject have yielded contradictory results and an interaction analysis of exposure to smoking and thrombolysis in a large, multicenter database is lacking. Consecutive AIS patients admitted within 12 h of symptom onset between 2009 and 2014 from the prospective, multicenter stroke registry (Dutch String-of-Pearls Stroke Study) were included for this analysis. We performed a generalized linear model for functional outcome 3 months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: age, smoking, hypertension, atrial fibrillation, diabetes mellitus, stroke severity, and stroke etiology. Out of 468 patients, 30.6% ( = 143) were smokers and median baseline NIHSS was 3 (interquartile range 1-6). Smoking alone had a crude and adjusted relative risk (RR) of 0.99 (95% CI 0.89-1.10) and 0.96 (95% CI 0.86-1.01) for good outcome (modified Rankin Score ≤ 2), respectively. A combination of exposure variables (smoking and thrombolysis) did not change the results significantly [crude RR 0.87 (95% CI 0.74-1.03], adjusted RR 1.1 (95%CI 0.90-1.30)]. Smoking alone had an adjusted RR of 1.2 (95% CI 0.6-2.7) for recanalization following thrombolysis ( = 88). In patients with mild to moderate AIS admitted within 12 h of symptom onset, smoking did not modify treatment effect of thrombolysis.
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July 2020

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Analysis of the WAKE-UP Trial.

Front Neurol 2019 22;10:1239. Epub 2019 Nov 22.

Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.

The "smoking paradox" indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. We performed a pre-specified subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; = 0.02) or atrial fibrillation (3.8% vs. 15.3%; < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451-0.978], = 0.04). In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Main trial (WAKE-UP):, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.
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November 2019

Hyperintense Vessels, Collateralization, and Functional Outcome in Patients With Stroke Receiving Endovascular Treatment.

Stroke 2018 03 19;49(3):675-681. Epub 2018 Feb 19.

From the Center for Stroke Research Berlin (A.H.N., A.K., U.G., M. Endres, J.B.F., C.H.N., M. Ebinger), Klinik und Hochschulambulanz für Neurologie (A.H.N., M. Endres, C.H.N.), Institut für Neuroradiologie (E.S., S.K., T.L., J.B.F.), and Department of Biostatistics and Clinical Epidemiology (U.G.), Charité-Universitätsmedizin Berlin, Germany; German Center for Cardiovascular Research (A.H.N., M. Endres,) and German Center for Neurodegenerative Disease (M. Endres), partner site Berlin; Berlin Institute of Health, Germany (A.H.N., M. Endres, C.H.N.); Neurologische Klinik (P.B., H.B.) and Klinik für diagnostische und interventionelle Neuroradiologie (H.H.), Klinikum Stuttgart, Germany; Psychiatrische Universitätsklinik Zürich, Switzerland (P.B.); and Medical Park Berlin Humboldtmühle, Neurologische Klinik, Germany (M. Ebinger).

Background And Purpose: Fluid-attenuated inversion recovery hyperintense vessels (FHV) are frequently observed on magnetic resonance imaging in acute stroke patients with proximal vessel occlusion. Whether FHV can serve as a surrogate for the collateral status and predict functional outcome of patients is still a matter of debate.

Methods: Acute ischemic stroke patients with M1-middle cerebral artery occlusion who received magnetic resonance imaging before endovascular treatment in 3 hospitals in Germany between January 2007 and June 2016 were eligible. Quantification of FHV was performed using an FHV-Alberta Stroke Program Early CT Score (ASPECTS) rating system. Functional outcome was evaluated with the modified Rankin Scale 3 months after stroke. Collateral status of patients was graded on baseline angiography using the American Society of Interventional and Therapeutic Neuroradiology grading system. Odds for good outcome (modified Rankin Scale score, 0-2) were determined using logistic regression analyses.

Results: Overall, 116 patients were analyzed (median age, 74; interquartile range [IQR], 64-79; median National Institutes of Health Stroke Scale, 14; IQR, 10-19). The median FHV-ASPECTS was 2 (IQR, 1-3). Good collateral status (American Society of Interventional and Therapeutic Neuroradiology grade 3-4) on angiography was more frequently observed in patients with FHV-ASPECTS ≤2 (83% versus 57%; =0.025). Patients with an FHV-ASPECTS ≤2 had a better functional outcome after 3 months (median modified Rankin Scale score, 2; IQR, 0-5), compared with patients with an FHV-ASPECTS >2 (median modified Rankin Scale score, 4; IQR, 3-6; =0.015). In multiple regression analyses, FHV-ASPECTS ≤2 was independently associated with good functional outcome (adjusted odds ratio, 5.3; 95% confidence interval, 1.5-18.2).

Conclusions: Low FHV-ASPECTS is associated with both better collateral status and better 3-month functional outcome in acute stroke patients with M1 vessel occlusion.
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March 2018

Infarct volume-based subgroup selection in acute ischemic stroke trials.

Stroke 2015 May 12;46(5):1368-70. Epub 2015 Mar 12.

From the Department of Neurology, Center for Stroke Research Berlin, Charité University Hospital Berlin, Germany (A.K., J.B.F.); Experimental Neurology, Department of Neurosciences, KU Leuven-University of Leuven, Leuven, Belgium (A.W., V.T.); Department of Neurology, BioClinica Bio-Imaging Technologies, Lyon France (L.B.); Department of Neurology, Sygnis Bioscience, Im Neuenheimer Feld 515, Heidelberg, Germany (R.L., A.S.); Department of Neurology, Evangelisches Krankenhaus Bielefeld, Germany (W.-R.S.); Department of Neuroradiology, Hospices Civils de Lyon, France (M.H.); VIB, Vesalius Research Center, Laboratory of Neurobiology, B-3000 Leuven, Belgium (V.T.); and Department of Neurology, University Hospitals Leuven, Leuven, Belgium (V.T.).

Background And Purpose: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL.

Methods: Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments.

Results: Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity.

Conclusions: Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume.

Clinical Trial Registration: URL: Unique identifier: NCT00927836.
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May 2015

Validity of negative high-resolution diffusion-weighted imaging in transient acute cerebrovascular events.

Stroke 2013 Sep 11;44(9):2598-600. Epub 2013 Jul 11.

Department of Neurology, Charité University Hospital Berlin, Berlin, Germany.

Background And Purpose: A significant amount of strokes are reported to be diffusion-weighted imaging (DWI) negative in acute imaging. We attempted to quantify the rate of false-negative high-resolution (hr) DWI and to identify a valid screening tool to guide follow-up MRI to diagnose infarction initially not visible on hrDWI.

Methods: An a priori-defined post hoc analysis of a prospective 3T MRI cohort of acute cerebrovascular events imaged within 24 hours of ictus. Basic demographics, risk factors, National Institute of Health Stroke Scale, and imaging parameters were recorded.

Results: Of 151 patients with negative acute hrDWI, 63 received follow-up scans depicting infarction in 7 cases (11.1%). Persistence of clinical symptoms as established by National Institute of Health Stroke Scale on the following day was strongly associated with infarction on follow-up MRI (odds ratios, 17.5; 95% confidence interval, 2.83-108.12). Negative predictive value of follow-up National Institute of Health Stroke Scale was 0.96.

Conclusions: Infarcts are frequently invisible on initial hrDWI, but we may well trust in negative hrDWI in completely transient cerebrovascular events.
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September 2013

Smoking-thrombolysis paradox: recanalization and reperfusion rates after intravenous tissue plasminogen activator in smokers with ischemic stroke.

Stroke 2013 Feb 3;44(2):407-13. Epub 2013 Jan 3.

Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Charitéplatz 1, Berlin 10117, Germany.

Background And Purpose: The so-called smoking-thrombolysis paradox of an improved outcome after thrombolysis was first described in smokers with myocardial infarction. We investigated whether reperfusion rates and clinical outcome differ between smokers and nonsmokers with ischemic stroke after intravenous tissue plasminogen activator.

Methods: Consecutive acute ischemic stroke patients, who had magnetic resonance imaging before and 1 day after thrombolysis, were included for analysis. All of the patients received intravenous tissue plasminogen activator within 4.5 hours. Reperfusion was defined as a 75% reduction in perfusion deficit (mean transit time >6 s) after thrombolysis compared with baseline. Magnetic resonance angiography was used to evaluate arterial stenosis and occlusion. Functional outcome was assessed 3 months after stroke using the modified Rankin Score.

Results: Of 148 patients, 21.6% were smokers (n=32). Smokers were younger (median, 61 years [SD, 9.4 years] versus 75 years [SD, 11.6 years]; P<0.001), less often women (28% versus 51%; P=0.03), had lower baseline glucose levels (median, 6.2 mmol/L [interquartile range, 5.7-6.8 mmol/L] versus 6.7 mmol/L [interquartile range, 6.1-8.2 mmol/L]; P<0.01) and higher baseline perfusion deficits (median, 53 mL [interquartile range, 13-141 mL] versus 17 mL [interquartile range, 2-66 mL]; P=0.04). In a backward stepwise regression analysis including age, sex, hypertension, glucose, perfusion deficit, and smoking, smoking had an odds ratio of 4 (95% confidence interval, 1-16; P=0.03) for reperfusion and 6 (95% confidence interval, 1-30; P=0.05) for recanalization (regression analysis for recanalization also included localization of arterial occlusion). Smokers had a better outcome (modified Rankin Score=0-2) than nonsmokers (77% versus 55%; P=0.05).

Conclusions: Smoking is independently associated with recanalization and reperfusion, indicating that thrombolytic therapy acts more effectively in smokers; because of small numbers, these results should be considered preliminary. Clinical Trial Registration- URL: Unique Identifier: NCT00715533.
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February 2013

Hyperintense vessels on acute stroke fluid-attenuated inversion recovery imaging: associations with clinical and other MRI findings.

Stroke 2012 Nov 28;43(11):2957-61. Epub 2012 Aug 28.

Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Martinistr 52, 20246 Hamburg, Germany.

Background And Purpose: Hyperintense vessels (HVs) have been observed in fluid-attenuated inversion recovery imaging of patients with acute ischemic stroke and been linked to slow flow in collateral arterial circulation. Given the potential importance of HV, we used a large, multicenter data set of patients with stroke to clarify which clinical and imaging factors play a role in HV.

Methods: We analyzed data of 516 patients from the previously published PRE-FLAIR study (PREdictive value of FLAIR and DWI for the identification of acute ischemic stroke patients≤3 and ≤4.5 hours of symptom onset-a multicenter study) study. Patients were studied by MRI within 12 hours of symptom onset. HV were defined as hyperintensities in fluid-attenuated inversion recovery corresponding to the typical course of a blood vessel that was not considered the proximal, occluded main artery ipsilateral to the diffusion restriction. Presence of HV was rated by 2 observers and related to clinical and imaging findings.

Results: Presence of HV was identified in 240 of all 516 patients (47%). Patients with HV showed larger initial ischemic lesion volumes (median, 12.3 versus 4.9 mL; P<0.001) and a more severe clinical impairment (median National Institutes of Health Stroke Scale 10.5 versus 6; P<0.001). In 198 patients with MR angiography, HVs were found in 80% of patients with vessel occlusion and in 17% without vessel occlusion. In a multivariable logistic regression model, vessel occlusion was associated with HV (OR, 21.7%; 95% CI, 9.6-49.9; P<0.001). HV detected vessel occlusion with a specificity of 0.86 (95% CI, 0.80-0.90) and sensitivity of 0.76 (95% CI, 0.69-0.83).

Conclusions: HVs are a common finding associated with proximal arterial occlusions and more severe strokes. HVs predict arterial occlusion with high diagnostic accuracy.
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November 2012

Fluid-attenuated inversion recovery images and stroke outcome after thrombolysis.

Stroke 2012 Feb 27;43(2):539-42. Epub 2011 Oct 27.

CSB, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.

Background And Purpose: We investigated if hyperintensities on fluid-attenuated inversion recovery (FLAIR) sequences in arteries and parenchyma are associated with poor outcome 3 months after thrombolysis.

Methods: Consecutive acute stroke patients with known time of symptom onset who had an MRI before and 1 day after thrombolysis were included in this study. Blinded to follow-up imaging and outcome, 2 raters independently judged the presence or absence of arterial and parenchymal FLAIR hyperintensities. Functional outcome (modified Rankin Scale) was assessed after 3 months.

Results: Out of 90 patients, 22 had parenchymal FLAIR hyperintensities and 42 had hyperintense vessels. The combination of FLAIR hyperintensities in arteries and parenchyma occurred in 15 patients. Stepwise forward regression analysis revealed an adjusted odds ratio of 14.5 for a worse outcome (modified Rankin Scale score >2) in patients with FLAIR hyperintensities in arteries and parenchyma (95% confidence interval, 1.3-158.5; P=0.03).

Conclusions: FLAIR hyperintensities in arteries and parenchyma are an easy-to-use MRI feature in acute ischemic stroke associated with poor outcome 3 months after thrombolysis.
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February 2012