FLAIR Vascular Hyperintensities in Acute ICA and MCA Infarction: A Marker for Mismatch and Stroke Severity?

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1 Original Paper DOI: / Received: November 30, 2011 Accepted: April 17, 2012 Published online: June 28, 2012 FLAIR Vascular Hyperintensities in Acute ICA and MCA Infarction: A Marker for Mismatch and Stroke Severity? M. Hohenhaus W.U. Schmidt P. Brunecker C. Xu B. Hotter M. Rozanski J.B. Fiebach G.J. Jungehülsing Center for Stroke Research Berlin and Department of Neurology, Charité University Medicine Berlin, Berlin, Germany Key Words Stroke Magnetic resonance imaging FLAIR vascular hyperintensities Mismatch Thrombolysis Abstract Background: Vascular hyperintensities of brain-supplying arteries on stroke FLAIR MRI are common and represent slow flow or stasis. FLAIR vascular hyperintensities (FVH) are discussed as an independent marker for cerebral hypoperfusion, but the impact on infarct size and clinical outcome in acute stroke patients is controversial. This study evaluates the association of FVH with infarct morphology, clinical stroke severity and infarct growth in patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Methods: MR images of 84 patients [median age 73 years (IQR 65 80), 56.0% male, median NIHSS 7 (IQR 3 13)] with acute stroke due to symptomatic ICA or MCA occlusion or stenosis were reviewed. Vessel occlusions were identified by MRA time of flight and graded with the TIMI score. Diffusion and perfusion deficit volumes on admission and FLAIR lesion volumes on discharge were assessed. The presence and number of FVH were evaluated according to MCA-ASPECT areas, and associations with MR volumes, morphology of infarction, recanalization status, presence of white matter disease and hemorrhagical transformation as well as with stroke severity (NIHSS), stroke etiology and thrombolysis rate were analyzed. Results: FVH were detectable in 75 (89.3%) patients. The median number of FVH was 4 (IQR 2 7). Patients with FVH 14 presented with more severe strokes due to NIHSS (p = 0.021), had larger initial DWI lesions (p = 0.008), perfusion deficits (p = 0.001) and mismatch volumes/ratios (p = 0.005). The final infarct volume was larger (p = 0.005), and hemorrhagic transformation was more frequent (p = 0.029) in these patients. Conclusions: The presence of FVH indicates larger ischemic areas in brain parenchyma predominantly caused by proximal anterior circulation vessel occlusion. A high count of FVH might be a further surrogate marker for initial ischemic mismatch and stroke severity. Copyright 2012 S. Karger AG, Basel Introduction FLAIR vascular hyperintensities (FVH) are circular or serpentine brightenings in brain parenchyma or on the cortical surface bordering the subarachnoidal space [1]. M.H. and W.U.S. contributed equally to this work. Fax karger@karger.ch S. Karger AG, Basel /12/ $38.00/0 Accessible online at: Marc Hohenhaus Center for Stroke Research Berlin (CSB) Charité University Medicine Berlin, Charitéplatz 1 DE Berlin (Germany) Tel /4145, charite.de

2 decreased ischemic lesion volumes. In both studies, the presence of FVH was related to the clinical impairment. Lee et al. [4] characterized a larger mismatch between initial DWI and perfusion imaging (PI) lesion, implicating a functional role for the undersupplied tissue by the FVH. The aim of this study was to characterize the association of FVH and the number of affected branches to the initial infarct morphology, the final infarct volume and to clinical severity in a cohort of acute stroke patients with symptomatic ICA or MCA occlusion or stenosis. M e t h o d s A large prospective stroke MRI database was reviewed with data from patients admitted between September 2008 and July 2010 [8]. Inclusion criteria were acute stroke (detection of ischemic lesion on diffusion-weighted images on admission) and appropriate vessel occlusion or symptomatic stenosis of ICA and/or MCA. Patients with a clinical TIA were excluded. Clinical impairment was rated by the NIHSS [9]. Stroke etiology was assessed according to the TOAST classification [10]. The study was approved by the local ethics committee. MRI examinations were performed with a 3.0-tesla MRI scanner (Tim Trio; Siemens AG, Erlangen, Germany). Detailed imaging parameters are published elsewhere [8]. In short, the MRI protocol for patients with acute stroke included the following sequences: T 2 -weighted imaging, DWI (TE = 93.1 ms, TR = 7600 ms, field of view = 230 mm, matrix, 192 = 192, 2.5 mm slice thickness with no interslice gap), time-of-flight (TOF) MR angiography, FLAIR (TE = 100 ms, TR = 8,000 ms, inversion time = 2,370.5 ms, field of view = 220 mm, matrix 256 = 232, 5 mm slice thickness with a 0.5 mm interslice gap) and PI ( fig. 1 ). Vessel occlusions were identified by MRA TOF and graded with the TIMI score [no (TIMI 0), minimal (TIMI 1), partial (TIMI 2), or complete (TIMI 3; re-) perfusion] [11, 12]. Perfusion deficits were analyzed using the mean transit time maps generated on the scanner with the Siemens Tim Trio Neuro Perfusion Evaluation software (Tim Trio; Siemens). Arterial input functions were selected by an experienced neuroradiologist in distal branches of the MCA contralateral to the suspected ischemia [13]. Credible perfusion deficits were manually delineated by an experienced neuroradiologist (J.B.F.). Hemorrhagic transformation was rated according to ECASS criteria with the HT/PH classification [14, 15]. Cerebral microangiopathy was rated by the Wahlund score for detection of age-related white matter changes [16]. Stroke morphology was categorized into territorial infarction (single DWI-positive larger lesion in one vascular territory), scattered territorial infarction (scattered DWI lesions in one vascular territory or subsegment territory), lacunar infarction (DWI lesion in white matter without cortical involvement), cardioembolic pattern (scattered DWI lesions in multiple vascular territories) and border zone infarctions based on clinical and radiological experience (G.J.J., J.B.F., W.U.S.). FVH were defined, in line with previous studies in this field, as circular or serpentine hyperintensities compared to cortical tissue ( fig. 2 and 3 ). The presence and number of FVH were evala b c Fig. 1. MRI example of a 76-year-old patient. a Diffusion-weighted images day 1. b Perfusion images day 1. c FLAIR images day 5. FLAIR is based on a T 2 -weighted sequence and CSF signal suppression is applied to provide better lesion perceptibility in brain parenchyma when a lesion has direct contact to CSF space. In addition, slow flow and stasis cause a high signal on FLAIR in contrast to the normal flow void phenomenon of arteries [2]. A differentiation between proximal (internal carotid artery, ICA, or M1-middle cerebral artery, M1-MCA) hyperintensities and distal (Sylvian fissure or cortical surface) FVH is essential because it is assumed that proximal vessel signs in the MCA territory represent thrombus, whereas distal FVH represent slow blood flow [1, 3]. A comparison of MRI and digital subtraction angiography showed that FVH are most likely caused by slow leptomeningeal collateral flow [2] which might be of functional relevance for infarct evolution. The presence of FVH in the first 3 h after onset of stroke symptoms is described in 66 77% of such acute stroke patient population [4, 5]. Furthermore, FVH are discussed as an independent marker for cerebral hypoperfusion [6]. FVH are mostly seen in stroke patients with large vessel occlusions, ipsilateral to the symptomatic hemisphere and distal to the stenotic vessel, and seem to be transient phenomena [2, 5]. The association of FVH to infarct size or clinical outcome is controversial. Kamran et al. [7] showed larger infarcted or hypoperfused areas in stroke patients with FVH on MRI, while Lee et al. [4] assessed 64 Hohenhaus/Schmidt/Brunecker/Xu/ Hotter/Rozanski/Fiebach/Jungehülsing

3 a b a b Fig. 2. MRI example of a 71-year-old patient with FVH ^4 on admission. a FLAIR image at the level of the ventricles immediately above the basal ganglia (M4 M6). b FLAIR image at the level of the basal ganglia (insular, M1 M3). Fig. 3. MRI example of a 59-year-old patient with FVH 1 4 on admission. a FLAIR image at the level of the ventricles immediately above the basal ganglia (M4 M6). b FLAIR image at the level of the basal ganglia (insular, M1 M3). uated in MCA-ASPECT areas and according to axial baselines where M1 M3 are at the level of the basal ganglia and M4 M6 are at the level of the ventricles immediately above the basal ganglia [17]. Detected hyperintense vessels were assigned to the matching boundaries of the ASPECT territories. M1 represents the anterior MCA cortex corresponding to frontal operculum, M2 the MCA cortex lateral to insular ribbon corresponding to anterior temporal lobe and M3 the posterior MCA cortex corresponding to posterior temporal lobe. M4, M5 and M6 represent the anterior, lateral and posterior MCA territory immediately superior to M1, M2 and M3, respectively. To count the FVH, corresponding slices of the FLAIR sequences were chosen manually. Follow-up images after 24 h and 5 7 days were processed concerning the number of FVH and lesion volumes if available. Patients were dichotomized into two groups, which were FVH ^ 4 (including those without FVH) and FVH 1 4. The cutoff was chosen based on the median number of FVH in all patients on admission. A rescue ratio Q was calculated using the lesion volumes at onset and follow up: We divided the initial mismatch volume by the difference between the final infarction volume and the initial stroke lesion. Statistical analysis was performed with SPSS (version PASW Statistics 18) with standard statistics. The Mann-Whitney U test was applied to detect differences of metrical, not normally distributed data. The 2 test was applied to detect a coherence of categorical data. Correlation analysis was performed with Pearson s correlation coefficient or Spearman rank correlation coefficient, when normal distribution was not met. A p value of! 0.05 was considered significant. Table 1. Baseline characteristics (n = 84) FVH 4 (n = 43) FVH >4 (n = 41) p value Male 22 (51.2%) 25 (61.9%) Age, years 74 (68 81) 69 (62 79) ASPECT score day 1 7 (5 8) 6 (4 8) NIHSS day 1 6 (3 14) 7 (3 13) Time stroke onset to MRI, min 180 (96 609) 118 (84 597) Location of occlusion ICA 9 3 ICA + M M M M3 6 2 Vascular risk factors Diabetes mellitus II Hyperlipidemia Hypertension Atrial fibrillation Prior stroke V alues for age, ASPECT score, NIHSS and time are expressed as median (IQR). Other parameters are number of patients. R e s u l t s Eighty-four patients [median age 73 (IQR 65 80) years, 56.0% male, median NIHSS 7 (IQR 3 13)] with symptomatic ICA and/or MCA occlusion or stenosis were included for data analysis ( table 1 ). FVH were detectable in 75 (89.3%) of all patients. The median number of FVH was 4 (IQR 2 7). FVH were predominantly detectable at the insular, M2 and M5 region of ASPECT territory surfaces ( fig. 4 ). Dichotomization into FVH ^ 4 and FVH 14 showed no significant differences in baseline demographics between the groups, except for the higher rate of FLAIR Vascular Hyperintensities in Acute ICA and MCA Infarction 65

4 Number of FVH Insular region (n = 66) M1 (n = 2) M2 (n = 60) M3 (n = 20) M4 (n = 4) ASPECTS territories M5 (n = 50) M6 (n = 18) Fig. 4. Boxplots demonstrate location and frequencies of FVH according to the surface of ASPECTS territories. In parentheses, corresponding number of patients in whom these FVH were present. Outliers marked with asterisks or open circle. prior stroke in patients with FVH ^ 4 (p = 0.027; table 1 ). Both groups did not differ significantly regarding the location of initial vascular occlusion. Forty-eight patients received complete follow-up imaging [median age 71 (IQR 65 78) years; 62.5% male; ASPECT score on admission 7 (IQR 4 8); median number of FVH 5 (IQR 2 7); median NIHSS 7 (IQR 2 14)]. In this group, the median number of FVH on follow-up MRI after 24 h was 1 (IQR 0 3). On discharge, median NIHSS was 6 (IQR 1 13) and ASPECT score 6 (IQR 4 7). Stroke etiology according to the TOAST classification revealed large artery atherosclerosis in 26 (54.2%), cardioembolism in 19 (39.6%), and other or undetermined etiology in 2 and 1 patient, respectively. Twenty-one (43.8%) patients received thrombolytic therapy with rt- PA within 270 min after onset [median 109 min (IQR )]. The rate of hemorrhagic transformation was 10.4% (5 patients) on admission and 33.3% (16 patients) within 24 h after onset. Of the latter, 8 patients (50%) were treated with rt-pa. Small vessel disease was present in 40 patients (83.3%) with a median Wahlund score of 5 (IQR 2 8). Dichotomization into FVH ^ 4 and FVH 1 4 in this group (n = 48) showed no significant differences concerning infarct morphology, stroke etiology, thrombolysis frequency, Wahlund score and recanalization status on follow-up MRI 24 h later ( table 2 ). Six patients with an initial low-grade stenosis (TIMI 2) were excluded from the evaluation of the recanalization status. None of those received thrombolytic therapy. Frequency of hemorrhagic transformation on follow-up MRI 24 h after initial measurement was higher in patients with FVH 1 4 (p = 0.029; table 2 ). Correlation analysis revealed a positive and significant correlation for the number of FVH and perfusion lesions of (p = 0.013), NIHSS on admission of (p = 0.020), Q of (p = 0.016) and final infarct volume of (p = 0.046). A negative correlation for age was found with a Pearson s coefficient of (p = 0.009). Initial (DWI) and final (FLAIR) infarct volumes as well as perfusion volumes (PI) on admission were significantly larger in patients with FVH 1 4 (p! 0.05 for DWI, FLAIR and PI; table 2 ). Initial DWI/PI mismatch was enlarged in patients with more than 4 FVH as well (p = 0.005), but ratio Q showed no significant differences. Initial NIHSS scores were higher in patients with FVH 1 4 (p = 0.021; table 2 ). Discussion We showed that the number of FVH was associated with larger infarctions and DWI/PI mismatch due to proximal vessel occlusion in the anterior circulation. In general, the occurrence of FVH was common in our cohort of acute stroke patients with symptomatic vessel occlusion. Previous studies reported a prevalence of 98% in patients examined in the first 6 h after onset of stroke symptoms [1]. Patients with large territorial infarctions showed more FVH, and the quantity of FVH correlated with DWI and PI volumes, final infarction volumes and clinical impairment. This is in contrast to a previous study in patients prior to t-pa treatment, where higher numbers of FVH indicated smaller DWI lesions and a better neurological outcome [4]. When more than 4 FVH were seen, the initial mismatch was increased, so that there was a large area of tissue at risk, which is in line with previous studies [4]. Proportional infarct evolution was smaller in patients with more than 4 FVH. The rescue ratio Q represents a relation between tissue at risk and tissue that becomes necrotic after the initial measurement. The higher the rescue ratio was, the less tissue at risk was irreversibly damaged. The high Q value in more than 4 FVH patients implicates a functional role of FVH in the hypoperfused tissue. Certainly, it is generated by collateral flow through 66 Hohenhaus/Schmidt/Brunecker/Xu/ Hotter/Rozanski/Fiebach/Jungehülsing

5 Table 2. Parameters of patients (n = 48) with follow-up examinations on days 2 and 5 7 FVH 4 (n = 23) FVH >4 (n = 25) p value Male 13 (56.5%) 17 (68.0%) Age, years 74 (71 84) 68 (58 78) NIHSS Day 1 4 (1 11) 13 (5 15) Day (0 11) 9 (2 13) ASPECT score Day 1 7 (6 8) 6 (4 8) Day (5 7) 5 (4 7) Infarction morphology Territorial 9 (39.1%) 16 (64.0%) Cardioembolic 1 (4.3%) 2 (8.0%) Scattered territorial 10 (43.5%) 7 (28%) Lacunar 1 (4.3%) 0 Border zone 2 (8.7%) 0 Thrombolysis 9 (39.1%) 12 (48.0%) Recanalization day (26.1%) 12 (48.0%) Received rt-pa 5 7 Hemorrhagic transformation Day 1 1 (4.3%) 3 (12.0%) Day 2 4 (17.4%) 12 (48.0%) Received rt-pa 2 6 Wahlund score 6 (2 11) 4 (1 6) TOAST criteria Large artery atherosclerosis 12 (52.2%) 14 (56.0%) Cardioembolism 11 (47.8%) 8 (32.0%) Small artery occlusion 0 0 Other cause 0 2 (8.0%) Undetermined 0 1 (4.0%) Lesion volumes in cm 3 DWI day ( ) ( ) PI day ( ) ( ) Mismatch day ( ) ( ) PI day ( ) ( ) FLAIR day ( ) ( ) Q 1.60 ( ) 2.80 ( ) V alues are expressed as median (IQR) unless otherwise indicated. For the Q ratio, the initial mismatch volume was divided by the difference between the final infarct volume (FLAIR) and the initial lesion volume (DWI). 1 Six patients from group 1 were not included in recanalization analysis because of initial low-grade stenosis. leptomeningeal collaterals on the cortical surface, represented by the FVH [2]. Frequency and rate of FVH were similar in patients with proximal and complete vessel occlusion, which is in contrast to previous studies [4]. FVH were predominantly located in the central surface area (insular, M2 and M5 region) of the affected hemisphere distal to the vessel occlusion. In contrast to Sanossian et al. [2] and Lee et al. [4], we could not detect FVH proximal to the vessel occlusion. FVH were a temporary phenomenon that commonly disappeared within the first h after onset. Sanossian et al. [2] found a persistence of FVH in patients with persistent vessel occlusions. There were no differences in sociodemographics or risk factors between patients with a smaller or a larger number of FVH on the initial FLAIR sequences. Prior stroke or TIA was more frequent in patients with a smaller number of FVH, which might indicate less collaterals FLAIR Vascular Hyperintensities in Acute ICA and MCA Infarction 67

6 resulting in a less reserve to compensate acute ischemic events after proximal vessel occlusion. Whether patients with less or no FVH are at higher risk for suffering a stroke due to a less sufficient collateral supply cannot be answered based on the data of our population. For the isolated recanalization of occluded vessels, our analysis showed no differences between the two groups, so efficacy of thrombolysis might not be influenced by FVH. However, in theory, the benefit could be greater in patients with higher numbers of FVH because of a potentially larger mismatch. Such information could be useful in early evaluation of acute stroke patients, and could thereby influence the indication of a thrombolytic therapy. A higher rate of hemorrhagic transformation in patients with numerous FVH on day 2 might be a consequence of infarct morphology and larger necrotic areas. We dichotomized our population into patients with ^ 4 FVH including zero and patients with 1 4 FVH for statistical reasons based on the median of FVH of 84 stroke patients, and could show a positive correlation of initial perfusion deficits and NIHSS on admission with the total number of FVH. Nevertheless, manual counting of vascular hyperintensities is an interference-prone procedure, and besides the process of counting the underlying FLAIR imaging protocol is essential. Our retrospective observational study has some limitations and some methodological shortcomings that need further discussion. The cohort is rather small and shows heterogeneity of infarct morphologies, but they did not differ between both subgroups. Even by a computerguided reading procedure counting duplicates between different two ASPECT levels cannot finally be excluded. But with the stipulated rating levels an arbitrary counting was minimized. We used our imaging protocol for clinical routine, and analyzed it retrospectively so that a FLAIR sequence aiming at visualization of vessel occlusion and/or thrombus signal by adapting inversion time might reveal other results. A further limitation is the evaluation of vessel stenosis in TOF-MRA. TOF-MRA has a sensitivity of 84.2% and a specificity of 84.6% for detection of intracranial stenoses compared to conventional angiograms [18]. Disadvantages of the 3D-MRA TOF include overestimation of stenoses [19] and a relatively long acquisition time resulting in a high vulnerability for movement artefacts. Since we retrospectively analyzed the imaging database of acute stroke patients, a digital subtraction or CT angiogram in the emergency setting was not available. We rated the initial grade of stenosis or occlusion with the TIMI Score, which is an angiogram grading score developed to describe flow in coronary arteries broadly used to evaluate recanalization in the cerebrovascular circulation [11]. Especially the differentiation of TIMI I and II is often difficult and might influence the description of perfusion lesions and therefore the presence of FVH as markers of collateral flow. Furthermore, the TIMI score does not take distal vessel patency and perfusion into account. Finally, perfusion volumes were delineated visually only. We did not use a dedicated postprocessing since available postprocessing programs still show a wide variety of results [20], and we aimed to analyze the implications of FVH in clinical routine. Therefore, we used perfusion maps generated by a commercially available scanner. To conclude, FVH were common in our population, and a higher number of FVH indicated a large ischemic area in brain parenchyma with corresponding higher NIHSS on admission predominantly caused by a proximal vessel occlusion in the anterior circulation. Future studies will provide further insights into the role of FVH in MRI mismatch and vascular analysis concepts. Acknowledgements The research leading to these results has received funding from the Federal Ministry of Education and Research via grants from the Center for Stroke Research Berlin (01 EO 0801). Disclosure Statement J.B.F. received consulting, lecture and advisory board fees from BMS, Siemens, Perceptive, Synarc, BioImaging Technologies, Novartis, Wyeth, Pfizer, Boehringer Ingelheim, Lundbeck and Sygnis. G.J.J. has participated in advisory board meetings of Bayer Health Care and Sanofi Aventis, and has received lecture honaria from Bayer Healthcare, Boehringer-Ingelheim, Genzyme, Novartis, Pfizer, Sanofi-Aventis and Takeda. 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