Elsevier

The Lancet Neurology

Volume 10, Issue 11, November 2011, Pages 978-986
The Lancet Neurology

Articles
DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): a multicentre observational study

https://doi.org/10.1016/S1474-4422(11)70192-2Get rights and content

Summary

Background

Many patients with stroke are precluded from thrombolysis treatment because the time from onset of their symptoms is unknown. We aimed to test whether a mismatch in visibility of an acute ischaemic lesion between diffusion-weighted MRI (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI (DWI-FLAIR mismatch) can be used to detect patients within the recommended time window for thrombolysis.

Methods

In this multicentre observational study, we analysed clinical and MRI data from patients presenting between Jan 1, 2001, and May 31, 2009, with acute stroke for whom DWI and FLAIR were done within 12 h of observed symptom onset. Two neurologists masked to clinical data judged the visibility of acute ischaemic lesions on DWI and FLAIR imaging, and DWI-FLAIR mismatch was diagnosed by consensus. We calculated predictive values of DWI-FLAIR mismatch for the identification of patients with symptom onset within 4·5 h and within 6 h and did multivariate regression analysis to identify potential confounding covariates. This study is registered with ClinicalTrials.gov, number NCT01021319.

Findings

The final analysis included 543 patients. Mean age was 66·0 years (95% CI 64·7–67·3) and median National Institutes of Health Stroke Scale score was 8 (IQR 4–15). Acute ischaemic lesions were identified on DWI in 516 patients (95%) and on FLAIR in 271 patients (50%). Interobserver agreement for acute ischaemic lesion visibility on FLAIR imaging was moderate (κ=0·569, 95% CI 0·504–0·634). DWI-FLAIR mismatch identified patients within 4·5 h of symptom onset with 62% (95% CI 57–67) sensitivity, 78% (72–84) specificity, 83% (79–88) positive predictive value, and 54% (48–60) negative predictive value. Multivariate regression analysis identified a longer time to MRI (p<0·0001), a lower age (p=0·0009), and a larger DWI lesion volume (p=0·0226) as independent predictors of lesion visibility on FLAIR imaging.

Interpretation

Patients with an acute ischaemic lesion detected with DWI but not with FLAIR imaging are likely to be within a time window for which thrombolysis is safe and effective. These findings lend support to the use of DWI-FLAIR mismatch for selection of patients in a future randomised trial of thrombolysis in patients with unknown time of symptom onset.

Funding

Else Kröner-Fresenius-Stiftung, National Institutes of Health.

Introduction

International guidelines and approval criteria for use of intravenous thrombolysis exclude patients with stroke whose time of symptom onset is unknown.1, 2 However, many patients who have had a stroke present with unknown time of symptom onset (eg, if symptoms occur during sleep and are recognised only when the patient awakes) and, as with myocardial infarction, patients are more likely to have a stroke in the morning.3, 4 An estimated 25% of ischaemic strokes occur during sleep,4, 5, 6 which means that this large group of patients are precluded from thrombolysis—the only approved and effective specific treatment for acute ischaemic stroke. This dissatisfying situation has raised great interest in surrogate markers of lesion age. Moreover, clinical and imaging findings in patients waking with stroke symptoms were reported to be much the same as in patients with symptom onset known to be within 3–6 h,5, 6, 7 indicating that some of these patients might benefit from thrombolysis.

Multiparametric MRI has been suggested as a means to identify patients who are likely to benefit from thrombolysis, by use of different sequences that are sensitive to different aspects of tissue pathophysiology in acute cerebral ischaemia.6, 8, 9 Alterations of water diffusion can be detected with diffusion-weighted imaging (DWI) within 3 min from onset of ischaemia,10 whereas a net increase of water can be detected as an increase of T2 signal within 1–4 h from onset of ischaemia.11, 12 Fluid-attenuated inversion recovery (FLAIR) imaging is a T2-weighted imaging sequence13 and an integral part of common multiparametric stroke MRI protocols. FLAIR imaging is highly sensitive to subacute ischaemic brain lesions,14 but typically cannot be used to detect ischaemic lesions within the first few hours.15, 16

The mismatch of visibility of an acute ischaemic lesion between DWI and FLAIR has been suggested to enable identification of patients with acute ischaemic stroke who are likely to be within the 3-h time window. In a single centre study,9 a DWI-FLAIR mismatch identified patients within 3 h of symptom onset with high specificity (93%) and positive predictive value (PPV; 94%), although sensitivity and negative predictive value (NPV) were low. These findings have been reproduced in studies from other groups.17, 18, 19 All these studies showed a clear time dependency, with acute ischaemic lesion visibility on FLAIR imaging increasing during the first 6 h after stroke onset and approaching nearly 100% thereafter, a finding that is well known from experimental stroke.11 Taken together, the results from these studies are promising with regard to the use of DWI-FLAIR mismatch to estimate lesion age in patients with unknown time of stroke onset.

In some centres, multiparametric MRI incorporating the absence of a lesion on FLAIR imaging is already used to decide whether thrombolytic drugs should be given to patients who wake up with symptoms of stroke.8, 20, 21 However, neither safety nor efficacy of MRI-based thrombolysis in patients who awake with stroke have been shown. Thus, more data on the benefits of DWI-FLAIR mismatch in clinical practice are needed. Four reliable but retrospective single-centre studies lend support to such use of DWI-FLAIR mismatch,6, 17, 18, 19 but several questions remain unanswered—eg, reproducibility in a multicentre setting and the effect of potential confounding factors such as leukoaraiosis, lesion volume, and infarct location. Before DWI-FLAIR mismatch can be used to guide use of thrombolysis in patients with unknown time of symptom onset, its safety and efficacy should be assessed in a randomised controlled trial, and before such a trial, the diagnostic accuracy of this approach needs to be confirmed in a large multicentre study. In the PREdictive value of FLAIR and DWI for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR) study, we aimed to test whether DWI-FLAIR mismatch can be used to identify patients within 4·5 h of symptom onset with high specificity and PPV, and thus to assess the possibility of using DWI-FLAIR mismatch in a future randomised controlled trial of MRI-based thrombolysis.

Section snippets

Study design and patients

The PRE-FLAIR study was a multicentre observational study of patients with acute ischaemic stroke with known time of symptom onset who had undergone MRI with DWI and FLAIR within 12 h of symptom onset. We tested the predefined hypothesis that DWI-FLAIR mismatch can be used to identify patients within 4·5 h of symptom onset with high specificity in a retrospective cohort of patients studied within 12 h of symptom onset, presenting between Jan 1, 2001, and May 31, 2009. The study was done by an

Results

Figure 1 shows the study profile. Figure 2 shows examples of DWI and FLAIR images, including poor quality MRI scans for which some patients were excluded. At least one observer judged imaging to be of poor quality on DWI in 26 cases (4·0%), on FLAIR in 29 cases (5%), and on both DWI and FLAIR in 7 cases (1%). Table 1 shows baseline characteristics of the study sample.

Interobserver agreement for the detection of acute DWI was 93·9% with a κ of 0·506 (95% CI 0·361–0·651). Interobserver agreement

Discussion

Our assessment of a large multicentre dataset yielded three main findings. First, we showed that the DWI-FLAIR mismatch can be used to identify patients within 4·5 h of symptom onset with high specificity and high PPV. This finding substantiates those from some of the previous smaller single-centre studies,9, 17, 19 lending support to the use of DWI-FLAIR mismatch as a surrogate marker to identify patients with acute stroke who are eligible for intravenous thrombolysis (panel). Second, the

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