Patterns and Predictors of Blood–Brain Barrier Permeability Derangements in Acute Ischemic Stroke
Background and Purpose— MRI permeability imaging is a promising approach to identify patients with acute ischemic stroke with an increased propensity for hemorrhagic transformation (HT). Permeability imaging provides direct visualization of blood–brain barrier derangements in ischemic fields.
Methods— We retrospectively analyzed clinical and MRI data on patients with acute cerebral ischemia within the middle cerebral artery territory to identify the frequency, patterns, and predictors of permeability derangements and their association with HT types.
Results— A total of 179 permeability scans was obtained in 127 patients (59 men; mean age, 66.8 years). Among 179 image sets (82 pre-/no treatment and 97 posttreatment), permeability derangements were present in 29 images, frequently at the basal ganglia (n=23) and rarely at the juxta-cortical area (n=6). After adjusting for covariates, diastolic pressure (OR, 1.12, per 1-mm Hg increase; 95% CI, 1.02 to 1.22) and s-glucose (OR, 1.04, per 1-mg/dL increase; 95% CI, 1.01 to 1.07) were independently associated with pretreatment permeability derangements, whereas low-density lipoprotein cholesterol (OR, 0.97, per 1-mg/dL increase; 95% CI, 0.94 to 0.99), malignant MRI profile (OR, 24.84; 95% CI, 1.50 to 412.93), and time from onset to recanalization therapy (OR, 1.47, per 1-hour increase; 95% CI, 1.10 to 1.96) were independently associated with permeability derangements after recanalization therapy. Types of HT varied among the patients with permeability derangements (no HT, 4; hemorrhagic infarct type, 12; and parenchymal hematoma, 13) and transient derangements (without subsequent HT) and normalization of derangements (in the presence of HT) on permeability images was observed in several cases.
Conclusions— Permeability derangements, a dynamic process associated with ischemic stroke pathophysiology and recanalization therapy, vary in pattern and evolution toward HT. Several prognostic and therapeutic predictors for HT are independently associated with pre- and posttreatment permeability derangements.
- collateral circulation
- hemorrhagic transformation
- magnetic resonance imaging
- stroke, ischemic
Intracerebral hemorrhage is a feared complication of recanalization therapy for acute ischemic stroke. There have been numerous efforts to predict hemorrhagic transformation (HT) in patients with ischemic stroke. Several studies have identified clinical and laboratory predictors of HT after thrombolytic treatment for stroke.1–8 Multimodal MRI offers an additional wealth of data regarding tissue status and potential propensity for HT.7,9 The volume of severe diffusion abnormality and the volume of severe perfusion abnormality correlate with increased risk of HT after recanalization therapy.10–12 Additional MRI parameters have variably been reported in association with an increased risk of HT after thrombolysis: leukoaraiosis,13 prior cerebral microbleeds visualized with T2*-weighted MRI sequences,12 early parenchymal enhancement,14 and early colony stimulating factor hyperintensity.15
MRI permeability imaging is a promising potential additional and distinctive marker to identify patients with an increased propensity to HT. In recent years, dedicated MRI acquisitions have been used to identify blood–brain barrier (BBB) permeability derangements surrounding brain tumors for the purpose of tumor grading,16–18 and in patients with acute ischemic stroke treated with supportive care.19 We recently reported that pretreatment permeability images derived from routine perfusion-weighted imaging (PWI) source data, or slope images, may identify patients at risk for HT after recanalizaiton therapy with high specificity in a small series of patients.20 However, a study of a larger cohort of patients is required to delineate the frequency, patterns, and determinants of permeability derangements in acute ischemic stroke and the association of permeability abnormalities with different subtypes of HT. MRI guidance of interventional decision-making may be improved by supplementing standard penumbral imaging with the use of slope imaging that identifies individuals with BBB disruption who are at high risk for HT.
Patients and Methods
We analyzed the clinical and MRI data on consecutive patients in a prospectively maintained database admitted with acute cerebral ischemia within the middle cerebral artery territory at a university medical center from January 2004 to June 2007. Patients received recanalization therapy (intravenous or intra-arterial thrombolytic therapy, endovascular mechanical clot retrieval, and/or angioplasty with and without stenting) or conservative care.
All patients underwent MRI (1.5 T; Siemens Medical System). The MRI protocol included diffusion-weighted images (DWI), gradient-recalled echo (repetition time, 800 ms; echo time, 15 ms), fluid-attenuated inversion-recovery sequences (repetition time, 7000 ms; echo time, 105 ms, inversion time, 2000 ms; matrix size, 256×256; field of view, 240 mm; slice thickness, 5 to 7 mm; gap, 2.5 mm), and T2* PWI sequences using MRI methods previously described.21 DWI was performed with 2 levels of diffusion sensitization (b=0 and 1000 s/mm2; 5- to 7-mm slice thickness, no gap, and 17 to 20 slices). PWI was performed with a timed contrast-bolus passage technique (0.1 mg/kg contrast administered into an antecubital vein with a power injector at a rate of 5 cm3/s). PWI parameters were as follows: repetition time, 2000 ms; echo time, 60 ms; 20 slices; slice thickness, 7 mm; no gap; matrix size, 128×96; and field of view, 240 mm. Maps of Tmax ≥2 seconds were generated by deconvolution of an arterial input function and tissue concentration curves.22
Patients were categorized according to their baseline diffusion–perfusion MRI profile using the DEFUSE trial algorithm.7 The “mismatch” profile was defined as a PWI lesion ≥10 mL and ≥120% of the DWI lesion. The “small lesion” profile was defined as a DWI and PWI volume both <10 mL. The “no mismatch” profile was defined as a PWI volume <120% of the DWI lesion volume (patients with the Small Lesion profile excluded). The “malignant profile” was defined as a baseline DWI lesion ≥100 mL or more and/or a PWI lesion of ≥100 mL with ≥8 seconds of Tmax delay. MRI volume measures were performed by a neuroradiologist (Y.S.R.) who was blinded to the clinical information.
Derivation of Permeability Images
Permeability images were retrospectively derived from already acquired standard PWI source image data sets.20 In all tissues, T2* signal intensity normally decreases with bolus passage of gadolinium contrast through the cerebral vasculature followed by a return to baseline signal intensity. However, some tissues will then demonstrate a late, secondary decline at the terminal phase of scan acquisition. Late signal intensity decrease at the terminal phase of scan acquisition after contrast bolus passage, rather than the expected return to baseline signal intensity after contrast clearance, reflects accumulation of contrast within tissue parenchyma presumed to be due to BBB disruption. In patients with BBB compromise, gadolinium will extravasate out of the vasculature and into surrounding tissue, which will result in persisting or even falling T2* intensity (Supplemental Figure I, available online at http://stroke.ahajournals.org).
The analysis was confined to cases with sufficient scan acquisition times (≥60 seconds) to permit BBB leakage to be discerned from analysis of late transit phases of gadolinium passage associated with contrast bolus. For each voxel, signal intensities on serial PWI source images at the terminal 10 seconds (between 50 to 60 seconds after contrast injection) portion of the PWI acquisition were used to calculate the slope of late signal intensity change. Voxel specific rates of terminal signal intensity change were determined using linear regression techniques on the ImageJ platform (ImageJ version 1.36b; National Institutes of Health, Bethesda, Md). In permeability image displays, voxels with negative signal intensity slopes over the terminal phase of scan acquisition corresponding to increasing gadolinium concentration were colored black. Background noise was subtracted from signal intensity slope images using the baseline T2* map.
Hemorrhagic Transformation Image Analysis
Patients underwent recanalization therapy with control MRI or CT 24 hours after symptom onset. All patients had additional imaging for any worsening in neurological status. HT was defined and classified into 5 subtypes (modified from Berger and colleagues23): hemorrhagic infarct type 1 (HI-1); small petechiae along the margins of the infarct; hemorrhagic infarct type 2 (HI-2); more confluent petechiae within the infarcted area but without space-occupying effect; parenchymal hematoma type 1 (PH-1), defined as a hematoma in less than 30% of the infarcted area with some space-occupying effect; parenchymal hematoma type 2 (PH-2), hematoma in more than 30% or the infarcted area with substantial space-occupying effect; and subarachnoid hemorrhage. Patients could have more than one hemorrhage type.
Two investigators who were blinded to the follow-up images and clinical information independently reviewed MRIs to determine the presence of signal changes on permeability images. The local Institutional Review Board approved the study.
Differences between the groups were examined by χ2 test and Fisher exact test for categorical data and Student t test for continuous data. Independent factors associated with permeability derangements were evaluated using logistic regression; pre- and posttreatment MRIs were analyzed separately. All potential predictors were entered into a logistic regression model with permeability derangements as the dependent variable and potential risk factors as independent variables. Potential factors considered for inclusion in the model were (1) age, diabetes, and atrial fibrillation; (2) National Institutes of Health Stroke Scale (NIHSS) scores at admission; (3) systolic and diastolic blood pressures at emergency room arrival; (4) daily use of statins and antithrombotic medications in the week before stroke onset; (5) mode of recanalization treatment (fibrinolytics versus mechanical versus combined) and vessel recanalization (the Thrombolysis In Myocardial Infarction grade)24; (6) laboratory findings including glucose levels on admission, fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol; (7) MRI findings including DWI lesion volumes and the MRI diffusion–perfusion profile; and (8) time intervals from symptom onset to scanning time of permeability images.1,2,4,7,25 Potential factors that were not significant (P<0.2) were sequentially deleted from the full model. Excluded variables were reintroduced at various stages of model development until only significant predictors remained. Significance was established at the P<0.05 levels.
Among 237 patients who admitted for acute cerebral ischemia within the middle cerebral artery territory during the study period, 127 patients met study entry criteria. MRI was contraindicated in 21 patients, PWI was not performed in 17 (mostly lacunar stroke), and PWI acquisitions were obtained over too brief a time window (<60 seconds) in 72.
Characteristics of patients are shown in Table 1. Thirty-six received fibrinolytic therapy; 39 endovascular mechanical therapy, including clot retrieval therapy (MERCI Retrieval System) and angioplasty and/or stenting; 10 combined fibrinolytics plus mechanical therapy; and 42 no active recanalization therapy. Thirty-eight patients experienced HT; 9 were HI-1, 10 HI-2, 8 PH-1, 9 PH-2, and 2 subarachnoid hemorrhage alone. Follow-up images were not performed in 6.
Frequency and Patterns of Permeability Derangements
A total 179 permeability images were acquired in 127 patients. Mean time from last known well to permeability image was 30.8±59.9 hours (range, 0.7 hour to 23 days). Among 179 permeability images, 82 were pretreatment permeability imaging in patients undergoing recanalization therapy or permeability imaging in patients treated with supportive care; median time from last known well to permeability imaging was 5.0 hours (interquartile range, 2.2 to 8.3 hours). The remainder of the 97 was posttreatment images; median time from last known well to posttreatment permeability imaging was 12.1 hours (interquartile range, 7.7 to 66.0 hours).
Permeability images revealed regions of progressive signal intensity decrease consistent increased permeability and BBB contrast leakage in 29 (16%) studies among 26 of 127 (20%) patients. Among the 29 abnormal permeability studies, increased permeability was most frequently observed at the innermost or deep regions of the diffusion restriction and perfusion defect (23 scans [79%]; the deep pattern), whereas the remainder (6 scans [21%]) had increased permeability in the juxtacortical or border-zone area (Figure 1; the superficial pattern). Among the 20 patients with the deep pattern, 16 (80%) received recanalization therapy (fibrinolytics, mechanical, or both) and 9 showed PH; in contrast, among the 6 patients with the superficial pattern, 2 (33.3%) received recanalization therapy and only one had PH. The increased permeability areas always fell within the region of the diffusion restriction area. The concordance rate in detecting the presence of increased permeability was 94.4% between readers.
Factors Associated With Permeability Derangements
Comparisons of the clinical and laboratory results in patients with and without permeability derangements are shown in Tables 2 and 3⇓. Patients with permeability derangements on pretreatment imaging had higher levels of systolic and diastolic blood pressure on admission and more likely to have used anticoagulation before the index event. Patients with permeability derangements were older and more often had higher NIHSS scores and s-glucose levels on admission than those without permeability derangements, although statistically insignificant (Table 2). Other risk factors and stroke subtypes were not associated with permeability derangements. After adjusting for covariates, diastolic pressure (OR, 1.12, per 1-mm Hg increase; 95% CI, 1.02 to 1.22), s-glucose (OR, 1.04, per 1-mg/dL increase; 95% CI, 1.01 to 1.07), and time from last known well to imaging (OR, 1.08, per 1-hour increase; 95% CI, 1.02 to 1.14) were independently associated with permeability derangements.
On the contrary, factors associated with permeability derangements on posttreatment imaging were lower total and LDL cholesterol levels, longer time from last known well to recanalization therapy, and large DWI lesion volumes and the malignant profile on baseline MRI (P<0.05 in all the cases; Table 3; Figure 2). Patients with permeability derangements more often had atrial fibrillation and higher NIHSS scores than those without permeability derangements, although statistically insignificant. The mode of recanalization therapy was not different between the groups, although patients who received combination of fibrinolytics and mechanical therapy were more likely to have permeability derangements (18.2% versus 6.7%, P=0.281). Multivariate testing showed that malignant MRI profile (OR, 24.84; 95% CI, 1.50 to 412.93), time from onset to treatment (OR, 1.47, per 1-hour increase; 95% CI, 1.10 to 1.96), and LDL cholesterol (OR, 0.97, per 1-mg/dL increase; 95% CI, 0.94 to 0.99) were strongly associated with posttreatment permeability derangement. Atrial fibrillation (OR, 3.75; 95% CI, 0.94 to 14.97) and diastolic pressure (OR, 1.04, per 1-mm Hg increase; 95% CI, 0.99 to 1.09) were also independently associated with permeability derangements, although statistically insignificant.
Relationship Between Permeability Derangements and Types of Hemorrhagic Transformation
Types of HT varied among patients with permeability derangements, and not all the patients with permeability derangements showed HT on CT or gradient-recalled echo. Among 26 patients with permeability derangements, 4 developed no HT, 6 HI-1, 5 HI-2, 4 PH-1, 6 PH-2, and one subarachnoid hemorrhage (Supplemental Figure II). There was no significant difference in clinical or radiological characteristics between patients with PH type and those with non-PH type (no HT, HI, or subarachnoid hemorrhage; Supplemental Table I, available online at http://stroke. ahajournals.org). However, there was a tendency that patients with non-PH type had smaller initial DWI lesion volume (33.9±39.8 versus 66.6±66.3 mL) and lower NIHSS score (16.6±7.0 versus 21.5±9.6) than those with PH-type HT (P=0.112 and 0.119, respectively).
Pretreatment permeability derangements were present in 6 of 21 patients with HT and one of the 61 patients without HT on follow-up images (Supplemental Figure III). The sensitivity and specificity of pretreatment permeability derangements for HT were 29% and 98%, respectively. Most patients with permeability derangements on pretreatment images developed HI types (one no HT, 3 HI-1, 2 HI-2, and one PH-2), whereas patients with permeability derangements on posttreatment images frequently developed PH types (3 no HT, 3 HI-1, 3 HI-2, 4 PH-1, 8 PH-2, and one subarachnoid hemorrhage), suggesting the treatment’s effect on the permeability and HT types.
There were several cases with discrepancy between permeability images and CT or gradient-recalled echo: (1) transient permeability derangements after fibrinolytics without subsequent HT; and (2) normalization of permeability derangement on permeability images performed at 5 days after onset in the presence of HT (Figure 3). These features suggest dynamic changes in the BBB permeability after ischemic stroke per se or fibrinolytic use.
The major findings of this study suggest that (1) permeability derangement is a dynamic process associated with ischemic stroke pathophysiology and recanalization therapy; (2) even if BBB leakage is present, the patterns and destiny of permeability derangement varies. It could be benign in certain conditions; and (3) several prognostic and therapeutic predictors for HT are also independently associated with permeability derangements and a predictor for permeability derangements may be different between pre- and posttreatment setting.
There have been several investigations of predictors for HT after recanalization therapy; NIHSS score on admission,1,5 advanced age,5 pretreatment CT findings of brain edema and mass effects1 or early ischemic changes,5 atrial fibrillation,6 site of vascular occlusion,6 and the use of tissue plasminogen activator5 have been reported to be independent predictor for HT after recanalization therapy. Large early ischemic lesions have been found to be associated with a higher incidence of symptomatic HT and worse outcome;4,7,8 patients with high s-glucose levels25 and those with large baseline DWI lesion volumes who achieved early reperfusion8 or malignant MRI profile7 are at great risk of symptomatic HT after tissue plasminogen activator therapy. In the present study, elevated glucose levels and diastolic pressure were independently associated with pretreatment permeability derangements, whereas atrial fibrillation, low LDL cholesterol levels, malignant MRI profile, and time from onset to recanalization therapy were independently associated with permeability derangements, suggesting that predictors for HT are also independently associated with permeability derangements. Our results also suggested that the factors for permeability derangements may be different between pretreatment and posttreatment settings. However, further studies are needed because of the small number of patients with pretreatment permeability derangements. Moreover, our patients were treated with a variety of recanalization therapies, including therapies with high systemic (intravenous), high local (intraarterial), and no exposure to pharmacological thrombolysis (Merci/stent deployment). The therapeutic approach or type of intervention may also affect the presence of permeability abnormalities.
Disruption of the BBB is a necessary, albeit not sufficient, condition for intracerebral hemorrhage. Our data showed that permeability derangement may not be accompanied by HT in some patients; even so, most patients were imaged with gradient-recalled echo (105 patients [82.7%]). In addition, PH-type HT was observed in less than half of patients with permeability derangements. Our findings are supported by a recent perfusion CT study; using a first-pass dynamic perfusion CT technique, Lin and colleagues reported that most (44 of 50) patients with acute ischemic stroke showed focal permeability derangements regardless of the presence of subsequent HT.26 Several factors likely influence the types of HT (PH type versus non-PH type) in the setting of deranged BBB permeability. First, the degree (volume and amplitude) and pattern of permeability change may determine the destiny of increased permeability area (intrinsic or permeability factor). In the present study, patients who showed PH-type HT had the deep pattern on permeability image. Further permeability MRI studies are needed concerning the degree of permeability changes.26 Second, local or systemic factors may determine the destiny of increased permeability area (extrinsic factor). Our present study showed that several prognostic and therapeutic variables were independently associated with permeability derangements. Interestingly, when permeability derangements were present, there was a trend that patients who showed PH-type had a larger DWI lesion volume on baseline MRI and received recanalization therapy. These findings suggest that severe ischemia may predispose to more overt BBB derangements in acute ischemic stroke. In addition, HT phenotype or propensity may be modifiable even if patients had permeability derangements; by avoiding more aggressive recanalization intervention in these patients, it may be possible to avoid clinical deterioration. In the present study, we failed to find the significant HT phenotype determinants in the presence of permeability derangement due to the small sample size. Factors that determine HT types after permeability derangement merit further study with a larger number of patients.
In the present study, false-negative findings were noted in a significant proportion of patients with HT. The method of permeability imaging used in this study was derived from standardly acquired T2*-weighted PWI data. Prior studies of permeability imaging in humans in a variety of disease states have used specially designed MRI sequences and typically required prolonged acquisition times.16–19 Our technique uses shorter scan acquisition times and a simple postprocessing algorithm that may be run on any standard computer. Although these features are highly desirable in the hyperacute stroke setting, further studies to improve sensitivity of permeability images are needed. In the present study, false-negative findings were noted in most commonly HT other than PH-2. It was reported that only PH-2 independently caused clinical deterioration and impaired prognosis,23 and the sensitivity of our method for PH-2 was 75%.
In conclusion, our results indicate that BBB permeability is a dynamic process and HT types varied, even when BBB breakdown is present. Further studies concerning modifiable factor for the HT phenotype are needed.
UCLA MRI Permeability Investigators: Oh Young Bang, MD, PhD; Jeffrey L. Saver, MD; Brian H Buck, MD; Jeffry R. Alger, PhD; Sidney Starkman, MD; Bruce Ovbiagele, MD; Doojin Kim, MD; Latisha K. Ali, MD; Samir H. Shah, MD; John Panagotacos, MD; Arbi Ohanian, MD; Sa Rah Yoon, MD; Reza Jahan, MD; Noriko Salamon, MD; Gary R. Duckwiler, MD; J. Pablo Villablanca; Fernando Viñuela, MD; and David S. Liebeskind, MD.
Source of Funding
This work was supported by National Institutes of Health/National Institute of Neurological Diseases and Stroke 1K23NS054084-01A1 (to D.S.L.).
- Received April 10, 2008.
- Revision received May 10, 2008.
- Accepted June 20, 2008.
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