Diffusion-weighted imaging (DWI) ischemic volume is related to FLAIR hyperintensity-DWI mismatch and functional outcome after endovascular therapy

Introduction

Acute ischemic stroke (AIS) is a cerebrovascular disease that is seriously harmful to human life and has high mortality and disability rates (1,2). It is very important to predict outcomes early in the treatment and rehabilitation of stroke patients. Currently available studies have reported that valuable imaging markers that can predict stroke patient outcomes include National Institutes of Health Stroke Scale (NIHSS) scores, Alberta Stroke Program Early Computed Tomography Scores (ASPECTS), and collateral circulation, and diffusion-weighted imaging (DWI) infarct volume (3-7). Some studies have suggested that AIS patients with larger infarct volumes have worse clinical outcomes following intravenous thrombolysis (8,9). Research investigating the changes in DWI volume after thrombolysis has demonstrated a consistent correlation with clinical outcome (10,11). The quantification of infarction evolution has been considered capable of determining the efficacy of therapy and may also be used as a surrogate outcome measure for stroke trials (12,13).

Fluid-attenuated inversion recovery (FLAIR) and DWI sequences are part of acute stroke magnetic resonance imaging (MRI) protocols in institutions using MR imaging as a first-line diagnostic tool (14-16). The earliest MRI finding, occurring within minutes after occlusion of cerebral blood flow, is restricted diffusion on DWI, correlating with cytotoxic edema in ATP-deprived cells (17-19). On the other hand, there is a gradual increase in FLAIR signal intensity in the infarcted region, which may not be observed until a few hours after abnormal DWI signal appears. FLAIR vascular hyperintensities (FVH) appear as a circular or serpentine brightening in the brain parenchyma or the cortical surface bordering the subarachnoid space (20). FVH precedes DWI abnormalities (21) and can be seen beyond the boundaries of the DWI lesion (22). Some studies have reported that FVH may provide prognostic information (14). FVH-DWI mismatch focuses on FVH beyond the boundaries of the cortical DWI lesion, ignoring FVH adjacent to the DWI lesion. Currently, available studies have generally focused on whether the FVH-DWI mismatch predicts PWI-DWI mismatch or ischemic penumbra (23). The associations between DWI volume and FVH-DWI mismatch, as well as those between the effect of DWI volume and DWI volume growth on functional outcome, have not been reported.

Therefore, in this study, we sought to assess whether DWI volume and DWI volume growth were associated with FVH-DWI mismatch, and the effect of DWI volume and DWI volume growth on functional outcome at 3 months after acute stroke in patients who received thrombectomy therapy. We hypothesized that DWI volume and DWI volume growth would be associated with FVH-DWI mismatch, and could provide functional outcome information in acute stroke patients.

Methods

Subjects and clinical data

The hospital review board of Nanjing Medical University approved the study protocol. The prospective registry of AIS patients was evaluated with data obtained at the Nanjing First Hospital between January 2017 and March 2019. All patients were treated according to the guidelines for managing AIS (24). Patients who met the criteria for intravenous thrombolytic therapy received intravenous thrombolysis (Alteplase; rt-PA) within 4.5 h of stroke onset after a CT scan, and an MRI examination immediately followed. If a large vessel [the middle cerebral artery (MCA) -M1 or/and the internal carotid artery (ICA)] occlusion was found on magnetic resonance angiography (MRA) within 6 h of stroke onset, thrombectomy was immediately performed. The patients included in the present study presented the following: (I) a first-ever acute anterior circulation stroke or a previous stroke with hemiplegia sequelae that did not affect the neurological score; (II) acute stroke saw ≤6 h within symptom onset; (III) CT scan after admission; (IV) pretreatment MRI with DWI, FLAIR, and MRA; (V) receiving thrombectomy therapy; (VI) follow-up MRI was performed within 24 h after thrombectomy therapy; and (VII) a clinical follow-up with a modified Rankin scale (mRS) score at 3 months. The exclusion criteria were as follows: (I) cerebral hemorrhage, tumor, or trauma detected on a CT scan; (II) any contraindication for MRI; (III) any missing mRS at 3 months after stroke; (IV) refusal of thrombectomy therapy; and (V) any MRI or DSA that could not be evaluated due to a motion artifact.

Age, gender, homocysteine levels (blood test level >15 µmol/L), NIHSS score (>5 score) at admission, history of hypertension (>140/90 mmHg), diabetes mellitus [fasting plasma glucose ≥126 mg/dL (7.00 mmol/L) or 2-h plasma glucose after a 75-g oral glucose tolerance test ≥200 mg/dL (11.1 mmol/L)], hyperlipidemia [blood serum total cholesterol >150 mg/dL (1.70 mmol/L)/triglyceride >220 mg/dL (5.72 mmol/L)/low density lipoprotein-cholesterol >140 mg/dL (3.64 mmol/L)], and atrial fibrillation, were collected. The functional outcome at 3 months was assessed using the mRS. A good functional outcome was defined as an mRS score ≤ of 2 at 3 months (25). All patients had written informed consent signed by themselves or their family members prior to their participation in this study. The study was approved by the local ethics committee of the Nanjing Medical University.

MRI protocol

All patients underwent an MRI examination before thrombectomy and after thrombectomy therapy within 24 h. The MRI data were acquired using a 3T MR scanner (Ingenia, Philips Medical Systems, Best, the Netherlands) with an 8-channel receiver array head coil. The standard MRI scanning protocol included FLAIR, DWI, and MRA. The imaging parameters for the FLAIR were as follows: 7,000/120 ms TR/TE, 356*151 matrix, 230*230 mm² field of view (FOV), 90° FA, 18 slices, 6-mm-thick sections, and 1.3 mm intersection gap. The imaging parameters for the DWI were as follows: 2,245/90 ms [repetition time (TR)/echo time (TE)], b_max=1,000 s/mm², 140*109 matrix, 210*210 mm² FOV, 6-mm-thick sections, and 1.3 mm intersection gap. The imaging parameters for the 3D-MRA were as follows: fast field echo (FFE) sequence, 4.9/1.82 ms TR/TE, 528*531 matrix, 330*330 mm² FOV, and 1.2-mm-thick sections.

Image analysis

Two experienced neuroradiologists (H.Y.C and M.Y.P) who were blinded to the clinical data, independently evaluated these images. In cases of discrepant assessment results between the two readers, images were reviewed, and a consensus was established. DWI volume was measured using a Philips MRI scanner postprocessing workstation. DWI volume was automatically calculated after delineating the region of interest of infarct volume on DWI images. DWI volume growth was defined as DWI volume on follow-up minus DWI volume on admission. FVH was defined as focal, tubular, or serpentine hyperintensity present in the subarachnoid space relative to cerebrospinal fluid with a typical arterial course (20). The FVH score was assessed according to their spatial distribution in the ASPECTS of cortical areas (insula, M1-M6) (26). FVH-DWI mismatch was assessed based on axial FLAIR and DWI images, and the FVH-DWI mismatch was considered present when FVHs extended beyond the boundaries of the cortical DWI lesion (i.e., when ≥1 FVH was facing the isointense cortex on DWI). No FVH-DWI mismatch was defined as no FVH or all FVHs facing the hyperintense cortex on DWI.

Two experienced interventional neuroradiologists (H.B.S and B.X.Z) who were blinded to the clinical information assessed the baseline angiography data of stroke patients. The collateral grading score was evaluated using the American Society of Interventional and Therapeutic Neuroradiology (ASITN) scoring system (0 = no collaterals, 4 = complete and rapid collateral perfusion of the ischemic territory) (27). Good collateral status was defined as an ASITN grade of 3–4 (28).

Statistical analysis

All statistical analyses were conducted using commercially available software (SPSS for Windows, version 19.0; SPSS). Continuous data are described as the mean ± SD and were compared using independent-samples t-test or the Mann-Whitney U test, while categorical variables are presented as a number (percentage), and were compared using chi-squared test or Fisher’s exact tests. P<0.05 was considered to indicate statistical significance. Receiver operating characteristic (ROC) curve analysis was used to assess the value of DWI volume to predict functional outcome in patients with AIS after thrombectomy.

Results

Comparison of FVH/DWI mismatch and no FVH/DWI mismatch with acute stroke patients

Among the 94 patients in the study, 53 (29 males and 24 females; aged: mean ± SD, 70.06±9.341 years old, range, 41–80 years old) fulfilled the inclusion criteria. Forty-one patients were excluded (8 patients, no pretreatment MRI; 12 patients, severe artifacts on FLAIR or DWI sequences; 6 patients, did not undergo angiography; 10 patients, no posttreatment MR; 5 patients, no mRS at 3 months). Out of the 53 patients, 24 (45.28%) received thrombectomy therapy, and 29 (54.72%) received both intravenous thrombolysis and thrombectomy therapy. Thirty-two (60.38%) had FVH-DWI mismatch, with the interobserver agreement for FVH-DWI mismatch being k=0.95 (95% CI, 0.91–0.99) (Figure 1). As shown in Table 1, compared to the without FVH-DWI mismatch group, the FVH-DWI mismatch group had a smaller DWI volume on admission (13.86±19.58 vs. 65.07±52.21; t=−4.301, P=0.000), smaller DWI volume on follow-up (29.88±33.52 vs. 112.43±87.19; t=−4.143, P=0.000), lower DWI volume growth (16.02±19.90 vs. 47.36±40.06; t=−3.326, P=0.003), higher FVH scores (4.50±0.84 vs. 3.29±0.90; t=4.990, P=0.000), and a higher ASITN (2.69±0.64 vs. 1.81±0.93; t=4.069, P=0.000) (Figures 2-4). The 3-month outcome was better in patients with FVH-DWI mismatch (1.78±0.87) than that in patients without FVH-DWI mismatch (3.00±1.41) (t=−3.890; P=0.000) (Table 1).

Figure 1 Flowchart of the study.

Table 1 Comparison of FVH/DWI mismatch and no FVH/DWI mismatch with acute stroke patients
Full table

Figure 2 An fluid-attenuated inversion recovery vascular hyperintensity (FVH)-diffusion-weighted imaging (DWI) mismatch case. (A,B) DWI and (C,D,E,F) fluid-attenuated inversion recovery (FLAIR) images. Some FVH (red arrow) was observed beyond the boundaries of the DWI lesion. The patient was classified as FVH-DWI mismatch. FVH was found in the M2, M5, and M6, so the FVH score was 3.

Figure 3 A no fluid-attenuated inversion recovery vascular hyperintensity (FVH)-diffusion-weighted imaging (DWI) mismatch case. (A,B) Diffusion-weighted imaging (DWI) images and (C,D,E,F) fluid-attenuated inversion recovery (FLAIR) images. FVH facing the hyperintense cortex on DWI (red arrow). No FVH was found beyond the boundaries of the DWI lesion. The patient had no FVH-DWI mismatch. FVH was found in the M4, so the FVH score was 1.

Figure 4 Diffusion-weighted imaging (DWI) volume histogram between fluid-attenuated inversion recovery vascular hyperintensity (FVH)-DWI mismatch and no FVH-DWI mismatch. (A) Good functional outcome and (B) poor functional outcome.

Comparison of good functional outcome and poor functional outcome with acute stroke patients

The analysis of 53 AIS patients revealed that 33 patients (62.26%) had a good functional outcome (mRS at 3 months 0–2), and 20 (37.74%) had a poor functional outcome (mRS at 3 months 3–6). The good functional outcome group had a smaller DWI volume on admission (13.30±13.26 vs. 68.56±54.28; t=−5.611, P=0.000), smaller DWI volume on follow-up (27.65±18.80 vs. 120.25±90.37; t=−5.720, P=0.000), and lower DWI volume growth (14.35±15.06 vs. 51.69±41.17; t=−4.737, P=0.001) than those of the poor functional outcome group (Figure 4). In addition, the good functional outcome group had a higher FVH score (4.33±1.08 vs. 3.50±0.76; t=3.021; P=0.004), a higher FVH-DWI mismatch ratio (75.76% vs. 35%; t=8.647; P=0.004), and a higher ASITN grade (2.67±0.82 vs. 1.80±0.67; t=3.953; P=0.000) than those of the poor functional outcome group. There were no significant differences in gender, hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, or homocysteine levels between the two groups (P>0.05) (Table 2).

Table 2 Comparison of good functional outcome and poor functional outcome with acute stroke patients
Full table

ROC analysis for the functional outcome with acute stroke patients

ROC analysis showed the findings for the DWI volume on admission, DWI volume on follow-up, and DWI volume growth to predict functional outcome in stroke patients were 0.820 (95% CI, 0.679–0.962), 0.839 (95% CI, 0.702–0.977), and 0.818 (95% CI, 0.694–0.943) respectively. When the optimal cut-off value of DWI volume on admission was 33.50 mL, the sensitivity and specificity for predicting functional outcome were 65% and 96.97%, respectively; DWI volume on follow-up was 48.6 mL, and had the sensitivity and specificity of 80% and 87.88%, respectively; DWI volume growth was 22.25 mL, and had a sensitivity and specificity of 70% and 87.88%, respectively (Figure 5).

Figure 5 Receiver operating characteristic (ROC) curves for the functional outcome based on diffusion-weighted imaging (DWI) volume on admission (AUC: 0.820; sensitivity and specificity: 65% and 96.97%, respectively), DWI volume on follow-up (AUC: 0.839; sensitivity and specificity: 80% and 87.88%, respectively), and DWI volume growth (AUC: 0.818; sensitivity and specificity: 70% and 87.88%, respectively).

Discussion

From our analysis of patients with acute stroke, we found that FVH-DWI mismatch had a smaller DWI volume on admission, smaller DWI volume on follow-up, lower DWI volume growth, and better functional outcome than those of patients with FVH-DWI mismatch. In addition, patients with good functional outcomes had a higher FVH-DWI mismatch ratio, smaller DWI volume on admission, smaller DWI volume on follow-up, and lower DWI volume growth than those of patients in the poor functional outcome group. DWI volume on admission, DWI volume on follow-up, and DWI volume growth had higher sensitivity and specificity in predicting functional outcome in stroke patients. Comprehensively evaluating DWI volume on admission, DWI volume on follow-up and DWI volume growth could provide the prognostic information of acute stroke patients after thrombectomy.

Although the mechanisms underlying this MRI sign and its clinical implications have been controversial, FVH is considered an emergent radiographic marker, which likely represents disordered or sluggish blood flow and is often observed in acute stroke with large vessel occlusion. Slow flow and stasis cause a high signal on FLAIR, which contrasts the normal flow void phenomenon of arteries. Proximal FVH in the MCA territory most often represents thrombus, while distal FVH is likely to represent slow blood flow (29). FVH may represent slow collateral flow effective in maintaining perfusion to penumbral regions, restricting the progress of ischemic lesions, and improving outcome (26,30). Conversely, FVH also seems to correspond to a perfusion deficit, larger lesions, and poor outcome (31,32). This stark discrepancy may be the result of different FVH methods being used, the heterogeneity of samples, or varying symptom-to-MR imaging times. Shang et al. demonstrated that FVH was associated with an unfavorable outcome within 6 hours to 14 days of onset, while distal FVH may be favorable beyond 14 days of onset in MCA infarction (33). At present, there are many methods to evaluate the extent of FVH (30-32,34), each method has its drawbacks, and the most reliable method has not yet been identified. FVH-DWI mismatch focuses on FVHs beyond the boundaries of the cortical DWI lesion and ignores FVHs adjacent to the DWI lesion. There are several advantages to using FVH-DWI mismatch when evaluating FVH extent (35): it is a reproducible method, it does not require gadolinium contrast, and it is easily and directly assessable by the naked eye without the need for postprocessing. In our study, patients with FVH-DWI mismatch had a higher FVH score and a higher ASITN than those of patients with FVH-DWI mismatch, which is consistent with previous research (36). This research demonstrated that FVH is independently associated with better collateral grades (36). There is accumulating evidence indicating that FVH distal to an arterial occlusion represents good collaterals in the early time window. AIS usually involves hemodynamic impairment and slow retrograde collateral leptomeningeal blood flow. As previously described, the FVH score reflects the number of leptomeningeal collateral vessels recruited during the acute disruption of blood flow in the MCA. Thus, the greater the FVH score, the more collateral vessels appear on FLAIR, the higher the rate of the FVH-DWI mismatch. In this study, patients with FVH-DWI mismatch had more abundant collateral circulation, and greater collateral circulation was associated with better functional outcomes.

Good collateral vessels can improve the odds of achieving a larger volume of surviving brain tissue by sustaining the ischemic penumbra (37,38) and are associated with better clinical outcomes (39). In our study, we compared the association between DWI volume and FVH-DWI mismatch. We found that FVH-DWI mismatch patients had a smaller DWI volume on admission, smaller DWI volume on follow-up, and lower DWI volume growth than those of patients without FVH-DWI mismatch. This finding is consistent with Lee et al. (40), who proposed that patients with more prominent distal hyperintense vessels had smaller initial and 24-hour ischemic lesion volumes. In contrast, Hohenhaus et al. (41) suggested that patients with FVH >4 had larger initial DWI lesions and final infarct volume. The reason for some of the differences among studies may be the use of different FVH scoring methods. In addition, we also found that DWI volume on admission, DWI volume on follow-up, and DWI volume growth in good functional outcome groups were smaller than those in patients with poor functional outcomes. DWI lesion volume has been shown to influence the response to thrombectomy therapy; a large DWI lesion on admission is recognized as a useful marker for poor treatment response (42,43). A large DWI infarct volume on admission (>70 mL) is one of the more established imaging markers for poor clinical outcome in acute stroke (42,44-46). Certain studies have suggested that a DWI infarct volume of >70–100 mL represents a malignant profile that has a higher risk of a poor outcome (8,9). In our study, ROC analysis showed that when the optimal cut-off value of DWI volume on admission was 33.50 mL, the sensitivity and specificity for predicting functional outcome was 65% and 96.97%, respectively; DWI volume on follow-up was 48.6 mL, and had a sensitivity and specificity of 80% and 87.88%, respectively; DWI volume growth was 22.25 mL, and had a sensitivity and specificity of 70% and 87.88% respectively. Thus, DWI volume on admission, DWI volume on follow-up, and DWI volume growth could be clinically useful markers of functional outcome.

Despite these informative findings, our study has some limitations that should be addressed. First, the sample size was rather small, and although many AIS patients in the early stage were included, many heterogeneous cases were excluded after rigorous screening. Second, this was a single-center study. Moreover, due to ethical considerations, we performed the MRI scanning immediately after intravenous thrombolysis in patients who qualified for intravenous thrombolysis after CT scanning, without ruling out the effect of intravenous thrombolysis on the MRI. Finally, our results cannot be generalized to all acute stroke patients, especially those who do not undergo thrombectomy therapy. A study of larger sample size with the inclusion of stroke patients with different therapies from many centers should be conducted in the future.

Conclusions

Smaller DWI volume on admission, DWI volume on follow-up, and DWI volume growth were more likely to cause FVH-DWI mismatch, and usually had a good functional outcome with stroke patients. Comprehensively evaluating DWI volume on admission, DWI volume on follow-up and DWI volume growth could provide the prognostic information of acute stroke patients after thrombectomy.

Acknowledgments

Funding: This work was funded by the Jiangsu Provincial Special Program of Medical Science (BE2017614).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: All patients had written informed consent signed by themselves or their family members prior to their participation in this study. The study was approved by the local ethics committee of the Nanjing Medical University.

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