Jan Sobesky

Nosocomial Pneumonia After Acute Stroke. Implications for Neurological Intensive Care Medicine

Background and Purpose— Pneumonia has been estimated to occur in about one third of patients after acute stroke. Only limited data are available on stroke-associated pneumonia (SAP) in specialized neurological intensive care units (NICUs). Methods— We enrolled 124 patients with acute stroke who were treated at our university hospital NICU in a prospective observational study. Incidence rates and risk factors of SAP and long-term clinical outcome were determined. Results— SAP incidence was 21% with a spectrum of pathogens, which is comparable to previously published data on general ICU patients. Mechanical ventilation, multiple location, and vertebrobasilar stroke, as well as dysphagia and abnormal chest x-ray findings, were identified as risk factors for the disease. SAP patients showed higher mortality rates than nondiseased subjects (acute, 26.9% versus 8.2%; long-term, 35.3% versus 14.3%) and a significantly poorer long-term clinical outcome (Barthel Index, 50.5±42.4 versus 81.5±27.8; Rankin Scale, 3.5±1.7 versus 2.2±1.6). Conclusions— Our data underline the considerable epidemiological and prognostic impact of SAP for the treatment of acute stroke patients in a specialized NICU setting. They demonstrate that the occurrence of SAP deteriorates clinical outcome in these patients. Our results allow us to identify high-risk stroke patients at time of NICU admission in whom the use of preventive treatment strategies is most promising.

MRI-Based and CT-Based Thrombolytic Therapy in Acute Stroke Within and Beyond Established Time Windows An Analysis of 1210 Patients

Background and Purpose— The use of intravenous thrombolysis is restricted to a minority of patients by the rigid 3-hour time window. This window may be extended by using modern imaging-based selection algorithms. We assessed safety and efficacy of MRI-based thrombolysis within and beyond 3 hours compared with standard CT-based thrombolysis. Methods— Five European stroke centers pooled the core data of their CT- and MRI-based prospective thrombolysis databases. Safety outcomes were predefined as symptomatic intracranial hemorrhage and mortality. Primary efficacy outcome was a favorable outcome (modified Rankin Scale 0 to 1). We performed univariate and multivariate analyses for all end points, including age, National Institutes of Health Stroke Scale, treatment group (CT <3 hours, MRI <3 hours and >3 hours), and onset to treatment time as variables. Results— A total of 1210 patients were included (CT <3 hours: N=714; MRI <3 hours: N=316; MRI >3 hours: N=180). Median age, National Institutes of Health Stroke Scale, and onset to treatment time were 69, 67, and 68.5 years (P=0.66); 12, 13, and 14 points (P=0.019); and 130, 135, and 240 minutes (P<0.001). Symptomatic intracranial hemorrhage rates were 5.3%, 2.8%, and 4.4% (P=0.213); mortality was 13.7%, 11.7%, and 13.3% (P=0.68). Favorable outcome occurred in 35.4%, 37.0%, and 40% (P=0.51). Age and National Institutes of Health Stroke Scale were independent predictors for all safety and efficacy outcomes. The overall use of MRI significantly reduced symptomatic intracranial hemorrhage (OR: 0.520, 95% CI: 0.270 to 0.999, P=0.05). Beyond 3 hours, the use of MRI significantly predicted a favorable outcome (OR: 1.467; 95% CI: 1.017 to 2.117, P=0.040). Within 3 hours and for all secondary end points, there was a trend in favor of MRI-based selection over standard <3-hour CT-based treatment. Conclusion— Despite significantly longer time windows and significantly higher baseline National Institutes of Health Stroke Scale scores, MRI-based thrombolysis is safer and potentially more efficacious than standard CT-based thrombolysis.

Does the Mismatch Match the Penumbra? Magnetic Resonance Imaging and Positron Emission Tomography in Early Ischemic Stroke

Background and Purpose— In ischemic stroke, diffusion-weighted (DW) and perfusion-weighted (PW) magnet resonance imaging (MRI) is used to define the mismatch as the therapeutic target. With positron emission tomography (PET), we characterized the metabolic patterns of tissue compartments identified by MRI and compared the volumes of mismatch to those of PET-defined penumbra. Methods— In 6 acute (median, 5.2 hours) and 7 chronic (median, 10 days) stroke patients in whom a mismatch was defined by PW/DW MRI, PET was performed (median, 120-minute delay). Cerebral blood flow (CBF), oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF) was determined in the areas of DWI lesion, mismatch, and oligemia. Then, the mismatch volume was compared with the volume of penumbra. Results— DWI lesions showed impaired tissue integrity (low CMRO2 and low OEF). Mismatch areas were viable (normal CMRO2) but showed largely varying OEF. Oligemic areas had metabolic patterns comparable to normal tissue. A mismatch volume was found in all 13 patients. However, only 8 of 13 had a corresponding penumbra volume that covered only a part of the mismatch. Conclusion— Our comparative PET/MRI study confirmed the current pathophysiological hypothesis for the DWI lesion and for the oligemic areas. However, the mismatch area did not reliably detect elevated OEF and overestimated the penumbra defined by PET.

Outcome and Symptomatic Bleeding Complications of Intravenous Thrombolysis Within 6 Hours in MRI-Selected Stroke Patients: Comparison of a German Multicenter Study With the Pooled Data of ATLANTIS, ECASS, and NINDS tPA Trials

Background and Purpose— We compared outcome and symptomatic bleeding complications of intravenous tissue plasminogen activator (IV-tPA) within 6 hours of symptom onset in MRI-selected patients with acute middle cerebral artery infarction with the pooled data of the large stroke tPA trials. Methods— Patients were examined by perfusion-weighted and diffusion-weighted imaging ≤6 hours. Within 3 hours, patients were treated according to Second European-Australasian Acute Stroke Study (ECASS II) criteria. After 3 to 6 hours, treatment with IV-tPA was performed based on MRI findings. Favorable outcome was assessed after 90 days using a dichotomized modified Rankin scale score of 0 to 1. Intracerebral bleeding complications were assessed on follow-up MRI or computed tomography. Data were compared with the pooled placebo and pooled tPA patients of the ATLANTIS, ECASS, and National Institute of Neurological Disorders and Stroke (NINDS) tPA trials. Results— From 174 MRI-selected tPA patients, 62% (n=108) were treated in ≤3 hours and 38% (n=66) after 3 to 6 hours. Favorable outcome was more frequent in MRI-selected tPA patients (48% [95% CI, 39 to 54]) compared with pooled placebo (33% [95% CI, 31 to 36]; P<0.001) and pooled tPA patients (40% [95% CI, 37 to 42]; P=0.046). Odds ratios for favorable outcome in the MRI-selected tPA group were 1.82 (1.32 to 2.51) compared with the pooled placebo and 1.39 (1.01 to 1.92) compared with the pooled tPA group. The rate of symptomatic intracerebral hemorrhage in MRI-selected tPA patients (3% [95% CI, 0 to 5]) was lower than in the pooled tPA group (8% [95% CI, 7 to 10]; P=0.012) and comparable to the pooled placebo group (2% [95% CI, 1 to 3]; P=0.392). Conclusions— This study supports that it is safe and effective to expand the time window for IV-tPA up to 6 hours in patients with tissue at risk as defined by MRI.

Differentiating multiple system atrophy from Parkinson’s disease: contribution of striatal and midbrain MRI volumetry and multi-tracer PET imaging

Objectives: The differential diagnosis between typical idiopathic Parkinson’s disease (PD) and the striatonigral variant of multiple system atrophy (MSA-P) is often difficult because of the presence of signs and symptoms common to both forms of parkinsonism, particularly at symptom onset. This study investigated striatal and midbrain findings in MSA-P and PD patients in comparison with normal controls with the use of positron emission tomography (PET) and three dimensional magnetic resonance imaging (3D MRI) based volumetry to increase the differential diagnostic accuracy between both disease entities. Methods: Nine patients with MSA-P, 24 patients with PD, and seven healthy controls were studied by MRI and PET with 6-[18F]-fluoro-L-dopa (FDOPA), [18F]fluoro-deoxyglucose (FDG), and 11-C-Raclopride (RACLO). Striatal and extrastriatal volumes of interest (VOI) were calculated on the basis of the individual MRI data. The PET data were transferred to the VOI datasets and subsequently analysed. Results: MSA-P differed significantly from PD patients in terms of decreased putaminal volume, glucose metabolism, and postsynaptic D2 receptor density. The striatal FDOPA uptake was equally impaired in both conditions. Neither MRI volumetry nor PET imaging of the midbrain region further contributed to the differential diagnosis between PD and MSA-P. Conclusions: The extent and spatial distribution of functional and morphological changes in the striatum permit the differentiation of MSA-P from PD. Both, multi-tracer PET and 3D MRI based volumetry, may be considered equivalent in the assessment of different striatal abnormality in both disease entities. In contrast, MRI and PET imaging of the midbrain does not provide a further gain in diagnostic accuracy.

Which time-to-peak threshold best identifies penumbral flow? A comparison of perfusion-weighted magnetic resonance imaging and positron emission tomography in acute ischemic stroke

Background and Purpose— In acute ischemic stroke, the hypoperfused but viable tissue is the main therapeutic target. In clinical routine, time-to-peak (TTP) maps are frequently used to estimate the hemodynamic compromise and to calculate the mismatch volume. We evaluated the accuracy of TTP maps to identify penumbral flow by comparison with positron emission tomography (PET). Methods— Magnetic resonance imaging (MRI) and PET were performed in 11 patients with acute ischemic stroke (median 8 hours after stroke onset, 60 minutes between MRI and PET imaging). The volumes defined by increasing TTP thresholds (relative TTP delay of >2, >4, >6, >8, and >10 seconds) were compared with the volume of hypoperfusion (<20 mL/100 g per min) assessed by 15O-water PET. In a volumetric analysis, each threshold’s sensitivity, specificity, and predictive values were calculated. Results— The median hypoperfusion volume was 34.5 cm3. Low TTP thresholds included large parts of the hypoperfused but also large parts of normoperfused tissue (median sensitivity/specificity: 93%/60% for TTP >2) and vice versa (50%/91% for TTP >10). TTP >4 seconds best identifies hypoperfusion (84%/77%). The positive predictive values increased with the size of hypoperfusion. Conclusion— This first comparison of quantitative PET-CBF with TTP maps in acute ischemic human stroke indicates that the TTP threshold is crucial to reliably identify the tissue at risk; TTP >4 seconds best identifies penumbral flow; and TTP maps overestimate the extent of true hemodynamic compromise depending on the size of ischemia. Only if methodological restrictions are kept in mind, relative TTP maps are suitable to estimate the mismatch volume.

Prediction of Malignant Course in MCA Infarction by PET and Microdialysis

BACKGROUND AND PURPOSE To predict malignant course in patients with large middle cerebral artery (MCA) infarction, we combined PET imaging and neuromonitoring, including microdialysis. METHODS Thirty-four patients with stroke of >50% of the MCA territory in early cerebral CT scan were included. Probes for microdialysis and measurement of intracranial pressure and tissue oxygen pressure (Pto2) were placed into the ipsilateral frontal lobe. PET was performed with 11C-flumazenil to assess CBF and irreversible neuronal damage. RESULTS PET measurements within 24 hours after stroke showed larger volumes of ischemic core (mean, 144.5 versus 62.2 cm3) and larger volumes of irreversible neuronal damage (157.9 versus 47.0 cm3) in patients with malignant course (ie, edema formation with midline shift) than in patients with benign course. Mean cerebral blood flow values within the ischemic core were significantly lower and the volume of the ischemic penumbra was smaller in the malignant than in the benign group. In patients with malignant course, cerebral perfusion pressure dropped to <50 to 60 mm Hg 22 to 72 hours (mean, 52.0 hours) after onset of symptoms; subsequently, Pto2 dropped and glutamate increased, indicating secondary ischemia. Maximal changes in the monitored variables reached significant levels for glutamate, aspartate, GABA, glycerol, lactate-to-pyruvate ratio, hypoxanthine, intracranial pressure, cerebral perfusion pressure, and Pto2. CONCLUSIONS PET allowed prediction of malignant MCA infarction within the time window suggested for hemicraniectomy. Neuromonitoring helped to classify the clinical courses by characterizing pathophysiological sequelae of malignant edema formation. In contrast to PET, however, it did not predict fatal outcome early enough for successful implementation of invasive therapies.

Identifying Thresholds for Penumbra and Irreversible Tissue Damage

Diffusion-weighted MRI (DWI) in combination with perfusion-weighted MRI (PWI) has become a widely accepted modality for the selection of patients amenable for acute therapy, if a mismatch between these procedures suggests viable penumbral tissue. However, DWI as well as PWI yields semiquantitative measures limiting the definitions of irreversible damage and of potentially viable penumbral tissue. These limitations of PWI/DWI may be better understood if findings in individual patients are compared with the results from measurements of blood flow, oxygen metabolism, and benzodiazepine receptor binding obtained with positron emission tomography (PET). Comparative studies with PET and MRI were performed in 3 groups of patients: (1) In 12 acute stroke patients, results from DWI (median, 6.5 hours after symptom onset) and 11C-flumazenil (FMZ) PET (median, 85 minutes between DWI and PET) were compared with infarct extension 24 to 48 hours later on T2-weighted MRI. (2) In 11 acute stroke patients, results from PWI (median, 8 hours after symptom onset) were compared with cerebral blood flow measurements obtained with [15O]H2O PET (interval, 60 minutes between PWI and PET). (3) In 10 patients with acute (n=5) or chronic stroke (n=5), results from PWI/DWI were compared with PET of cerebral blood flow and oxygen consumption to detect mismatch or increased oxygen extraction fraction as surrogate markers of penumbra. Results were: (1) from regions with increased DWI intensity, decreased apparent diffusion coefficient (ADC) and decreased FMZ binding probability curves were computed for eventual infarction, and 95% prediction limits were determined. These limits predicted 83.5% (FMZ), 84.7% (DWI), and 70.9% (ADC) of the final infarct volume. However, the false-positive predictions were much higher for the DWI variables (5.1 and 3.6 cm3 for DWI and ADC versus a median of 0 for FMZ). (2) The comparison of volumes generated by different time to peak (TTP) thresholds (PWI) and hypoperfusion <20 mL/100 g per minute (PET) indicates that a TTP delay of 4 to 6 seconds yields a fair estimate of hypoperfusion. (3) The PWI/DWI mismatch with TTP >4 seconds did not reliably correspond to the penumbra as assessed by PET (oxygen extraction fraction >150%). Only 6 of 10 patients with a mismatch had areas of penumbra. In these cases, the penumbra volume was overestimated by MRI. DWI correlates with FMZ results and, with a few exceptions, yields a good estimate of acute tissue damage and final infarct volume. PWI measures seem to be less reliable; the TTP prolongation of >4 seconds assessed only 83% of the volume of hypoperfusion <20 mL/100 g per minute. The mismatch volume imprecisely depicts increased oxygen extraction fraction, and, despite its clinical role for selection of patients for eventual therapy, it does not to seem to be a reliable correlate of penumbra.

Permanent Cortical Damage Detected by Flumazenil Positron Emission Tomography in Acute Stroke

BACKGROUND AND PURPOSE Therapy of acute ischemic stroke can only be effective as long as neurons are viable and tissue is not infarcted. Since gamma-aminobutyric acid receptors are abundant in the cortex and sensitive to ischemic damage, specific radioligands to their subunits, the central benzodiazepine receptors (BZR), may be useful as indicators of neuronal integrity and as markers of irreversible damage. To test this hypothesis we studied the binding of the BZR ligand [11C]flumazenil (FMZ) early after ischemic stroke in comparison to the extent of final infarcts and hypometabolic cortical areas. METHODS In 10 patients cerebral blood flow, cerebral metabolic rate for oxygen (CMRO2), oxygen extraction fraction (OEF), and FMZ binding were studied by positron emission tomography 3.5 to 16 hours after onset of their first hemispheric stroke. Early changes in flow, oxygen metabolism, and FMZ binding were compared with permanent disturbances in glucose metabolism, and the size of the final infarcts was determined on MRI or CT 12 to 22 days after the stroke. RESULTS In all patients except one cerebral blood flow was disturbed, with marked decreases in eight and a hyperperfusion in one patient corresponding to the location of neurological deficits. In these areas CMRO2 was also reduced but to a variable degree, inducing highly variable OEF. Areas with markedly decreased CMRO2 (<60 micromol/100 g per minute) corresponded to regions with decreased FMZ binding (<4.0 times the mean value in the white matter). In all patients the final cortical infarcts were visible on the early FMZ images. Infarcts could be discriminated from noninfarcted cortex by decreased FMZ binding despite a wide range of OEF. In finally hypometabolic cortex FMZ binding was initially decreased or normal, with OEF covering a wide range; this suggested neuronal loss and/or deactivation as the cause of metabolic disturbance. Additionally, a highly significant correlation was found between FMZ distribution within the first 2 minutes after injection and regional cerebral blood flow. CONCLUSIONS These results demonstrate that permanently and irreversibly damaged cortex can be detected by reduced FMZ binding early after stroke. Since FMZ distribution additionally images regional cerebral perfusion, BZR radioligands have a potential as clinically useful tracers in patients with acute ischemic stroke. The evidence of tissue damage furnished by these tracers might be of relevance for the selection of individual therapeutic strategies.

Two Tales: Hemorrhagic Transformation but Not Parenchymal Hemorrhage After Thrombolysis Is Related to Severity and Duration of Ischemia: MRI Study of Acute Stroke Patients Treated With Intravenous Tissue Plasminogen Activator Within 6 Hours

Background and Purpose— Intracerebral hemorrhage represents the most feared complication of treatment with intravenous tissue plasminogen activator. We studied whether perfusion-weighted imaging and diffusion-weighted imaging has the potential to identify patients at risk of severe intracerebral hemorrhage after treatment with intravenous tissue plasminogen activator. Methods— We analyzed data of prospectively studied MRI selected acute ischemic stroke patients treated with intravenous tissue plasminogen activator within 6 hours. All patients were examined by perfusion- and diffusion-weighted imaging ≤6 hours. Perfusion- and diffusion-weighted imaging lesion volumes were calculated. Hemorrhagic transformation was assessed on follow-up CT or MRI and diagnosed as hemorrhagic transformation, parenchymal hemorrhage, or symptomatic intracerebral hemorrhage according to ECASS II criteria. Results— Of 152 patients, hemorrhagic transformation was seen in 60 (39.5%), parenchymal hemorrhage in 15 (9.9%), and symptomatic intracerebral hemorrhage in 4 (2.6%). Multiple logistic regression analysis identified onset to treatment time after 3 to 6 hours (P<0.001), a larger perfusion-weighted imaging lesion volume (P=0.002), and, as a tendency, a higher score on the National Institutes of Health Stroke Scale on admission (P=0.068) as independent predictors of hemorrhagic transformation. Neither MRI lesion volumes nor severity of symptoms, but rather only an older age tended to be associated with parenchymal hemorrhage (P=0.087). Conclusion— Our results further support the concept of a different pathogenesis for hemorrhagic transformation and parenchymal hemorrhage. Whereas hemorrhagic transformation should be regarded as a clinically irrelevant epiphenomenon of ischemic damage and reperfusion, parenchymal hemorrhage appears to be related to biologic effects of tissue plasminogen activator and other pre-existing pathologic conditions, which deserve further investigation.