Henry Ma

Penumbral selection of patients for trials of acute stroke therapy.

After ischaemic stroke onset, potentially viable (ie, penumbral) tissue might be salvageble for as long as 48 h. By increasing the therapeutic time window for treatment of stroke with intravenous alteplase from 3-4.5 h to 9 h, many more patients could be treated. Use of a combination of diffusion-weighted and perfusion-weighted MRI or perfusion CT might improve selection of patients with penumbral tissue. Several phase II trials of alteplase lend strong biological support to the use of this strategy for up to 6 h after stroke. However, the negative results of the phase III Desmoteplase In Acute ischaemic Stroke trial (DIAS-2) with desmoteplase given up to 9 h after stroke suggest that some refinements are needed. For trials of neuroprotection, the concept of freezing the penumbra (ie, preventing further deterioration of the vulnerable tissue) might be a more realistic expectation. Recent advances in penumbral imaging technology should enable a phase III alteplase trial to be done beyond 4.5 h by use of techniques to select patients with penumbral tissue.

A multicentre, randomized, double-blinded, placebo-controlled phase III study to investigate EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

Background and hypothesis Thrombolytic therapy with tissue plasminogen activator is effective for acute ischaemic stroke within 4·5 h of onset. Patients who wake up with stroke are generally ineligible for stroke thrombolysis. We hypothesized that ischaemic stroke patients with significant penumbral mismatch on either magnetic resonance imaging or computer tomography at three- (or 4·5 depending on local guidelines) to nine-hours from stroke onset, or patients with wake-up stroke within nine-hours from midpoint of sleep duration, would have improved clinical outcomes when given tissue plasminogen activator compared to placebo. Study design EXtending the time for Thrombolysis in Emergency Neurological Deficits is an investigator-driven, Phase III, randomized, multicentre, double-blind, placebo-controlled study. Ischaemic stroke patients presenting after the three- or 4·5-h treatment window for tissue plasminogen activator and within nine-hours of stroke onset or with wake-up stroke within nine-hours from the midpoint of sleep duration, who fulfil clinical (National Institutes of Health Stroke Score ≥4–26 and prestroke modified Rankin Scale <2) will undergo magnetic resonance imaging or computer tomography. Patients who also meet imaging criteria (infarct core volume <70 ml, perfusion lesion : infarct core mismatch ratio >1·2, and absolute mismatch >10 ml) will be randomized to either tissue plasminogen activator or placebo. Study outcome The primary outcome measure will be modified Rankin Scale 0–1 at day 90. Clinical secondary outcomes include categorical shift in modified Rankin Scale at 90 days, reduction in the National Institutes of Health Stroke Score by 8 or more points or reaching 0–1 at day 90, recurrent stroke, or death. Imaging secondary outcomes will include symptomatic intracranial haemorrhage, reperfusion and or recanalization at 24 h and infarct growth at day 90.

Inflammation following stroke.

Stroke is one of the leading causes of mortality and morbidity. The stroke process triggers an inflammatory reaction that may last up to several months. Suppression of inflammation using a variety of drugs reduces infarct volume and improves clinical outcomes in animal models of stroke. This benefit occurs even with the initiation of therapy after 3 hours of onset of stroke, beyond the therapeutic window for thrombolysis with tPA. The use of neuroprotectants to suppress inflammation may widen the therapeutic time window for tPA while lessening its side-effects. Suppression of inflammation may also improve outcomes in animal models of haemorrhagic stroke. To date, clinical trials with anti-inflammatory agents in acute ischaemic stroke have failed to improve clinical outcomes. However, because of the potential for broader applicability across all aspects of stroke, a better understanding of anti-inflammatory mechanisms is important.

Ischemic Thresholds for Gray and White Matter. A Diffusion and Perfusion Magnetic Resonance Study

Background and Purpose— Although gray matter (GM) and white matter (WM) have differing neurochemical responses to ischemia in animal models, it is unclear whether this translates into differing thresholds for infarction. We studied this issue in ischemic stroke patients using magnetic resonance (MR) techniques. Methods— MR studies were performed in patients with acute hemispheric ischemic stroke occurring within 24 hours and at 3 months. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and apparent diffusion coefficient (ADC) were calculated. After segmentation based on a probabilistic map of GM and WM, tissue-specific diffusion and perfusion thresholds for infarction were established. Results— Twenty-one patients were studied. Infarction thresholds for CBF were significantly higher in GM (median 34.6 mL/100 g per minute, interquartile range 26.0 to 38.8) than in WM (20.8 mL/100 g per minute; interquartile range 18.0 to 25.9; P<0.0001). Thresholds were also significantly higher in GM than WM for CBV (GM: 1.67 mL/100 g; interquartile range 1.39 to 2.17; WM: 1.19 mL/100 g; interquartile range 0.94 to 1.53; P<0.0001), ADC (GM: 918×10−6 mm2/s; 868 to 975×10−6; WM: 805×10−6; 747 to 870×10−6; P<0.001), and there was a trend toward a shorter MTT in GM (GM 4.94 s, 4.44 to 5.38; WM 5.15, 4.11 to 5.68; P=0.11). Conclusions— GM has a higher infarction threshold for CBF, CBV, and ADC than WM in patients within 24 hours of ischemic stroke onset. Hence, when assessing patients for potential therapies, tissue-specific rather than whole-brain thresholds may be a more precise measure of predicting the likelihood of infarction.

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

Cerebral β-amyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator-related hemorrhage†‡

Cerebral amyloid angiopathy (CAA) may be an important predisposing factor for the hemorrhagic complications of recombinant tissue‐type plasminogen activator (rt‐PA) therapy. We studied patients treated within 3 hours of onset of ischemic stroke with rt‐PA using positron emission tomography to compare Pittsburgh compound B (PiB) (a cerebral β‐amyloid ligand) retention in those with and without parenchymal hemorrhage (PH) and normal controls. Neocortical PiB retention was higher among patients with PH compared with patients without PH and normal controls, suggesting underlying CAA as a predisposing factor for rt‐PA–related hemorrhage. This finding may provide an impetus for the development of a more practical rapid pretreatment screening technique. Ann Neurol 2010

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.

Penumbral mismatch is underestimated using standard volumetric methods and this is exacerbated with time.

Background and aim: The mismatch between perfusion weighted images (PWI) and diffusion weighted images (DWI) using MR is increasingly being applied in patient selection for therapeutic trials. Two approaches to the calculation of the mismatch volume exist—the commonly used volumetric and the more precise co-registration method, the latter of which considers lesion topography. That there are differences in the mismatch volume analysed by each method and that these are time dependent was hypothesised. Methods: Patients within 48 h of ischaemic stroke onset had baseline MR PWI/DWI mismatch and T2 outcome volumes at 3 months. Volumetric mismatch volume was defined as PWI minus DWI lesion. Co-registration mismatch volume was defined as the PWI defect lesion not overlapped by the co-registered DWI lesion. Results: 72 patients of median age 74.0 years were studied. Median baseline MR was at 5.9 h (IQR 3.0, 20.4 h) after stroke onset. Consistent underestimation of the mismatch volume occurred using the volumetric method (volumetric median 9.3 ml, IQR 0, 63 ml; co-registration median 20.1 ml, IQR 3.2, 69.8 ml; p<0.0001). This difference increased with time from stroke onset (p = 0.006). Conclusions: Volumetric analysis consistently underestimates the PWI/DWI mismatch volume compared with the more precise co-registration method. This effect increases with time.

Validating a Local Arterial Input Function Method for Improved Perfusion Quantification in Stroke

In bolus-tracking perfusion magnetic resonance imaging (MRI), temporal dispersion of the contrast bolus due to stenosis or collateral supply presents a significant problem for accurate perfusion quantification in stroke. One means to reduce the associated perfusion errors is to deconvolve the bolus concentration time-course data with local Arterial Input Functions (AIFs) measured close to the capillary bed and downstream of the arterial abnormalities causing dispersion. Because the MRI voxel resolution precludes direct local AIF measurements, they must be extrapolated from the surrounding data. To date, there have been no published studies directly validating these local AIFs. We assess the effectiveness of local AIFs in reducing dispersion-induced perfusion error by measuring the residual dispersion remaining in the local AIF deconvolved perfusion maps. Two approaches to locating the local AIF voxels are assessed and compared with a global AIF deconvolution across 19 bolus-tracking data sets from patients with stroke. The local AIF methods reduced dispersion in the majority of data sets, suggesting more accurate perfusion quantification. Importantly, the validation inherently identifies potential areas for perfusion underestimation. This is valuable information for the identification of at-risk tissue and management of stroke patients.