Jorge A. Zavala

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.

Neuroprotection and thrombolysis: combination therapy in acute ischaemic stroke

The administration of oral aspirin within 48 h and tissue plasminogen activator within 3 h of ischaemic stroke onset remain the only treatments that have been shown to have clinical benefit. There has been much excitement about neuroprotection over the last two decades, as it may minimise the harmful effects of ischaemic neuronal damage. Although each step along the ischaemic cascade offers a potential target for therapeutic intervention, and neuroprotection has shown benefit in animal studies, this has been difficult to translate to humans. Some hope has been offered by the recent finding that the free radical scavenger NXY-059 may improve outcomes in patients presenting within 6 h of onset of ischaemic stroke. There is logic to the idea that neuroprotection may be most effective when reperfusion has occurred with thrombolysis, as the neuroprotectant will have greater access to ischaemic tissue and the opportunity is presented to minimise free radical-mediated reperfusion injury. Numerous studies in animal models support this view, but the concept has not, as yet, been rigorously tested in humans.

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

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 (pu200a=u200a0.006). Conclusions: Volumetric analysis consistently underestimates the PWI/DWI mismatch volume compared with the more precise co-registration method. This effect increases with time.

Aortic arch atheroma

Severe atheroma of the aortic arch has now been established as an important risk factor and mechanism for stroke and peripheral embolism. The odds ratio for stroke or peripheral embolism in patients with severe arch atheroma is greater than four, and for mobile atheroma it is greater than 12. The prevalence of severe arch atheroma among patients presenting with acute ischaemic stroke, at over 20%, is in the same order as that of atrial fibrillation and carotid atherosclerosis. In patients with ischaemic stroke for which no cause has been identified, it is reasonable to determine as to whether they have severe arch atheroma by performing a transoesophageal echocardiogram. Recurrent stroke is common in patients with aortic arch atheroma that are thicker than 4 mm or with mobile components, particularly in the elderly, cigarette smokers, and those with hypertension or diabetes. Patients found to have severe atheroma are at high risk of recurrent events (14·2% per year) and may, therefore, need an aggressive secondary prevention strategy. Currently, there is uncertainty as to what this should be, but either combination antiplatelet therapy (aspirin plus clopidogrel) or anticoagulation with warfarin (target INR 2·0–3·0) are commonly used. Which of these is most effective will be evident after the completion of the aortic arch related cerebral hazard trial.

Salvage of the PWI/DWI mismatch up to 48 h from stroke onset leads to favorable clinical outcome

Background and Purpose In acute ischemic stroke perfusion/diffusion-weighted image, mismatch using magnetic resonance imaging approximates the ischemic penumbra. For early time windows, mismatch salvage improves clinical outcomes, but uncertainty exists at later time epochs. We hypothesized that (a) mismatch may exist up to 48 h; (b) the proportion of mismatch salvage is time independent; and (c) when salvaged, it improves clinical outcomes. Methods Magnetic resonance imaging was performed within 48 h of ischemic stroke. Perfusion-weighted image was defined by relative Tmax two-second delay. Perfusion/diffusion-weighted image mismatch was the perfusion-weighted image not overlapped by the diffusion-weighted image when coregistered. Infarct volume and disability (modified Rankin Score) were assessed at three-months. Mismatch salvage was the region not overlapped by final infarction. Favorable outcome was defined as modified Rankin Score 0–1. Results Sixty-six patients were studied [mean age 69·9 years (standard deviation 13·1), initial median National Institute of Health Stroke Scale 9·0 (interquartile range 6·0, 18·3)]. There was no relationship between time of stroke onset and the proportion of mismatch salvaged (P = 0·73). Age (adjusted odds ratio = 0·92, 95% confidence interval 0·86–0·98, P = 0·01), initial National Institute of Health Stroke Scale (adjusted odds ratio = 0·80, 95% confidence interval 0·70–0·92, P < 0·01), mismatch volume (adjusted odds ratio = 0·98, 95% confidence interval 0·968–0·1, P = 0·05), and percentage of mismatch salvage (adjusted odds ratio = 1·04, 95% confidence interval 0·99–1·07, P = 0·05) were independently associated with favorable outcome. Conclusion Using coregistered perfusion/diffusion-weighted image criteria, mismatch persists up to 48 h post stroke. For the whole group, the proportion of mismatch salvage remains independent of time and, although the effect is small, its salvage is independently associated with improved clinical outcomes at three-months. Larger sample sizes are needed to determine the time limit for mismatch salvage.

Subacute Ischemic Stroke Is Associated With Focal 11C PiB Positron Emission Tomography Retention But Not With Global Neocortical Aβ Deposition

Background and Purpose— Conflicting evidence exists as to whether focal cerebral ischemia contributes to cerebral amyloid deposition. We aimed to look at A&bgr; deposits, detected by N-methyl-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (PiB) positron emission tomography, in patients with recent ischemic stroke. Specifically, we hypothesized that patients with recent ischemic stroke have higher local and neocortical PiB positron emission tomography retention and that this may be associated with major vascular risk factors. Methods— Ischemic stroke patients were studied using PiB positron emission tomography within 30 days and compared to age-matched controls. Distribution volume ratio maps were created using Logan graphical analysis with the cerebellar cortex as a reference. Results— Among the 21 ischemic stroke patients (median age, 76 years; interquartile range, 68–77), the ipsilateral peri-infarct region PiB retention was higher compared to the contralateral mirror region, with a PiB distribution volume ratio difference of 0.29 (95% CI, 0.2–0.44; P=0.001) at median 10 (interquartile range, 7–14) days after stroke. Two patients also had higher PiB retention within the infarct compared to the contralateral side. There was no difference in the neocortical PiB retention elsewhere in the brain among ischemic stroke patients compared with 22 age-matched normal controls (P=0.22). Among the risk factors in the ischemic stroke patients, diabetes was associated with a higher neocortical PiB retention (Spearman Rho=0.48; 95% CI, 0.28–0.72). Conclusions— PiB retention was higher in the peri-infarct region among patients with recent ischemic stroke. This did not translate into a higher global neocortical PiB retention except possibly in patients with diabetes. The cause of the focal PiB retention is uncertain and requires further investigation.

Fragmentation of the Classical Magnetic Resonance Mismatch “Penumbral” Pattern With Time

Background and Purpose— The classical mismatch pattern in the middle cerebral artery territory stroke on MR is defined by a central diffusion-weighted image core with surrounding mismatch tissue. Because of variable rates of tissue salvage, we hypothesized that this pattern may fragment over time and may be influenced by vessel patency, mismatch volume, and infarct core location. Methods— Patients were recruited with MR studies performed within 48 hours of ischemic stroke. Mismatch patterns based on diffusion-weighted/perfusion-weighted images were categorized as classical (majority of the diffusion-weighted image within the perfusion-weighted image lesion) or nonclassical (fragmented) patterns. The proportion of patterns was assessed with reference to time, vessel patency, mismatch volume, and infarct core location. Results— Sixty-seven patients (33 classical [49.3%] and 34 nonclassical patterns [50.7%]) were studied within 48 hours (median age, 74.0 years). Compared to the nonclassical pattern, the classical pattern had a shorter time to MR (3.4 hours vs 10.4 hours; P=0.004) and a larger mismatch volume (62.0 mL vs 3.5 mL; P<0.0001). The positive predictors for the classical pattern were earlier time, vessel occlusion, superficial core location, and larger mismatch volume. Conclusion— The classical mismatch pattern may fragment with time. Over 48 hours the classical pattern is seen earlier after stroke onset, with higher rates of vessel occlusion and larger mismatch volumes.

The Hidden Mismatch: An Explanation for Infarct Growth Without Perfusion-Weighted Imaging/Diffusion-Weighted Imaging Mismatch in Patients With Acute Ischemic Stroke

Background and Purpose— In ischemic stroke, MR perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) mismatch represents tissue at risk for infarction. Infarct growth should only take place in the presence of mismatch, although there have been reports of this occurring. We hypothesized that this observation may be attributable to the presence of undetected “hidden mismatch,” which may become obvious when coregistration techniques are used. Methods— MR PWI/DWI was performed within 48 hours of stroke onset and a final T2-weighted image at ≈3 months. Volumetric-subtraction mismatch volume was defined as PWI minus DWI volume and infarct growth was defined as T2 minus DWI volume. Coregistration mismatch volume was PWI not overlapped by DWI. Mismatch salvage was the proportion of coregistered mismatch tissue that had not progressed to infarction. Results— Thirty-four patients were studied with MR at a median of 4.9 hours (interquartile range, 2.9–21.1 hours). With the volumetric-subtraction technique, 5 patients (14.7%; 95% CI, 0.05%–0.31%) had infarct growth exceeding mismatch volume, 11 patients (32.0%) had no mismatch and, among these, 3 (27.3%) had infarct growth (median volume, 2.2 mL; interquartile range, 1.0–6.5 mL). All patients had mismatch volume identified by coregistration method that was greater than infarct growth volume. The proportion of this volume salvaged was 77.7% (interquartile range, 63.0%–98.9%). Conclusions— The illogical finding of infarct growth volume being greater than the presence of mismatch volume can be explained by the presence of “hidden mismatch,” which may be detected by coregistration methods.