Quantification of infarct core signal using CT imaging in acute ischemic stroke

Abstract

In stroke care, the extent of irreversible brain injury, termed infarct core, plays a key role in determining eligibility for acute treatments, such as intravenous thrombolysis and endovascular reperfusion therapies. Many of the pivotal randomized clinical trials testing those therapies used MRI Diffusion-Weighted Imaging (DWI) or CT Perfusion (CTP) to define infarct core. Unfortunately, these modalities are not available 24/7 outside of large stroke centers. As such, there is a need for accurate infarct core determination using faster and more widely available imaging modalities including Non-Contrast CT (NCCT) and CT Angiography (CTA). Prior studies have suggested that CTA provides improved predictions of infarct core relative to NCCT; however, this assertion has never been numerically quantified by automatic medical image computing pipelines using acquisition protocols not confounded by different scanner manufacturers, or other protocol settings such as exposure times, kilovoltage peak, or imprecision due to contrast bolus delays. In addition, single-phase CTA protocols are at present designed to optimize contrast opacification in the arterial phase. This approach works well to maximize the sensitivity to detect vessel occlusions, however, it may not be the ideal timing to enhance the ischemic infarct core signal (ICS). In this work, we propose an image analysis pipeline on CT-based images of 88 acute ischemic stroke (AIS) patients drawn from a single dynamic acquisition protocol acquired at the acute ischemic phase. We use the first scan at the time of the dynamic acquisition as a proxy for NCCT, and the rest of the scans as a proxy for CTA scans, with bolus imaged at different brain enhancement phases. Thus, we use the terms "NCCT" and "CTA" to refer to them. This pipeline enables us to answer the questions "Does the injection of bolus enhance the infarct core signal?" and "What is the ideal bolus timing to enhance the infarct core signal?" without being influenced by aforementioned factors such as scanner model, acquisition settings, contrast bolus delay, and human reader errors. We use reference MRI DWI images acquired after successful recanalization acting as our gold standard for infarct core. The ICS is quantified by calculating the difference in intensity distribution between the infarct core region and its symmetrical healthy counterpart on the contralateral hemisphere of the brain using a metric derived from information theory, the Kullback-Leibler divergence (KL divergence). We compare the ICS provided by NCCT and CTA and retrieve the optimal timing of CTA bolus to maximize the ICS. In our experiments, we numerically confirm that CTAs provide greater ICS compared to NCCT. Then, we find that, on average, the ideal CTA acquisition time to maximize the ICS is not the current target of standard CTA protocols, i.e., during the peak of arterial enhancement, but a few seconds afterward (median of 3 s; 95% CI [1.5, 3.0]). While there are other studies comparing the prediction potential of ischemic infarct core from NCCT and CTA images, to the best of our knowledge, this analysis is the first to perform a quantitative comparison of the ICS among CT based scans, with and without bolus injection, acquired using the same scanning sequence and a precise characterization of the bolus uptake, hence, reducing potential confounding factors.

Keywords: Acute ischemic stroke; CTA; CTA timing; Infarct core; Infarct core signal; NCCT.

Fig. 1

a) Diagram of the brain showing 4 different regions (infarct core region, contralateral region, affected hemisphere, and contralateral hemisphere) and median intensity in Hounsfield Units (HU) of those 4 regions of the brain for each time point of the CTP-SI of one patient of the dataset. Four different time points are indicated, the first time point in red (equivalent to a NCCT) and the time points corresponding to the early arterial phase (in yellow), mid arterial phase (in green), and delayed venous phase (in blue). NCCT: non-contrast CT. b) For the same patient, axial slices of the NCCT (1st row), early arterial CTA (2nd row), mid arterial CTA (3rd row), delayed venous CTA (4th row), and MRI DWI and manual infarct core segmentation overlayed in white (4th row). Note how the vessel's enhancement changes in the CTP-SI at different time points (from no enhancement in the NCCT to increasing enhancement in the other CTAs) and the difficulty to visually distinguish the infarct core region from these low radiation CTAs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Quantification of ICS using the KL divergence. First, the intensity probability distributions are estimated for these two regions. Then, the KL divergence is computed between the two probability distributions as in the formula.

Fig. 3

Percentage of patients providing the highest ICS at 7 different time levels: (1) before the early arterial phase (1.1 %), (2) at the early arterial phase (0 %), (3) between the early and the mid arterial phases (5.7 %), (4) at the mid arterial phase (9.1 %), (5) between the mid and the delayed venous phases (69.3 %), (6) at the delayed venous phase (4.5 %) (7) and after the delayed venous phase (10.2 %). The highest ICS corresponds to the highest Kullback-Leibler divergence between the contralateral region and the infarct core region and for most cases (69.3 %) it is provided by a CTA scan acquired between the mid arterial phase and the delayed venous phase.

Fig. 4

Boxplots of ICS and OCS for 6 different scans (NCCT; Early arterial CTA; Mid arterial CTA; Delayed venous CTA; Ideal CT(A); group-level Ideal CT(A)) representing the distribution over the 88 patients of the Kullback-Leibler divergence between the contralateral region and the infarct core region (ICS) and between hemispheres (OCS). Ideal CT(A): time point providing the highest Kullback-Leibler divergence between the contralateral region and the infarct core region, specific for each patient. Group-level Ideal CT(A): CTA at 3 s after the mid arterial phase. Pairwise ICS numerical comparisons, including statistical significance are available in Table 3.

Fig. 5

a) Axial slices of 5 brain scans of 1 patient of the dataset (5 rows for each of the 5 different scans) and corresponding overlayed ground truth infarct core contour in green. B) For the same patient as in a), axial slices of the Kullback-Leibler divergence (KL) brain maps were obtained from the same 5 scans and corresponding overlayed ground truth infarct core contour in green. Scans: non-contrast CT (NCCT), Early arterial CTA, Mid arterial CTA, Ideal CT(A), Delayed venous CTA. The ideal CT(A) corresponds to the CT scan at which the KL between the contralateral region and the infarct core region is higher. For each CTA, the scan starting time after contrast injection is indicated in parenthesis. Note the ability of KL to detect the infarct core region from the Ideal CT(A) (4th row in b), detecting more voxels from the infarct core region than in the case of the mid arterial CTA and leading to fewer false positives than in the case of the delayed venous CTA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)