- Top of page
- Conflict of interest
Systemic thrombolysis with tissue plasminogen activator (tPA) still represents the only approved treatment that has shown efficacy in randomized clinical trials [1, 2]. In recent years, the usage of tPA has continuously increased , most probably related to the widening of the timeframe for administration (4.5 h after symptom onset; ), global information campaigns, increased availability of specialized treatment units , and increased confidence in drug safety. At the same time, magnetic resonance imaging (MRI) has increasingly been used for baseline imaging in stroke patients eligible to tPA, whereas requirements for licensed use of tPA require exclusion of hemorrhage typically by computed tomography (CT; [1, 2]).
Previous studies indicated that MRI employing fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences may provide a useful tool for identifying recent symptom onset in patients in whom this important information cannot be determined clinically from history [5-11]. Despite different techniques of visualization, MRI sequences had also been discussed to indicate structural brain damage after ischemia comparable with hypodensity on CT as an already established risk factor for secondary hemorrhage [1, 5, 11, 12]. Consequently, a previous study had demonstrated that an increasing size of DWI lesions is associated with the risk of symptomatic intracerebral hemorrhage (ICH) after systemic or intra-arterial thrombolysis within 6 h after symptom onset . However, the usefulness of pretreatment FLAIR und DWI sequences captured within the very early hours as the striven time window for systemic thrombolysis remains to be further elucidated.
This study aimed to investigate the predictive impact of FLAIR- and DWI-positive lesions seen on baseline MRI in ischemic stroke patients undergoing systemic thrombolysis with tPA in a timeframe of 3 h after symptom onset. While focusing on ICH as probably most-serious complication of tPA treatment, relationships to both sole existence and size of detected lesions were explored.
- Top of page
- Conflict of interest
The present study examined whether specific MRI sequences obtained prior to systemic thrombolysis in acute ischemic stroke patients might be useful to predict secondary hemorrhage after systemic treatment with tPA initiated within 3 h after symptom onset. In our study population, the CT-based rate of any intracerebral bleeding after thrombolysis was 33%, which is in good agreement with previous reports (ECASS II, 43.0% ; ECASS III, 27.0% ).
The incidence of 25.8% for FLAIR-positive lesions in pretreatment MRI of acute stroke patients treated within <3 h after symptom onset agrees with earlier studies that have reported FLAIR-positive rates between 15%  and about 50% [6, 16], including quite different timeframes. However, as the incidence of FLAIR hyperintensities is known to increase over time [6, 8, 15], the rate of about one-fourth observed in the present study might represent an adequate proportion for the first 3 h.
We found that FLAIR-positive lesions within diffusion-restricted areas detected on MRI prior to intravenous treatment with tPA was significantly and strongly associated with an increased risk for ICH (odds ratio 20.0). A previous report from Cho et al.  found an odds ratio of 13.64 of symptomatic ICH in FLAIR-positive patients compared with FLAIR-negative patients treated with intravenous and/or intra-arterial thrombolysis up to 6 h after symptom onset. However, Campbell et al.  failed to link the existence of FLAIR hyperintensities with ICH in patients ranging from 3 to 6 h after symptom onset, leading to the suggestion that time-of FLAIR positivity may be associated with development of ICH only when detected in the very early period (i.e., within 3 h) after symptom onset. The apparently different impact of FLAIR positivity in the early period (0–3 h) and the late period (3–6 h) might be attributed to the rate of recanalization, which has been found to decrease over time , and the maintenance of blood supply via collaterals.
The sensitivity of our study was enhanced by considering any type of ICH, irrespective of clinical manifestations. This approach was based on a previous report indicating that delayed neurological deterioration may occur even after small bleedings by virtue of delayed hematoma growth , and further, on the observation that the presence of small and clinically asymptomatic hemorrhages represents a negative predictor for clinical outcome independent of hematoma growth . On the other hand, mild hemorrhagic transformation – irrespective of FLAIR status – has also been discussed to represent a marker of early recanalization, associated with an improved clinical outcome [21, 22].
Nevertheless, the emerging evidence from our and previous studies suggest the perspective that FLAIR-positive lesions detected in the pretreatment MRI with 3 h after symptom onset might represent a useful marker to predict tPA-associated bleeding complications potentially leading to poor clinical outcome. However, as an earlier report demonstrated that the FLAIR status in an extended timeframe of up to 4.5 h after symptom onset was not predictive of either worse neurological outcome at day 1 or growth of the ischemic lesion , it may be premature to exclude FLAIR-positive patients from systemic thrombolysis. On the other hand, as clinical deterioration may occur at later stages, FLAIR positivity within 3 h from symptom onset may raise clinical alertness to developing treatment complications.
We also found a significant association of DWI lesion size and risk of ICH. When the DWI lesion comprised at least 1/3 of the vascular territory, the rate of bleeding complications due to tPA was remarkably increased. Although recent evidence has criticized the earlier concept of a distinct relationship between DWI and definitely infarcted brain tissue , increased risk of tPA-induced ICH in patients with extended DWI lesions appears to support a link between restricted diffusion and tissue infarction.
In our population with symptom onset strictly limited to the first 3 h, we found substantial variability of ratios of FLAIR/DWI across patients. As a separate finding, our data provide circumstantial evidence to suggest that the time of stroke onset cannot be easily and confidently inferred from a combination of FLAIR-negative and DWI-positive stroke lesion, a finding at variance from previous claims [5-7, 9, 15]. Further, the present data do not support the hypothesis that the extension of FLAIR-positive lesions in relation to the diffusion-restricted area influences the risk of ICH, at least when FLAIR/DWI proportion was stratified into three categories (<1/3, 1/3–2/3 and >2/3). In CT-based studies, bleeding risk after tPA was increased in patients exhibiting signs of infarction in at least 33% of the middle cerebral artery territory on pretreatment CT [11, 24]. In a study utilizing MR stroke imaging the number of FLAIR-positive lesions, but not their volume, was found to correlate with DWI lesion size 1 day after ischemia onset in a subset of stroke patients not undergoing thrombolysis , indicating a complex relationship between FLAIR-positive areas, diffusion restriction and infarction. Because in the present study, the proportion of FLAIR-positive lesions was calculated based on the area of restricted diffusion, but not on vascular territory it remains a possibility that a significant association would have emerged from a traditional analysis based on vascular territory.
The present study has some limitations: First, the retrospective design only allowed processing of imaging data from a standardized time-saving scanning protocol. Future studies might therefore focus on the relationship between FLAIR-positive lesions and parameters more closely capturing functional aspects as for instance the cerebral blood flow. However, such increase on data acquisition prior to treatment is generally hampered by the fact that treatment should not be delayed by extensive diagnostics. Second, bleeding complications were assessed by CT as an established technique for screening of ICH. As MR imaging has recently been discussed to be more sensitive for the detection of hemorrhagic transformation , future studies might use a homogenous setup in cerebral imaging with MRI at both time points (pre- and post-treatment).
Based on a large data set, this study has revealed a dramatically increased risk for development of any ICH when FLAIR-positive lesions within DWI-restricted areas are present on pretreatment MRI in stroke patients undergoing systemic thrombolysis within 3 h after symptom onset. An increase rate of intracerebral bleeding was also noted in patients characterized by a DWI lesions size of at least 1/3 of the vascular territory. Our findings might be helpful to raise clinical alertness and to guide treatment decisions in patients with FLAIR-positive lesions.