Searching for salvageable brain: the detection of ischemic penumbra using various imaging modalities?

Various imaging modalities are used to identify the ischemic penumbra in patients with acute ischemic stroke. Although single-photon emission computed tomography (CT), perfusion-weighted magnetic resonance imaging (MRI), and perfusion CT are used to evaluate residual cerebral blood flow in the ischemic area, validation of the perfusion threshold for the penumbra has not been established. The ischemic core corresponds generally to areas with early ischemic changes, such as parenchymal hypoattenuation on CT, restricted apparent diffusion coefficient on diffusion-weighted MRI, or very low cerebral blood volume on perfusion CT. A mismatch of these abnormalities is thought to correspond to the ischemic penumbra and has been used in clinical trials. Although new ligands, such as (18)F-fluoromisonidazole, that bind to hypoxic but viable ischemic tissue are currently available, positron emission tomography has yet to be developed as a clinical tool.

Hirano T 《-》

Extension of therapeutic window in ischemic stroke by selective mismatch imaging.

Heiss WD ，Zaro-Weber O 《-》

Perfusion computed tomography thresholds defining ischemic penumbra and infarct core: studies in a rat stroke model.

Perfusion computed tomography is becoming more widely used as a clinical imaging tool to predict potentially salvageable tissue (ischemic penumbra) after ischemic stroke and guide reperfusion therapies. The study aims to determine whether there are important changes in perfusion computed tomography thresholds defining ischemic penumbra and infarct core over time following stroke. Permanent middle cerebral artery occlusion was performed in adult outbred Wistar rats (n = 6) and serial perfusion computed tomography scans were taken every 30 mins for 2 h. To define infarction thresholds at 1 h and 2 h post-stroke, separate groups of rats underwent 1 h (n = 6) and 2 h (n = 6) of middle cerebral artery occlusion followed by reperfusion. Infarct volumes were defined by histology at 24 h. Co-registration with perfusion computed tomography maps (cerebral blood flow, cerebral blood volume, and mean transit time) permitted pixel-based analysis of thresholds defining infarction, using receiver operating characteristic curves. Relative cerebral blood flow was the perfusion computed tomography parameter that most accurately predicted penumbra (area under the curve = 0.698) and also infarct core (area under the curve = 0.750). A relative cerebral blood flow threshold of < 75% of mean contralateral cerebral blood flow most accurately predicted penumbral tissue at 0.5 h (area under the curve = 0.660), 1 h (area under the curve = 0.659), 1.5 h (area under the curve = 0.636), and 2 h (area under the curve = 0.664) after stroke onset. A relative cerebral blood flow threshold of < 55% of mean contralateral most accurately predicted infarct core at 1 h (area under the curve = 0.765) and at 2 h (area under the curve = 0.689) after middle cerebral artery occlusion. The data provide perfusion computed tomography defined relative cerebral blood flow thresholds for infarct core and ischemic penumbra within the first two hours after experimental stroke in rats. These thresholds were shown to be stable to define the volume of infarct core and penumbra within this time window.

McLeod DD ，Parsons MW ，Hood R ，Hiles B ，Allen J ，McCann SK ，Murtha L ，Calford MB ，Levi CR ，Spratt NJ ... -  《-》

Comparison of computed tomography perfusion and magnetic resonance imaging perfusion-diffusion mismatch in ischemic stroke.

Campbell BC ，Christensen S ，Levi CR ，Desmond PM ，Donnan GA ，Davis SM ，Parsons MW ... -  《-》

The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. The Johann Jacob Wepfer award 2011.

The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with the blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed 'penumbra', and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and duration of critically reduced blood flow was established - proving that the lower the flow, the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterized by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarizations, the peri-infarct spreading depression-like depolarizations, inducing activation of ion pumps and liberation of excitatory transmitters, have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood supply. The translation of experimental concept into the basis for efficient treatment of stroke requires non-invasive methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue that can benefit from therapeutic interventions. Positron emission tomography (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. From these variables, clear definitions of irreversible tissue damage and critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool, perfusion/diffusion-weighted (PW/DW) MRI is used, and the 'mismatch' between the PW and the DW abnormalities serve as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET have pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusion thresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking, its use as a surrogate marker of outcome is limited.

Heiss WD 《-》