Prolonged persistence of substantial volumes of potentially viable brain tissue after stroke - A correlative PET-CT study with voxel-based data analysis

Background and Purpose The existence in humans of brain tissue at risk for infarction but potentially viable leg, the penumbra) remains unproven. One retrospective operational definition of such tissue includes its final infarction despite a relatively preserved or even normal cerebral metabolic rate of oxygen (CMRO(2)) in the early hours after stroke onset. Although previous positron emission tomography (PET) studies identified tissue whose CMRO, declined from the acute to the subacute stage, in principle compatible with deteriorating penumbra, they all lacked a coregistered CT scan mapping of final infarct and an objective three-dimensional PET data analysis, while many patients were studied in the subacute (up to 48 hours) phase. We have evaluated whether tissue with CMRO(2) ranging above a threshold for presumably irreversible damage in the first 18 hours of middle cerebral artery territory stroke, but below it in the chronic stage, could be retrospectively identified within the final infarct volume. Methods Our data bank comprises 30 consecutive patients with first-ever middle cerebral artery territory stroke prospectively studied with PET within the first 18 hours after clinical onset; the O-15 equilibrium method was used to measure cerebral blood flow and CMRO(2). All survivors with the following criteria were eligible for the present study: (1) technically adequate chronic-stage PET performed in the same stereotaxic conditions, (2) coregistered CT scan also performed in the chronic stage, and (3) an infarct of sufficient dimension (>16 mm diameter) on late CT. Corresponding er scan cuts and PET slices were exactly realigned, and the outlines of CT hypodensities were superimposed on the corresponding CMRO(2) matrix. Infarcted voxels with CMRO: values less than or greater than 1.40 mL/100 mt per minute (ie, the generally accepted threshold for irreversible damage) were automatically identified and projected on matrices of all other PET parameters and for both PET studies. Results Eight patients (mean age, 78 years) were eligible for the present study. The acute-stage PET study was performed 7 to 17 hours after stroke onset and the chronic-stage PET 13 to 41 days later. Within the final infarct, mean CMRO(2) fell significantly from the acute- to the chronic-stage PET study (P<.001). Eventually infarcted voxels with acute-stage CMRO(2) values above the threshold were found in each of these eight patients; they were most often situated near the infarct borders and constituted 10% to 52% (mean, 32%) of the final infarct volume. The acute-stage CMRO(2) in these voxels ranged up to 4.13 mL/100 mt per minute but fell below 1.40 mL/100 mt per minute in 93% of them at the chronic-stage PET. In 7 of 8 patients the acute-stage mean cerebral blood flow ranged from 10 to 22 mL/100 mt per minute, and the mean oxygen extraction fraction was markedly increased (>0.70) in these voxels, consistent with a penumbral state. Conclusions In a strictly homogeneous sample of prospectively studied patients, we have identified, up to 17 hours after stroke onset, substantial volumes of tissue with CMRO(2) well above the assumed threshold for viability that nevertheless spontaneously evolved toward necrosis. This tissue exhibited penumbral ranges of both cerebral blood flow and oxygen extraction fraction and thus could represent the part of penumbra that might be saved with appropriate therapy.