Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats.

Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.

Tissue at risk of infarction rescued by early reperfusion: a positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke.

Thrombolytic therapy of acute ischemic stroke can be successful only as long as there is penumbral tissue perfused at rates between the thresholds of normal function and irreversible structural damage, respectively. To determine the proportion of tissue at risk of infarction, cerebral perfusion was studied in 12 patients with acute ischemic stroke who underwent treatment with systemic recombinant tissue plasminogen activator (0.9 mg/kg body weight according to National Institute of Neurological Disorders and Stroke protocol) within 3 hours of onset of symptoms, using [15O]-H2O positron emission tomography (PET) before or during, and repeatedly after thrombolysis. The size of the regions of critically hypoperfused gray matter were identified on the initial PET scans, and changes of perfusion in those areas were related to the clinical course (followed by the National Institutes of Health stroke scale) and to the volume of infarcted gray matter demarcated on magnetic resonance imaging 3 weeks after the stroke. Whereas the initial clinical score was unrelated to the size of the ischemic area, after 3 weeks there was a strong correlation between clinical deficit and volume size of infarcted gray matter (Spearman's rho, 0.96; P < 0.001). All patients with a severely hypoperfused (< 12 mL/100 g/min) gray matter region measuring less than 15 mL on first PET showed full morphologic and clinical recovery (n = 5), whereas those with ischemic areas larger than 20 mL developed infarction and experienced persistent neurologic deficits of varying degree. Infarct sizes, however, were smaller than expected from previous correlative PET and morphologic studies of patients with acute stroke: only 22.7% of the gray matter initially perfused at rates below the conventional threshold of critical ischemia became necrotic. Actually, the percentage of initially ischemic voxels that became reperfused at almost normal levels clearly predicted the degree of clinical improvement achieved within 3 weeks. These sequential blood flow PET studies demonstrate that critically hypoperfused tissue can be preserved by early reperfusion, perhaps related to thrombolytic therapy. The results correspond with experimental findings demonstrating the prevention of large infarcts by early reperfusion to misery perfused but viable tissue.

Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: residual perfusion and efficacy of postischemic reperfusion.

The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarctions. We used high-resolution positron emission tomography (PET) to assess cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) before, during, and up to 24 h after middle cerebral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6-20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immediately reduced CBF in the MCA territory to < 40% of control, while CMRO2 was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60- and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After 30-min MCAO, the reperfusion period was characterized by a transient reactive hyperemia and fast normalization of CBF, CMRO2, and CMRglc, and no or only small infarcts in the deep nuclei were found in histology. After 60- and 120-min MCAO, the extent of hyperperfusion was related to the severity of ischemia, decreased CMRO2 and CMRglc persisted, and cortical/subcortical infarcts of varying sizes developed. A clear difference was found in the flow/metabolic pattern between surviving and dying cats: In cats dying during the observation period, extended postischemic hyperperfusion accompanied large defects in CMRO2 and CMRglc, large infarcts developed, and intracranial pressure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic episode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.

11C-methionine PET for differential diagnosis of low-grade gliomas.

Management of low-grade gliomas continues to be a challenging task, because CT and MRI do not always differentiate from nontumoral lesions. Furthermore, tumor extent and aggressiveness often remain unclear because of a lack of contrast enhancement. Previous studies indicated that large neutral amino acid tracers accumulate in most brain tumors, including low-grade gliomas, probably because of changes of endothelial and blood-brain barrier function. We describe 11C-methionine uptake measured with PET in a series of 196 consecutive patients, most of whom were studied because of suspected low-grade gliomas. Uptake in the most active lesion area, relative to contralateral side, was significantly different among high-grade gliomas, low-grade gliomas, and chronic or subacute nontumoral lesions, and this difference was independent from contrast enhancement in CT or MRI. Corticosteroids had no significant effect on methionine uptake in low-grade gliomas but reduced uptake moderately in high-grade gliomas. Differentiation between gliomas and nontumoral lesions by a simple threshold was correct in 79%. Recurrent or residual tumors had a higher uptake than primary gliomas. In conclusion, the high sensitivity of 11C-methionine uptake for functional endothelial or blood-brain barrier changes suggests that this tracer is particularly useful for evaluation and follow-up of low-grade gliomas.

High-resolution PET in cats: application of a clinical camera to experimental studies.

UNLABELLED: A commercial high-resolution scanner designed for clinical PET studies was tested for its applicability to investigate cerebral metabolism and blood flow in cats. METHODS: Cerebral blood flow, CMRO2, CBV and CMRglc were determined repeatedly using 15O steady-state oxygen methods and 18F-fluorodeoxyglucose (FDG). Metabolic and blood flow images of 14 contiguous 3-mm PET slices were compared to histological sections in four control animals. In another six cats, hemodynamic and metabolic changes were followed by serial multi-tracer PET for 24 hr after permanent occlusion of the left middle cerebral artery (MCA). Pattern and extent of changes of the physiological variables were related to the final infarct verified in matched histological sections. RESULTS: At spatial resolutions (FWHM) of 3.6 mm in transaxial planes and 4.0 mm axially, details of the gross anatomy of the cat brain were distinguished best in the FDG images. Cerebral blood flow, CMRO2 and CMRglc values measured in the cortex, white matter and basal ganglia were in the range of common autoradiographic results. Immediately after MCA occlusion, there was widespread decrease in blood flow, but metabolism was preserved at values, which suggest viable tissue. With time, the areas of increased oxygen extraction fraction (OEF) moved from the center to the periphery of the MCA territory. CONCLUSION: High-resolution PET can be used for repeat, quantitative imaging of blood flow and metabolism in small animals such as the cat. After MCA occlusion, the changes in blood flow and metabolism can be followed over time and can be related to the final morphological lesion.

Heterogeneity of cerebral hemodynamics and metabolism in carotid artery disease.

METHODS: Eight patients with severe unilateral carotid stenosis (> 70%) were evaluated using PET to assess parametric changes in cerebral blood flow, blood volume, metabolic rate for oxygen, metabolic rate for glucose, oxygen extraction fraction and glucose extraction fraction. We performed these examinations because clinical history and physical exam results suggested possible cerebral vascular disease. Four patients were neurologically asymptomatic with other signs of peripheral vascular disease (e.g., episodic vertigo, TIA and claudication). All patients had normal neurologic examinations and normal CT or MRI studies. PET images were analyzed by two methods. First, regions of interest were used for the entire hemisphere, vascular territories and borderzones. Regions ipsilateral to the carotid stenosis were compared to respective regions in the contralateral hemisphere using Student's t-test. Second, visual inspection of each image was performed. RESULTS: Statistical analysis demonstrated no significant differences between hemodynamic and metabolic parameters for regions ipsilateral to the carotid stenosis and contralateral homotopic reference regions. Upon visual examination, however, all patients had focal changes in either cerebral blood flow, blood volume, glucose extraction fraction and/or oxygen extraction fraction. CONCLUSION: Visual inspection is important in the evaluation of pathophysiological changes caused by unilateral carotid stenosis. Clinical decisions in patients with carotid artery disease should be based on careful visual examinations and statistical analyses of appropriately selected regions.

Moyamoya syndrome: impaired hemodynamics on ECD SPECT after EEG controlled hyperventilation.

BACKGROUND AND PURPOSE: Ischemic symptoms in children with Moyamoya syndrome are typically provoked by hyperventilation (HV) and are accompanied by the "re-build-up" phenomenon in EEG. The value of scintigraphic detection of HV-provoked perfusion deficits remains to be elucidated. PATIENTS AND METHODS: In seven children with Moyamoya syndrome regional cerebral blood flow was assessed by 99mTc-ethyl-cysteine-dimer (ECD) single photon emission computed tomography (SPECT) after HV and under baseline conditions to identify ischemia prone regions. RESULTS: Regional marked hypoperfusion after HV was found in all patients. Predominant perfusion deficits were detected in the frontal lobes. CONCLUSION: ECD SPECT is a potential tool for the preoperative evaluation of cerebral hemodynamics and for monitoring angiosurgical therapies in Moyamoya disease.

Long-term results of carpal tunnel decompression. Assessment of 60 cases.

The long-term prognosis of 60 patients operated on for carpal tunnel syndrome has been assessed in a prospective study with a median follow-up period of 5.5 years (range 2-11 years). Analysis of motor, sensory, trophic, and electrodiagnostic findings and assessment of pain were performed pre- and post-operatively using a standardized grading system. The results were generally favourable with a variable degree of improvement in 86% of cases. Statistical evaluation using multiple Dunn-Rankin tests revealed pain to be the most prominent pre-operative finding. On post-operative re-examination, pain was found to be improved to a significantly greater extent than any other variable. Analysis of several potential prognostic factors showed that pain lasting for more than 5 years prior to surgery indicates a poor prognosis. Only patients with diabetes mellitus exhibited a trend toward less pain relief.

Automatic control device for the continuous administration of (15)O labeled gaseous tracers for PET measurements.

An automatic control device for the administration of (15)O labelled gaseous PET tracers with constant dose per time (continuous inhalation) is presented. The system controls the flow through the target, the flow to the patient and the dose to the patient simultaneously. The desired values for the dose and the flow to the patient are variable. The dose to the patient is kept constant with +/- 4% even if the beam current raises or if the beam is off for some seconds.

Drug-induced changes in cerebral glucose consumption in bifrontal epilepsy.

PURPOSE: Positron emission tomography (PET) using 18F-radiolabeled deoxyglucose (18F-FDG) is a sensitive procedure for detection of epileptogenic foci. Although alterations in glucose consumption are not restricted to the area of seizure generation itself, the magnitude and extent of cerebral metabolic disturbances induced by epileptic discharges can be detected. Despite two decades of epilepsy research using 18F-FDG-PET, little is known about the metabolic changes during therapy of focal epilepsy. We report on a child with frontal epilepsy with severe glucose hypometabolism that was nearly completely normalized during drug therapy. METHODS: Interictal 18F-FDG-PET was performed at the onset of epilepsy and after optimized drug therapy in a 5-year-old boy with behavioral abnormalities and repetitive seizures of frontal origin with bifrontal interictal EEG slowing for 8 weeks. Both scans were anatomically matched; initial and intratherapeutic glucose metabolism were compared. RESULTS: In accordance with the epileptogenic focus as identified by EEG and ictal/interictal perfusion single-photon emission tomography (SPECT), bifrontal hypometabolism was depicted by 18F-FDG-PET. Magnetic resonance imaging (MRI) was unremarkable. After dual-drug therapy (valproate, carbamazepine), the boy became seizure free, and his initial behavioral deficits disappeared. A control PET study after 3 months of therapy showed restored glucose consumption; the frontal EEG slowing was normalized. CONCLUSIONS: This case demonstrates that reduction of glucose metabolism in epileptogenic foci may be a result of reversible neuronal dysfunction that correlates with the electroclinical follow-up.

Estimation of regional cerebral blood flow levels in ischemia using [(15)O]water of [(11)C]flumazenil PET without arterial input function .

Determination of residual flow within the ischemic brain may be important in patients eligible for thrombolytic therapy. Conventional cerebral blood flow (CBF) quantification often cannot be achieved in these cases because arterial blood sampling required for the input function is prohibited. Quantitative CBF was measured in 20 patients with ischemic stroke using [(15)O]water and [(11)C]flumazenil PET with arterial blood sampling and compared with normalized nonquantified data of the same patients. For both comparisons, percentiles were derived, allowing the determination of a normalized blood flow level corresponding to an absolute CBF value below which 95% of all pixels are located. These normograms can be used to derive absolute CBF levels in milliliters per 100 g per minute from normalized data without the need for measuring an arterial input function.

Evaluation of the extension of cerebral gliomas by scintigraphy.

BACKGROUND: Single photon emission computed tomography (SPECT) with 201Tl and 123I-alpha-methyl tyrosine (123I-IMT) are routine methods for the evaluation of brain tumors. 123I-IMT transport across the blood brain barrier is mediated by an amino acid carrier, 201Tl accumulation is analogous to cerebral potassium uptake. PATIENTS AND METHODS: To determine the differences in glioma extension as shown by the 2 methods, 17 patients with malignant gliomas were included in this comparative imaging study: astrocytoma III: n = 6, ependymoma III: n = 1, oligodendroglioma III: n = 1, glioblastoma IV: n = 9. The tomographic image sets were matched anatomically and the slices showing maximal tumor extension were identified in both image sets respectively. Tumor spread was compared visually and the tumor extension was quantified. RESULTS: In gliomas WHO III tumor extension was delineated significantly larger by 123I-IMT-SPECT than by 201Tl-SPECT (mean +/- SD: 816 +/- 281 pixels vs 600 +/- 220 pixels, n = 8, p < 0.05). The size of glioblastomas was shown in a comparable manner by the 2 methods (977 +/- 571 vs 1.051 +/- 588, n = 9, ns, p = 0.57), but there were considerable regional differences between the area of 201Tl uptake and amino acid retention. In the whole group a weak but significant negative correlation between intensity of 201Tl uptake on the one hand and a ratio of the area as depicted by 123I-IMT vs area as depicted by 201Tl on the other hand, was found (n = 17, r = 0.49, p < 0.05). Thus the differences in the delineation of areas became smaller with increasing 201Tl uptake. CONCLUSIONS: These preliminary data indicate that the extension of gliomas is depicted differently by the 2 methods. 123I-IMT-SPECT shows a larger tumor extension especially in gliomas WHO III. Since 201Tl uptake has previously been shown to correlate with disruption of the blood brain barrier, 123I-IMT-SPECT may delineate tumor parts without endothelial leakage. This additional information may be helpful in planning surgical or radiation therapy. The advantages of 123I-IMT in this respect decrease with increasing 201Tl uptake and with increasing malignancy.

Early detection of irreversibly damaged ischemic tissue by flumazenil positron emission tomography in cats.

BACKGROUND AND PURPOSE: Ligands for cerebral benzodiazepine receptors were used in the past to indicate the intactness of cortical neurons in subacute to chronic states after stroke and thus to differentiate among brain regions with complete or incomplete infarction and with functional deactivation. For planning acute interventional therapy, however, a marker of irreversible damage in early ischemia is needed. We studied the applicability of [11C]flumazenil (FMZ) for differentiation between tissue with and without potential of recovery in the first hours after focal experimental ischemia. METHODS: In 11 cats, cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction, and FMZ binding were studied repeatedly by positron emission tomography before, during, and up to 12 hours after transient middle cerebral artery occlusion (MCAO) (30 minutes in 2, 60 minutes in 7, and 120 minutes in 2 cats, respectively). Development of the defects in energy metabolism were compared with the defects in FMZ binding (2 to 3 hours and 8 to 9 hours after MCAO), with the pattern of disturbed glucose metabolism (determined 12 hours after MCAO), and with the size of the infarcts (determined approximately 15 hours after MCAO). RESULTS: Irrespective of the level of reperfusion, defects in FMZ binding (2 to 3 hours after MCAO) were closely related to areas with severely depressed oxygen consumption and predicted the size of the final infarcts, whereas preserved FMZ binding indicated intact cortex. Depression of glucose metabolism was in all animals larger than the defects in FMZ binding and the infarcts, indicating functional deactivation of brain areas beyond the permanent morphological damage. In addition, FMZ distribution within 2 minutes after injection was significantly correlated to flow and yielded reliable perfusion images. CONCLUSIONS: The reduction of FMZ binding early after focal ischemia reflects irreversible neuronal damage that otherwise only can be detected by multitracer studies. Our experimental data and first clinical applications suggest that FMZ has potential as an indicator of developing infarction. Since FMZ distribution additionally images perfusion, this tracer might be useful for the selection of patients who would benefit from acute therapeutic intervention.

Positron emission tomography findings relevant to neurosurgery for epilepsy.

Using the 2-[F-18]fluorodeoxyglucose method, 213 positron emission tomographic (PET) studies of local brain glucose metabolism (CMRglu) were performed in 124 patients with various forms of epilepsy. Interictal PET scans of primary epileptics typically showed some global metabolic depression and decreased functional activity of insular, basal and anterior temporal cortex. Epilepsia partialis continua Kozevnikov was characterized by hypo- or hyper-metabolism of perirolandic cortex. Tuberous sclerosis was distinguished by neocortical foci of significantly decreased glucose consumption. Even in the interictal resting state, with regard to sensitivity (greater than 90%) and accuracy of focus localization. PET was superior to other diagnostic methods in typical temporal lobe epilepsy. Averaging 23% below normal CMRglu, the majority of hypometabolic foci were found in mesial temporal structures. Improved distinction between the epileptogenic area and the surrounding tissue showing comparatively normal functional responsiveness, was achieved by psychophysical activation using emotional speech or continuous visual recognition during PET scanning. In patients who had undergone total cerebral hemispherectomy because of uncontrolled epilepsy, remarkable recruitment of association areas was observed on both motor and speech activation.

High uptake of L-3-[123I]iodo-alpha-methyl tyrosine in pilocytic astrocytomas.

Despite a favourable prognosis, pilocytic astrocytomas may exhibit signs of malignancy on various neuroimaging modalities. This retrospective analysis was conducted to determine whether scintigraphic features of malignancy are also found on single-photon emission tomography (SPET) using L-3-[123I]iodo-alpha-methyl tyrosine (IMT) as a tracer. Twenty patients with pilocytic astrocytomas were retrospectively selected from a large series of patients referred for the evaluation of primary or recurrent brain tumours. IMT SPET was performed in 16 patients, positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (FDG) was available in 10 of the patients and SPET using technetium-99m tetrofosmin or thallium-201 had been performed in 11. Image analysis was performed using standard protocols to determine how many patients exceeded the respective thresholds of malignancy. Features of malignancy were found in 7/16 IMT SPET studies, in 7/10 FDG PET studies and in 7/11 of the residual SPET investigations. A significant correlation of tumour size and IMT uptake in primary pilocytic astrocytomas indicated partial volume effects to partly account for the differential uptake behaviour (n = 10, r = 0.87, P < 0.05). Differences in IMT uptake in primaries (1.7 +/- 0.6, n = 10) and in recurrent tumours (2.3 +/- 0.7, n = 6) did not attain statistical significance. IMT SPET results indicative of malignancy are regularly found in pilocytic astrocytomas, despite their good prognosis. No uptake may be detected in largely cystic or in small tumours.

Sequential scintigraphic strategy for the differentiation of brain tumours.

Both thallium-201 and iodine-123 alpha-methyltyrosine (123I-IMT) have been shown to be useful in the diagnostic evaluation of brain tumours. The aim of this study was to investigate the respective contributions of 201Tl and 123I-IMT single-photon emission tomography (SPET) in the non-invasive evaluation of intracerebral tumours. We analysed 65 patients with the following brain tumours: 8 non-neoplastic lesions, 4 meningiomas, 12 low-grade gliomas, 28 high-grade gliomas, 11 metastases and 2 high-grade lymphomas. 201Tl SPET and 123I-IMT SPET were performed [start of 201Tl SPET: 15 min p.i. (early) and 180 min p.i. (delayed); start of 123I-IMT SPET: 15 min p.i.]. The intensity of uptake was quantified as the ratio between tracer accumulation in the tumour and in the contralateral hemisphere. None of the non-neoplastic lesions or low-grade gliomas expressed marked 201Tl uptake. All malignant tumours except one small metastasis and all meningiomas except one small, cystic and degenerated lesion showed significant 201Tl accumulation [Tl(15')>2.0]; 123I-IMT uptake was either absent or intermediate in non-malignant lesions except in two low-grade gliomas; the highest levels were observed in high-grade gliomas followed by metastases and lymphomas (mean IMT: 2.7 vs. 2.1 vs. 1.8), with metastases showing a high variability in 123I-IMT uptake (range: 0.8-3.6). Using 201Tl to distinguish non-neoplastic lesions from malignant tumours and meningiomas, 63 of 65 patients were characterised correctly. In the latter group, high-grade gliomas were correctly identified in 27 of 28 cases by their amino acid uptake. It is concluded that the combination of 201Tl and 123I-IMT surpasses the accuracy of each single test in the differentiation of space-occupying lesions of the brain. Based on these preliminary results, a sequential strategy is proposed involving an initial 201Tl SPET study and an additional 123I-IMT SPET study in the event of positive 201Tl uptake.