Edwin Bennink

A fast nonlinear regression method for estimating permeability in CT perfusion imaging

Blood–brain barrier damage, which can be quantified by measuring vascular permeability, is a potential predictor for hemorrhagic transformation in acute ischemic stroke. Permeability is commonly estimated by applying Patlak analysis to computed tomography (CT) perfusion data, but this method lacks precision. Applying more elaborate kinetic models by means of nonlinear regression (NLR) may improve precision, but is more time consuming and therefore less appropriate in an acute stroke setting. We propose a simplified NLR method that may be faster and still precise enough for clinical use. The aim of this study is to evaluate the reliability of in total 12 variations of Patlak analysis and NLR methods, including the simplified NLR method. Confidence intervals for the permeability estimates were evaluated using simulated CT attenuation-time curves with realistic noise, and clinical data from 20 patients. Although fixating the blood volume improved Patlak analysis, the NLR methods yielded significantly more reliable estimates, but took up to 12 x longer to calculate. The simplified NLR method was ~4 x faster than other NLR methods, while maintaining the same confidence intervals (CIs). In conclusion, the simplified NLR method is a new, reliable way to estimate permeability in stroke, fast enough for clinical application in an acute stroke setting.

Imaging Findings Associated with Space-Occupying Edema in Patients with Large Middle Cerebral Artery Infarcts.

BACKGROUND AND PURPOSE: Prominent space-occupying cerebral edema is a devastating complication occurring in some but not all patients with large MCA infarcts. It is unclear why differences in the extent of edema exist. Better knowledge of factors related to prominent edema formation could aid treatment strategies. This study aimed to identify variables associated with the development of prominent edema in patients with large MCA infarcts. MATERIALS AND METHODS: From the Dutch Acute Stroke Study (DUST), 137 patients were selected with large MCA infarcts on follow-up NCCT (3 ± 2 days after stroke onset), defined as ASPECTS ≤4. Prominent edema was defined as a midline shift of ≥5 mm on follow-up. Admission patient and treatment characteristics were collected. Admission CT parameters used were ASPECTS on NCCT and CBV and MTT maps, and occlusion site, clot burden, and collaterals on CTA. Permeability on admission CTP, and day 3 recanalization and reperfusion statuses were obtained if available. Unadjusted and adjusted (age and NIHSS) odds ratios were calculated for all variables in relation to prominent edema. RESULTS: Prominent edema developed in 51 patients (37%). Adjusted odds ratios for prominent edema were higher with lower ASPECTS on NCCT (adjusted odds ratio, 1.32; 95% CI, 1.13–1.55) and CBV (adjusted odds ratio, 1.26; 95% CI, 1.07–1.49), higher permeability (adjusted odds ratio, 2.35; 95% CI, 1.30–4.24), more proximal thrombus location (adjusted odds ratio, 3.40; 95% CI, 1.57–7.37), higher clot burden (adjusted odds ratio, 2.88; 95% CI, 1.11–7.45), and poor collaterals (adjusted odds ratio, 3.93; 95% CI, 1.78–8.69). CONCLUSIONS: Extensive proximal occlusion, poor collaterals, and larger ischemic deficits with higher permeability play a role in the development of prominent edema in large MCA infarcts.

CT perfusion analysis by nonlinear regression for predicting hemorrhagic transformation in ischemic stroke

PURPOSE Intravenous thrombolysis can improve clinical outcome in acute ischemic stroke patients but increases the risk of hemorrhagic transformation (HT). Blood-brain barrier damage, which can be quantified by the vascular permeability for contrast agents, is a potential predictor for HT. This study aimed to assess whether this prediction can be improved by measuring vascular permeability using a novel fast nonlinear regression (NLR) method instead of Patlak analysis. METHODS From a prospective ischemic stroke multicenter cohort study, 20 patients with HT on follow-up imaging and 40 patients without HT were selected. The permeability transfer constant K(trans) was measured in three ways; using standard Patlak analysis, Patlak analysis with a fixed offset, and the NLR method. In addition, the permeability-surface (PS) area product and the conventional perfusion parameters (blood volume, flow, and mean transit time) were measured using the NLR method. Relative values were calculated in two ways, i.e., by dividing the average in the infarct core by the average in the contralateral hemisphere, and by dividing the average in the ipsilateral hemisphere by the average in the contralateral hemisphere. Mann-Whitney U tests and receiver operating characteristic (ROC) analyses were performed to assess the discriminative power of each of the relative parameters. RESULTS Both the infarct-core and whole-hemisphere averaged relative K(trans) (rK(trans)) values, measured with the NLR method, were significantly higher in the patients who developed HT as compared with those who did not. The rK(trans) measured with standard Patlak analysis was not significantly different. The relative PS (rPS), measured with NLR, had the highest discriminative power (P = 0.002). ROC analysis of rPS showed an area under the curve (AUC) of 0.75 (95% confidence interval: 0.62-0.89) and a sensitivity of 0.75 at a specificity of 0.75. The AUCs of the Patlak rK(trans), the Patlak rK(trans) with fixed offset, and the NLR rK(trans) were 0.58, 0.66, and 0.67, respectively. CONCLUSIONS CT perfusion analysis may aid in predicting HT, but standard Patlak analysis did not provide estimates for rK(trans) that were significantly higher in the HT group. The rPS, measured in the infarct core with NLR, had superior discriminative power compared with K(trans) measured with either Patlak analysis with a fixed offset or NLR, and conventional perfusion parameters.

CT Brain Perfusion Protocol to Eliminate the Need for Selecting a Venous Output Function

BACKGROUND AND PURPOSE: In CTP, an arterial input function is used for cerebral blood volume measurement. AIFs are often influenced by partial volume effects resulting in overestimated CBV. A venous output function is manually selected to correct for partial volume. This can introduce variability. Our goal was to develop a CTP protocol that enables AIF selection unaffected by partial volume. MATERIALS AND METHODS: First, the effects of partial volume on artery sizes/types including the MCA were estimated by using a CTP phantom with 9 protocols (section thicknesses of 1, 1.8, and 5 mm and image resolutions of 0.5, 1, and 1.5 mm). Next, these protocols were applied to clinical CTP studies from 6 patients. The influence of the partial volume effect was measured by comparison of the time-attenuation curves from different artery locations with reference veins. RESULTS: AIFs from MCAs were unaffected by partial volume effects when using high image resolution (1 mm) and medium section thickness (1.8 mm). For the clinical data, a total of 104 arteries and 60 veins was selected. The data confirmed that high image resolution and thin section thickness enable selection of MCAs for AIFs free of partial volume influences. In addition, we found that large veins were not insusceptible to partial volume effects relative to large arteries, questioning the use of veins for partial volume correction. CONCLUSIONS: A CTP protocol with 1.8-mm section thickness and 1-mm image resolution allows AIF selection unaffected by partial volume effects in MCAs.

Comparison of DCE-CT models for quantitative evaluation of K-trans in larynx tumors

Dynamic contrast enhanced CT (DCE-CT) can be used to estimate blood perfusion and vessel permeability in tumors. Tumor induced angiogenesis is generally associated with disorganized microvasculature with increased permeability or leakage. Estimated vascular leakage (K(trans)) values and their reliability greatly depend on the perfusion model used. To identify the preferred model for larynx tumor analysis, several perfusion models frequently used for estimating permeability were compared in this study. DCE-CT scans were acquired for 16 larynx cancer patients. Larynx tumors were delineated based on whole-mount histopathology after laryngectomy. DCE-CT data within these delineated volumes were analyzed using the Patlak and Logan plots, the Extended Tofts Model (ETM), the Adiabatic Approximation to the Tissue Homogeneity model (AATH) and a variant of AATH with fixed transit time (AATHFT). Akaikes Information Criterion (AIC) was used to identify the best fitting model. K(trans) values from all models were compared with this best fitting model. Correlation strength was tested with two-tailed Spearmans rank correlation and further examined using Bland-Altman plots. AATHFT was found to be the best fitting model. The overall median of individual patient medians K(trans) estimates were 14.3, 15.1, 16.1, 2.6 and 22.5 mL/100 g min(  -  1) for AATH, AATHFT, ETM, Patlak and Logan, respectively. K(trans) estimates for all models except Patlak were strongly correlated (P  <  0.001). Bland-Altman plots show large biases but no significant deviating trend for any model other than Patlak. AATHFT was found to be the preferred model among those tested for estimation of K(trans) in larynx tumors.

Automatic Localization of Cochlear Implant Electrode Contacts in CT

Objectives: Determining the exact location of cochlear implant (CI) electrode contacts after implantation is important, as it helps quantifying the relation between CI positioning and hearing outcome. Unfortunately, localization of individual contacts can be difficult, because the spacing between the electrode contacts is near the spatial resolution limit of high-resolution clinical computed tomography (CT) scanners. This study introduces and examines a simple, automatic method for the localization of intracochlear electrode contacts. CI geometric specifications may provide the prior knowledge that is essential to accurately estimate contact positions, even though individual contacts may not be visibly resolved. Design: The prior knowledge in CI geometry is used to accurately estimate intracochlear electrode contact positions in high-resolution CT scans of seven adult patients implanted with a CI (Cochlear Ltd.). The automatically detected electrode contact locations were verified against locations marked by two experienced observers. The interobserver errors and the errors between the averaged locations and the automatically detected locations were calculated. The estimated contact positions were transformed to a cylindrical cochlear coordinate system, according to an international consensus, in which the insertion angles and the radius and elevation were measured. Results: The linear correlation of the automatically detected electrode contact positions with the manually detected locations was high (R2 = 0.98 for the radius, and R2 = 1.00 for the insertion angle). The errors in radius and in insertion angle between the automatically detected locations and the manually detected locations were 0.12 mm and 1.7°. These errors were comparable to the interobserver errors. Geometrical measurements were in line with what is usually found in human cochleae. The mean insertion angle of the most apical electrode was 410° (range: 316° to 503°). The mean radius of the electrode contacts in the first turn of the cochlear spiral was 3.0 mm, and the mean radius of the remainder in the second turn was 1.7 mm. Conclusions: With implant geometry as prior knowledge, automatic analysis of high-resolution CT scans enables accurate localization of CI electrode contacts. The output of this method can be used to study the effect of CI positioning on hearing outcomes in more detail.

Comparison of partial volume effects in arterial and venous contrast curves in CT brain perfusion imaging.

Purpose In brain CT perfusion (CTP), the arterial contrast bolus is scaled to have the same area under the curve (AUC) as the venous outflow to correct for partial volume effects (PVE). This scaling is based on the assumption that large veins are unaffected by PVE. Measurement of the internal carotid artery (ICA), usually unaffected by PVE due to its large diameter, may avoid the need for partial volume correction. The aims of this work are to examine i) the assumptions behind PVE correction and ii) the potential of selecting the ICA obviating correction for PVE. Methods The AUC of the ICA and sagittal sinus were measured in CTP datasets from 52 patients. The AUCs were determined by i) using commercial CTP software based on a Gaussian curve-fitting to the time attenuation curve, and ii) by simple integration of the time attenuation curve over a time interval. In addition, frames acquired up to 3 minutes after first bolus passage were used to examine the ratio of arterial and venous enhancement. The impact of selecting the ICA without PVE correction was illustrated by reporting cerebral blood volume (CBV) measurements. Results In 49 of 52 patients, the AUC of the ICA was significantly larger than that of the sagittal sinus (p = 0.017). Measured after the first pass bolus, contrast enhancement remained 50% higher in the ICA just after the first pass bolus, and 30% higher 3 minutes later. CBV measurements were significantly lowered when the ICA was used without PVE correction. Conclusions Contradicting the assumptions underlying PVE correction, contrast in the ICA was significantly higher than in the sagittal sinus, even 3 minutes after the first pass of the contrast bolus. PVE correction might lead to overestimation of CBV if the CBV is calculated using the AUC of the time attenuation curves.

Image quality of conventional images of dual‐layer SPECTRAL CT: A phantom study

Purpose Spectral CT using a dual layer detector offers the possibility of retrospectively introducing spectral information to conventional CT images. In theory, the dual‐layer technology should not come with a dose or image quality penalty for conventional images. In this study, we evaluate the influence of a dual‐layer detector (IQon Spectral CT, Philips Healthcare) on the image quality of conventional CT images, by comparing these images with those of a conventional but otherwise technically comparable single‐layer CT scanner (Brilliance iCT, Philips Healthcare), by means of phantom experiments. Methods For both CT scanners, conventional CT images were acquired using four adult scanning protocols: (a) body helical, (b) body axial, (c) head helical, and (d) head axial. A CATPHAN 600 phantom was scanned to conduct an assessment of image quality metrics at equivalent (CTDI) dose levels. Noise was characterized by means of noise power spectra (NPS) and standard deviation (SD) of a uniform region, and spatial resolution was evaluated with modulation transfer functions (MTF) of a tungsten wire. In addition, contrast‐to‐noise ratio (CNR), image uniformity, CT number linearity, slice thickness, slice spacing, and spatial linearity were measured and evaluated. Additional measurements of CNR, resolution and noise were performed in two larger phantoms. Results The resolution levels at 50%, 10%, and 5% MTF of the iCT and IQon showed small, but significant differences up to 0.25 lp/cm for body scans, and up to 0.2 lp/cm for head scans in favor of the IQon. The iCT and IQon showed perfect CT linearity for body scans, but for head scans both scanners showed an underestimation of the CT numbers of materials with a high opacity. Slice thickness was slightly overestimated for both scanners. Slice spacing was comparable and reconstructed correctly. In addition, spatial linearity was excellent for both scanners, with a maximum error of 0.11 mm. CNR was higher on the IQon compared to the iCT for both normal and larger phantoms with differences up to 0.51. Spatial resolution did not change with phantom size, but noise levels increased significantly. For head scans, IQon had a noise level that was significantly lower than the iCT, on the other hand IQon showed noise levels significantly higher than the iCT for body scans. Still, these differences were well within the specified range of performance of iCT scanners. Conclusions At equivalent dose levels, this study showed similar quality of conventional images acquired on iCT and IQon for medium‐sized phantoms and slightly degraded image quality for (very) large phantoms at lower tube voltages on the IQon. Accordingly, it may be concluded that the introduction of a dual‐layer detector neither compromises image quality of conventional images nor increases radiation dose for normal‐sized patients, and slightly degrades dose efficiency for large patients at 120 kVp and lower tube voltages.

Computed Tomography Perfusion Derived Blood-Brain Barrier Permeability Does Not Yet Improve Prediction of Hemorrhagic Transformation

Introduction: Hemorrhagic transformation (HT) in acute ischemic stroke can occur as a result of reperfusion treatment. While withholding treatment may be warranted in patients with increased risk of HT, prediction of HT remains difficult. Nonlinear regression analysis can be used to estimate blood-brain barrier permeability (BBBP). The aim of this study was to identify a combination of clinical and imaging variables, including BBBP estimations, that can predict HT. Materials and Methods: From the Dutch acute stroke study, 545 patients treated with intravenous recombinant tissue plasminogen activator and/or intra-arterial treatment were selected, with available admission extended computed tomography (CT) perfusion and follow-up imaging. Patient admission treatment characteristics and CT imaging parameters regarding occlusion site, stroke severity, and BBBP were recorded. HT was assessed on day 3 follow-up imaging. The association between potential predictors and HT was analyzed using univariate and multivariate logistic regression. To compare the added value of BBBP, areas under the curve (AUCs) were created from 2 models, with and without BBBP. Results: HT occurred in 57 patients (10%). In univariate analysis, older age (OR 1.03, 95% CI 1.006–1.05), higher admission National Institutes of Health Stroke Scale (NIHSS; OR 1.13, 95% CI 1.08–1.18), higher clot burden (OR 1.28, 95% CI 1.16–1.41), poor collateral score (OR 3.49, 95% CI 1.85–6.58), larger Alberta Stroke Program Early CT Score cerebral blood volume deficit size (OR 1.26, 95% CI 1.14–1.38), and increased BBBP (OR 2.22, 95% CI 1.46–3.37) were associated with HT. In multivariate analysis with age and admission NIHSS, the addition of BBBP did not improve the AUC compared to both independent predictors alone (AUC 0.77, 95% CI 0.71–0.83). Conclusion: BBBP predicts HT but does not improve prediction with age and admission NIHSS.

Influence of Thin Slice Reconstruction on CT Brain Perfusion Analysis.

Objectives Although CT scanners generally allow dynamic acquisition of thin slices (1 mm), thick slice (≥5 mm) reconstruction is commonly used for stroke imaging to reduce data, processing time, and noise level. Thin slice CT perfusion (CTP) reconstruction may suffer less from partial volume effects, and thus yield more accurate quantitative results with increased resolution. Before thin slice protocols are to be introduced clinically, it needs to be ensured that this does not affect overall CTP constancy. We studied the influence of thin slice reconstruction on average perfusion values by comparing it with standard thick slice reconstruction. Materials and Methods From 50 patient studies, absolute and relative hemisphere averaged estimates of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and permeability-surface area product (PS) were analyzed using 0.8, 2.4, 4.8, and 9.6 mm slice reconstructions. Specifically, the influence of Gaussian and bilateral filtering, the arterial input function (AIF), and motion correction on the perfusion values was investigated. Results Bilateral filtering gave noise levels comparable to isotropic Gaussian filtering, with less partial volume effects. Absolute CBF, CBV and PS were 22%, 14% and 46% lower with 0.8 mm than with 4.8 mm slices. If the AIF and motion correction were based on thin slices prior to reconstruction of thicker slices, these differences reduced to 3%, 4% and 3%. The effect of slice thickness on relative values was very small. Conclusions This study shows that thin slice reconstruction for CTP with unaltered acquisition protocol gives relative perfusion values without clinically relevant bias. It does however affect absolute perfusion values, of which CBF and CBV are most sensitive. Partial volume effects in large arteries and veins lead to overestimation of these values. The effects of reconstruction slice thickness should be taken into account when absolute perfusion values are used for clinical decision making.