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Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion-diffusion mismatch
Abstract
The use of diffusion-weighted imaging (DWI) to define irreversibly damaged infarct core is challenged by data suggesting potential partial reversal of DWI abnormalities. However, previous studies have not considered infarct involution. We investigated the prevalence of DWI lesion reversal in the EPITHET Trial.
EPITHET randomized patients 3-6 hours from onset of acute ischemic stroke to tissue plasminogen activator (tPA) or placebo. Pretreatment DWI and day 90 T2-weighted images were coregistered. Apparent reversal of the acute ischemic lesion was defined as DWI lesion not incorporated into the final infarct. Voxels of CSF at follow-up were subtracted from regions of apparent DWI lesion reversal to adjust for infarct atrophy. All cases were visually cross-checked to exclude volume loss and coregistration inaccuracies.
In 60 patients, apparent reversal involved a median 46% of the baseline DWI lesion (median volume 4.9 mL, interquartile range 2.6-9.5 mL) and was associated with less severe baseline hypoperfusion (p < 0.001). Apparent reversal was increased by reperfusion, regardless of the severity of baseline hypoperfusion (p = 0.02). However, the median volume of apparent reversal was reduced by 45% when CSF voxels were subtracted (2.7 mL, interquartile range 1.6-6.2 mL, p < 0.001). Perfusion-diffusion mismatch classification only rarely altered after adjusting the baseline DWI volume for apparent reversal. Visual comparison of acute DWI to subacute DWI or day 90 T2 identified minor regions of true DWI lesion reversal in only 6 of 93 patients.
True DWI lesion reversal is uncommon in ischemic stroke patients. The volume of apparent lesion reversal is small and would rarely affect treatment decisions based on perfusion-diffusion mismatch.
... [1][2][3] Although DWI intensities have been traditionally thought to represent the ischemic core, a number of studies have found that such lesions are, in fact, reversible, thereby implying that DWI intensity may also represent salvageable penumbra. [4][5][6][7][8][9] As such, DWI reversibility may have important implications for clinical decision-making. Indeed, several studies have demonstrated DWI reversibility to be associated with treatment efficacy and neurological improvement. ...
... Of the 10 studies, four examined the percentage of patients experiencing posttreatment DWI reversal, 10,14-16 three studies reported the degree to which the lesion reversed, reported as the reversal of acute diffusion (RAD), 5,17,18 whereas three examined both variables. 6,8,19 RAD is defined as the percentage of voxels in the initial, acute DWI lesion that did not overlap with the voxels in the follow-up DWI lesion. Seven articles were published after Jan 1, 2008, whereas three studies were published between 2003 and 2008. ...
... 15 In addition, Chemmanam et al defined true reversal as any reduction in DWI lesion volume following the subtraction of CSF-voxels in the follow-up DWI scan, adjusting for infarct atrophy. 6 Finally, three studies did not specify explicit criteria regarding the designation of DWI reversal and reported the number of patients who experienced any reduction in DWI lesion volume, regardless of size. 8,10,19 ...
BACKGROUND AND PURPOSE
Diffusion‐weighted magnetic resonance imaging (DWI) detects early infarction in acute stroke. With the substantial progress in stroke therapies, the frequency of posttreatment DWI reversibility in modern stroke cohorts is currently unknown. The purpose of this study was to perform a systematic literature review examining the relationship between characteristics of patients with ischemic stroke and DWI reversibility following treatment with lytic therapy.
METHODS
A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, yielding a total of 422 unique articles. Studies that were nonclinical or did not report data pertaining to DWI reversibility in the context of an acute stroke series were excluded. Characteristics regarding presentation, diagnosis, intervention, and the timing of DWI reversibility were collected for each study.
RESULTS
After full‐text review, 10 studies were identified as meeting inclusion criteria. The number of patients with DWI reversal ranged from .9% to 50%, whereas the extent of reversal ranged from 1.8% to 72.7%. Studies reporting on younger patients describe greater rates of reversibility following stroke treatment.
CONCLUSIONS
These data suggest that early DWI signal may not represent the definitive DWI burden in recanalized populations. However, substantial heterogeneity exists regarding the rate of DWI reversal following recanalization. Additional studies are needed to elucidate the relationship among time to treatment, early reversal rates, and clinical outcomes. Physicians should use caution when basing clinical decisions on DWI lesion volumes, as these likely change to some degree with recanalization.
... Diffusion-weighted MR imaging (DWI) is widely used to identify the infarct core in acute ischaemic stroke patients, 4,5 and diffusion-perfusion mismatch is considered to indicate ischaemic penumbra or salvageable brain tissue. [6][7][8][9] DLR after recanalization treatment has been documented in both clinical practice [10][11][12][13][14][15][16][17][18][19][20][21] and experimental settings. [22][23][24] Early abnormalities on DWI thus overestimate the infarct core by including part of the penumbra, and the actual 'salvageable brain tissue' includes the D-P mismatch area and DLR. ...
... 11,12,14,16 However, whether DLR is sustained in the long-term remains controversial, and several studies have reported that most DLRs are miscalculated due to inaccurate coregistration and infarct shrinkage over time, apparent early diffusion lesion reversal (eDLR) is transient, and permanent DLR is uncommon and typically involves only a small volume of tissue. 12,17,18 However, there are limitations to achieving actual DLR in clinical practice because most IA treatments require 1 h or more to recanalize occluded arteries and pre-IA treatment magnetic resonance images (MRIs) do not reflect pre-reperfusion maximal diffusion lesions. Furthermore, there is no standard definition for sustained diffusion lesion reversal (sDLR). ...
... The final infarction was segmented into segments of sufficient size to include the adjacent CSF space and cystic parenchymal defect area, as in previous studies. 17,18 DLRs at 2 weeks ( 2W DLR, n ¼ 7) and 3 weeks ( 3W DLR, n ¼ 6) were also calculated to compare with the results of e-and sDLRs. ...
Although early diffusion lesion reversal after recanalization treatment of acute ischaemic stroke has been observed in clinical settings, the reversibility of lesions observed by diffusion-weighted imaging remains controversial. Here, we present consistent observations of sustained diffusion lesion reversal after transient middle cerebral artery occlusion in a monkey stroke model. Seven rhesus macaques were subjected to endovascular transient middle cerebral artery occlusion with in-bore reperfusion confirmed by repeated prospective diffusion-weighted imaging. Early diffusion lesion reversal was defined as lesion reversal at 3 h after reperfusion. Sustained diffusion lesion reversal was defined as the difference between the ADC-derived pre-reperfusion maximal ischemic lesion volume (ADCD-P Match) and the lesion on 4-week follow-up FLAIR magnetic resonance imaging. Diffusion lesions were spatiotemporally assessed using a 3-D voxel-based quantitative technique. The ADCD-P Match was 9.7 ± 6.0% (mean ± SD) and the final infarct was 1.2–6.0% of the volume of the ipsilateral hemisphere. Early diffusion lesion reversal and sustained diffusion lesion reversal were observed in all seven animals, and the calculated percentages compared with their ADCD-P Match ranged from 8.3 to 51.9% (mean ± SD, 26.9 ± 15.3%) and 41.7–77.8% (mean ± SD, 65.4 ± 12.2%), respectively. Substantial sustained diffusion lesion reversal and early reversal were observed in all animals in this monkey model of transient focal cerebral ischaemia.
... Hence it is uncommon for the infarct core to be significantly underestimated on DWI. 10,11 Use of an apparent diffusion coefficient threshold further minimizes inclusion of ischemic but viable tissue in the infarct core estimate. Despite the greater accuracy of DWI for detection of irreversible tissue injury, CT is more widely used because it is faster and easier to access. ...
... Although this has been described as transient, there is some evidence that DWI reversal may be more frequent and substantial than previously thought in patients who are reperfused within 3 hours of stroke onset and in those who undergo early thrombectomy. 10,11,30,31 ...
Background and Purpose—
The aim of this study is to determine the spatial and volumetric accuracy of infarct core estimates from relative cerebral blood flow (rCBF) by comparison with near-contemporaneous diffusion-weighted imaging (DWI), and evaluate whether it is sufficient for patient triage to reperfusion therapies.
Methods—
One hundred ninety-three patients enrolled in the DEFUSE 2 (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) and SENSE 3 (Sensitivity Encoding) stroke studies were screened, and 119 who underwent acute magnetic resonance imaging with DWI and perfusion imaging within 24 hours of onset were included. Infarct core was estimated using reduced rCBF at 12 thresholds (<0.20–<0.44) and compared against DWI (apparent diffusion coefficient <620 10 ⁻⁶ mm2/s). For each threshold, volumetric agreement between the rCBF and DWI core estimates was assessed using Bland-Altman, correlation, and linear regression analyses; spatial agreement was assessed using receiver operating characteristic analysis.
Results—
An rCBF threshold of 0.32 yielded the smallest mean absolute volume difference (14.7 mL), best linear regression fit (R ² =0.84), and best spatial agreement (Youden index, 0.38; 95% CI, 0.34–0.41) between rCBF and DWI, with high correlation ( r =0.91, P <0.05), a small mean volume difference (1.3 mL) and no fixed bias ( P <0.05). At this threshold, 110 of 119 (92.4%) patients were correctly triaged when applying 70 mL as the volume limit for thrombectomy. Spatial agreement was better for prediction of large infarcts (>70 mL) than small infarcts (≤70 mL), with Youden indices of 0.53 (95% CI, 0.49–0.56) and 0.34 (95% CI, 0.30–0.37), respectively.
Conclusions—
Strong correlation and agreement with near-contemporaneous DWI indicate that infarct core estimates obtained using rCBF are sufficiently accurate for patient triage to reperfusion therapies. The identified optimal rCBF threshold of 0.32 closely approximates the threshold currently used in clinical practice.
... The cutoff range of ASPECTS 0-5 for large core cerebral infarcts is widely agreed upon and is not controversial (10,15). The ASPECTS is often evaluated utilizing either DWI-MRI or NCCT, both of which provide highly specific indicators from a pathophysiological standpoint (16,17). The trials confirmed the efficacy of ASPECTS 3-5 in EVT; however, they did not demonstrate the efficacy of ASPECTS 0-2. ...
Four randomized controlled trials of large infarct core volume (LICV) included three imaging modalities: non-contrast CT (NCCT)-Alberta Stroke Program Early CT Score (ASPECTS), diffusion-weighted imaging (DWI)-ASPECTS, and NCCT-ASPECTS combined with CTP (CT perfusion). However, there is no clear consensus on the optimal imaging modality for endovascular thrombectomy (EVT) trials of large core infarcts. The variety and complexity of imaging modalities make it difficult to apply them in clinical practice. By familiarizing ourselves with these imaging modalities, we can better apply them in the clinic and correctly screen patients with large core infarcts in the anterior circulation who can benefit from EVT therapy.
... Magnetic resonance imaging (MRI) is commonly used for the diagnosis and evaluation of ischemic stroke, in which diffusionweighted imaging (DWI) is particularly sensitive to reveal the range of cytotoxic edema (7,8). Diffusion kurtosis imaging (DKI) complements the directionality of molecular diffusion (9). ...
Background and purpose
Significant differences in the outcomes observed in patients with acute ischemic stroke (AIS) have led to research investigations for identifying the predictors. In this retrospective study, we aimed to investigate the relationship of different clinical and imaging factors with the prognosis of AIS.
Materials and methods
All clinical and imaging metrics were compared between the good and poor prognosis groups according to the modified Rankin Scale (mRS) score at 90 days after discharge. Clinical factors included gender, age, NIHSS scores at admission, and other medical history risk factors. Imaging markers included the lesion’s size and location, diffusion, and perfusion metrics of infarction core and peripheral regions, and the state of collateral circulation. Spearman’s correlations were analyzed for age and imaging markers between the different groups. The Chi-square test and Cramer’s V coefficient analysis were performed for gender, collateral circulation status, NIHSS score, and other stroke risk factors.
Results
A total of 89 patients with AIS were divided into the good (mRS score ≤ 2) and poor prognosis groups (mRS score ≥ 3). There were differences in NIHSS score at the admission; relative MK (rMK), relative MD (rMD), relative CBF (rCBF) of the infarction core; relative mean transit time (rMTT), relative time to peak (rTTP), and relative CBF (rCBF) of peripheral regions; and collateral circulation status between the two groups (p < 0.05). Among them, the rMK of infarction lesions had the strongest correlation with the mRS score at 90 days after discharge (r = 0.545, p < 0.001).
Conclusion
Perfusion and diffusion metrics could reflect the microstructure and blood flow characteristics of the lesion, which were the key factors for the salvage ability and prognosis of the infarction tissue. The characteristics of the infarction core and peripheral regions have different effects on the outcomes. Diffusion of infarction core has strong relations with the prognosis, whereas the time metrics (MTT, TTP) were more important for peripheral regions. MK had a more significant association with prognosis than MD. These factors were the primary markers influencing the prognosis of cerebral infarction patients.
... DWI is the preferred reference standard for defining the acute infarct lesion, being able to detect alterations in water diffusion within minutes from onset of ischemia [6]. A potential limitation of DWI is partial reversibility of early DWI infarct lesions especially after reperfusion, but this is relatively uncommon [7]. FLAIR is an alternative to DWI to define the acute infarct core [8]. ...
Introduction:
In patients with acute ischemic stroke, the location and volume of an irreversible infarct core determine prognosis and treatment. We aimed to determine if automated CT perfusion (CTP) is non-inferior to diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) in predicting the acute infarct core.
Methods:
In this systematic review and meta-analysis, we searched MEDLINE and EMBASE from 1960 to December 2020. Five outcome measures were examined: volumetric difference, volumetric correlation, sensitivity and specificity at the patient level, Dice coefficient, and sensitivity and specificity at the voxel level. A random-effects meta-analysis was performed for volumetric difference and correlation.
Results:
From 3,986 studies retrieved, 48 studies met our inclusion criteria with 46 studies on anterior circulation, one study on posterior circulation, and one study on lacunar infarct strokes. In anterior circulation stroke, there were no significant mean volumetric differences between CTP and acute DWI (cerebral blood flow [CBF] 0.52 mL, 95% CI [-0.07, 1.11], I2 0.0%; relative CBF [rCBF] 3.01 mL, 95% CI [-0.46, 6.48], I2 82.6%; relative cerebral blood volume [rCBV] -12.84 mL, 95% CI [-38.56, 12.88], I2 96.2%) and between CTP and delayed DWI or FLAIR (rCBF -1.29 mL, 95% CI [-6.49, 3.92], I2 91.8%; rCBV -5.80 mL, 95% CI [-16.20, 4.60], I2 84.2%). Mean correlation between CTP and acute DWI was 0.90 (95% CI [0.80, 0.95], I2 60.0%) for rCBF and 0.84 (95% CI [0.58, 0.94], I2 93.5%) for rCBV. Mean correlation between CTP and delayed DWI or FLAIR was 0.74 (95% CI [0.57, 0.85], I2 94.6%) for rCBF and 0.90 (95% CI [0.69, 0.97], I2 93.1%) for rCBV. Sensitivity and specificity at the patient level were reported by three studies and Dice coefficient by four studies. Statistical analysis could not be performed for sensitivity and specificity at the voxel level. Limited evidence was available for posterior circulation or lacunar infarct strokes.
Conclusion:
Due to significant heterogeneity and insufficient high-quality studies reporting each outcome, there is insufficient evidence to reliably determine the accuracy of CTP prediction of the infarct core compared to DWI or FLAIR.
... In the sphere of perfusion imaging, DWI hyperintensity is considered a gold standard to define ischemic core; however, this metric is also not without challenges. For example, diffusion reversal, even though is rare, does occur [76][77][78][79][80]. Automated segmentation of DWI lesions is prone to errors as well [77,78]. ...
... [8][9][10] While some resolve on serial imaging, 11 only a minority truly disappear. 12 Animal studies have correlated these infarcts with future strokes and behavioural abnormalities. [13][14][15] Related literature on spontaneous (non-iatrogenic) silent brain infarcts has linked subtle clinical deficits like fine motor impairment, dizziness, visual field defects, and depressive symptoms with apparently silent infarcts, 3,16,17 and these patients are at higher risk of subsequent major strokes. ...
Background:
Small iatrogenic brain infarcts are often seen on diffusion-weighted MRI (DWI) following surgical or endovascular procedures, but there are few data on their clinical effects. We examined the association of iatrogenic infarcts with outcomes in the ENACT (Evaluating Neuroprotection in Aneurysm Coiling Therapy) randomized-controlled trial of nerinetide in patients undergoing endovascular repair of intracranial aneurysms.
Methods:
In this post-hoc analysis, we used multi-variable models to evaluate the association of the presence and number of iatrogenic infarcts on DWI with neurological impairment (National Institutes of Health Stroke Scale[NIHSS]), functional status (modified Rankin Scale[mRS]), cognitive and neuropsychiatric outcomes (30-minute test battery) at 1-4 days and 30-days post-procedure. We also related infarct number to a Z-score-derived composite outcome score using quantile regression.
Results:
Among 184 patients (median age 56,IQR 50-64), 124 (67.4%) had post-procedural DWI lesions (median 4,IQR 2-10.5). Nerinetide treatment was associated with fewer iatrogenic infarcts but no overall significant clinical treatment effects. Patients with infarcts had lower Mini-Mental State Exam(MMSE) scores at 2-4 days (median 28 vs 29, adjusted-coefficient[acoef]: -1.11, 95%CI -1.88 to -0.34,p=0.005). Higher lesion counts were associated with worse day-1 NIHSS (aOR for NIHSS≥1:1.07, 1.02-1.12,p=0.009), day 2-4 mRS (adjusted common odds-ratio[aOR]: 1.05,1.01-1.09,p=0.005), and day 2-4 MMSE (acoef:-0.07,-0.13 to -0.003,p=0.040) scores. At 30-days, infarct number remained associated with worse mRS (aOR:1.04,1.01-1.07,p=0.016) and Hopkins Verbal Learning Test(HVLT) delayed-recall scores (acoef:-0.21,-0.39 to -0.03,p=0.020). Patients with infarcts trended towards lower 30-day Digit Symbol Substitution Test(DSST) scores (acoef:-3.73,-7.36 to -0.10,p=0.044). Higher lesion count was associated with worse composite outcome scores at both 1-4 days and 30-days (30-days acoef:-0.12,95%CI -0.21 to -0.03,p=0.008). Among those with infarcts, day-1 NIHSS and day 2-4 mRS correlated with 30-day NIHSS, DSST, HVLT, and mRS scores, whilst day 2-4 MMSE correlated with 30-day NIHSS and DSST scores (Spearman-Rho:0.47,p=0.001).
Conclusions:
Iatrogenic brain infarcts were associated with subtle differences in post-procedural (1-4 days) and 30-day outcomes on different measures in this middle-aged cohort, with earlier dysfunction correlating with later differences.
Clinical trials registration:
ClinicalTrials.gov, number NCT00728182.
... [28][29][30] This finding is in opposition to previously published data that led to the wide use of CBV as the clinical threshold to define the infarct core. [31][32][33][34][35] CT perfusion has been shown to be comparable to xenonenhanced CT for the evaluation of regional CBF. 36 However, CT perfusion is faster and easier to use. ...
Chapter 411: Neurovascular Imaging, Youmans & Winn Neurological Surgery, 8e
... Furthermore, the MRI perfusion weighted imaging (PWI)/DWI mismatch pattern has been studied as an effective marker of ischemic penumbra. [6][7][8][9] Therefore, for patients with PWI/DWI mismatch, it seems that early reperfusion can be achieved from the perfusion-diffusion MRI, and better recovery can be achieved. ...
Background:
Intravenous thrombolysis (IVT) is an effective way for treating acute ischemic stroke (AIS). However, its effects have not been established among AIS patients with unclear stroke symptoms or with stroke onset for >4.5 h.
Methods:
We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and Google Scholar databases for randomized controlled trials that compared IVT (IVT group) and placebo or usual care (control group [CG]) in AIS patients with disease onset for >4.5 h. The outcomes of interest included the favorable functional outcome (defined as modified Rankin Scale [mRS] scores 0-1) at 90 days, the functional independence (defined as mRS scores 0-2) at 90 days, proportion of patients with symptomatic intracerebral hemorrhage (sICH) and death at 90 days. We assessed the risk of bias using the Cochrane tool. Pre-specified subgroup analyses were performed by age (≤70 years or >70 years), National Institute of Health Stroke Scale (NIHSS, ≤10 or >10) and time window (4.5-9.0 h or >9.0 h).
Results:
Four trials involving 848 patients were eligible. The risk of bias of included trials was low. Patients in the IVT group were more likely to achieve favorable functional outcomes (45.8% vs. 36.7%; OR 1.48, 95% CI 1.12-1.96) and functional independence (63.8% vs. 55.7%; OR 1.43, 95% CI 1.08-1.90) at 90 days, but had higher risk of sICH (3.0% vs. 0.5%; OR 5.28, 95% CI 1.35-20.68) at 90 days than those in the CG. No significant difference in death at 90 days was found between the two groups (7.0% vs. 4.1%; OR 1.80; 95% CI 0.97-3.34).
Conclusions:
Use of IVT in patients with extended time window may improve their functional outcomes at 90 days, although IVT may induce increased risk of sICH. Care of these patients should well balance the potential benefits and harms of IVT.
... In our study, none of the patients showed reversible hyperintensities in follow-up DWI. Although few previous studies 15 have shown that some of the DWI changes can reverse, dichotomization of DWI will give us a fair estimate of the final infarct size, and minor changes are unlikely to change treatment decisions. Baseline MRI can fairly, even if not always, represent true regions of the brain, which are irreversibly dead, and not the ischemic tissue. ...
Background: Imaging of acute stroke patients in emergency settings is critical for treatment decisions. Most commonly, CT with CTA is used worldwide for acute stroke. However, MRI may be advantageous in certain settings. With advancements in endovascular clot retrieval techniques, there is a need to identify and use the best possible imaging for the diagnosis and outcome prediction of hyperacute stroke.
Methods: This mixed retrospective and prospective observational study was conducted over 2 years in patients who underwent reperfusion therapies. Patients were included in this study if they had a baseline as well as follow-up noncontrast CT and diffusion-weighted imaging (DWI) MRI. We compared them for estimating final infarct size and outcomes after reperfusion therapy.
Results: A total of 86 patients were included in the study. Baseline DWI found new infarcts in 33 patients compared to baseline CT. Sensitivity and specificity of CT and DWI in predicting the final infarct size was 75.3% and 76.9% and 97.2% and 92.3%, respectively. A positive correlation of 51.2% and 84.4% was noted between b-CT Alberta stroke programme early CT score (ASPECTS) and b-DWI with 72 hours DWI ASPECTS, respectively (p < 0.001). The positive predictive value of CT was 94.8% and DWI was 98.6%. None of the patients had reversible hyperintensities in the follow-up DWI.
Conclusion: MRI is more sensitive and specific than noncontrast CT in predicting final infarct volume. It predicts final outcomes better and could be an alternative if available in acute stroke settings.
... Dans la littérature, les travaux en rapport avec la réversion de la lésion DWI sont rares, et se contentent uniquement d'analyses descriptives à l'échelle du patient. Les quelques études existantes semblent converger pour affirmer que la réversion de la lésion DWI est associée à : (1) la recanalisation et/ou la reperfusion précoce rapide [111,112,113,106,114,108,115], (2) à un traitement thérapeutique [108], et (3) à une amélioration neurologique précoce et une amélioration de l'état clinique du patient à long terme [116,106,107,114,108]. Notons que l'association (3) est probablement plutôt dûe à une reperfusion précoce plutôt que la réversion DWI en elle-même [104], puisque l'amélioration de l'état clinique est déjà une conséquence reconnue de la reperfusion précoce. ...
L'accident vasculaire cérébral (AVC) ischémique constitue la première cause de handicap acquis et la troisième cause de décès dans les pays industrialisés. La prédiction de l'évolution des lésions observées en phase aiguë est un challenge clinique. Actuellement, cette question est abordée au moyen de l'imagerie par résonance magnétique (IRM). Deux modalités sont principalement utilisées : l'imagerie de diffusion qui montre l'étendue de l'œdème cytotoxique et l'imagerie dynamique de perfusion qui donne accès à l'état hémodynamique des tissus. L'imagerie de diffusion est connue pour être l'imagerie qui porte le potentiel prédictif le plus important pour détecter la zone d'infarctus irréversible. Une question ouverte est l'apport de l'imagerie de perfusion en phase aiguë pour réaliser cette prédiction. Plusieurs approches d'apprentissage automatique ont été testées et se sont avérées efficaces, mais les résultats témoignent que le problème est loin d'être résolu: la tâche de prédiction demeure complexe, dans la mesure où la lésion visible en phase aiguë évolue jusqu'à un mois après. La thèse s'articule autour des deux questions suivantes : (1) quel est la valeur de l'imagerie de perfusion pour la prédiction de l'AVC ischémique ? (2) comment fusionner l'imagerie de perfusion et de diffusion au sein de modèle d'apprentissage ? La première partie de la thèse répond à la question (1) en deux sous-parties : dans une première sous-partie, on démontrera l'intérêt d'apprendre directement sur l'imagerie de perfusion brute plutôt que sur des cartes paramétriques extraites. On discutera alors de différentes méthodes d'encodage de la perfusion brute, et de différents modèles capables d'en extraire les informations pertinentes pour prédire l'infarctus final. Ces premières expériences nous permettront aussi de comprendre quels sont les facteurs physiologiques déterminant qui semblent impacter l'apprentissage dans les différents modèles proposés. Dans une deuxième sous-partie, on proposera d'apprendre des modèles sur des données de perfusion brute simulées, et de les tester sur des données réelles. Ces données simulées sont issues d'un simulateur physique déjà publié, auquel nous proposerons des améliorations. Dans un deuxième temps, pour répondre à la question (2), on proposera des modèles présentant différentes stratégies de fusion de données. Dans un premier temps, on proposera pour la tâche de prédiction un modèle bayésien naïf fusionnant tardivement les différentes modalités d'entrée. Dans un second temps, on explorera de manière plus approfondie un modèle de réseau de neurones fusionnant tardivement les modalités d'entrée. Au travers de ce réseau de neurones, on discutera de l'impact de l'homogénéité de jeux d'apprentissage et notamment des paramètres physiologiques permettant cette stratification ; enfin on visera une explicabilité du modèle en détaillant ses échecs de prédictions lié à la complexité de la course naturelle de la maladie. Plus spécifiquement, on s'attardera sur l'étude de la réversion de la lésion aiguë de diffusion, une cause classique et récurrente d'échec de prédiction. Comme ouverture, on s'intéressera à la possibilité de prédire l'état clinique des patients après un AVC en intégrant des données en lien avec la phase « chronique » de la maladie. Avec l'émergence de l'internet des objets (IoT), de plus en plus de personnes sont équipées d'un smartphone et d'objets connectés remontant des informations sur l'activité de la personne voir sur sa physiologie. On étudiera de manière exploratoire comment ces nouveaux capteurs peuvent assurer un meilleur suivi et accompagnement des patients après un AVC, pendant leur rééducation
... High blood pressure of the veins is the most important risk factor on stroke. The risk of the disease falls on other risk factors, such as smoking, obesity, elevated blood cholesterol, diabetes, and hypertension [20][21][22][23][24]. Diagnosis is usually based on the clinical investigation and is assisted by medical imaging, such as CT or MRI scans [25][26][27][28][29]. CT scans may rule out bleeding, but ischemia, which usually does not appear early in the CT scan, may not necessarily be excluded [30][31][32][33]. ...
Cross-sectional imaging approaches play a key role in assessing bleeding brain injuries. Doctors commonly determine bleeding size and severity in CT and MRI. Separating and identifying artifacts is extremely important in processing medical images. Image and signal processing are used to classify tissues within images closely linked to edges. In CT images, a subjective process takes a stroke ‘s manual contour with less precision. This chapter presents the application of both image and signal processing techniques in the characterization of Brain Stroke field. This chapter also summarizes how to characterize the brain stroke using different image processing algorithms such as ROI based segmentation and watershed methods.
... While DWI reversal is possible after endovascular reperfusion therapy, it is most likely a transient phenomenon and not associated with clinical outcomes [22]. Other studies support the non-significance of DWI reversal and attest that this is an uncommon phenomenon [23,24]. Finally, the variability of apparent diffusion coefficient imaging to negate T2 shinethrough has also been previously documented [25]. ...
PurposeEndovascular thrombectomy (EVT) improves clinical outcomes in ischemic stroke with large vessel occlusion. Clinical benefits are inversely proportional to size of the pre-treatment ischemic core. This study compared estimated ischemic core volumes by two different CT perfusion (CTP) automated algorithms to the gold standard follow-up infarct volume using diffusion-weighted imaging (DWI) to assess for congruence, and thus eligibility for EVT.Methods
Retrospective, single-center cohort study of 102 patients presenting to a comprehensive stroke center between 2012 and 2018. Inclusion criteria were CT perfusion prior to EVT, successful EVT with mTIBI 2b-3 reperfusion, and DWI post-EVT. CTP data were retrospectively processed by two algorithms: “delay and dispersion insensitive deconvolution” (DISD, RAPID software) versus “delay and dispersion corrected single value decomposition” (ddSVD, Mistar software), using commercially available software. Core volumes were compared to follow up DWI using independent software (MRIcron). Agreement between each algorithm and DWI was estimated using Lin’s concordance coefficient and analyzed using reduced major axis regression.ResultsWe included 102 patients. Both algorithms had excellent agreement with DWI (Lin’s concordance coefficients: DISD 0.8 (95% CI: 0.73; 0.87), ddSVD 0.92 (95% CI: 0.89; 0.95). Compared to ddSVD (reduced major axis slope = 0.95), DISD exhibited a larger extent of proportional bias (slope = 1.12).Conclusion
The ddSVD algorithm better correlates with DWI follow-up infarct volume than DISD processing. The DISD algorithm overestimated larger ischemic cores which may lead to patient exclusion from thrombectomy based on selection by core volume.
... Transient DLR has been speculated to reflect salvage followed by secondary injury [69]. However, DLR changes have not been shown to correlate clinically with the expected neurological recovery and subsequent deterioration that this hypothesis might suggest [70]. ...
Purpose of Review
Urgent reperfusion treatment with intravenous thrombolysis or mechanical thrombectomy reduces disability after ischaemic stroke. Imaging plays an important role in identifying patients who benefit, particularly in extended time windows. However, the role of post-treatment neuroimaging is less well established. We review recent advances in neuroimaging after reperfusion treatment and provide a practical guide to the options and management implications.
Recent Findings
Post-treatment imaging is critical to identify patients with reperfusion-related haemorrhage and oedema requiring intervention. It also can guide the timing and intensity of antithrombotic medication. The degree of reperfusion on post-thrombectomy angiography and infarct volume and topography using CT or MRI carry important prognostic significance. Perfusion-weighted MRI and permeability analysis may help detect persistent perfusion abnormalities post-treatment and predict haemorrhagic complications.
Summary
Post-treatment neuroimaging provides clinically relevant information to identify complications, assess prognosis and perform quality assurance after acute ischaemic stroke. Recent advances in neuroimaging represent a potential avenue to explore post-reperfusion pathophysiology and uncover therapeutic targets for secondary ischaemic and haemorrhagic injury.
... Altogether, there is only scarce and partly contradictory data on the time course of diffusion changes in different tissue compartments in acute ischemic stroke and questions remain open as to the usefulness of the available diffusion parameters for clinical decision making (7)(8)(9)(10)(11)(12). Better understanding of the time course of alterations of the different diffusion parameters might improve the pathophysiological understanding of brain tissue changes in the different relevant tissue compartments and might also add to the definition of irreversibly damaged brain tissue in contrast to potentially salvageable tissue at risk of infarction. ...
Background and Purpose: The immediate decrease of the apparent diffusion coefficient (ADC) is the main characteristic change of water diffusion in acute ischemic stroke. There is only limited information on the time course of diffusion parameters in different tissue compartments of cerebral ischemia.
Materials and Methods: In a longitudinal study, we examined 21 patients with acute ischemic stroke by diffusion tensor imaging within 5 h after symptom onset, 3 h later, 2 days, and 1 month after symptom onset. Acute diffusion lesion and the fluid-attenuated inversion recovery (FLAIR) after 2 days were used as volumes of interest to define persistent core, lesion growth, and reversible acute diffusion lesion. For all diffusion parameters ratios between the stroke lesion VOIs and the mirror VOIs were calculated for each time point. ADC ratio, fractional anisotropy ratios, and eigenvalues ratios were measured in these volumes of interest and in contralateral mirror regions at each time points.
Results: In the persistent core, ADC ratio (0.772) and all eigenvalues ratios were reduced on admission up to 1 day after stroke and increased after 1 month (ADC ratio 1.067). Within the region of infarct growth time course of diffusion parameter changes was similar, but delayed. In the brain area with reversible diffusion lesion, a partial normalization of diffusion parameters over the time was observed, while after 1 month diffusion parameters did not show the signature of healthy brain tissue. There were significantly different trends for all parameters over time between the three tissue compartments.
Conclusion: Diffusion tensor imaging displays characteristic changes of water diffusion in different tissue compartments over time in acute ischemic stroke. Even regions with reversible diffusion lesion show diffusion signatures of persisting tissue alterations.
... 11 This is an important difference between ischemic core identification by CTP and MRI, as a low ADC value on MR reflects microstructural changes with a high probability of irreversible tissue damage. 12 While the CTP-derived ischemic core is a fairly close estimate of the true core in most instances, there are some notable exceptions. When the CTP is obtained ultra-early (within one hour of symptom onset), a more restrictive CBF threshold is likely needed to estimate the ischemic core. ...
... [17][18][19][20]. However, this potential reversibility may not be consistently associated with improve clinical outcomes nor with changes in the treatment decision [20,58,59] and the real reversibility could be re- sidual in both incidence and amount of tissue involved, as shown in the DEFUSE-EPITHET trial analysis (6.7% with a median volume of 2.3 cm3) [60]. ...
The recent approach to treat acute stroke is to extend treatment window in patients with salvageable peri-infarct ischemia which increases the application of the perfusion imaging, specifically computed tomography perfusion (CTP). In this paper, I am presenting a case of left middle cerebral artery infarction which was evaluated by CTP under “code stroke.” The patient had an incidental spinal canal meningioma which was out of field of view in CTP but mimicked right cerebellar ischemia on CTP. Although ischemia has been previously reported within the peripheral parenchymal edema surrounding a meningioma, in this patient there was no evidence of edema in the right cerebellum on magnetic resonance imaging. I believe the CTP findings are secondary to steal phenomena at right vertebral artery or compression upon the venous plexus. Recently, by using modern computed tomography scanners, it is common to cover the entire brain in CTP. The emergency radiologist should be aware of this pitfall that spinal canal pathologies which are out of field of view can mimic posterior fossa ischemia.
... [40,41] From a practical standpoint, clinical studies have shown that reversal of DWI lesions is rare, and typically involves small volumes of tissue, most of which eventually progresses to infarction. [42,43] Conceptually, the diffusion restriction that DWI detects is more closely related to the ischemic core than CBF reductions are, in that DWI effectively integrates the damage caused by ischemic events that have occurred over time. This theoretical notion is supported by studies in which the CBF threshold necessary to produce DWI changes in rat brains was shown to be higher when more time had elapsed since the onset of ischemia. ...
Background
Neuroimaging may guide acute stroke treatment by measuring the volume of brain tissue in the irreversibly injured “ischemic core.” The most widely accepted core volume measurement technique is diffusion-weighted MRI (DWI). However, some claim that measuring regional cerebral blood flow (CBF) with CT perfusion imaging (CTP), and labeling tissue below some threshold as the core, provides equivalent estimates. We tested whether any threshold allows reliable substitution of CBF for DWI.
Methods
58 patients with suspected stroke underwent DWI and CTP within six hours of symptom onset. A neuroradiologist outlined DWI lesions. In CBF maps, core pixels were defined by thresholds ranging from 0%-100% of normal, in 1% increments. Replicating prior studies, we used receiver operating characteristic (ROC) curves to select thresholds that optimized sensitivity and specificity in predicting DWI-positive pixels, first using only pixels on the side of the brain where infarction was clinically suspected (“unilateral” method), then including both sides (“bilateral”). We quantified each method and threshold’s accuracy in estimating DWI volumes, using sums of squared errors (SSE). For the 23 patients with follow-up studies, we assessed whether CBF-derived volumes inaccurately exceeded follow-up infarct volumes.
Results
The areas under the ROC curves were 0.89 (unilateral) and 0.90 (bilateral). Various metrics selected optimum CBF thresholds ranging from 29%-32%, with sensitivities of 0.79–0.81, and specificities of 0.83–0.85. However, for the unilateral and bilateral methods respectively, volume estimates derived from all CBF thresholds above 28% and 22% were less accurate than disregarding imaging and presuming every patient’s core volume to be zero. The unilateral method with a 30% threshold, which recent clinical trials have employed, produced a mean core overestimation of 65 mL (range: –82–191), and exceeded follow-up volumes for 83% of patients, by up to 191 mL.
Conclusion
CTP-derived CBF maps cannot substitute for DWI in measuring the ischemic core.
... Tissue recovery and normalization of diffusion with early reperfusion has been recognized. Reversibility of DWI lesions has been shown by some experimental and clinical documents [33—36] although it is usually uncommon in acute stroke patients and rarely affects decision-making [37]. The physiologic grading of CBV between gray and white matter is another factor. ...
Background and purpose:
Recent developments in treatment of ischemic stroke increased importance of defining limits of ischemic insult by imaging. Some studies postulated that CTP is a promising technique, which can discriminate between ischemic core and penumbra. In this study, we sought to evaluate diagnostic performance of CTP-CBV colour maps, regarded as a marker of acute infarct; in comparison with DWI.
Materials and methods:
We retrospectively analyzed 48 patients with CTA proved major ischemic stroke within 12hours of onset, they had DWI and CTP exams within 1hour of each other, regardless of order. DWI sizes were calculated. Sensitivity, specificity, PPV and NPV of CBV colour maps for identification of acute infarcts were calculated. ROC curve was constructed.
Results:
CBV colour maps missed a lot of small infarcts that were identified by DWI with an overall diagnostic accuracy of (62.5%) and low sensitivity (38.5%) for patients whom DWI size<70mL. Area under curve was 0.79. DWI size was an only predictor of abnormal CBV colour maps (P=0.005).
Conclusions:
Assuming direct equivalence of DWI and CBV-based core might be unrealistic for individual patients in clinical practice. CBV colour maps are highly specific for acute infarcts, but with lack of sufficient sensitivity; particularly for small sized infarcts.
Background:
Diffusion-weighted imaging lesion reversal (DWIR) is frequently observed after mechanical thrombectomy for acute ischemic stroke, but little is known about age-related differences and impact on outcome. We aimed to compare, in patients <80 versus ≥80 years old, (1) the effect of successful recanalization on DWIR and (2) the impact of DWIR on functional outcome.
Methods:
We retrospectively analyzed data of patients treated for an anterior circulation acute ischemic stroke with large vessel occlusion in 2 French hospitals, who underwent baseline and 24-hour follow-up magnetic resonance imaging, with baseline DWI lesion volume ≥10 cc. The percentage of DWIR (DWIR%), was calculated as follows: DWIR%=(DWIR volume/baseline DWI volume)×100. Data on demographics, medical history, and baseline clinical and radiological characteristics were collected.
Results:
Among 433 included patients (median age, 68 years), median DWIR% after mechanical thrombectomy was 22% (6-35) in patients ≥80, and 19% (interquartile range, 10-34) in patients <80 (P=0.948). In multivariable analyses, successful recanalization after mechanical thrombectomy was associated with higher median DWIR% in both ≥80 (P=0.004) and <80 (P=0.002) patients. In subgroup analyses performed on a minority of subjects, collateral vessels status score (n=87) and white matter hyperintensity volume (n=131) were not associated with DWIR% (P>0.2). In multivariable analyses, DWIR% was associated with increased rates of favorable 3-month outcomes in both ≥80 (P=0.003) and <80 (P=0.013) patients; the effect of DWIR% on outcome was not influenced by the age group (P interaction=0.185) Conclusions: DWIR might be an important and nonage-dependent effect of arterial recanalization, as it seems to beneficially impact 3-month outcomes of both younger and older subjects treated with mechanical thrombectomy for acute ischemic stroke and large vessel occlusion.
Background:
Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke).
Methods:
In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm2) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume-24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0-1), in a multivariable model.
Results:
In 363 patients, the median DWI volume was 3 (1-10) mL at baseline and 6 (2-20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0-2) or 28% (14-50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0-2), or 22% (9-38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09-3.17] and OR, 2.03 [95% CI, 1.18-3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17-4.51]).
Conclusions:
Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
This concise and informative Textbook of Stroke Medicine is aimed at doctors preparing to specialize in stroke care and strokologists looking for concise but in-depth scientific guidance on stroke management. Its practical approach covers all important issues of prevention, diagnosis, and treatment of cerebrovascular diseases. Dedicated chapters give a thorough review of all clinical issues. Fully revised throughout, the new edition has expanded sections on topics of rising practical importance, such as diagnostic imaging, stroke unit management, monitoring and management of complications including infections, recommendations for thrombolysis, interventions and neurosurgical procedures, and clear and balanced recommendations for secondary prevention. Neuropsychological syndromes are explained and an up-to-date view on neurorehabilitation is presented. The authors are all experts in their field and many of them have been working together in a teaching faculty for the European Master in Stroke Medicine Programme, which is supported by the European Stroke Organization.
Cytotoxic edema at the site of a lesion following cerebral infarction is shown as a high signal on diffusion-weighted imaging, with a corresponding decreased apparent diffusion coefficient value on magnetic resonance imaging. These imaging findings have been used clinically as imaging markers of the infarction core, implying irreversible ischemic damage. However, reversal of diffusion lesions has been reported in patients with small lesions, relatively higher values of the apparent diffusion coefficient, or rapid endovascular reperfusion. Herein, we report a case of reversal of a large ischemic lesion on diffusion-weighted imaging with corresponding low apparent diffusion coefficient values in an acute middle cerebral artery infarction after immediate spontaneous recanalization. This case suggests that large ischemic lesions revealed by diffusion-weighted imaging may be reversed upon timely reperfusion, and could be considered as therapeutic targets.
Timely and accurate diagnosis of acute ischemic stroke (AIS) and simultaneous functional imaging of cerebral oxygen saturation (sO2) are essential to improve the survival rate of stroke patients but remains challenging. Herein, we developed a pH-responsive manganese (Mn)-based nanoplatform as a magnetic resonance/photoacoustic (MR/PA) dual-modal contrast agent for AIS diagnosis. The Mn-based nanoplatform was prepared via a simple and green biomimetic method using bovine serum albumin (BSA) as a scaffold for fabrication of MnCO3 NPs as the T1 MR contrast agent and accommodation of indocyanine green (ICG) as the PA probe. The obtained MnCO3@BSA-ICG NPs were biocompatible and exhibited a pH-responsive longitudinal relaxation rate and a concentration-dependent PA signal. In vivo MR/PA dual-modal imaging demonstrated that MnCO3@BSA-ICG NPs quickly and efficiently led to the MR/PA contrast enhancements in the infarcted area while not in the normal region, allowing a timely and accurate diagnosis of AIS. Moreover, PA imaging could directly monitor the sO2 level, enabling a functional imaging of AIS. Therefore, MnCO3@BSA-ICG NPs could be applied as a potential MR/PA contrast agent for timely and functional imaging of AIS, benefiting both fundamental research and clinical practice.
Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer (CEST) MRI, has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models and in human stroke patients due to the sensitivity of the amide proton exchange rate to changes in pH within the physiological range. Recent studies have demonstrated the possibility of using APT‐MRI to detect acidosis of the ischemic penumbra enabling the assessment of stroke severity and risk of progression, monitoring of treatment progress, and prognostication of clinical outcome. This paper reviews current APT imaging methods actively used in ischemic stroke research and explores the clinical aspects of ischemic stroke and future applications for these methods.
Diffusion weighted imaging (DWI) is a widely used imaging technique to evaluate patients with stroke. It can detect brain ischemia within minutes of stroke onset. However, DWI has few potential pitfalls that should be recognized during interpretation. DWI lesion could be reversible in the early hours of stroke and the entire lesion may not represent ischemic core. False negative DWI could lead to diagnosis of DWI negative stroke or to a missed stroke diagnosis. Ischemic stroke mimics can occur on DWI with non-cerebrovascular neurological conditions. In this article, the history of DWI, its clinical applications, and potential pitfalls for use in acute ischemic stroke is reviewed. Advanced diffusion imaging techniques with reference to Diffusion Kurtosis Imaging and Diffusion Tensor Imaging that has been studied to evaluate ischemic core are discussed.
Objectives
This study aimed to investigate infarct growth patterns in stroke patients with large vessel occlusion (LVO) and successful recanalization by endovascular therapy (EVT).MethodsA total of 135 patients with LVO of the internal carotid artery or proximal segment of the middle cerebral artery admitted within 12 h after onset, having baseline National Institute of Health Stroke Scale score ≥ 5 points, and successfully recanalized by EVT were enrolled. Infarct growth pattern models were developed based on infarct volumes on diffusion-weighted imaging before and after reperfusion. Single pattern models of linear, logarithmic, and exponential shapes were initially tested. Their appropriateness was predetermined. If none of these patterns was suitable, the best pattern model, which was the most suitable pattern among the three shapes selected for each individual, was tested. Clinical correlates were explored.ResultsEach single pattern model was tested for their suitability. However, none of the single pattern models successfully represented infarct growth curves: Of all subjects, only 63.7%, 62.2%, and 54.1% of patients were explained by the logarithmic, linear, and exponential model, respectively. Compared with the single pattern models, the best pattern model explained 80.7% of the subjects. The linear shape fit best in 40 patients, the logarithmic in 51, and the exponential in 44. Those fit best for the logarithmic pattern showed more favorable outcomes at discharge (31.4%) than did the others (linear, 10.0%; exponential, 9.1%; p = 0.01).Conclusions
Infarct growth patterns may vary among individual patients with acute stroke due to LVO and successful treatment with EVT.Key Points
• Infarct growth during the acute stage of stroke is highly dynamic and the exact shape remains unknown.
• Infarct growth pattern models were developed based on infarct volumes on diffusion-weighted imaging before and after reperfusion.
• Infarct growth patterns may not be singular, rather various among individual patients with acute stroke due to LVO and successful treatment with EVT.
PurposeThis study aimed to evaluate the association between the development of cognitive impairment and the use of antidepressants among older women with breast cancer.Methods
This retrospective cohort study used the United States National Cancer Institute’s Surveillance, Epidemiology, and End Results-Medicare database to identify women who were 67 years old and older and had breast cancer between 2008 and 2013. Propensity scoring was used to account for confounding pre-treatment factors, and Cox proportional hazards modeling was used to examine the risk of developing cognitive impairment among patients based on whether they used antidepressants.ResultsA total of 3174 women taking antidepressants (mean age 75.2 ± 6.4) were matched with 3174 women not taking antidepressants (mean age 75.4 ± 6.7). Antidepressant use was associated with a significantly increased risk of cognitive impairment (hazard ratio [HR]: 1.33, 95%; confidence interval [CI]: 1.18–1.48). Additionally, we found that older women without a history of depression or anxiety who use antidepressants have a higher risk of developing cognitive impairment than those who did not use antidepressants (HR: 1.53, 95%; CI: 1.34–1.75 and HR: 1.39, 95%; CI: 1.23–1.56, respectively). Subgroup analysis showed that the use of non-tricyclic antidepressants (TCAs) was associated with a higher risk of cognitive impairment.Conclusion
We found that non-TCA antidepressant use in older women with breast cancer was associated with a higher risk of cognitive impairment. This association was also observed among older women without depression or anxiety who used antidepressants.
Objectives: The objectives of this study included the volumetric analysis of persistent infarction and lesion reversal in Diffusion-Weighted Imaging (DWI), as well as the assessment of accuracy of ADC thresholds to identify regions of persistent infarction in patients with acute ischemic stroke after successful endovascular treatment (EVT).
Materials and Methods: A retrospective analysis of patients with M1 or proximal M2 occlusions, treated between 01/2012 and 07/2017, who underwent successful EVT (≥TICI 2b) and both pre- and post-interventional Magnetic Resonance Imaging (MRI), led to the inclusion of N=90 patients. Administration of recombinant tissue plasminogen activator (rTPA) for intra-venous thrombolysis was performed ahead of intervention in 45 cases (N=45/90, 50%). The majority of patients (N=78/90, 86.7%) were treated with second-generation thrombectomy devices with or without intra-arterial urokinase. DWI at admission and 24-hour follow-up DWI data were co-registered. Acute ischemic changes at baseline DWI, 24-hour DWI lesion, and the affected gray/white matter regions were manually annotated. Persistent infarction was defined as acute ischemic changes on baseline DWI, which were sustained on 24-hour follow-up DWI. Based on the manual annotations, persistent infarction and DWI reversal were quantified in a voxel-wise analysis. Thresholds for the identification of persistent infarction using baseline ADC images were estimated by maximizing Youden's J statistic (ROC-analysis).
Results: Median age of the patients was 71.9 years (IQR 60.4-79.7 years), 55.6% were female, and NIHSS at admission was 11 (IQR 6-14). The median DWI lesion volume at baseline was 9.9 mL (IQR 3-23.6 mL) and the median DWI lesion volume around 24 hours was 12.1 mL (IQR 3.6-23.7 mL). Reversal of acute ischemic changes occurred frequently (49.8%, IQR 31.7%-65.4%; percentage of initial DWI lesion volume per subject). Sizeable DWI reversal (i.e. >10 mL and >10%) was observed in 26.7% (N=24/90) of the cases. Relative DWI reversal was significantly higher in white matter (58.6%, IQR 35.3-81.5%) than in gray matter (39.2%, IQR 24.9-56.6%; p<0.001). The volume of persistent infarction and DWI reversal were both significantly correlated with the DWI lesion volume at baseline (R=0.873-0.945, p<0.001), however, no correlations with time to reperfusion were found (relative volumes: R=-/+0.058, p=0.607). ROC analyses of ADC thresholds yielded optimal values which differed significantly for gray and white matter (p=0.003), and were lower than previously reported thresholds while having significantly improved accuracy (p≤0.015). No correlations between the estimated ADC thresholds and different covariates were found (time from imaging to reperfusion, time from baseline to follow-up imaging, volume of acute ischemic changes).
Conclusions: DWI reversal occurs frequently in successfully reperfused patients treated with modern EVT. Identification of persistent infarction using ADC thresholds in baseline DWI remains challenging with notable differences for gray and white matter.
Objectives
To systematically review the literature for reversible diffusion-weighted imaging (DWIR) lesions and to describe its prevalence, predictors, and clinical significance.
Methods
Studies were included if the first DWI MRI was performed within 24 hours of stroke onset and follow-up DWI or fluid-attenuated inversion recovery (FLAIR)/T2 was performed within 7 or 90 days, respectively, to measure DWIR. We abstracted clinical, imaging, and outcomes data.
Results
Twenty-three studies met the study criteria. The prevalence of DWIR was 26.5% in DWI-based studies and 6% in FLAIR/T2-based studies. DWIR was associated with recanalization or reperfusion of the ischemic tissue with or without the use of tissue plasminogen activator (t-PA) or endovascular therapy, earlier treatment with t-PA, shorter time to endovascular therapy after MRI, and absent or less severe perfusion deficit within the DWI lesion. DWIR was associated with early neurologic improvement in 5 of 6 studies (defined as improvement in the NIH Stroke Scale (NIHSS) score by 4 or 8 points from baseline or NIHSS score 0 to 2 at 24 hours after treatment or at discharge or median NIHSS score at 7 days) and long-term outcome in 6 of 7 studies (defined as NIHSS score ≤1, improvement in the NIHSS score ≥8 points, or modified Rankin Scale score up to ≤2 at 30 or 90 days) likely due to reperfusion.
Conclusions
DWIR is seen in up to a quarter of patients with acute ischemic stroke, and it is associated with good clinical outcome following reperfusion. Our findings highlight the pitfalls of DWI to define ischemic core in the early hours of stroke.
This chapter focuses on the imaging of hyperacute ischemic stroke patients within the first hours after stroke onset when the decisions to administer thrombolytics or perform thrombectomy are of paramount importance. The major goals of imaging during this hyperacute phase of ischemia include (1) the exclusion of intracerebral hemorrhage for thrombolysis, (2) the detection of acute ischemia in order to exclude stroke mimics, (3) emerging advanced imaging techniques to delineate ischemic but viable tissue for possible intervention beyond the current window, and (4) the imaging of pediatric acute stroke patients. The chapter provides an in-depth discussion of the literature supporting the use of specific modalities for each of the major goals listed.
Objective:
To determine to what degree stroke mimics skew clinical outcomes and the potential effects of incorrect stroke diagnosis.
Methods:
This retrospective analysis of data from 2005 to 2014 included IV tissue plasminogen activator (tPA)-treated adults with clinical suspicion for acute ischemic stroke who were transferred or admitted directly to our 2 hub hospitals. Primary outcome measures compared CT-based spoke hospitals' and MRI-based hub hospitals' mimic rates, hemorrhagic transformation, follow-up modified Rankin Scale (mRS), and discharge disposition. Secondary outcomes were compared over time.
Results:
Of the 725 thrombolysis-treated patients, 29% were at spoke hospitals and 71% at hubs. Spoke hospital patients differed from hubs by age (mean 62 ± 15 vs 72 ± 15 years, p < 0.0001), risk factors (atrial fibrillation, 17% vs 32%, p < 0.0001; alcohol consumption, 9% vs 4%, p = 0.007; smoking, 23% vs 13%, p = 0.001), and mimics (16% vs 0.6%, p < 0.0001). Inclusion of mimics resulted in better outcomes for spokes vs hubs by mRS ≤1 (40% vs 27%, p = 0.002), parenchymal hematoma type 2 (3% vs 7%, p = 0.037), and discharge home (47% vs 37%, p = 0.01). Excluding mimics, there were no significant differences. Comparing epochs, spoke stroke mimic rate doubled (9%-20%, p = 0.03); hub rate was unchanged (0%-1%, p = 0.175).
Conclusions:
Thrombolysis of stroke mimics is increasing at our CT-based spoke hospitals and not at our MRI-based hub hospitals. Caution should be used in interpreting clinical outcomes based on large stroke databases when stroke diagnosis at discharge is unclear. Inadvertent reporting of treated stroke mimics as strokes will artificially elevate overall favorable clinical outcomes with additional downstream costs to patients and the health care system.
Background and purpose:
The majority of patients enrolled in SWIFT PRIME trial (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke) had computed tomographic perfusion (CTP) imaging before randomization; 34 patients were randomized after magnetic resonance imaging (MRI).
Methods:
Patients with middle cerebral artery and distal carotid occlusions were randomized to treatment with tPA (tissue-type plasminogen activator) alone or tPA+stentriever thrombectomy. The primary outcome was the distribution of the modified Rankin scale score at 90 days. Patients with the target mismatch profile for enrollment were identified on MRI and CTP.
Results:
MRI selection was performed in 34 patients; CTP in 139 patients. Baseline National Institutes of Health Stroke Scale score was 17 in both groups. Target mismatch profile was present in 95% (MRI) versus 83% (CTP). A higher percentage of the MRI group was transferred from an outside hospital (P=0.02), and therefore, the time from stroke onset to randomization was longer in the MRI group (P=0.003). Time from emergency room arrival to randomization did not differ in CTP versus MRI-selected patients. Baseline ischemic core volumes were similar in both groups. Reperfusion rates (>90%/TICI [Thrombolysis in Cerebral Infarction] score 3) did not differ in the stentriever-treated patients in the MRI versus CTP groups. The primary efficacy analysis (90-day mRS score) demonstrated a statistically significant benefit in both subgroups (MRI, P=0.02; CTP, P=0.01). Infarct growth was reduced in the stentriever-treated group in both MRI and CTP groups.
Conclusions:
Time to randomization was significantly longer in MRI-selected patients; however, site arrival to randomization times were not prolonged, and the benefits of endovascular therapy were similar.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657461.
Neuroimaging is an important part of acute ischemic stroke trials. Its key components include vascular, ischemic core, and penumbral imaging. These can be acquired by two modalities: computed tomography (CT) and magnetic resonance imaging (MRI). This chapter provides an overview of common CT- and MRI-based angiographic, parenchymal, and perfusion imaging techniques, and their roles in patient selection in acute ischemic stroke trials.
Objective:
Advanced stroke imaging has generated much excitement for the early diagnosis of acute ischemic stroke (AIS) and facilitation of intervention. However, its therapeutic impact has not matched its diagnostic utility; most notably, lacking significant contributions to recent major AIS clinical trials. It is time to reexamine the fundamental hypotheses from the enormous body of imaging research on which clinical practices are based and reassess the current standard clinical and imaging strategies, or golden rules, established over decades for AIS. In this article, we will investigate a possible new window of opportunity in managing AIS through a better understanding of the following: first, the potential limitations of the golden rules; second, the significance of imaging-based parenchymal hypoperfusion (i.e., lower-than-normal relative cerebral blood flow [rCBF] may not be indicative of ischemia); third, the other critical factors (e.g., rCBF, collateral circulation, variable therapeutic window, chronicity of occlusion) that reflect more individual ischemic injury for optimal treatment selection; and, fourth, the need for penumbra validation in successfully reperfused patients (not in untreated patients).
Conclusion:
Individual variations in the therapeutic window, ischemic injury (rCBF), and chronicity of vascular lesion development have not been comprehensively incorporated in the standard algorithms used to manage AIS. The current established imaging parameters have not been consistently validated with successfully reperfused patients and rCBF to quantitatively distinguish between oligemia and ischemia and between penumbra and infarct core within ischemic tissue. A novel paradigm incorporating rCBF values or indirectly incorporating relative rCBF values with higher statistically powered imaging studies to more reliably assess the severity of ischemic injury and differentiate reversibility from viability within the area of imaging-based parenchymal hypoperfusion may provide a more personalized approach to treatment, including no treatment of infarction core, to further enhance outcomes.
The past year has seen rapid advances in acute stroke therapy based on advanced imaging selection [1-5]. The main aim of imaging in acute ischemic stroke (AIS) is to rule out hemorrhage and stroke mimics, to define the extension of established infarct (core), and to identify the occlusion site, which are the main factors involved in the acute treatment decision: conservative, IV thrombolysis, and mechanical thrombectomy [1-5]. Additional relevant information includes the extension of the core (or penumbra), the type and length of the clot, and the individual collateral circulation that may allow the individual AIS treatment strategies.
Prediction of the regions of the ischemic penumbra that are likely to progress to infarction is of great clinical interest. Whether lowered apparent diffusion coefficient (ADC) values were present in the ischemic penumbra of patients presenting with acute ischemic stroke and were specific to regions of the penumbra that proceeded to infarction was investigated.
Nineteen patients with hemispheric stroke of less than 6 hours' onset and with acute scans showing a perfusion lesion greater than a diffusion lesion (ischemic penumbra) were studied. Scans also were performed subacutely (days 3 to 5) and at outcome (day 90). The outcome scan was used to identify regions of the penumbra that proceeded to infarction.
The ADC ratios were significantly reduced (P <.00001) in regions of the penumbra that progressed to infarction on the outcome scan compared with those that remained normal. In regions that showed transition to infarction, the mean ADC ratios were typically 0.75 to 0.90.
Intermediate ADC values are present in the ischemic penumbra and are indicative of tissue at risk of infarction.
An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the "tissue-at-risk." It is unclear which "semiquantitative" perfusion parameter most closely identifies final infarct volume.
Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. "Semiquantitative" mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired > or =1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume.
Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient rho=0.68), intermediate for CBFsq (rho=0.55), and weakest for MTTsq (rho=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch.
Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. "DWI/PWI mismatch" does not identify lesion growth. Patients without "DWI/PWI mismatch" are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.
PurposeTo investigate the development of ischemic brain lesions, as present in the acute stroke phase, by diffusion-weighted magnetic resonance imaging (DWI), and in the subacute and chronic phases until up to four months after stroke, in fluid-attenuated inversion recovery (FLAIR)- and T2-weighted (T2W) magnetic resonance (MR) images.Materials and Methods
Twelve consecutive patients with their first middle cerebral artery (MCA) infarction were included. Lesion volumes were assessed on T2W images recorded with a turbo spin echo (TSE) and on images recorded with the FLAIR sequence on average on day 8 and after about four months. They were compared with acute lesion volumes in perfusion and DWI images taken within 24 hours of stroke onset.ResultsOn day 8, lesion volumes in images obtained with FLAIR exceeded the acute infarct volumes in DWI. The chronic lesion volumes were almost identical in T2W and FLAIR images but significantly reduced compared with the acute DWI lesions. The lesion volumes assessed on DWI images correlated highly with the lesions in the images obtained with TSE or FLAIR, as did the lesions in the images obtained with FLAIR and TSE. The secondary lesion shrinkage was accompanied by ventricular enlargement and perilesional sulcal widening, as most clearly visible in the images obtained with FLAIR.Conclusion
Our results show that the acute DWI lesions are highly predictive for the infarct lesion in the chronic stage after stroke despite a dynamic lesion evolution most evident in MR images obtained with FLAIR. J. Magn. Reson. Imaging 2004;20:201–207. © 2004 Wiley-Liss, Inc.
Lesion volume measured on MRI has been used as an objective surrogate marker for outcome in clinical trials. However, lesion volumes vary over time because of edema and tissue loss. This study aims to determine if lesion volumes measured at 30 and 90 days after ictus significantly differ.
We performed a retrospective study of 18 patients who had acute (<24 hours) DWI and follow-up fluid-attenuated inversion recovery imaging at 5, 30, and 90 days. Two expert readers segmented lesions and the mean volumes of both reads were used in all statistical analyses.
Patient age was 65.8 (SD, 13.7) years and median NIHSS at baseline was 11.5. Inter-rater variability for lesion volume measurements was 3.7 (5.8) mL. Acute DWI volume was 19.3 (17.3) mL. Fluid-attenuated inversion recovery volumes for 5, 30, and 90 days were 34.3 (23.5), 18.6 (14.0), and 15.9 (13.8) mL, respectively. These volumes differed significantly (P<0.001). Linear regression revealed a strong correlation (r=0.96; P<0.001) between lesion volumes at 30 and 90 days with a slope that did not vary significantly from 1.0 (P=0.448).
Lesions continue to evolve between 5 and 90 days, but by 30 days lesion volume approaches final infarct volume. While clinical response is the most meaningful outcome measure, our findings suggest that lesion volumes measured at 30 days may provide a sufficient approximation for final infarct volume for use in early phase clinical trials.
Lesion volume measured on follow-up magnetic resonance imaging (MRI) is commonly used as an outcome parameter in clinical stroke trials. However, few studies have evaluated the optimal sequence choice and the interrater reliability of this outcome measure. The objective of this study was to quantify the geometric interrater agreement for lesion delineation of chronic infarcts on T2-weighted and fluid-attenuated inverse recovery (FLAIR) MRI.
In a retrospective study of 14 patients, lesions on 90-day follow-up FLAIR and T2 fast spin echo MRI were outlined by 9 independent, blinded, experienced neuroradiologists. Voxel-wise interrater agreement was measured as (1) the volume of the intersection of individual rater's lesion outlines relative to the mean lesion volume (overlap ratio) and (2) the Hausdorff distance between the lesion markings.
Mean patient age was 64.4 years (range, 45 to 79). Lesion volumes on FLAIR were, on average, 2.5 mL greater than were T2 volumes (median; P<0.001). We found considerable differences between raters' lesion markings, but interrater agreement was consistently better on FLAIR than on T2 images, as measured by a greater overlap ratio (P<0.0001) and a smaller Hausdorff distance (P<0.0001) on FLAIR than on T2.
FLAIR should be used to quantify follow-up infarct size to minimize interrater variability. Our study suggests that imaging analysis performed by 1 or a few trained readers may be preferred. Future studies should address objective and preferably automated criteria for final lesion delineation.
Diffusion-weighted(DWI) hyperintensity is hypothesized to represent irreversibly infarcted tissue (ischemic core) in the setting of acute stroke [corrected]. Measurement of the ischemic core has implications for both prognosis and therapy. We wished to assess the level of evidence in the literature supporting this hypothesis.
We performed a systematic review of the literature relating to tissue outcomes of DWI hyperintense stroke lesions in humans. The methodologic rigor of studies was evaluated by using criteria set out by the Oxford Centre for Evidence-Based Medicine. Data from individual studies were also analyzed to determine the prevalence of patients demonstrating lesion progression, no change, or lesion regression compared with follow-up imaging.
Limited numbers of highly methodologically rigorous studies (Oxford levels 1 and 2) were available. There was great variability in observed rates of DWI lesion reversal (0%-83%), with a surprisingly high mean rate of DWI lesion reversal (24% of pooled patients). Many studies did not include sufficient data to determine the precise prevalence of DWI lesion growth or reversal.
The available tissue-outcome evidence supporting the hypothesis that DWI is a surrogate marker for ischemic core in humans is troublingly inconsistent and merits an overall grade D based on the criteria set out by the Oxford Centre for Evidence-Based Medicine.
Acute ischemic lesions with restricted diffusion can resolve after early recanalization. The impact of superimposed perfusion abnormalities on the fate of acute diffusion lesions is unclear.
Data were obtained from DEFUSE, a prospective multicenter study of patients treated with IV tPA 3 to 6 hours after stroke onset. Thirty-two patients with baseline diffusion and perfusion lesions and 30 day FLAIR scans were coregistered. The acute diffusion lesion was divided into 3 regions according to the Tmax delay of the superimposed perfusion lesion: normal baseline perfusion; mild-moderately hypoperfused (2 s<Tmax<or=8 s) and severely hypoperfused (Tmax >8 s). The reversal rate was calculated as the percentage of the acute diffusion lesion that did not overlap with the final infarct on 30-day FLAIR. Diffusion reversal rates were compared based on whether a favorable clinical response occurred and whether early recanalization was achieved.
On average, 54% of the acute diffusion lesion volume had normal perfusion. Diffusion reversal rates were significantly increased among cases with favorable clinical response and in patients with early recanalization, especially in regions with normal baseline perfusion. The portion of the diffusion lesion with normal perfusion had significantly higher mean apparent diffusion coefficient values and reversal rates.
Acute ischemic lesions with restricted diffusion are most likely to recover if reperfusion occurs within 6 hours of symptom onset, and reversibility is associated with early recanalization and favorable clinical outcome. We propose the term RADAR (Reversible Acute Diffusion lesion Already Reperfused) to describe regions of acute restricted diffusion with normal perfusion.
Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point.
In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients.
All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively.
These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.
We sought to assess whether the volume of the ischemic penumbra can be estimated more accurately by altering the threshold selected for defining perfusion-weighting imaging (PWI) lesions.
DEFUSE is a multicenter study in which consecutive acute stroke patients were treated with intravenous tissue-type plasminogen activator 3 to 6 hours after stroke onset. Magnetic resonance imaging scans were obtained before, 3 to 6 hours after, and 30 days after treatment. Baseline and posttreatment PWI volumes were defined according to increasing Tmax delay thresholds (>2, >4, >6, and >8 seconds). Penumbra salvage was defined as the difference between the baseline PWI lesion and the final infarct volume (30-day fluid-attenuated inversion recovery sequence). We hypothesized that the optimal PWI threshold would provide the strongest correlations between penumbra salvage volumes and various clinical and imaging-based outcomes.
Thirty-three patients met the inclusion criteria. The correlation between infarct growth and penumbra salvage volume was significantly better for PWI lesions defined by Tmax >6 seconds versus Tmax >2 seconds, as was the difference in median penumbra salvage volume in patients with a favorable versus an unfavorable clinical response. Among patients who did not experience early reperfusion, the Tmax >4 seconds threshold provided a more accurate prediction of final infarct volume than the >2 seconds threshold.
Defining PWI lesions based on a stricter Tmax threshold than the standard >2 seconds delay appears to provide more a reliable estimate of the volume of the ischemic penumbra in stroke patients imaged between 3 and 6 hours after symptom onset. A threshold between 4 and 6 seconds appears optimal for early identification of critically hypoperfused tissue.
Transient decreases of the apparent diffusion coefficient (ADC) of water as measured by fast diffusion-weighted imaging (DWI) in the ischemic border zone are thought to reflect cellular swelling associated with spreading depression. DWI and dynamic contrast-enhanced MRI were applied to study the characteristics of spreading depression and the correlation between ADC recovery time and tissue perfusion in focal ischemia.
Serial DWI was performed during remote middle cerebral artery occlusion in rats (n = 5) with an echo-planar imaging technique. ADC maps were calculated and ADC values displayed as a function of time in user-defined regions of interest with a time resolution of 12 to 16 seconds. Dynamic contrast-enhanced MRI was performed for qualitative correlation of ADC changes with tissue perfusion.
Recovery time of transient ADC decreases correlated with the degree of the perfusion deficit (r = .81, P < .001). Slowly recovering ADC declines were found close to the ischemic core and correlated with severe perfusion deficit, while short-lasting ADC declines were typically found in moderately malperfused or normal tissue. Transient ADC decreases originated in the subcortical and cortical ischemic border zones and propagated along the cortex with a velocity of 2.9 +/- 0.9 mm/min.
The variation in the recovery time of transient ADC decreases in the ischemic periphery reflects the gradient of the tissue perfusion. Severely delayed recovery time after spreading depression is thought to represent the ischemic penumbra.
This report evaluates several methods to map relative cerebral blood flow (rCBF) by applying both parametric and nonparametric techniques to deconvolve high resolution dynamic MRI measurements of paramagnetic bolus passages with noninvasively determined arterial inputs. We found a nonparametric (singular value decomposition (SVD)) deconvolution technique produced the most robust results, giving mean gray:white flow ratio of 2.7 +/- 0.5 (SEM) in six normal volunteers, in excellent agreement with recent PET literature values for age-matched subjects. Similar results were obtained by using a model-dependent approach that assumes an exponential residue function, but not for a Gaussian-shaped residue function or for either Fourier or regularization-based model-independent approaches. Pilot studies of our CBF mapping techniques in patients with tumor, stroke, and migraine aura demonstrated that these techniques can be readily used on data routinely acquired by using current echo planar imaging technology. By using these techniques, the authors visualized important regional hemodynamic changes not detectable with rCBV mapping algorithms.
We examined the utility of echoplanar magnetic resonance perfusion imaging and diffusion-weighted imaging (DWI) in predicting stroke evolution and outcome in 18 patients with acute hemispheric infarction.
Patients were studied within 24 hours (mean, 12.2 hours), subacutely (mean, 4.7 days), and at outcome (mean, 84 days). Comparisons were made between infarction volumes as measured on perfusion imaging (PI) and isotropic DWI maps, clinical assessment scales (Canadian Neurological Scale, Barthel Index, and Rankin Scale), and final infarct volume (T2-weighted MRI).
Acute PI lesion volumes correlated with acute neurologic state, clinical outcome, and final infarct volume. Acute DWI lesions correlated less robustly with acute neurologic state, but correlated well with clinical outcome and final infarct volume. Three of six possible patterns of abnormalities were seen: PI lesion larger than DWI lesion (65%), PI lesion smaller than DWI lesion (12%), and DWI lesion but no PI lesion (23%). A pattern of a PI lesion larger than the DWI lesion predicted DWI expansion into surrounding hypoperfused tissue (p < 0.05). In the other two patterns, DWI lesions did not enlarge, suggesting that no significant increase in ischemic lesion size occurs in the absence of a larger perfusion deficit.
Combined early PI and DWI can define different acute infarct patterns, which may allow the selection of rational therapeutic strategies based on the presence or absence of potentially salvageable ischemic tissue.
We sought to characterize the evolution of acute ischemic stroke by MRI and its relationship to patients' neurological outcome.
Fourteen patients with acute ischemic stroke underwent MRI within 13 hours of symptom onset (mean, 7.4+/-3 hours) and underwent repeated imaging and concurrent neurological examination at 8, 24, 36, and 48 hours and 7 days and >42 days after first imaging.
Diffusion-weighted imaging (DWI) lesion volumes increased between the first and second scans in 10 of 14 patients; scans with maximum DWI lesion volume occurred at a mean of 70.4 hours. Initial DWI lesion volume correlated with the largest T2 lesion volume (r=0.97; P<0.001). Final lesion volume was smaller than maximum lesion volume in 12 of 14 patients. There was positive correlation between the follow-up National Institutes of Health Stroke Scale score and the initial DWI lesion volume (r=0.67; P=0. 01) and maximum T2 lesion volume (r=0.77; P<0.01) and negative correlation with initial mean apparent diffusion coefficient ratio (ADCr) (r=-0.64; P<0.05). The ADCr was 0.73 at initial imaging and fell between the initial and second scans in 10 of 14 patients. Mean ADCr did not rise above normal until 42 days after stroke onset (P<0. 001).
Serial MRI demonstrates the dynamic nature of progressive ischemic injury in acute stroke patients developing over hours to days, and it suggests that both primary and secondary pathophysiological processes can be valuable targets for neuroprotective interventions.
Serial study of such MR parameters as diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC), ADC with fluid-attenuated inversion recovery (ADC(FLAIR)), and T2-weighted imaging may provide information on the pathophysiological mechanisms of acute ischemic stroke. Our goals were to establish the natural evolution of MR signal intensity characteristics of acute ischemic lesions and to assess the potential of using specific MR parameters to estimate lesion age.
Five serial echo-planar DWI studies with and without an inversion recovery pulse were performed in 27 patients with acute stroke. The following lesion characteristics were studied: 1) conventional ADC (ADC(CONV)); 2) ADC(FLAIR); 3) DWI signal intensity (SI(DWI)); 4) T2-weighted signal intensity (SI(T2)), and 5) FLAIR signal intensity (SI(FLAIR)).
The lesion ADC(CONV) gradually increased from low values during the first week to pseudonormal during the second week to supranormal thereafter. The lesion ADC(FLAIR) showed the same pattern of evolution but with lower absolute values. A low ADC value indicated, with good sensitivity (88%) and specificity (90%), that a lesion was less than 10 days old. All signal intensities remained high throughout follow-up. SI(DWI) showed no significant change during the first week but decreased thereafter. SI(T2) initially increased, decreased slightly during week 2, and again increased after 14 days. SI(FLAIR) showed the same initial increase as the SI(T2) but remained relatively stable thereafter.
Our findings further clarify the time course of stroke evolution on MR parameters and indicate that the ADC map may be useful for estimating lesion age. Application of an inversion recovery pulse results in lower, potentially more accurate, absolute ADC values.
Knowledge of the natural evolution of ischemic brain lesions may be a crucial aspect in the assessment of future stroke therapies.
To establish daily changes of ischemic cerebral lesion volume using diffusion-weighted magnetic resonance imaging.
Prospective cohort study.
Referral center.
Serial magnetic resonance imaging scans were performed in consecutive untreated stroke patients. The baseline scan was obtained within 48 hours after symptom onset; subsequent scans, 12 to 48 hours, 3 to 4 days, 5 to 7 days, and 30 days after baseline. Lesion volumes were measured on each scan by 2 independent observers.
Daily change in lesion volume.
A total of 112 magnetic resonance imaging scans were obtained in 24 patients. An early increase in lesion volume was seen in all patients. Maximum lesion volume was reached at a mean of 74 hours. Lesion volumes increased by a mean (+/- SEM) of 21% +/- 12% during day 2 and 10% +/- 12% during day 3. No significant change occurred during day 4. During days 5, 6, and 7, statistically significant mean (+/- SEM) decreases of 6% +/- 8%, 3% +/- 4%, and 4% +/- 5%, respectively, were observed.
Ischemic lesions follow a relatively consistent pattern of growth during the first 3 days and subsequent decrease in size. These data in conjunction with data regarding the evolution of lesion volume during the first 24 hours after symptom onset may be useful in the design of pilot studies of therapies for acute stroke.
A mismatch between diffusion- and perfusion-weighted MRI is thought to define tissue at risk of infarction. This concept is based on the assumption that diffusion slowing of and decreases in the apparent diffusion coefficient (ADC) serve as indicator of tissue proceeding to infarction. We tested this hypothesis.
MRI (diffusion weighted, perfusion weighted, MRA, T2 weighted) was performed in 15 patients with acute stroke within 2.9+/-0.8 hours (mean+/-SD) of onset and on days 1 and 7. After intraindividual realignment of the ADC maps, the development of ADC range volumes and ADC values was determined.
An increase (354%, group A1) in the total ADC-based lesion volume below a threshold of < 80% occurred in 4 patients on day 1, persisting on day 7 with a pronounced increase of ADC range volumes with low ADC values. An increase in total ADC-based lesion volume (201%, group A2) followed by a secondary drop to day 7 was found in 7 patients. A significant reduction in total ADC-based lesion volume (14%, group B) was found in 4 patients. ADC-based lesion volume increase was associated with persistent vessel occlusion in group A, whereas recanalization in group B resulted in ADC volume decrease. ADC normalization was observed independently from the degree of the initial ADC decrease on days 1 and 7 in group B.
In line with results from animal experiments, ADC decreases do not reliably indicate tissue infarction Even severely decreased ADC values may normalize in human stroke, and it seems likely that ADC normalization depends on the duration and severity of ischemia rather than the absolute value.
Diffusion- and perfusion-weighted magnetic resonance imaging provides important pathophysiological information in acute brain ischemia. We performed a prospective study in 19 sub-6-hour stroke patients using serial diffusion- and perfusion-weighted imaging before intravenous thrombolysis, with repeat studies, both subacutely and at outcome. For comparison of ischemic lesion evolution and clinical outcome, we used a historical control group of 21 sub-6-hour ischemic stroke patients studied serially with diffusion- and perfusion-weighted imaging. The two groups were well matched for the baseline National Institutes of Health Stroke Scale and magnetic resonance parameters. Perfusion-weighted imaging-diffusion-weighted imaging mismatch was present in 16 of 19 patients treated with tissue plasminogen activator, and 16 of 21 controls. Perfusion-weighted imaging-diffusion-weighted imaging mismatch patients treated with tissue plaminogen activator had higher recanalization rates and enhanced reperfusion at day 3 (81% vs 47% in controls), and a greater proportion of severely hypoperfused acute mismatch tissue not progressing to infarction (82% vs -25% in controls). Despite similar baseline diffusion-weighted imaging lesions, infarct expansion was less in the recombinant tissue plaminogen activator group (14cm(3) vs 56cm(3) in controls). The positive effect of thrombolysis on lesion growth in mismatch patients translated into a greater improvement in baseline to outcome National Institutes of Health Stroke Scale in the group treated with recombinant tissue plaminogen activator, and a significantly larger proportion of patients treated with recombinant tissue plaminogen activator having a clinically meaningful improvement in National Institutes of Health Stroke Scale of > or = 7 points. The natural evolution of acute perfusion-weighted imaging-diffusion-weighted imaging mismatch tissue may be altered by thrombolysis, with improved stroke outcome. This has implications for the use of diffusion- and perfusion-weighted imaging in selecting and monitoring patients for thrombolytic therapy.
Although animal models have demonstrated that late secondary cerebral injury after arterial occlusion and subsequent recanalization may limit the benefit of reperfusion therapy, this phenomenon has not been well characterized in humans. Diffusion-perfusion magnetic resonance imaging studies were performed before treatment, early after treatment, and at day 7 in patients undergoing vessel recanalization with intraarterial thrombolytics. Among 18 patients studied, mean age was 71 (range, 27-94), and median entry National Institutes of Health Stroke Scale score was 13 (range, 6-25). Early after recanalization, partial or complete normalization of diffusion imaging abnormalities occurred in 8 of 18 (44%) patients. Among the eight patients with early diffusion imaging reversal, late secondary injury by day 7 occurred in 5 (63%), and sustained normalization of all reversed tissue occurred in 3 (38%). Pretreatment apparent diffusion coefficient values were lowest in regions experiencing no reversal (mean apparent diffusion coefficient, 608 microm(2)/sec), intermediate in regions with reversal and secondary decline (617 microm(2)/sec), and highest in regions with sustained reversal (663 microm(2)/sec). There was a trend toward less improvement in neurological deficit in patients with secondary injury versus patients with sustained reversal. In the future, late secondary tissue injury may become an important therapeutic target for postreperfusion neuroprotective therapies, with treatment efficacy monitored by serial diffusion magnetic resonance imaging.
Identification of the ischemic penumbra in the acute stroke clinical setting is an important goal for stroke researchers and clinicians. Various models for imaging the penumbra with MRI have been proposed, including the pioneering diffusion-perfusion mismatch model and later multivariate approaches. A number of multicenter clinical trials are now under way to test these models and confirm the utility of MRI-based treatment decisions. Present knowledge about MRI visualization of the salvageable penumbra suggests a promising future in which MRI studies are performed routinely in the acute stroke setting and the data provided by these MRI studies assist in individualizing therapeutic decisions and identifying effective therapies that can be delivered at late time points.
We studied the microscopic features of 137 cases of human cerebral infarct. In each case, the age of the lesion was determined by measuring the time elapsed between initial clinical presentation and date of surgery or death. Multiple microscopic variables were analyzed on hematoxylin and eosin-stained sections. There were 104 (76%) male and 33 (24%) female patients with a median age of 64 years. The location of the infarcts included 129 cerebral, 5 cerebellar, and 1 each in the pons, midbrain and medulla. The age of the lesions ranged from 1 day to 53 years. All lesions were single and varied from lacunes to large infarcts in the distribution of one or more cerebral arteries. Key histologic features of the proposed classification are as follows: (1) phase of acute neuronal injury (11 cases studied), age 1-2 days, characterized by the presence of neuronal changes, and spongiosis of the neuropil and absence of neuronal ferrugination, chronic inflammation, macrophages, neo-vascularization and cavitation; (2) phase of organization subdivided into: (a) phase of acute inflammation (31 cases), age 3-37 days, characterized by coagulative necrosis, and frequent acute inflammation, and (b) phase of chronic inflammation (57 cases), age 10 days-53 years, characterized by the presence or absence of coagulative necrosis, neuronal injury, red neurons, macrophages, mononuclear inflammatory cells, perivascular cuffing, cavitation, gliosis, spheroids; absence of neutrophils; and (3) phase of resorption (38 cases), age 26 days-23 years, characterized by absence of an inflammatory response. Neuronophagia is not a feature of cerebral infarcts.
Magnetic resonance imaging (MRI) selection of stroke patients eligible for thrombolytic therapy is an emerging application. Although the efficacy of therapy within 3 hours after onset of symptoms with intravenous (IV) tissue plasminogen activator (tPA) has been proven for patients selected with computed tomography (CT), no randomized, double-blinded MRI trial has been published yet.
MRI screening of acute stroke patients before thrombolytic therapy is performed in some cerebrovascular centers. In contrast to the CT trials, MRI pilot studies demonstrate benefit of therapy up to 6 hours after onset of symptoms. This article reviews the literature that has lead to current controlled MRI-based thrombolysis trials. We examined the MRI criteria applied in 5 stroke centers. Along with the personal views of clinicians at these centers, the survey reveals a variety of clinical and MRI technical aspects that must be further investigated: the therapeutic consequence of microbleeds, the use of magnetic resonance angiography, dynamic time windows, and others.
MRI is an established application in acute evaluation of stroke patients and may suit as a brain clock, replacing the currently used epidemiological time clock when deciding whether to initiate thrombolytic therapy. MRI criteria for thrombolytic therapy are applied in some cerebrovascular centers, but the results of ongoing clinical trials must be awaited before it is possible to reach consensus.
Use of intravenous thrombolytic therapy in ischaemic stroke is restricted to a 3-h time window because of the proof of this time window in pivotal clinical trials. Thrombolysis is aimed at recanalization of occluded arteries and reperfusion of the ischaemic penumbra, a region of critically hypoperfused, functionally impaired, but potentially viable brain. There are a number of current prospective trials that are testing the hypothesis that the presence of the penumbra will predict thrombolytic responders beyond 3 h.
Using magnetic resonance imaging, a mismatch between a larger perfusion-weighted imaging lesion and smaller diffusion-weighted imaging lesion is considered to represent the ischaemic penumbra. Perfusion-weighted imaging provides semiquantitative cerebral blood flow imaging and diffusion-weighted imaging is an index of the largely irreversible ischaemic core. This definition has been modified with the recognition that the perfusion-weighted imaging lesion includes benign oligaemia and that a portion of the diffusion-weighted imaging core is potentially salvageable with rapid reperfusion. Most acute stroke patients have a magnetic resonance imaging-penumbral signature within 6 h of stroke onset. The penumbra is commonly, but not invariably, associated with proximal arterial occlusion and is time-dependent. Preliminary studies have shown benefit from thrombolytic therapy beyond the established 3-h window.
Penumbral imaging using magnetic resonance imaging with perfusion over diffusion weighted imaging mismatch can provide a physiological 'tissue clock' in individual patients. Based on this hypothesis, a number of prospective trials are being performed. These include EPITHET, DEFUSE, DIAS, MR RESCUE and ROSIE.
Apparent diffusion coefficient (ADC) thresholds for tissue infarction have been identified in acute stroke. IV tissue plasminogen activator (tPA) is associated with tissue salvage. We hypothesized that tPA would lower the ADC threshold for infarction.
ADC and mean transit time (MTT) maps were generated for 26 patients imaged within 6 hours of stroke onset (12 tPA and 14 conservatively managed controls). MTT maps and day-90 T2-weighted images were coregistered to ADC maps. Relative ADC (rADC) values were calculated for initial diffusion-weighted imaging (DWI) lesions, infarct growth regions (final infarct volume-the acute DWI lesion volume), and hypoperfused salvaged regions (HS; MTT map abnormality-the final infarct volume). When relevant, the DWI lesion was subdivided into DWI reversal and DWI infarct regions.
Mean DWI lesion rADC was 0.79 in tPA and 0.74 in untreated patients (P=0.097). Mean rADC in HS and infarct growth regions were similar in tPA patients (0.950 and 0.946) and untreated patients (0.957, P=0.76; 0.970, P=0.08, respectively). The rADC in HS tissue was directly correlated with the time to treatment with tPA (r=0.685; P=0.029). DWI reversal was seen in 67% of tPA-treated patients and in 36% of those conservatively managed (Fisher exact test; P=0.238). In the 13 patients with DWI reversal, the mean rADC in these regions (0.81+/-0.07) was significantly higher than in the acute DWI region that infarcted (0.74+/-0.07; P=0.02), although no absolute thresholds could be identified.
The peri-DWI lesion region contains tissue with intermediate ADC values. The fate of this tissue is variable and cannot be predicted based on the ADC alone. DWI expansion occurs in bioenergetically normal tissue, and this is attenuated by tPA in a time-dependent fashion.
To determine whether prespecified baseline magnetic resonance imaging (MRI) profiles can identify stroke patients who have a robust clinical response after early reperfusion when treated 3 to 6 hours after symptom onset.
We conducted a prospective, multicenter study of 74 consecutive stroke patients admitted to academic stroke centers in North America and Europe. An MRI scan was obtained immediately before and 3 to 6 hours after treatment with intravenous tissue plasminogen activator 3 to 6 hours after symptom onset. Baseline MRI profiles were used to categorize patients into subgroups, and clinical responses were compared based on whether early reperfusion was achieved.
Early reperfusion was associated with significantly increased odds of achieving a favorable clinical response in patients with a perfusion/diffusion mismatch (odds ratio, 5.4; p = 0.039) and an even more favorable response in patients with the Target Mismatch profile (odds ratio, 8.7; p = 0.011). Patients with the No Mismatch profile did not appear to benefit from early reperfusion. Early reperfusion was associated with fatal intracranial hemorrhage in patients with the Malignant profile.
For stroke patients treated 3 to 6 hours after onset, baseline MRI findings can identify subgroups that are likely to benefit from reperfusion therapies and can potentially identify subgroups that are unlikely to benefit or may be harmed.
Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI).
We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537.
We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Student's t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxon's test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion.
Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.