Yoshinari Nagakane

The infarct core is well represented by the acute diffusion lesion: sustained reversal is infrequent

Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion-diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion—diffusion mismatch (Tmax>6 seconds, ratio>1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion—diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.

Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion-diffusion mismatch

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

EPITHET: Positive result after reanalysis using baseline diffusion-weighted imaging/perfusion-weighted imaging co-registration

Background and Purpose— The Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) was a prospective, randomized, double-blinded, placebo-controlled, phase II trial of alteplase between 3 and 6 hours after stroke onset. The primary outcome of infarct growth attenuation on MRI with alteplase in mismatch patients was negative when mismatch volumes were assessed volumetrically, without coregistration, which underestimates mismatch volumes. We hypothesized that assessing the extent of mismatch by coregistration of perfusion and diffusion MRI maps may more accurately allow the effects of alteplase vs placebo to be evaluated. Methods— Patients were classified as having mismatch if perfusion-weighted imaging divided by coregistered diffusion-weighted imaging volume ratio was >1.2 and total coregistered mismatch volume was ≥10 mL. The primary outcome was a comparison of infarct growth in alteplase vs placebo patients with coregistered mismatch. Results— Of 99 patients with baseline diffusion-weighted imaging and perfusion-weighted imaging, coregistration of both images was possible in 95 patients. Coregistered mismatch was present in 93% (88/95) compared to 85% (81/95) with standard volumetric mismatch. In the coregistered mismatch patients, of whom 45 received alteplase and 43 received placebo, the primary outcome measure of geometric mean infarct growth was significantly attenuated by a ratio of 0.58 with alteplase compared to placebo (1.02 vs 1.77; 95% CI, 0.33–0.99; P=0.0459). Conclusions— When using coregistration techniques to determine the presence of mismatch at study entry, alteplase significantly attenuated infarct growth. This highlights the necessity for a randomized, placebo-controlled, phase III clinical trial of alteplase using penumbral selection beyond 3 hours.

The Effects of Alteplase 3 to 6 Hours After Stroke in the EPITHET–DEFUSE Combined Dataset Post Hoc Case–Control Study

Background and Purpose— Two phase 2 studies of alteplase in acute ischemic stroke 3 to 6 hours after onset, Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; a randomized, controlled, double-blinded trial), and Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution Study (DEFUSE; open-label, treatment only) using MR imaging-based outcomes have been conducted. We have pooled individual patient data from these to assess the response to alteplase. The primary hypothesis was that alteplase would significantly attenuate infarct growth compared with placebo in mismatch-selected patients using coregistration techniques. Methods— The EPITHET–DEFUSE study datasets were pooled while retaining the original inclusion and exclusion criteria. Significant hypoperfusion was defined as a Tmax delay >6 seconds), and coregistration techniques were used to define MR diffusion-weighted imaging/perfusion-weighted imaging mismatch. Neuroimaging, parameters including reperfusion, recanalization, symptomatic intracerebral hemorrhage, and clinical outcomes were assessed. Alteplase and placebo groups were compared for the primary outcome of infarct growth as well for secondary outcome measures. Results— From 165 patients with adequate MR scans in the EPITHET–DEFUSE pooled data, 121 patients (73.3%) were found to have mismatch. For the primary outcome analysis, 60 patients received alteplase and 41 placebo. Mismatch patients receiving alteplase had significantly attenuated infarct growth compared with placebo (P=0.025). The reperfusion rate was also increased (62.7% vs 31.7%; P=0.003). Mortality and clinical outcomes were not different between groups. Conclusions— The data provide further evidence that alteplase significantly attenuates infarct growth and increases reperfusion compared with placebo in the 3- to 6- hour time window in patients selected based on MR penumbral imaging. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00238537

Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: The SAMURAI-NVAF Study

Background Large clinical trials are lack of data on non-vitamin K antagonist oral anticoagulants for acute stroke patients. Aim To evaluate the choice of oral anticoagulants at acute hospital discharge in stroke patients with nonvalvular atrial fibrillation and clarify the underlying characteristics potentially affecting that choice using the multicenter Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-NVAF registry (ClinicalTrials.gov NCT01581502). Method The study included 1192 acute ischemic stroke/transient ischemic attack patients with nonvalvular atrial fibrillation (527 women, 77·7 ± 9·9 years old) between September 2011 and March 2014, during which three nonvitamin K antagonist oral anticoagulant oral anticoagulants were approved for clinical use. Oral anticoagulant choice at hospital discharge (median 23-day stay) was assessed. Results Warfarin was chosen for 650 patients, dabigatran for 203, rivaroxaban for 238, and apixaban for 25. Over the three 10-month observation periods, patients taking warfarin gradually decreased to 46·5% and those taking nonvitamin K antagonist oral anticoagulants increased to 48·0%. As compared with warfarin users, patients taking nonvitamin K antagonist oral anticoagulants included more men, were younger, more frequently had small infarcts, and had lower scores for poststroke CHADS2, CHA2DS2-VASc, and HAS-BLED, admission National Institutes of Health stroke scale, and discharge modified Rankin Scale. Nonvitamin K antagonist oral anticoagulants were started at a median of four-days after stroke onset without early intracranial hemorrhage. Patients starting nonvitamin K antagonist oral anticoagulants earlier had smaller infarcts and lower scores for the admission National Institutes of Health stroke scale and the discharge modified Rankin Scale than those starting later. Choice of nonvitamin K antagonist oral anticoagulants was independently associated with 20-day or shorter hospitalization (OR 2·46, 95% CI 1·87–3·24). Conclusions Warfarin use at acute hospital discharge was still common in the initial years after approval of nonvitamin K antagonist oral anticoagulants, although nonvitamin K antagonist oral anticoagulant users increased gradually. The index stroke was milder and ischemia-risk indices were lower in nonvitamin K antagonist oral anticoagulant users than in warfarin users. Early initiation of nonvitamin K antagonist oral anticoagulants seemed safe.

Evaluation of Factors Associated With Elevated Levels of Platelet-Derived Microparticles in the Acute Phase of Cerebral Infarction

Background: Platelet-derived microparticles (PDMPs) have attracted attention as blood coagulation-promoting, endothelial cell-activating factors. The objective of this study was to determine the parameters associated with elevated PDMP levels and examine their relationship with atherosclerotic lesions of main intracranial and extracranial arteries. Participants and Methods: Participants included a control group (C) of 61 patients with no apparent cerebral vascular lesions and 110 patients with acute-phase cerebral infarction, consisting of a small-vessel occlusion group (S) of 34 patients, a large-artery atherosclerosis group (L) of 41 patients, a cardioembolism group (CE) of 20 patients, and a stroke of undetermined etiology group (U) of 15 patients. Platelet-derived microparticle levels were measured using enzyme-linked immunosorbent assay (ELISA) at the time of admission, and the patients were reclassified into group CP (control level PDMPs), consisting of 70 patients with control PDMP levels, and group HP (high PDMPs), consisting of 40 patients with elevated PDMP levels. All patients underwent cranial magnetic resonance (MR) and carotid ultrasound examinations. Results: Platelet-derived microparticle levels were significantly higher in groups S and L than in group C (P < .01). Concomitant intima-media thickness (IMT; odds ratio [OR] = 1.29, P < .05) and concomitant intracranial stenosis (OR = 3.95, P < .01) were significantly correlated with elevated PDMP levels. Fibrinogen and high-sensitivity CRP levels were significantly higher in group HP than in group CP. Conclusion: Alterations in PDMP levels correlated with the presence of atherothrombotic lesions, and PDMP levels are expected to be useful as a clinical indicator, reflecting the presence of intracranial atherosclerotic lesions in the acute phase of cerebral infarction.

Assessment of arcuate fasciculus with diffusion-tensor tractography may predict the prognosis of aphasia in patients with left middle cerebral artery infarcts

IntroductionIt is often clinically difficult to assess the severity of aphasia in the earliest stage of cerebral infarction. A method enabling objective assessment of verbal function is needed for this purpose. We examined whether diffusion tensor (DT) tractography is of clinical value in assessing aphasia.MethodsThirteen right-handed patients with left middle cerebral artery infarcts who were scanned within 2 days after stroke onset were enrolled in this study. Magnetic resonance data of ten control subjects were also examined by DT tractography. Based on the severity of aphasia at discharge, patients were divided into two groups: six patients in the aphasic group and seven in the nonaphasic group. Fractional anisotropy (FA) and number of arcuate fasciculus fibers were evaluated. Asymmetry index was calculated for both FA and number of fibers.ResultsFA values for the arcuate fasciculus fibers did not differ between hemispheres in either the patient groups or the controls. Number of arcuate fasciculus fibers exhibited a significant leftward asymmetry in the controls and the nonaphasic group but not in the aphasic group. Asymmetry index of number of fibers was significantly lower (rightward) in the aphasic group than in the nonaphasic (P = 0.015) and control (P = 0.005) groups. Loss of leftward asymmetry in number of AF fibers predicted aphasia at discharge with a sensitivity of 0.83 and specificity of 0.86.ConclusionsAsymmetry of arcuate fasciculus fibers by DT tractography may deserve to be assessed in acute infarction for predicting the fate of vascular aphasia.

A Topographic Study of the Evolution of the MR DWI/PWI Mismatch Pattern and Its Clinical Impact A Study by the EPITHET and DEFUSE Investigators

Background and Purpose— The ischemic penumbra may be classical, with complete annular configuration around the infarct core, or nonclassical with a more fragmented pattern. We tested the hypotheses that these penumbral patterns may: be associated with specific predictive factors, influence infarct growth and clinical outcome, and influence the effect of tissue plasminogen activator (t-PA). Methods— Using the EPITHET/DEFUSE data set, in which patients received alteplase or placebo 3 to 6 hours poststroke, perfusion-weighted imaging and diffusion-weighted imaging images were analyzed. These mismatch patterns were defined as “classical” or “nonclassical.” Multivariate analysis was used to identify variables associated with mismatch patterns, the effect of t-PA, as well as the relationship between mismatch patterns, infarct growth, and clinical outcomes. Results— We included 158 patients (median age, 74 years; median National Institute of Health Stroke Scale score, 12). Multivariate analysis indicated that the factors associated with classical mismatch pattern type were large mismatch volume (P<0.001) and cortical infarct location (P=0.036). Infarct growth, clinical outcome, and the efficacy of t-PA were not statistically different between patterns. Conclusions— Coregistered mismatch volume and cortical location of infarction were the important factors associated with presence of the classical mismatch pattern. The lack of effect of the type of mismatch patterns on infarct growth, clinical outcomes, or the benefit of t-PA would suggest that mismatch topography is less important during the hyperacute phase of ischemic stroke than during subacute phase.

Moving Beyond a Single Perfusion Threshold to Define Penumbra: A Novel Probabilistic Mismatch Definition

Background and Purpose— The mismatch lesion volumes defined by perfusion-weighted imaging exceeding diffusion-weighted imaging have been used as a marker of ischemic penumbral tissue. Defining the perfusion lesion by thresholding has shown promise as a practical tool; several positron emission tomography studies have indicated a more probabilistic relationship between perfusion and infarction. Here, we used a randomized controlled trial dataset of tissue-type plasminogen activator 3 to 6 hours after stroke to: (1) quantify the relationship between severity of hypoperfusion (measured by Tmax) and risk of infarction; (2) exploit this relationship to present a novel definition of mismatch based on infarct probabilities rather than dichotomies; and (3) examine the treatment response in the subgroup of patients with mismatch by the new definition. Methods— Patients from the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) were included. Baseline perfusion-weighted imaging and 90-day T2-weighted imaging were coregistered. Perfusion-weighted imaging lesion volumes were divided into 10 Tmax delay strata, and infarct risk was defined as the fraction of the tissue at a given Tmax strata that progressed to infarction by day 90. Results— Sixty-two patients were studied. Infarct risk was an increasing function of Tmax for all subgroups, including the whole cohort. The probabilistic approach outperformed all Tmax thresholds, with exception of the Tmax ≥10 threshold, for which it was only favored by a trend. Conclusions— Infarct risk and treatment effect increased with severity of perfusion abnormalities. This suggests that a severity-weighted mismatch definition may define penumbral tissue more accurately.

Neurological and MRI Findings as Predictors of Progressive-Type Lacunar Infarction

Aims: To find neurological or neuroimaging signs to predict neurological deterioration in acute lacunar infarctions. Methods: Sixty-one consecutive patients with a supratentorial lacunar infarct, who were admitted within 48 h, were studied retrospectively. Progressive-type stroke (PS) was defined as progressive motor deficits that arose within 7 days after onset, by using the motor ratings of the National Institutes of Health Stroke Scale. Results: Sixteen patients (26%) were classified into the PS group. In the PS group, fluctuating or progressing onset (81 vs. 42%, p = 0.009), leg-predominant motor deficits on admission (63 vs. 16%, p = 0.001) and corona radiata lesion on diffusion-weighted MRI (100 vs. 69%, p = 0.013) were all more frequent than in the non-PS group. Conclusion: Bedside neurological assessment and MRI findings may allow us to predict PS and start early intensive treatment for preventing further neurological deterioration.