Relationships between selective neuronal loss and microglial activation after ischaemic stroke in man.

Modern ischaemic stroke management involves intravenous thrombolysis followed by mechanical thrombectomy, which allows markedly higher rates of recanalization and penumbral salvage than thrombolysis alone. However, <50% of treated patients eventually enjoy independent life. It is therefore important to identify complementary therapeutic targets. In rodent models, the salvaged penumbra is consistently affected by selective neuronal loss, which may hinder recovery by interfering with plastic processes, as well as by microglial activation, which may exacerbate neuronal death. However, whether the salvaged penumbra in man is similarly affected is still unclear. Here we determined whether these two processes affect the non-infarcted penumbra in man and, if so, whether they are inter-related. We prospectively recruited patients with (i) acute middle-cerebral artery stroke; (ii) penumbra present on CT perfusion obtained <4.5 h of stroke onset; and (iii) early neurological recovery as a marker of penumbral salvage. PET with 11C-flumazenil and 11C-PK11195, as well as MRI to map the final infarct, were obtained at predefined follow-up times. The presence of selective neuronal loss and microglial activation was determined voxel-wise within the MRI normal-appearing ipsilateral non-infarcted zone and surviving penumbra masks, and their inter-relationship was assessed both across and within patients. Dilated infarct contours were consistently excluded to control for partial volume effects. Across the 16 recruited patients, there was reduced 11C-flumazenil and increased 11C-PK11195 binding in the whole ipsilateral non-infarcted zone (P = 0.04 and 0.02, respectively). Within the non-infarcted penumbra, 11C-flumazenil was also reduced (P = 0.001), but without clear increase in 11C-PK11195 (P = 0.18). There was no significant correlation between 11C-flumazenil and 11C-PK11195 in either compartment. This mechanistic study provides direct evidence for the presence of both neuronal loss and microglial activation in the ipsilateral non-infarcted zone. Further, we demonstrate the presence of neuronal loss affecting the surviving penumbra, with no or only mild microglial activation, and no significant relationship between these two processes. Thus, microglial activation may not contribute to penumbral neuronal loss in man, and its presence in the ipsilateral hemisphere may merely reflect secondary remote degeneration. Selective neuronal loss in the surviving penumbra may represent a novel therapeutic target as an adjunct to penumbral salvage to further improve functional outcome. However, microglial activation may not stand as the primary therapeutic approach. Protecting the penumbra by acutely improving perfusion and oxygenation in conjunction with thrombectomy for example, may be a better approach. 11C-flumazenil PET would be useful to monitor the effects of such therapies.

Biased visualization of hypoperfused tissue by computed tomography due to short imaging duration: improved classification by image down-sampling and vascular models.

OBJECTIVES: Lesion detection in acute stroke by computed-tomography perfusion (CTP) can be affected by incomplete bolus coverage in veins and hypoperfused tissue, so-called bolus truncation (BT), and low contrast-to-noise ratio (CNR). We examined the BT-frequency and hypothesized that image down-sampling and a vascular model (VM) for perfusion calculation would improve normo- and hypoperfused tissue classification. METHODS: CTP datasets from 40 acute stroke patients were retrospectively analysed for BT. In 16 patients with hypoperfused tissue but no BT, repeated 2-by-2 image down-sampling and uniform filtering was performed, comparing CNR to perfusion-MRI levels and tissue classification to that of unprocessed data. By simulating reduced scan duration, the minimum scan-duration at which estimated lesion volumes came within 10% of their true volume was compared for VM and state-of-the-art algorithms. RESULTS: BT in veins and hypoperfused tissue was observed in 9/40 (22.5%) and 17/40 patients (42.5%), respectively. Down-sampling to 128 × 128 resolution yielded CNR comparable to MR data and improved tissue classification (p = 0.0069). VM reduced minimum scan duration, providing reliable maps of cerebral blood flow and mean transit time: 5 s (p = 0.03) and 7 s (p < 0.0001), respectively). CONCLUSIONS: BT is not uncommon in stroke CTP with 40-s scan duration. Applying image down-sampling and VM improve tissue classification. KEY POINTS: • Too-short imaging duration is common in clinical acute stroke CTP imaging. • The consequence is impaired identification of hypoperfused tissue in acute stroke patients. • The vascular model is less sensitive than current algorithms to imaging duration. • Noise reduction by image down-sampling improves identification of hypoperfused tissue by CTP.

Influence of stroke infarct location on functional outcome measured by the modified rankin scale.

BACKGROUND AND PURPOSE: In the early days after ischemic stroke, information on structural brain damage from MRI supports prognosis of functional outcome. It is rated widely by the modified Rankin Scale that correlates only moderately with lesion volume. We therefore aimed to elucidate the influence of lesion location from early MRI (days 2-3) on functional outcome after 1 month using voxel-based lesion symptom mapping. METHODS: We analyzed clinical and MRI data of patients from a prospective European multicenter stroke imaging study (I-KNOW). Lesions were delineated on fluid-attenuated inversion recovery images on days 2 to 3 after stroke onset. We generated statistic maps of lesion contribution related to clinical outcome (modified Rankin Scale) after 1 month using voxel-based lesion symptom mapping. RESULTS: Lesion maps of 101 patients with middle cerebral artery infarctions were included for analysis (right-sided stroke, 47%). Mean age was 67 years, median admission National Institutes of Health Stroke Scale was 11. Mean infarct volumes were comparable between both sides (left, 37.5 mL; right, 43.7 mL). Voxel-based lesion symptom mapping revealed areas with high influence on higher modified Rankin Scale in regions involving the corona radiata, internal capsule, and insula. In addition, asymmetrically distributed impact patterns were found involving the right inferior temporal gyrus and left superior temporal gyrus. CONCLUSIONS: In this group of patients with stroke, characteristic lesion patterns in areas of motor control and areas involved in lateralized brain functions on early MRI were found to influence functional outcome. Our data provide a novel map of the impact of lesion localization on functional stroke outcome as measured by the modified Rankin Scale.

Diffusion and perfusion correlates of the 18F-MISO PET lesion in acute stroke: pilot study.

PURPOSE: Mapping the ischaemic penumbra in acute stroke is of considerable clinical interest. For this purpose, mapping tissue hypoxia with (18)F-misonidazole (FMISO) PET is attractive, and is straightforward compared to (15)O PET. Given the current emphasis on penumbra imaging using diffusion/perfusion MR or CT perfusion, investigating the relationships between FMISO uptake and abnormalities with these modalities is important. METHODS: According to a prospective design, three patients (age 54-81 years; admission NIH stroke scale scores 16-22) with an anterior circulation stroke and extensive penumbra on CT- or MR-based perfusion imaging successfully completed FMISO PET, diffusion-weighted imaging and MR angiography 6-26 h after stroke onset, and follow-up FLAIR to map the final infarction. All had persistent proximal occlusion and a poor outcome despite thrombolysis. Significant FMISO trapping was defined voxel-wise relative to ten age-matched controls and mapped onto coregistered maps of the penumbra and irreversibly damaged ischaemic core. RESULTS: FMISO trapping was present in all patients (volume range 18-119 ml) and overlapped mainly with the penumbra but also with the core in each patient. There was a significant (p ≤ 0.001) correlation in the expected direction between FMISO uptake and perfusion, with a sharp FMISO uptake bend around the expected penumbra threshold. CONCLUSION: FMISO uptake had the expected overlap with the penumbra and relationship with local perfusion. However, consistent with recent animal data, our study suggests FMISO trapping may not be specific to the penumbra. If confirmed in larger samples, this preliminary finding would have potential implications for the clinical application of FMISO PET in acute ischaemic stroke.

Is neural activation within the rescued penumbra impeded by selective neuronal loss?

After stroke, penumbral salvage determines clinical recovery. However, the rescued penumbra may be affected by selective neuronal loss, as documented both histopathologically in animals and using the validated in vivo positron emission tomography marker (11)C-flumazenil in humans. However, whether the non-infarcted penumbra is capable of neuronal activation, and how selective neuronal loss may interfere, is unknown. Here we prospectively mapped the topographical relationships between functional magnetic resonance imaging responses and non-infarcted penumbra, and tested the hypothesis that the former do take place in the latter, but only in its subsets spared selective neuronal loss. Seven patients (mean age 74 years; three thrombolysed) with first-ever acute anterior circulation stroke, presence of penumbra on computed tomography perfusion performed within 6 h of onset, and substantial deficit on admission but good outcome at 1-3 months (National Institute of Health Stroke Score range 6-13 and 0-1, respectively, P = 0.001), were studied. At follow-up, patients underwent structural magnetic resonance imaging to map the infarct, functional magnetic resonance imaging (three tasks selected to probe the right or left hemisphere), and (11)C-flumazenil positron emission tomography generating binding potential maps. Patients with significant carotid or middle-cerebral artery disease or impaired vasoreactivity were excluded. Following image coregistration, the non-infarcted penumbra comprised all acutely ischaemic voxels (identified on acute computed tomography perfusion using previously validated thresholds) not part of the final infarct. To test our hypotheses, the overlap between functional magnetic resonance imaging activation clusters and non-infarcted penumbra was mapped, and binding potential values then computed both within and outside this overlap. In addition, the overlap between functional magnetic resonance imaging activation clusters and areas of significantly reduced binding potential (determined using Statistical Parametric Mapping against 16 age-matched control subjects) was assessed in each patient. An overlap between non-infarcted penumbra and functional magnetic resonance imaging clusters was present in seven of seven patients, substantial in four. Binding potential was significantly reduced in the whole non-infarcted penumbra (P < 0.01) but not within the functional magnetic resonance imaging overlap. Clusters with significantly reduced binding potential showed virtually no overlap with functional magnetic resonance imaging activation compared with 12 age-matched controls (P = 0.04).The results from this proof of principle study suggest that 1-3 months after stroke the non-infarcted penumbra is capable of neuronal activation, consistent with its established role in recovery of neurological functions. However, although the non-infarcted penumbra as a whole was affected by selective neuronal loss, activations tended to occur within portions spared selective neuronal loss, suggesting the latter impedes neuronal activation. Although its clinical correlates are still elusive, selective neuronal loss may represent a novel therapeutic target in the aftermath of ischaemic stroke.

Infarction of 'non-core-non-penumbral' tissue after stroke: multivariate modelling of clinical impact.

There is considerable intersubject variability in early neurological course after anterior circulation stroke, yet the pathophysiology underlying this variability is not fully understood. Here, we hypothesize that, although not predicted by current pathophysiological models, infarction of 'non-core-non-penumbral' (i.e. clinically silent) brain tissue may nevertheless occur, and negatively influence clinical course over and above the established positive impact of penumbral salvage. In order to test this hypothesis, non-core-non-penumbral tissue was identified in two independent prospectively recruited cohorts, using computed tomography perfusion, and magnetic resonance perfusion- and diffusion-weighted imaging, respectively. Follow-up structural magnetic resonance imaging was obtained about 1 month later in all patients to map the final infarct. The volumes of both the acutely silent but eventually infarcted tissue, and the eventually non-infarcted penumbra, were determined by performing voxel-wise analysis of the acute and follow-up image sets, using previously validated perfusion thresholds. Early neurological course was expressed as change in National Institutes of Health Stroke Scale scores between the acute and 1-month assessments, relative to the acute score. The relationship between the acutely silent but eventually infarcted tissue volume and early neurological course was tested using a multivariate regression model that included the volume of non-infarcted penumbra. Thirty-four and 58 patients were recruited in the computed tomography perfusion and magnetic resonance perfusion cohorts, respectively (mean onset-to-imaging time: 136 and 156 min; 27 and 42 patients received intravenous thrombolysis, respectively). Infarction of acutely silent tissue was identified in most patients in both cohorts. Although its volume (median 0.2 and 2 ml, respectively) was much smaller than that of salvaged penumbra (59.3 and 93 ml, respectively), it was substantial in ∼10% of patients. As expected, salvaged penumbra strongly positively influenced early neurological course. Even after correcting for the latter effect in the multivariate model, infarction of acutely silent tissue independently negatively influenced early neurological course in both cohorts (P=0.018 and 0.031, respectively). This is the first systematic study to document infarction of acutely silent tissue after anterior circulation stroke, and to show that it affects a sizeable fraction of patients and has the predicted negative impact on clinical course. These findings were replicated in two independent cohorts, regardless of the perfusion imaging modality used. Preventing infarction of the tissue not initially at risk should have direct clinical benefit.

Predicting infarction within the diffusion-weighted imaging lesion: does the mean transit time have added value?

BACKGROUND AND PURPOSE: There is ample evidence that in anterior circulation stroke, the diffusion-weighted imaging (DWI) lesion may escape infarction and thus is not a reliable infarct predictor. In this study, we assessed the predictive value of the mean transit time (MTT) for final infarction within the DWI lesion, first in patients scanned back-to-back with 15O-positron emission tomography and MR (DWI and perfusion-weighted imaging; "Cambridge sample") within 7 to 21 hours of clinical onset, then in a large sample of patients with anterior circulation stroke receiving DWI and perfusion-weighted imaging within 12 hours (85% within 6 hours; "I-KNOW sample"). METHODS: Both samples underwent structural MRI at approximately 1 month to map final infarcts. For both imaging modalities, MTT was calculated as cerebral blood volume/cerebral blood flow. After image coregistration and matrix resampling, the MTT values between voxels of interest that later infarcted or not were compared separately within and outside DWI lesions (DWI+ and DWI-, respectively) both within and across patients. In the I-KNOW sample, receiver operating characteristic curves were calculated for these voxel of interest populations and areas under the curve and optimal thresholds calculated. RESULTS: In the Cambridge data set (n=4), there was good concordance between predictive values of MTT (positron emission tomography) and MTT (perfusion-weighted imaging) for both DWI+ and DWI- voxels of interest indicating adequate reliability of MTT (perfusion-weighted imaging) for this purpose. In the I-KNOW data set (N=42), the MTT significantly added to the DWI lesion to predict infarction in both DWI- and DWI+ voxels of interest with areas under the curve approximately 0.78 and 0.64 (both P<0.001) and optimal thresholds approximately 8 seconds and 11 seconds, respectively. CONCLUSIONS: Despite the relatively small samples, this study suggests that adding MTT (perfusion-weighted imaging) may improve infarct prediction not only as already known outside, but also within, DWI lesions.

Hemodynamic factors and perfusion abnormalities in early neurological deterioration.

BACKGROUND AND PURPOSE: Early neurological deterioration (END) is a relatively common unfavorable course after anterior circulation ischemic stroke that can lead to worse clinical outcome. None of the END predictors identified so far is sufficiently reliable to be used in clinical practice and the mechanisms underlying END are not fully understood. We review the evidence from the literature for a role of hemodynamic and perfusion abnormalities, more specifically infarction of the oligemia, in END: SUMMARY OF REVIEW: After an overview of the neuroimaging, including perfusion imaging, predictors of END, we review the putative mechanisms of END with a special focus on hemodynamic factors. The evidence relating perfusion abnormalities to END is addressed and potential hemodynamic mechanisms are suggested. CONCLUSIONS: Hemodynamic factors and perfusion abnormalities are likely to play a critical role in END: Infarction of the oligemic tissue surrounding the penumbra could be the putative culprit leading to END as a result of perfusion, but also physiological and biochemical abnormalities. Further studies addressing the role of the oligemia in END and developing measures to protect its progression to infarction are now needed.

Total mismatch: negative diffusion-weighted imaging but extensive perfusion defect in acute stroke.

BACKGROUND AND PURPOSE: The perfusion-weighted imaging (PWI)/diffusion-weighted imaging (DWI) mismatch may identify patients who benefit from thrombolysis. However, some patients exhibit a "total mismatch," ie, negative DWI but extensive PWI defect. We aimed to assess clinical and MRI data of these patients. METHODS: From June 2007 to December 2008, patients with anterior circulation ischemic stroke were evaluated for a "total mismatch" profile. MRI was performed at admission and at day 1. The score was assessed at baseline and the modified Rankin scale score was assessed at day 30. RESULTS: Among 52 patients, 3 showed a total mismatch with arterial occlusion confirmed on magnetic resonance angiography. All had fluctuating symptoms (National Institutes of Health Stroke Scale scores, 0 to 10) and received intravenous tissue plasminogen activator. Day 1 DWI disclosed minimal changes in all patients. Outcome was favorable in all patients (day 30 modified Rankin scale, 0-1). CONCLUSION: PWI may be helpful for treatment decisions in patients without DWI damage and fluctuating clinical course.

Stroke management.

INTRODUCTION: Stroke is the third most common cause of death in most developed countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of decompressive hemicraniectomy in acute ischaemic stroke? What are the effects of surgical evacuation for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), decompressive hemicraniectomy, neuroprotective agents (calcium channel blockers, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists), specialised stroke care, systemic anticoagulation (heparinoids, specific thrombin inhibitors, low molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.

Stroke management.

INTRODUCTION: Stroke is the third most common cause of death in most resource-rich countries. It is a worldwide problem; about 4.5 million people die from stroke each year. Stroke can occur at any age, but half of all strokes occur in people aged over 70 years. About 80% of all acute strokes are ischaemic, usually resulting from thrombotic or embolic occlusion of a cerebral artery. The remainder are caused either by intracerebral or subarachnoid haemorrhage. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of specialised care in people with acute stroke? What are the effects of medical treatment in people with acute ischaemic stroke? What are the effects of surgical treatment for intracerebral haematomas? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 42 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: acute reduction in blood pressure, aspirin, evacuation (early surgical evacuation, or conservative treatment), neuroprotective agents (calcium channel antagonists, citicoline, gamma-aminobutyric acid agonists, glycine antagonists, lubeluzole, magnesium, N-methyl-D-aspartate antagonists, tirilazad), specialised stroke care, systemic anticoagulation (heparinoids, low or specific thrombin inhibitors, molecular weight heparin, oral anticoagulants, unfractionated heparin), and thrombolysis.