Brain, Vol. 124, No. 1, 20-29,
January 2001
© 2001 Oxford University Press
Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia
Max-Planck-Institut für neurologische Forschung and Neurologische Universitätsklinik Köln, Köln, Germany
Correspondence to:
Professor W.-D. Heiss, Max-Planck-Institut für neurologische Forschung, Gleueler Strasse 50, 50931 Köln, Germany E-mail: wdh{at}pet.mpin-koeln.mpg.de
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Abstract |
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Active treatment of acute ischaemic stroke can only be successful as long as tissue in the area of ischaemic compromise is still viable. Therefore, the identification of the area of irreversible damage, and its distinction from the penumbral zone, may improve the estimation of the potential efficacy of various therapeutic strategies. Ten patients (seven male, three female, aged 52–75 years) with acute ischaemic stroke, in whom MRI delineated an infarct involving the cortex 3 weeks after the attack, were studied by [11C]flumazenil (FMZ) PET to assess their neuronal integrity, and regional cerebral blood flow (CBF) was measured by H215O PET 2–12 h (median interval 6 h) after onset of symptoms. Cortical volumes of interest (3 mm radius) were placed on co-registered CBF, FMZ and on late MRI scans. Using initial CBF and FMZ binding data from volumes of interest finally located within or outside the cortical infarct, cumulative probability curves were computed to predict eventual infarction or non-infarction. Positive (at least 95% chance of infarct) and negative (at least 95% chance of non-infarct) prediction limits for CBF (4.8 and 14.1 ml/100 g/min, respectively) and for FMZ binding (3.4 and 5.5 times the mean of normal white matter, respectively) were determined to define the penumbral range. Using the lower FMZ binding threshold of 3.4 for irreversible tissue damage and the upper CBF value of 14.1 ml/ 100 g/min for the threshold of critical perfusion at or above which tissue will likely be preserved, various cortical subcompartments were identified: of the final cortical infarct (median size 25.7 cm3) a major portion comprising, on average, 55.1% showed FMZ binding critically decreased, thus predicting necrosis. In 20.5% of the final infarct, on average, CBF was in the penumbral range (<14.1 ml/100 g/min) and FMZ binding was above the critical threshold of irreversible damage. Only 12.9% of the final infarct exhibited neuronal integrity and CBF values above the penumbral range. Therefore, most of the final infarct is irreversibly damaged already at the time of the initial evaluation, when studied several hours after stroke onset. A much smaller portion is still viable but suffers from insufficient blood supply: this tissue may be salvaged by effective reperfusion. Only an even smaller compartment is viable and sufficiently perfused, but eventually becomes necrotic, mainly owing to delayed mechanisms, and may benefit from neuroprotective or other measures targeted at secondary damage. Therefore, early reperfusion is crucial in acute ischaemic stroke.
CBF; flumazenil; ischaemic stroke; outcome prediction; probability thresholds
BZR = benzodiazepine receptor; CMRO2 = cerebral metabolic rate of oxygen; DW-MRI = diffusion-weighted; FMZ = flumazenil; PW-MRi = perfusion-weighted MRI; rCBF = regional cerebral blood flow; rt-PA = recombinant tissue plasminogen activator
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Introduction |
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The definition of irreversibly damaged tissue in the early phase of an ischaemic stroke and its distinction from functionally impaired but morphologically intact, `penumbral' tissue is of utmost importance for the selection of therapeutic interventions. Of course, reperfusion or neuroprotective therapies can only be effective in viable tissue, and especially aggressive treatment aimed at reperfusion, e.g. by thrombolysis, may be harmful if morphological integrity has not been preserved. X-ray computed tomography (CT), the method most widely applied in the early diagnosis of stroke victims (Grotta, 2000
), does not disclose the full extent of irreversible damage during the first hours after stroke onset, even when scrutinized for early signs of infarction (Toni et al., 1995; Grond et al., 1997, 2000; von Kummer et al., 1997; Fiorelli et al., 2000). The same holds true for T2-weighted MRI, which depicts the infarct only at later time points (Bryan et al., 1991; Yuh et al., 1991). The results of diffusion-weighted MRI (DW-MRI), which usually demonstrates irreversible tissue damage, can be misleading for various reasons (Warach et al., 1997): lesions with pathological apparent diffusion coefficients were observed in patients with transient ischaemic attacks (Kidwell et al., 1999) and were reversible with thrombolytic therapy in some instances (Marks et al., 1999; Kidwell et al., 2000). At present, the only reliable method to detect irreversibly damaged tissue is quantitative measurement of blood flow and oxygen consumption by PET, where a threshold for the cerebral metabolic rate of oxygen (CMRO2) predicts necrotic transformation (Baron et al., 1984; Powers et al., 1985; Marchal et al., 1999). This procedure, however, requires sophisticated and expensive equipment and necessitates arterial blood sampling, which is not feasible when invasive reperfusion therapies are intended.
The assessment of viable but functionally compromised, i.e. penumbral tissue, which is amenable to therapy is even more difficult since there is no convincing method to prove morphological integrity in functionally impaired and critically perfused tissue according to the original definition of penumbra (Astrup et al., 1981). The most widely used definition for clinical purposes is the evidence of misery perfusion (Baron et al., 1984), where blood flow is critically decreased but oxygen consumption is preserved at a level sufficient for tissue survival for a limited period of time. Consequently, oxygen extraction is increased in such areas. However, it has been shown repeatedly (Wise et al., 1983; Hakim et al., 1989; Heiss et al., 1992) that most of the tissue suffering from misery perfusion in the acute stage of an ischaemic stroke progresses to infarction in the further course. In a limited number of cases, recovery of small regions within the boundaries of misery perfusion was demonstrated, and only in rare cases did large ischaemic regions completely recover without succumbing to necrosis (Heiss et al., 1993; Furlan et al., 1996; Baron, 1999). Therefore, it might be concluded that in most acutely ischaemic regions exhibiting increased oxygen extraction fraction, this compensatory mechanism is not very efficient and a considerable number of neurons will eventually become necrotic. In such regions, post-acute oxygen uptake is at a low level, sufficient only to support a limited number of neurons and glial cells, but not enough to warrant survival of the network required for clinical recovery.
The definition of the penumbra as the difference in the abnormalities detected by diffusion-weighted (DW) and perfusion-weighted (PW) MRI, being indicative of compromised perfusion without irreversible tissue damage (Baird and Warach, 1998), bears several uncertainties: first, the upper limit of critical perfusion is not clearly defined, since flow still cannot be reliably quantified using PW images in pathological conditions and, therefore, sufficiently supplied, hypoperfused areas outside the penumbra are typically included in the analysis. Secondly, the distinction of the lower threshold of penumbra is inaccurate because of the uncertainties in the identification by DW-MRI of irreversibly damaged tissue.
Therefore, a method is needed that can clearly separate irreversibly damaged from critically hypoperfused but viable tissue early after onset of ischaemic stroke. Since GABA (
-aminobutyric acid) receptors are abundant in the cortex and sensitive to ischaemic damage (Schwartz et al., 1992), specific radioligands to their subunits, the cerebral benzodiazepine receptors, can be used as markers of preserved morphological integrity (Abadie and Baron, 1991; Sette et al., 1993). Previous studies in experimental focal ischaemia (Heiss et al., 1997) as well as in patients with acute ischaemic stroke (Heiss et al., 2000) have demonstrated that irreversibly damaged cortex can be reliably detected in the first hours after onset of symptoms by a sharp decrease in the binding of the 11C-labelled benzodiazepine receptor (BZR) ligand flumazenil (FMZ). It was the purpose of this study to investigate the value of this marker of neuronal integrity for the identification of that portion of the final infarct, which was irreversibly damaged already in the first hours after stroke, and to define the hypoperfused cortical compartment still amenable to appropriate therapy. To this avail, H215O and FMZ-PET studies performed in stroke patients within the first 12 h after the onset of their symptoms were compared with the final infarcts as demonstrated by MRI 3 weeks after the stroke.
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Patients and methods |
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Ten consecutive patients (seven male, three female, aged 52 to 75 years; median age, 64 years) with acute hemispheric stroke were included in this study. In all of them, blood flow and BZR binding was studied with PET, 2–12 h (median 6 h) after symptom onset. All developed an infarct involving the cortex 3 weeks later. The diagnosis was established clinically, based on focal neurological deficits of acute onset that more or less persisted throughout the 3-week study period. Initial assessment included general medical and neurological examinations, ECG, chest radiography, routine blood chemistry and haematology testing and CT scanning. During the following days, neck and transcranial Doppler sonography, EEG and, if necessary, recordings of visual and somatosensory-evoked potentials were performed, and CT scanning was repeated to render a complete picture of the patient's condition. Fully informed consent to the study was obtained from the patients and from their next of kin. The study was approved by the Ethics Committee of the University of Cologne.
The following patients were those excluded from the study, whose state was complicated by other medical conditions including uncontrolled hypertension (systolic pressure >180 mmHg or diastolic pressure >100 mmHg), diabetes mellitus (blood glucose >200 mg/100 ml on admission), severe liver disease, severe congestive heart failure or severe arrhythmias. CT excluded haemorrhagic or non-ischaemic lesions as well as subarachnoid haemorrhage. Comatose patients or those suffering from other neurological disorders including a previous cerebrovascular accident were excluded on clinical grounds, as were patients treated with anticoagulants and those with some known haemorrhagic condition. The PET studies were started immediately after the initial clinical examination (including CT), within 2–12 h of onset of symptoms. Concurrently, systemic rt-PA treatment was initiated in patients 8–10, as described previously (Heiss et al., 2000). The other patients, all of whom had arrived beyond the 3-h time window, received standard medical therapy. Size and location of the final infarcts was determined 3 weeks later on T1-weighted MRI scans obtained on a 1.0-T Magnetom Impact (Siemens Medical Systems) as 64 transaxial, 2.5-mm-thick slices acquired simultaneously using a three-dimensional, fast, low-angle shot sequence.
Cerebral blood flow (CBF) was measured according to the intravenous bolus method (Herscovitch et al., 1983) using 60 mCi (2.2 GBq) H215O. PET studies were performed in a resting state on an ECAT EXACT HR scanner (Siemens/CTI, Knoxville, Tenn., USA) in two- or three-dimensional data acquisition mode providing 47 contiguous 3-mm slices at 5 mm full-width, half-maximum, in-plane reconstructed resolution (Wienhard et al., 1994). Arterial blood activity was measured with a commercial automated blood sampling system (Eriksson et al., 1988). From the multiple brain activity frames accumulated after H215O injection and the time-activity curves of the blood after decay correction, the computer (SUN SPARC, Sun Microsystems Inc., Mountain View, Calif., USA) calculated pixel by pixel absolute values of CBF, using the operational equation of Mintun and colleagues (Mintun et al., 1984). As each patient contributed a different number of data points to the final analysis of pooled data, thus introducing additional variance by unequal subject weighting and individual offset of absolute values, and to facilitate comparison with semiquantitative studies, cortical H215O uptake in the affected hemisphere relative to the contralateral hemispheric mean was also used as an interchangeable measure of blood flow (Löttgen et al., 1998).
Ten minutes after the start of the 15O-studies, 20 mCi (740 MBq) [11C]flumazenil was injected intravenously, and the distribution and accumulation of this tracer was followed for 60 min by serial scanning. BZR density was estimated from the distribution of [11C]flumazenil, 30–60 min after bolus injection (Frey et al., 1991). Since quantification of receptor density was not generally feasible, ratios of cortical FMZ binding in the affected hemisphere relative to contralateral oval centre activity were used in further analyses.
Those early PET findings were compared with the extent of morphological damage on MRI obtained 3 weeks after the stroke. Using an interactive programme (Pietrzyk et al., 1994), all PET images were individually co-registered with the respective MRI volume along the anterior–posterior commissural line. Subsequently, the cerebral hemispheres and the cortical part of the infarct were segmented from the MRI volume by means of an interactive data language (Research Systems Inc., Boulder, Col., USA) and C-based image analysis system operating at a spatial resolution of 1 mm3 (von Stockhausen et al., 1996). The cortical rim was defined by thresholding the FMZ images at 3x white matter activity and mirroring the non-infarcted hemisphere to the side of infarction along a plane in the interhemispheric fissure. Thus, the outer cortical border was defined by the contour from MRI, while the inner border was defined by FMZ (and, in the area of infarction, by the mirrored FMZ) PET. Since FMZ binds preferably to cerebral cortex, only cortical areas were used in the comparative analysis of early PET findings and persistent morphological defects.
To investigate the predictive value of initial changes in flow and FMZ binding on final outcome, cortical areas were categorized as infarcted or normal according to their appearance on late MRI. To avoid large variances inherent in pixel data, contiguous spherical volumes of interest with a radius of 3 mm were fitted into the cortical rim so as to cover the infarct and more than twice the volume of surrounding, non-infarcted cortex. That way, depending on the individual infarct size, each patient contributed 6–95 volumes of interest (median 43), with each case representing ~30% infarct and 70% non-infarcted tissue to permit data pooling. For all values of blood flow and FMZ binding across all patients' volumes of interest, the threshold probability integrals of final infarction or non-infarction were iteratively computed. As illustrated in Fig. 1, the positive prediction curve was obtained by gradually moving the CBF/FMZ test threshold from the lowest to the highest observed values and by calculating the positive prediction rate [a/(a + b)] at each step, i.e. the proportion of infarcted cortical areas of all volumes of interest exhibiting values at or below the respective threshold. Likewise, the negative prediction curve obtained by iteratively computing the negative prediction rate [d/(c + d)] represents the proportion of non-infarcted cortical areas of all volumes of interest at or above a given CBF/FMZ value. a, b, c and d represent the observed frequencies of volumes of interest in four cells. From those curves, the positive and negative 95% prediction limits of blood flow and FMZ binding were obtained as the values on the abscissa at the prediction rate of 0.95. The standard deviation of those limits was computed from the sum of squares of the residuals along the abscissa, i.e. from the horizontal difference between each patient's data points and the corresponding pooled data curve. Cortical tissue subcompartments defined by those CBF and FMZ binding limits and by morphological outcome were analysed voxel by voxel to estimate their relative sizes. The descriptive statistics of variables exhibiting a non-normal distribution are given as median and range.
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Results |
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The patients included in this study suffered from hemispheric ischaemic strokes of different severity, leading to infarcts involving the cortex in the middle cerebral artery territory to a variable degree. Their clinical deficit ranged from mild monoparesis of an arm to severe hemisyndromes. Age, time elapsed from onset of symptoms to PET, carotid artery status, size of cortical infarct, tissue outcome and the volume of cortical tissue initially showing blood flow and FMZ binding values below and above critical thresholds are listed in Table 1
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Early rCBF and morphological outcome
Two to twelve hours after onset of stroke symptoms, median absolute CBF in the hemisphere contralateral to the acutely ischaemic side was decreased to 31.6 (range 26.0–32.6) ml/100 g/min. The distribution of regional cortical blood flow values measured in the affected hemisphere (Fig. 2
) exhibited a distinct positive skew in eventually infarcted volumes of interest, as opposed to the rather symmetric distribution in eventually non-infarcted volumes of interest. There also was considerable overlap of those distributions. The relationship between cortical blood flow and the tissue condition found on late MRI scans can be seen in greater detail from the prediction curves shown in Fig. 3. Using conventional probability levels of 0.95, those prediction curves yielded the weighted mean positive or negative 95% prediction limits of early cortical blood flow. Pertinent summary statistics are listed in Table 2. Those prediction limits mark the wide range of rCBF in cortical tissue of uncertain prognosis: cortex exhibiting flow within that range is <95% likely to turn into infarction or to preserve its morphological integrity. This is the CBF penumbra ranging from 4.8 to 14.1 ml/100 g/min in this study. Due to the relatively steeper slope of the negative prediction curve around the 0.95 margin, the (upper) negative 95% prediction limit may be clinically more useful as the operational threshold of critical flow at or above which tissue will probably not become infarcted.
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Early FMZ binding and morphological outcome
Histograms (Fig. 4
) and prediction curves (Fig. 5) relating early cortical FMZ binding behaviour to the appearance of that cortex on late MRI scans were derived as for CBF and showed similar characteristics. However, the penumbral range of FMZ binding was considerably narrower (3.4–5.5) and it was the positive prediction curve that exhibited the much steeper slope around the 0.95 margin. Therefore, FMZ binding would appear to be particularly well suited for the early demonstration of cortical tissue eventually succumbing to necrosis, when its value relative to white matter in the unaffected hemisphere does not exceed the (lower) positive 95% prediction limit (Table 2
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Size of subcompartments within and outside final infarcts
As all prediction curves were essentially monotonic, they could be combined for a more reliable definition of the penumbral range based on early PET measurements. Using the mean positive 95% prediction limit of FMZ binding (3.4 times contralateral white matter) as the lower threshold and the mean negative 95% prediction limit of CBF (14.1 ml/100 g/min, 54.3% of contralateral mean) as the upper threshold, six distinct cortical subcompartments (SC I–VI) of cortical tissue were identified (Fig. 6
). Their median volume sizes determined on a voxel basis across all patients are given in Table 3. Most (median 55.1, range 15.0–94.4%) of the final infarct (median 25.7, range 2.9–151.1 cm3) showed reduced FMZ binding in the early PET study (SC I+II), whereas no region with FMZ binding initially reduced to or below 3.4 was observed outside the final infarct (SC V). Within the eventually infarcted area, a large portion (median 82.2, range 19.4–93.4%) exhibited critically reduced flow (SC I+III). In contrast, the volume of critically perfused cortex outside the final lesion was only 12.8 (range 0.0–100.5) cm3 (SC VI). Within the volume (median 22.0, range 0.8–140.2 cm3) of critical hypoperfusion finally infarcted (SC I and III), not more than 4.0 (range 0.0–27.3) cm3 had FMZ binding above the critical limit (SC III). Only 12.9 (range 3.3–61.5)% on average of the final infarct showed FMZ binding and CBF above the limits (SC IV). The eventual damage to this cortical region must be ascribed to secondary events occurring after the initial ischaemia. The present data support the high predictive value for final infarction of critically reduced FMZ binding: this tissue compartment was irreversibly damaged already at the time of the PET study. A smaller portion (median 20.5, range 0.3–55.9%) of the final infarct was still viable, according to preserved function of BZR receptors, but was critically hypoperfused (SC III).
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Discussion |
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The identification of flow thresholds predictive of ultimately infarcted or non-infarcted tissue is still a matter of controversy (Baron, 1999
). In early PET studies of acute ischaemic stroke (Baron et al., 1984; Powers et al., 1985; Ackerman et al., 1989), CBF values <12 ml/100 g/min were usually found in regions which later became the infarct. On the other hand, values of up to 22 ml/100 g/min were measured in regions causing transient ischaemic attack (Powers et al., 1987), and therefore the upper limit of the penumbral range was set to this or to a slightly lower level (Hakim et al., 1989). The wide effective range of the penumbra, i.e. of tissue bearing the potential for both recovery and necrosis, was demonstrated in meticulous analyses of PET data collected in a sample of patients studied 7–16 h after acute stroke. Since voxels exhibiting flow rates between 10 and 22 ml/100 g/min were initially found in the area of the final cortical–subcortical infarcts, the upper flow threshold of tissue which might become infarcted was set to 22 ml/100 g/min (Marchal et al., 1996). On the other hand, voxels meeting the same penumbral criteria (CBF <22 ml/100 g/min, CMRO2 >1.4 ml/100 g/min, OEF >0.7) escaped infarction. In these cases, the improvement of neurological symptoms was related to the volume of eventually non-infarcted penumbral tissue (Furlan et al., 1996); minimum CBF of salvageable tissue was found to be 7 ml/100 g/min. These observations from two independent studies are supported by our findings in a group of patients with cortical infarcts: the prediction curves computed from their data set the limits for 95% infarcted and 95% non-infarcted tissue to 4.8 and 14.1 ml/100 g/min, respectively. Of course, one has to bear in mind that H215O-PET estimates of low flow, particularly those obtained by the bolus method, suffer from large methodological errors inherent in both the variability of measurements of low tracer concentrations and in the diffusion limitation of water. The variability of flow values finally leading to infarction is also highly influenced by the time of measurement in the course of acute ischaemia, since the development of damage depends on both duration and severity of the flow disturbance (Heiss and Rosner, 1983). Therefore, repeated flow measurements affording an estimate of the duration of the flow decrease below a certain level would be required to establish more accurate predictive outcome measures. In contrast, estimation of irreversible damage from a reduction of FMZ binding is more reliable: irrespective of the time elapsed since onset of clinical symptoms, whenever FMZ binding is reduced to or <3.4 times the mean value in normal white matter, 95% of that cortical tissue will become infarcted. As recently demonstrated (Heiss et al., 2000), such areas cannot benefit from reperfusion and turn into infarction, despite rt-PA treatment initiated within 3 h of stroke onset. False positive prediction from reduced FMZ binding of infarcted tissue was not observed in this series, thus justifying also, in retrospect, the inclusion of three rt-PA-treated patients.
The results from this study are restricted to cortical grey matter, and therefore the described tissue compartments cannot be compared directly with thresholded mixed-tissue compartments with uncertain proportions of grey and white matter (Marchal et al., 1999), since the tolerance of ischaemia is considerably greater in white than in grey matter (Graf et al., 2001).
The lower and upper prediction limits determined in our volumes of interest-based analyses set the ground for a voxel-based analysis of subcompartments of ultimately infarcted and non-infarcted cortex. Tissue characterized by FMZ binding at or <3.4 times the normal white matter mean was entered into this analysis as irreversibly damaged. Tissue exhibiting flow rates <14.1 ml/100 g/min (54.3% of contralateral hemispheric mean tracer uptake) was considered penumbral, with uncertain outcome, and cortex perfused at rates above that threshold was expected to survive. Despite all the limitations of this clinical pilot study of cortical infarction, the results of our volumetric analysis suggest that PET can help in the selection of promising therapeutic strategies at a given point in the course of ischaemic stroke. Any treatment can only salvage or preserve tissue that has not been too severely altered—irreversibly damaged tissue cannot be rescued at all. In this study, on average, 55.1% of the final infarct was identified as not being amenable to therapy already at the time of PET. Treatment must be targeted towards the subcompartment of the final infarct (SC III comprising 20.5% in this study) that is not yet irreversibly damaged (FMZ binding >3.4 times the normal white matter mean) but perfused in the penumbral range (<14.1 ml/100 g/min or 54.3% of the contralateral mean hemispheric tracer uptake) and, therefore, only at risk of infarction. At the time of PET, this tissue compartment can still benefit from improved blood flow and thus be preserved like the initially hypoperfused cortical compartment (SC VI) found outside the infarct upon late MRI. In this study, only a small portion of the final infarct (12.9%, SC IV) had sufficient initial blood supply and neuronal integrity. It is in these regions that the final damage may be caused by secondary mechanisms involved in the delayed cascade of ischaemia (De Keyser et al., 1999; Dirnagl et al., 1999; Schulz et al., 1999) or by some recurrent disturbance of blood flow. The relative smallness of that fraction of the final infarct that can be attributed to secondary and delayed mechanisms may explain the discrepancy between the success of neuroprotective, anti-inflammatory and anti-apoptotic strategies for the prevention of persistent damage in experimental ischaemia on one side (Chan, 1996; Chopp and Zhang, 1996; Barinaga, 1998; Choi, 1998; DeGraba, 1998) and the relative lack of clinical efficacy of those therapeutics in human stroke on the other (Grotta, 1994; Lees, 1998; Dorman et al., 2000). Nevertheless, there may be a special role for those treatments in combination with reperfusion therapy by prolonging the time window of opportunity in penumbral tissue. However, the concept of combination therapy of acute ischaemic stroke still awaits validation from clinical trials.
In conclusion, the described positive and negative prediction limits derived from early FMZ binding and CBF studies can be used to identify various cortical subcompartments in acutely ischaemic tissue, which can or cannot benefit from active treatment. When, on average, 6 h are allowed to elapse from onset of ischaemia to PET, as in this study, more than half of the finally infarcted cortical tissue is already irreversibly damaged and cannot be salvaged by treatment. A small portion is only hypoperfused. This compartment has a potential for recovery, if reperfusion is sufficient (Heiss et al., 2000), and represents the substrate of the effect of, e.g. thrombolytic therapy of acute ischaemic stroke (Hacke et al., 1995, 1998; NINDS, 1995; Furlan et al., 1999). Another even smaller compartment does not suffer from ischaemia at the time of measurement, but becomes damaged in the further course—probably by secondary pathobiochemical processes, or perhaps by recurrent ischaemia. Only the latter portion can benefit from neuroprotective or other strategies, whose efficacy, however, is limited by the relative smallness of the volume of tissue it comprises.
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Received May 24, 2000. Revised August 8, 2000. Accepted September 11, 2000.
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