Original Paper Received: September 18, 2013 Accepted: November 19, 2013 Published online: January 30, 2014
Cerebrovasc Dis 2014;37:141–146 DOI: 10.1159/000357422
Early Time Course of FLAIR Signal Intensity Differs between Acute Ischemic Stroke Patients with and without Hyperintense Acute Reperfusion Marker Ann-Christin Ostwaldt a, b Michal Rozanski a, c Wolf U. Schmidt a Christian H. Nolte a, c Benjamin Hotter a Gerhard J. Jungehuelsing a Kersten Villringer a Jochen B. Fiebach a
a c
Center for Stroke Research Berlin (CSB), b International Graduate Program Medical Neurosciences and Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Key Words Magnetic resonance imaging · Blood-brain barrier · Ischemic stroke · Time course
Abstract Background: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed ‘hyperintense acute reperfusion marker’ (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched. Methods: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for
© 2014 S. Karger AG, Basel 1015–9770/14/0372–0141$39.50/0 E-Mail [email protected] www.karger.com/ced
CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B0 images for each time point. Results: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3–5 MRI examinations on the first day and 1–2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B0 images. Conclusion: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B0 images excludes a pure T2 effect. © 2014 S. Karger AG, Basel
Ann-Christin Ostwaldt Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin Hindenburgdamm 30 DE–12200 Berlin (Germany) E-Mail ann-christin.ostwaldt @ charite.de
Introduction
In acute ischemic stroke, a disruption in the bloodbrain barrier (BBB) can occur [1, 2]. In animal models, the time course of BBB disruption after stroke has been studied elaborately. Most of these studies showed a biphasic opening of the BBB after recanalization [3, 4]. In stroke patients, leakage of MR contrast agent into the cerebrospinal fluid (CSF)-filled spaces or enhancement of brain tissue is considered a sign of BBB disturbances. The bright appearance of the CSF-filled space on fluid attenuated inversion recovery (FLAIR) images due to leakage of gadolinium was termed ‘hyperintense acute reperfusion marker’ (HARM) [5, 6]. Some studies showed its association with a higher rate of hemorrhagic transformation [5, 6], others found no such relationship [7, 8]. No detailed longitudinal examinations of changes in the BBB in stroke patients exist. Moreover, it is not yet clear whether HARM is also associated with extravasation of contrast agent into the parenchyma.
sis Tool for Neuro Imaging Data; Institute of Computational Neuroscience, Hamburg, Germany) was used to create regions of interest (ROI) on DW images for all time points, as described elsewhere [9]. In brief, DWI lesions were roughly delineated and subsequently reduced to those voxels that were 2 SD more hyperintense than on the contralateral side. The DWI ROI were mirrored to the contralateral side (mirrored DWI ROI) along the manually defined interhemispheric fissure. The lesion and the mirrored DWI ROI for each time point were then segmented and corrected for CSFfilled space, using the first apparent diffusion coefficient (ADC) image of each patient (fig. 1). ROI were subsequently checked for quality on FLAIR and ADC images and residual voxels containing CSF were manually removed. The final lesion ROI and mirrored ROI were used to determine the rSI as follows: rSI = mean SI lesion ROI/mean SI mirrored ROI. An rSI was determined for FLAIR, ADC and B0 images for all time points. For statistical analysis, the data were pooled into time slots containing only 1 examination per patient. Statistical analysis was performed with SPSS, using the independent-sample MannWhitney U test for interval data and Pearson’s χ2 or Fisher’s exact test for nominal data.
Results Methods This is a substudy of the 1000Plus study (NCT00715533). We included acute ischemic stroke patients who had a first MRI examination in our facility within 5 h from symptom onset and were able to give written informed consent. All patients received repeated 3-tesla MRI examinations: an examination approximately every 2 h on the day of admission (day 1) and 1–2 examinations on day 2. The final infarct volume was determined on days 5–6. The MRI protocols for the first examinations on days 1 and 2 contained: diffusion-weighted imaging (DWI; TE = 93 ms, TR = 8,000 ms, 2.5 mm slice thickness without gap); FLAIR (TE = 100 ms, TR = 8,000 ms, 5.0 mm slice thickness); T2*-weighted imaging (TE = 20 ms, TR = 620 ms, 5.0 mm slice thickness); time-of-flight MR angiography and perfusion imaging (PI). For PI, a fixed dose of 5 ml Gadovist® (gadobutrol, 1 M; Bayer Schering Pharma AG, Berlin, Germany) followed by a 20-ml intravenous saline flush was used. The MRI protocol for the remaining examinations on days 1, 2 and 5–6 contained T2*-weighted images, FLAIR imaging and DWI, and – depending on medical decisions – also PI. Clinical stroke severity was measured by the NIHSS (National Institutes of Health Stroke Scale). The occurrence of HARM was judged by visual inspection jointly by 2 readers (A.-C.O. and M.R.). HARM was defined as CSF enhancement in the sulcal space in the affected vascular territory or within the ventricles [6] compared with the first FLAIR image, which was always made before any administration of contrast agent. The occurrence of hemorrhagic transformation was evaluated on the T2*-weighted images. For calculation of relative signal intensities (rSI), all images of 1 patient were coregistered to the first DWI image of that patient, using SPM (Statistical Parametric Mapping; Wellcome Trust Center for Neuroimaging, 2008). The software tool AnToNIa (Analy-
142
Cerebrovasc Dis 2014;37:141–146 DOI: 10.1159/000357422
Nineteen patients were included in the study. We excluded 1 patient due to a final lesion volume of
Cerebrovasc Dis 2014;37:141–146 DOI: 10.1159/000357422
Early Time Course of FLAIR Signal Intensity Differs between Acute Ischemic Stroke Patients with and without Hyperintense Acute Reperfusion Marker Ann-Christin Ostwaldt a, b Michal Rozanski a, c Wolf U. Schmidt a Christian H. Nolte a, c Benjamin Hotter a Gerhard J. Jungehuelsing a Kersten Villringer a Jochen B. Fiebach a
a c
Center for Stroke Research Berlin (CSB), b International Graduate Program Medical Neurosciences and Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Key Words Magnetic resonance imaging · Blood-brain barrier · Ischemic stroke · Time course
Abstract Background: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed ‘hyperintense acute reperfusion marker’ (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched. Methods: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for
© 2014 S. Karger AG, Basel 1015–9770/14/0372–0141$39.50/0 E-Mail [email protected] www.karger.com/ced
CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B0 images for each time point. Results: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3–5 MRI examinations on the first day and 1–2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B0 images. Conclusion: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B0 images excludes a pure T2 effect. © 2014 S. Karger AG, Basel
Ann-Christin Ostwaldt Center for Stroke Research Berlin (CSB), Charité – Universitätsmedizin Berlin Hindenburgdamm 30 DE–12200 Berlin (Germany) E-Mail ann-christin.ostwaldt @ charite.de
Introduction
In acute ischemic stroke, a disruption in the bloodbrain barrier (BBB) can occur [1, 2]. In animal models, the time course of BBB disruption after stroke has been studied elaborately. Most of these studies showed a biphasic opening of the BBB after recanalization [3, 4]. In stroke patients, leakage of MR contrast agent into the cerebrospinal fluid (CSF)-filled spaces or enhancement of brain tissue is considered a sign of BBB disturbances. The bright appearance of the CSF-filled space on fluid attenuated inversion recovery (FLAIR) images due to leakage of gadolinium was termed ‘hyperintense acute reperfusion marker’ (HARM) [5, 6]. Some studies showed its association with a higher rate of hemorrhagic transformation [5, 6], others found no such relationship [7, 8]. No detailed longitudinal examinations of changes in the BBB in stroke patients exist. Moreover, it is not yet clear whether HARM is also associated with extravasation of contrast agent into the parenchyma.
sis Tool for Neuro Imaging Data; Institute of Computational Neuroscience, Hamburg, Germany) was used to create regions of interest (ROI) on DW images for all time points, as described elsewhere [9]. In brief, DWI lesions were roughly delineated and subsequently reduced to those voxels that were 2 SD more hyperintense than on the contralateral side. The DWI ROI were mirrored to the contralateral side (mirrored DWI ROI) along the manually defined interhemispheric fissure. The lesion and the mirrored DWI ROI for each time point were then segmented and corrected for CSFfilled space, using the first apparent diffusion coefficient (ADC) image of each patient (fig. 1). ROI were subsequently checked for quality on FLAIR and ADC images and residual voxels containing CSF were manually removed. The final lesion ROI and mirrored ROI were used to determine the rSI as follows: rSI = mean SI lesion ROI/mean SI mirrored ROI. An rSI was determined for FLAIR, ADC and B0 images for all time points. For statistical analysis, the data were pooled into time slots containing only 1 examination per patient. Statistical analysis was performed with SPSS, using the independent-sample MannWhitney U test for interval data and Pearson’s χ2 or Fisher’s exact test for nominal data.
Results Methods This is a substudy of the 1000Plus study (NCT00715533). We included acute ischemic stroke patients who had a first MRI examination in our facility within 5 h from symptom onset and were able to give written informed consent. All patients received repeated 3-tesla MRI examinations: an examination approximately every 2 h on the day of admission (day 1) and 1–2 examinations on day 2. The final infarct volume was determined on days 5–6. The MRI protocols for the first examinations on days 1 and 2 contained: diffusion-weighted imaging (DWI; TE = 93 ms, TR = 8,000 ms, 2.5 mm slice thickness without gap); FLAIR (TE = 100 ms, TR = 8,000 ms, 5.0 mm slice thickness); T2*-weighted imaging (TE = 20 ms, TR = 620 ms, 5.0 mm slice thickness); time-of-flight MR angiography and perfusion imaging (PI). For PI, a fixed dose of 5 ml Gadovist® (gadobutrol, 1 M; Bayer Schering Pharma AG, Berlin, Germany) followed by a 20-ml intravenous saline flush was used. The MRI protocol for the remaining examinations on days 1, 2 and 5–6 contained T2*-weighted images, FLAIR imaging and DWI, and – depending on medical decisions – also PI. Clinical stroke severity was measured by the NIHSS (National Institutes of Health Stroke Scale). The occurrence of HARM was judged by visual inspection jointly by 2 readers (A.-C.O. and M.R.). HARM was defined as CSF enhancement in the sulcal space in the affected vascular territory or within the ventricles [6] compared with the first FLAIR image, which was always made before any administration of contrast agent. The occurrence of hemorrhagic transformation was evaluated on the T2*-weighted images. For calculation of relative signal intensities (rSI), all images of 1 patient were coregistered to the first DWI image of that patient, using SPM (Statistical Parametric Mapping; Wellcome Trust Center for Neuroimaging, 2008). The software tool AnToNIa (Analy-
142
Cerebrovasc Dis 2014;37:141–146 DOI: 10.1159/000357422
Nineteen patients were included in the study. We excluded 1 patient due to a final lesion volume of
