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Current guidelines on thrombolysis post stroke with recombinant tissue plasminogen activator (rt-PA) exclude its use where time of onset is unknown, thus denying some patients potentially beneficial treatment. Contrast enhanced perfusion computed tomography (pCT) imaging can be used together with plain CT and information on clinical deficits to decide whether or not thrombolysis should be initiated even though the exact time of stroke onset is unknown. Based on the results of pCT and CT, rt-PA was administered to two patients with unknown time of stroke onset; one of the patients also underwent suction thrombectomy. Results in both cases were excellent. [ABSTRACT FROM AUTHOR]

We describe three unrelated patients presenting with a spinal cord syndrome and neuroimaging features consistent with multiple sclerosis (MS). All harbored a pathogenic OPA1 mutation. Although the neurological phenotype resembled neuromyelitis optica (NMO), anti-aquaporin 4 antibodies were not detected and the disorder followed a slow progressive course. The coincidental occurrence of OPA1 mutations and an MS-like disorder is likely to have modulated the phenotypic manifestations of both disorders, but unlike the previously reported association of Leber hereditary optic neuropathy and MS (Harding disease), the optic neuropathy in patients with OPA1 mutations and an MS-like disorder can be mild with a good visual prognosis.

Depicting the salvageable tissue is increasingly used in the clinical setting following stroke. As absolute cerebral blood flow (CBF) is difficult to measure using perfusion magnetic resonance or computed tomography and has limitations as a penumbral marker, time-based variables, particularly the mean transit time (MTT), are routinely used as surrogates. However, a direct validation of MTT as a predictor of the penumbra threshold using gold-standard positron emission tomography (PET) is lacking. Using (15)O-PET data sets obtained from two independent acute stroke samples (N=7 and N=30, respectively), we derived areas under the curve (AUCs), optimal thresholds (OTs), and 90%-specificity thresholds (90%-Ts) from receiver operating characteristic curves for absolute MTT, MTT delay, and MTT ratio to predict three penumbra thresholds ('classic': CBF <20  mL/100  g per min; 'normalized': CBF ratio <0.5; and 'stringent': both CBF <20  mL/100  g per min and oxygen extraction fraction >0.55). In sample 1, AUCs ranged from 0.79 to 0.92, indicating good validity; OTs ranged from 7.8 to 8.3  seconds, 2.8 to 4.7  seconds, and 151% to 267% for absolute MTT, MTT delay, and MTT ratio, respectively, while as expected, 90%-Ts were longer. There was no significant difference between sample 1 and sample 2 for any of the above measurements, save for a single MTT parameter with a single penumbra threshold. These consistent findings from gold-standard PET obtained in two independent cohorts document that MTT is a very good surrogate to CBF for depicting the penumbra threshold.

Background: Mapping high oxygen extraction fraction (OEF) in acute stroke is of considerable interest to depict the at-risk tissue. Being sensitive to deoxyhemoglobin, T2*-weighted MRI has been suggested as a potential marker of high OEF., Methods: We compared T2*-weighted images from pre-contrast arrival perfusion scans against quantitative positron emission tomography in 5 patients studied 7-21 h after onset of carotid territory stroke. OEF and T2* signal were obtained in the voxels with significantly high OEF., Results: All patients showed increased OEF. No significant relationship between OEF and T2*-weighted signal was found either within or between subjects., Conclusion: We found no indication that T2*-weighted MRI in the way implemented in this investigation was sensitive to high OEF in acute stroke., (Copyright (c) 2009 S. Karger AG, Basel.)

Selective neuronal loss (SNL) in the rescued penumbra could account for suboptimal clinical recovery despite effective early reperfusion. Previous studies of SNL used single-photon emission tomography (SPECT), did not account for potential volume loss secondary to collapse of the infarct cavity, and failed to show a relationship with initial hypoperfusion. Here, we obtained acute-stage computerized tomography (CT) perfusion and follow-up quantitative (11)C-flumazenil (FMZ)-PET to map SNL in the non-infarcted tissue and assess its relationship with acute-stage hypoperfusion. We prospectively recruited seven patients with evidence of (i) acute (<6 h) extensive middle cerebral artery territory ischaemia based on clinical deficit (National Institutes of Health stroke scale, NIHSS score range: 8-23) and CT Perfusion (CTp) findings and (ii) early recanalization (spontaneous or following thrombolysis) based on spectacular clinical recovery (DeltaNIHSS > or =6 at 24 h), good clinical outcome (NIHSS < or =5) and small final infarct (6/7 subcortical) on late-stage MRI. Ten age-matched controls were also studied. FMZ image analysis took into account potential post-stroke volume loss. Across patients, clusters of significantly reduced FMZ binding were more prevalent and extensive in the non-infarcted middle cerebral artery cortical areas than in the non-affected hemisphere (P = 0.028, Wilcoxon sign rank test). Voxel-based between-group comparisons revealed several large clusters of significantly reduced FMZ binding in the affected peri-insular, superior temporal and prefrontal cortices (FDR P < 0.05), as compared with no cluster on the unaffected side. Finally, comparing CTp and PET data revealed a significant negative correlation between FMZ binding and initial hypoperfusion. Applying correction for volume loss did not substantially alter the significance of these results. Although based on a small patient sample sometimes studied late after the index stroke, and as such preliminary, our results establish the presence and distribution of FMZ binding loss in ultimately non-infarcted brain areas after stroke. In addition, the data suggest that this binding loss is proportional to initial hypoperfusion, in keeping with the hypothesis that the rescued penumbra is affected by SNL. Although its clinical counterparts remain uncertain, it is tempting to speculate that peri-infarct SNL could represent a new therapeutic target.

Background: To investigate what the hyperintense lesion in diffusion-weighted imaging (DWI) of acute ischaemic stroke represents metabolically, we prospectively imaged acute carotid-territory stroke patients with DWI along with fully quantitative positron emission tomography (PET), which gives physiological maps of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2) and the oxygen extraction fraction (OEF)., Method: Of 10 patients who consented, 5 (3 males, 2 females, 53-84 years, NIHSS 6-16) completed the imaging protocol of back-to-back DWI and PET within 21 (mean 15.7, range 7-21) h of stroke onset. All images were co-registered with the DWI lesion forming a region of interest (ROI) that was transferred to the PET parametric maps (OEF, CBF, CMRO2). Patterns of blood flow and metabolism were assessed within the DWI ROI., Results: Within the DWI lesions, the following patterns were observed: very low CBF and CMRO2/variable OEF; low CBF/high OEF, and high CBF/low OEF. There was a heterogeneity of patterns between and within DWI lesions. In addition, areas of hyperperfusion (with low OEF) and areas of hypoperfusion (with high OEF) were seen outside the DWI lesions., Conclusion: The DWI lesion does not have a single flow/metabolism counterpart, suggesting that it reflects various stages of the ischaemic process., (Copyright 2005 S. Karger AG, Basel.)

In acute ischemic stroke, the diffusion-weighted imaging (DWI) lesion is widely held to represent the core of irreversible damage and is therefore crucial in selecting patients for thrombolysis. However, recent research suggests it may also represent penumbra. An illustrative patient was imaged 7 hours after stroke onset with back-to-back 3T diffusion tensor imaging and quantitative positron emission tomography, which showed a DWI lesion and misery perfusion, respectively. Using previously validated voxel-based probabilistic CBF, CMRO2, and Oxygen Extraction Fraction (OEF) thresholds, the authors show that the DWI lesion contained not only core but also substantial proportions of penumbra. Also, severe apparent diffusion coefficient reductions were present within the potentially salvageable penumbra as well as in the core. These findings have potential implications regarding treatment decisions.

Background and Purpose: Evidence now exists for a pathogenic role for neutrophils in acute cerebral ischemia. We have studied the patterns and temporal profile of cerebral neutrophil recruitment to areas of acute ischemic stroke (IS) and have attempted to correlate this with neurological status and outcome., Methods: Patients with cortical middle cerebral artery (MCA) IS were recruited within 24 hours of clinical onset. Neutrophil recruitment was studied using indium-111 (111In) troponolate-labeled neutrophils, planar imaging, and single-photon emission computed tomography (SPECT). Volume of brain infarction was calculated from concurrent computed tomography (CT). Hematoxylin and eosin sections were obtained postmortem (n=2). Outcome was measured using Barthel, Rankin, and National Institute of Health Stroke (NIHSS) scales., Results: Fifteen patients were studied. Significant 111In-neutrophil recruitment to ipsilateral hemisphere, as measured by asymmetry index (AI), was demonstrated within 24 hours of onset in 9 patients; this response was heterogenous between patients and on repeated measurement attenuated over time. Histologically, recruitment was confirmed within intravascular, intramural, and intraparenchymal compartments. Interindividual heterogeneity in neutrophil response did not correlate with infarct volume or outcome. In an exploratory analysis, neutrophil accumulation appeared to correlate significantly with infarct expansion (Spearman rho=0.66; P=0.03, n=12)., Conclusions: Neutrophils recruit to areas of ischemic brain within 24 hours of symptom onset. This recruitment attenuates over time and is confirmed histologically. While neutrophil accumulation may be associated with either the magnitude or the rate of infarct growth, these results require confirmation in future studies.

Purpose of Review: Imaging the penumbra is essential, not only to identify patients who might benefit from thrombolysis, but also to further understanding of the ischaemic process, thereby potentially revealing new opportunities for therapeutic intervention. Here we review recent imaging studies of the acute stroke process., Recent Findings: Perfusion-computed tomography and computed tomography angiography enable assessment of the haemodynamic status and site of occlusion, leading to their promising use in guiding thrombolysis. The magnetic resonance concept of the diffusion-perfusion 'mismatch' being representative of penumbra appears to be an oversimplification. The mapping of simple variables such as time-to-peak might not directly reveal true penumbral perfusion levels. Also, lesions seen with diffusion-weighted imaging may be reversible as a result of early reperfusion. This reversal with subsequent normalization may represent selective neuronal damage. Late secondary injury, as indicated by the reappearance of the diffusion-weighted imaging lesion, has recently been documented; the mechanisms are unknown but form potential targets for future therapies. Despite these caveats, diffusion-weighted imaging-perfusion-weighted imaging remains the most useful approach to map the pathophysiology of stroke in the clinical setting. Acute/subacute flumazenil positron emission tomography studies are being used as markers of neuronal integrity to help shed further light on infarction thresholds, and potentially document selective neuronal loss. F-labelled fluoromisonidazole positron emission tomography imaging of brain hypoxia documents the temporal and spatial progression of the penumbra., Summary: The goal of understanding the complex process that is acute ischaemia in stroke, and subsequently the development of therapeutic strategies, continues to be advanced by imaging the penumbra in novel ways.