Assessment of Regional Cerebral Blood Volume in Acute Human Stroke by Use of Single-Slice Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging
Background and Purpose The purpose of this study was to evaluate the clinical usefulness of dynamic susceptibility contrast-enhanced MRI (DSC-MRI) in acute cerebral ischemia.
Methods During bolus injection of gadolinium-diethylenetriamine pentaacetic acid, a series of rapid T2*-weighted images was recorded from one slice. Concentration-time curves and images of regional cerebral blood volume (rCBV) were calculated from this data set. DSC-MRI, MR angiography, conventional spin-echo MRI (SE-MRI), and CT were performed in 11 patients within 6 hours after stroke onset and before thrombolytic or anticoagulant treatment was begun. A follow-up MRI examination was performed 24 to 48 hours after stroke onset.
Results In 7 of 11 patients (group 1) with territorial infarcts of the middle (n=6) or posterior cerebral artery (n=1), DSC-MRI showed reduced rCBV in the affected territory before conventional SE-MRI displayed ischemic lesions. DSC-MRI was helpful to differentiate severely ischemic tissue from peri-infarct parenchyma. Partial reperfusion (n=3), unchanged reduction of rCBV (n=2), and progressive reduction of rCBV (n=2) were observed in the follow-up study. Normal DSC-MRI findings were present in 4 of 11 patients (group 2) with lacunar infarcts.
Conclusions DSC-MRI accomplished the detection of the ischemic territory in the very early stage (<6 hours) before SE-MRI delivered unequivocal results. DSC-MRI might be helpful to discriminate completely ischemic tissue from potentially salvageable ischemic parenchyma at risk and may play an important role in stroke therapy and evaluation.
Although MRI is highly sensitive for changes associated with ischemic stroke,1 detection of acute cerebral infarction in humans usually is impossible <6 to 12 hours postictus on conventional spin-echo images.2 This time interval is too long to influence acute stroke therapy, and there is a strong demand for an imaging modality that provides information about location and spatial extent of the ischemic lesion, severity of the perfusion disturbance, vessel pathology, and extent of the collateral blood supply, as well as the presumed stroke mechanism. As long as the assessment of these pathophysiological changes is not available within the first few hours after ictus, acute stroke therapy will continue to deal with a black hole.
Recent perfusion and diffusion MR imaging studies demonstrated their potential to discriminate complete from partial ischemia in animal models3 4 and in humans.5 In the present study, DSC-MRI was used as an easy-to-perform, add-on examination to routine SE-MRI that provides data about the relative rCBV and tissue perfusion within the early stage of ischemia.6 7 8 9 10 The purpose of the present study was to prospectively evaluate the potential of single-slice DSC-MRI in combination with SE-MRI and MRA in the management of acute stroke patients.
Subjects and Methods
Fifteen patients with acute stroke were studied within the first 6 hours after onset of symptoms. Fourteen patients presented with severe hemiparesis that was eventually accompanied by additional neurological deficits, while in 1 patient, acute hemianopia was the predominant clinical finding. Of the original 15 patients, 4 were eliminated because motion artifacts resulted in poor-quality MR images that were deemed uninterpretable. The remaining 11 patients (7 women, 4 men; mean age, 65.9 years; range, 53 to 79 years old) provided informed consent before entry into the study. The neurological deficit was evaluated according to the SSS (mean score, 29.8; range, 17 to 40) before the MR examination and again on day 2 and day 30. All patients had SSS scores <40 (except 1 with acute hemianopia). Stroke therapy was begun immediately after the end of the MR study and within 6 hours of stroke onset. An initial CT scan was performed before the first MR examination. The MR protocol was repeated 24 to 48 hours after the initial study.
Seven patients participated in the ECASS trial, and five of these patients received rTPA (Alteplase; Dr Karl Thomae GmbH, Biberach an der Riss, Germany) intravenously (1 mg/kg). Two patients received placebo and were treated with intravenous heparin after 24 hours as described below. The remaining four patients who were not part of the ECASS trial were treated with intravenous heparin therapy from the beginning and received an intravenous bolus of 5000 U and continued subsequent heparin infusion that was designed to duplicate the activated partial thromboplastin time.
MRI and MRA
MR examination was performed with a 1.5-T superconductive unit (Magnetom 63 SP, Siemens Medical Systems). The study protocol began with a sagittal T2-weighted gradient-echo sequence (2D FLASH; TR, 400 ms; TE, 18 ms; flip angle, 15°) and was followed by a conventional T2- and proton density–weighted spin-echo sequence (TR, 2200 ms; TE, 20/80 ms). 3D time-of-flight MRA was accomplished by use of a first-order, flow-compensated, gradient-echo technique (3D fast imaging with steady-state precession; TR, 30 ms; TE, 7 ms; flip angle, 15°; 200-mm field of view; 192×256 matrix; slab thickness, 64 mm; number of excitations, 1; 64 partitions). Velocity compensation was performed in the readout and slice-selection direction. One or two transverse acquisition slabs with a thickness of 64 mm were measured. A maximum intensity projection algorithm was used for MRA image formation.
MRA was followed by DSC-MRI using a T2*-weighted gradient-echo sequence (FLASH 2D images; TR, 27 ms; TE, 22 ms; flip angle, 8°; 210-mm field of view; 64×256 matrix and half-Fourier technique [39 phase-encoding steps and zero filling to 64 Fourier lines]; acquisition time, 1 minute; effective time resolution, 1.1 seconds). Gd-DTPA (0.1 mmol/kg) was administered as a bolus via an antecubital vein over a time period of 4 to 5 seconds. Before, during, and after the intravenous bolus injection, a series of 50 sequential images was taken in a single slice to follow the bolus passage of the contrast medium through the brain parenchyma. The signal intensity changes during the first bolus passage were computed pixel by pixel, which resulted in a signal intensity–time curve. We calculated concentration-time curves assuming an exponential relationship between the relative signal reduction and the local contrast agent concentration. By application of tracer kinetic principles, rCBV images of the measured slice were calculated on the basis of a gamma variate fit (for more details, see Reference 1010 ). The positioning of the slice in the ischemic region was guided by the neurological symptoms and indirect stroke signs derived from the SE-MRI (intravascular signal abnormalities) and MRA studies (signal loss in intracranial arteries). For the follow-up measurement, the same slice position was used.
The study ended with a gadolinium-enhanced T1-weighted spin-echo sequence (TR, 550 ms; TE, 14 ms). The total study time did not exceed 30 to 40 minutes.
CT and MR data were reviewed retrospectively by a neurologist (J.R.) and two neuroradiologist/radiologists (A.S., F.G.). Evaluation of the CT scans, SE-MRI, MRA, and DSC-MRI was performed in separate reading sessions without patients’ names and clinical information. The reviewers compared the imaging data after separate evaluation and made the diagnosis by consensus in case of disagreement. For the evaluation of CT scans, previously described criteria, such as loss of the insular ribbon11 and early subtle hypodensity,12 were adopted.
MRI criteria for ischemic stroke were detection of signal intensity in T2- or proton density–weighted images and local cortical swelling. Particular attention was directed to the arterial, meningeal, and parenchymal enhancement in contrast-enhanced T1-weighted SE-MRI and to the presence of flow void signals in the intracranial arteries. Additionally, extracranial or intracranial artery occlusion or stenosis was evaluated according to signal loss in MRA.
For evaluation of the DSC-MRI findings, rCBV images and concentration-time curves of ROIs in the major arterial territories on both hemispheres were used. The rCBV images were judged for the presence of reduced perfusion as indicated by black areas and compared with the follow-up examination. In two patients with infarction of the MCA territory, concentration-time curves of multiple ROIs in the infarct core and the peri-infarct tissue were evaluated. The peak height, peak width, and peak delay of the concentration-time curves were compared with corresponding contralateral areas. Care was taken not to include large vessels in ROI measurements. Examples are depicted in Figs 1⇓ and 2⇓.
Imaging Data: Group 1 With Positive DSC-MRI Findings
Group 1 comprised seven patients with reduced rCBV in the clinically suspected arterial territory in the initial DSC-MRI study. Two patients presented an rCBV reduction in the MCA territory (patients 1 and 6) and one patient in the posterior cerebral artery territory (patient 7). The lenticulostriate territory was affected in four patients (patients 2, 3, 4, and 5).
The concentration-time curves measured from multiple ROIs within the areas of reduced rCBV did not show a signal change due to the bolus passage. In two patients (patients 1 and 6) with reduced rCBV in the complete MCA territory, the evaluation of multiple ROIs established three different patterns: pattern 1, no variation in the signal intensity during the bolus passage (“1” in Fig 1c⇑ and “1” in Fig 2c⇑); pattern 2, delayed bolus passage with a reduced peak and increased width of the concentration-time curve (“2” and “3” in Fig 1c⇑); and pattern 3, reduced peak of the concentration-time curve without significant changes of the width of the curve (“2” and “3” in Fig 2c⇑).
The comparison of the rCBV images, the plots of the concentration-time curves in different ROIs, and the conventional SE-MRI in the initial study and the follow-up investigation in patients 1 and 6 revealed the following correlations: regions that showed pattern 1, with total loss of signal variation during the bolus passage, did not recover and resulted in a complete ischemia in the follow-up study, as demonstrated by hyperintense lesions on the T2-weighted SE-MRI. Pattern 2, with a bolus delay, reduced peak, and increased width of the concentration-time curve, was found in areas adjacent to pattern 1. These areas did not show any signal abnormalities in the follow-up SE-MRI but demonstrated pattern 3 instead of pattern 2 in the DSC-MRI follow-up study, thus indicating tissue recovery (Figs 1⇑ and 2⇑).
Two patients (patients 4 and 5) showed an increase of the perfusion deficit on rCBV images in the follow-up examination. Both patients had findings suggestive of internal carotid or MCA occlusion in MRA. Three patients demonstrated unchanged findings in the follow-up investigation. The infarct area in the follow-up SE-MRI mimicked the area of reduced rCBV in the initial rCBV image.
One patient presented with a discrete hyperintensity of the insula in T2- and proton-density–weighted SE-MRI (patient 6) and another had a hyperdense media sign on CT (patient 2) within the acute stage. AE in the initial contrast-enhanced T1-weighted SE-MRI was present in six patients (patients 1, 2, 4, 5, 6, and 7) and ME was present in one patient (patient 2). All patients with AE or ME demonstrated intravascular signal abnormalities in the carotid siphon (4 of 7 patients) and/or MRA findings that indicated intracranial artery obstruction (5 of 7). AE and ME persisted in the follow-up MRI study, and additional ME or parenchymal enhancement was found in three patients (patients 1, 4, and 5).
MRA demonstrated a partial recanalization in four patients (patients 4, 5, 6, and 7) and unchanged occlusion in one patient (patient 2). In one patient (patient 1), recanalization was evidenced by reconstitution of normal flow void signal in the carotid siphon on T1- and T2-weighted SE-MRI.
Imaging Data: Group 2 With Negative DSC-MRI Findings
Four patients did not show any initial abnormalities either on DSC-MRI or on CT or SE-MRI studies. Follow-up examination revealed lacunar brain-stem infarcts (n=2) or a small subcortical infarct (n=2) on SE-MRI with consistently normal DSC-MRI. The patient with a paramedian pontine brain-stem infarction (patient 8) presented with a basilar artery stenosis on MRA.
Because of the small number of patients and the incongruity of the study group, a correlation between MRI findings and clinical results with the drug regimen was not attempted. The therapeutic regimen of the individual patients is listed in the tables.
The efficacy of thrombolytic therapy to reduce ischemic cell injury is greatest in the first hours after stroke onset.13 The safe and efficient use of thrombolytic agents, however, is limited, because standard neuroimaging procedures such as CT scans and SE-MRI fail to reliably detect stroke within the first day after onset of symptoms.2
DSC-MRI has the potential to deliver information about perfusion deficits within the acute stage of stroke.5 8 9 10 When DSC-MRI is combined with SE-MRI and MRA, important information about the location and extent of the ischemia can be acquired within a single MRI study that otherwise could be obtained only by the combination of lengthy, costly, and often invasive procedures such as angiography, positron emission tomography, or single photon emission computed tomography.
To the best of our knowledge, this is the first study to use DSC-MRI to monitor tissue perfusion before and after acute thrombolytic or anticoagulant therapy. The extent and localization of the acute infarct area was characterized in 7 of 11 patients (group 1) before the infarcted tissue was unequivocally delineated by SE-MRI. Pretreatment DSC-MRI displayed reduced rCBV in well-defined arterial territories, whereas follow-up measurements after treatment provided information about partial reperfusion (decreased areas of rCBV deficit; n=3), progressive worsening (increased areas of rCBV deficit; n=2), or unchanged perfusion deficits (n=2). Patients without obvious rCBV changes in major intracerebral vascular territories (group 2) displayed lacunar infarcts in the follow-up examination.
The disappointing result of the ECASS trial has emphasized the strong demand for a noninvasive imaging modality that delivers early information on the extent of the perfusion deficit.14 The combination of DSC-MRI with MRA and SE-MRI characterizes the acute infarct within the therapeutic window and has the potential to improve early patient selection and guide stroke therapy, because patients with reduced rCBV in an arterial territory and with vessel obstruction in MRA can be discriminated from patients without major perfusion disturbances in the suspected territory. While the first group of patients may be considered candidates for thrombolytic therapy, it seems reasonable to assume that the latter group will not benefit from thrombolysis and therefore high-risk interventions can be avoided.
The different patterns of the relative concentration-time curves found in two patients with large perfusion deficits are in agreement with recently published experimental4 and human5 stroke data. We observed a complete loss of the bolus passage as a pattern that indicated severe ischemia (pattern 1). The ROIs with this pattern developed permanent infarction as shown by the SE-MRI follow-up study, and we conclude that this pattern might be predictive for the infarct core. A delayed bolus passage, reduced peak, and increased width of the concentration-time curve were found in the adjacent parenchyma (pattern 2). The bolus delay is caused by an increased transit time for the contrast bolus that is, for instance, due to a proximal artery stenosis or artery occlusion with collateral filling. The reduced area under the concentration-time curve correlates with the reduced rCBV of the ischemic injured tissue, whereas the increased width of the curve correlates with the prolonged contrast-agent transit time through the affected parenchyma and reflects a reduced tissue perfusion.
Tissue that exemplifies pattern 2 is thought to represent potentially salvageable tissue, especially since the follow-up study after treatment showed a normal signal in T2-weighted SE-MRI (Fig 2⇑). DSC-MRI follow-up studies of the areas with pattern 2 demonstrated a third pattern (pattern 3) that was not present in the acute stage of infarction in these two patients. Pattern 3 characteristically showed a slightly reduced peak and a minimal bolus delay without increased width of the concentration-time curve. This pattern seems to indicate a discrete residual perfusion disturbance around the infarct core with a slightly increased vascular transit time and a minimal decrease of rCBV. It seems likely that a gradual transition between these three patterns exists that depends on the severity of the ischemia and the quality of collateral blood flow. Previously described results in patients with hemodynamically severe extracranial or intracranial artery stenosis show that these patterns probably relate to the severity of proximal stenosis and the efficacy of collateral pathways.5 8 9 10
The present study was performed on a conventional MR scanner and was limited to a single-slice technique. This must be considered a drawback, because clinical symptoms do not reliably predict infarct location and the ischemic area might be missed because of incorrect slice positioning. However, the combination of clinical topodiagnosis with MRA and indirect early stroke signs such as intravascular signal abnormalities from SE-MRI are helpful in choosing the imaging slice. In the future, use of an MR scanner with an echo planar imaging option will permit the use of multiple slices during a single contrast bolus injection5 and improve the conspicuity of the technique for small ischemic lesions in unexpected locations in the brain. Recent technical modifications15 allow a quantification of rCBV and might expand the clinical value of DSC-MRI.
MRA proved to be a valuable tool to detect intracranial artery pathology16 17 18 and to support the differentiation between territorial, lacunar, or small subcortical infarcts.19 In the present study, all patients with territorial reduction of rCBV displayed severe vessel obstruction in MRA, whereas patients with negative DSC-MRI findings had normal MRA or showed findings such as a basilar artery stenosis that directed attention to an unexpected infarct location.
The earliest stroke changes that can be detected on SE-MRI are loss of flow void signals in case of major vessel occlusion. Hyperintense intravascular signals in SE-MRI were found in 5 of 11 patients in the distal internal carotid artery or the MCA, which confirmed MRA findings and occasionally specified the vessel pathology.
AE in contrast-enhanced T1-weighted SE sequences has been detected within the first 1 to 3 days after infarction and has been shown to be related to arterial slow flow and vasodilatation.2 20 21 22 In the present study, AE was present in six of seven patients in group 1 and one of four patients in group 2 within the first 6 hours. The presence of AE obviously depends on the extent of the infarcted area,20 and only one patient (patient 3) with reduced rCBV in the territory of the lenticulostriate arteries and with a small lenticulostriate infarct in the follow-up SE-MRI study did not display AE. Time evolution of ME was reported 1 to 3 days postictus, and parenchymal enhancement was reported 2 to 3 days postictus.20 We found ME as early as 6 hours postictus in one patient with a complete MCA infarct, and parenchymal enhancement developed after 48 hours in another patient. These results in a small number of acute patients demonstrate that the MRI features of acute infarction are still poorly characterized and that the variation of characteristics over time seems to be widespread.
Although discrete signs of cerebral ischemia in CT have been described within the first 6 hours after stroke onset,12 23 we did not find CT helpful to reliably determine the localization and extent of the infarct. This may be because CT was performed before MR examination, as early as 3 hours after stroke onset in 3 patients. SE-MRI did not prove to be more useful than CT in early infarct detection: only 2 of 11 patients showed a discrete hyperintensity in SE-MRI. In summary, CT and SE-MRI did not serve as reliable tools to characterize cerebral infarction in the very acute stage. In particular, they did not contribute to the discrimination between territorial and lacunar infarcts, a differentiation that might be of future importance for the safety of thrombolytic treatment.14
On the basis of our experience in very acute stroke patients, we conclude that the combination of DSC-MRI with SE-MRI and MRA serves as a valuable tool for early stroke characterization, stroke monitoring, and evaluation of stroke therapy. The combination of DSC-MRI and diffusion-weighted MRI might improve our understanding of acute ischemic injury and help to further establish typical stroke patterns that predict potentially salvageable ischemic tissue. The future prospects of acute stroke therapy could include treatment of stroke patients in the MR scanner and monitoring of the effect of thrombolytic and/or cytoprotective drugs on tissue perfusion and diffusion by means of ultrafast MR sequences.
Selected Abbreviations and Acronyms
|DSC-MRI||=||dynamic susceptibility contrast-enhanced MRI|
|ECASS||=||European Cooperative Acute Stroke Study|
|FLASH||=||fast low-angle shot|
|Gd-DTPA||=||gadolinium diethylenetriamine pentaacetic acid|
|MCA||=||middle cerebral artery|
|rCBV||=||regional cerebral blood volume|
|ROI||=||region of interest|
|rTPA||=||recombinant tissue-type plasminogen activator|
|SSS||=||Scandinavian Stroke Scale|
|TE||=||time to echo in MR spin-echo pulse sequences|
We thank Susan K. Lemieux, PhD, for helpful discussion and rereading of the English text.
- Received October 17, 1995.
- Revision received January 9, 1996.
- Accepted February 26, 1996.
- Copyright © 1996 by American Heart Association
Yuh WTC, Crain MR, Loes DJ, Greene GM, Ryals TJ, Sato Y. MR imaging of cerebral ischemia: findings in the first 24 hours. AJNR Am J Neuroradiol. 1991;12:621-629.
Warach S, Wielopolski P, Edelman RR. Identification and characterization of the ischemic penumbra of acute human stroke using echo planar diffusion and perfusion imaging. In: Abstracts of the 12th annual meeting of the Society of Magnetic Resonance in Medicine (SMRM); 1993:249. Abstract.
Minematsu K, Fisher M, Li L, Sotak CH. Diffusion and perfusion magnetic resonance imaging studies to evaluate a noncompetitive N-methyl-d-aspartate antagonist and reperfusion in experimental stroke in rats. Stroke. 1993;24:2074-2081.
Bozzao L, Bastianello S, Fantozzi LM, Argentino C, Fieschi C. Correlation of angiographic and sequential CT findings in patients with evolving cerebral infarction. AJNR Am J Neuroradiol. 1989;10:1215-1222.
Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL, Spilker J, Kongable GL, Massey S, Reed R. Urgent therapy for stroke, I: pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23:632-640.
Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-1025.
Röther J, Wentz KU, Schwartz A, Rautenberg W, Hennerici M. Magnetic resonance angiography of vertebrobasilar ischemia. Stroke. 1993;24:1310-1315.
Röther J, Humburg-Röther S, Kühnen J, Schwartz A. Stroke typology of the posterior circulation. Cerebrovasc Dis. 1994;4:232. Abstract.
Crain MR, Yuh WT, Greene GM, Loes DJ, Ryals TJ, Sato Y, Hart MN. Cerebral ischemia: evaluation with contrast-enhanced MR imaging. AJNR Am J Neuroradiol. 1991;12:631-639.
Mueller DP, Yuh WTC, Fisher DJ, Chandran KB, Crain MR, Kim YH. Arterial enhancement in acute cerebral ischemia: clinical and angiographic correlation. AJNR Am J Neuroradiol. 1993;14:661-668.
von Kummer R, Meyding-Lamade U, Forsting M, Rosin L, Rieke K, Hacke W, Sartor K. Sensitivity and prognostic value of early CT in occlusion of the middle cerebral artery trunk. AJNR Am J Neuroradiol. 1994;15:9-15.