Perfusion quantification of vascular malformations using contrast-enhanced ultrasound (CEUS) with time intensity curve analysis before and after treatment: First results

Abstract

AIM: Aim of this pilot-study was to quantify perfusion changes of vascular malformations before and after the first interventional treatment using contrast-enhanced ultrasound (CEUS).

MATERIAL AND METHODS: 29 patients (10 male, 19 female) between 6 and 63 years (mean 28.1 years) with 12 arterio-venous (AVM) and 17 venous malformations (VM) were examined before and after their first percutaneous interventional treatment. CEUS was performed with a 2.4 ml bolus injection of sulfur-hexafluorid microbubbles, and a 6–9 MHz mulitfrequency transducer. A 60 sec cine sequence was recorded and regions of interest (10 mm×30 mm) were defined in the centre, and the margins of the vascular malformation as well as in the surrounding healthy tissue. Time Intensity Curves (TIC) were analysed, and Time to Peak (TTP) as well as Area under the Curve (AUC) were calculated.

RESULTS: For VM there was a significant perfusion difference (p < 0.05) in AUC between centre and the surrounding tissue before (323.1 vs. 130.4 rU) and after treatment (331.0 vs. 106.9 rU). There was no significant difference for TTP in ROIs of VM (19.1 vs. 26.5 sec). After the treatment there was a significant decrease in AUC for all three regions in AVMs, and an increase in TTP for AVM. However TTP for AVM in the centre ROI still remained shorter than in the surrounding tissue even after therapy (20.9 vs. 25.4 sec).

CONCLUSION: CEUS with TIC analysis is a promising imaging method for the evaluation of perfusion before and after percutaneous treatment of vascular malformations. AUC decrease indicates therapy-induced changes in perfusion of VM whereas an increase in TTP shows therapy-related changes in AVM.

Keywords

Contrast-enhanced ultrasound (CEUS)venous malformation arterio-venous malformation TIC analysis

1 Introduction

Ultrasound is important for the diagnosis of peripheral vascular malformations. With the help of CCDS (colour coded Doppler sonography) or power Doppler hemodynamic changes can be depicted down to small capillary vessels if the flow is adapted appropriately [4]. This is especially helpful for aneurysms, shunts and fistulas. It is more difficult to achieve an artifact free flow detection for slow flow malformations or primary capillary changes [6]. Even when using low flow adjustments, capillary flow can hardly be detected using CCDS and cannot be evaluated quantitatively. Regardless of the angle CEUS can detect and evaluate blood flow down to capillaries [3 , 14] quantitatively by using sulfur-hexafluorid microbubbles (SonoVue Bracco^®, Italy). If the mechanical index is low (MI <0.16) a time intensity curve (TIC) can be formed using contrast harmonic imaging (CHI) [1, 10]. For these examinations with CEUS a TIC analysis can be performed for the detection of peripheral vascular malformations. The aim of this study was to examine perfusion changes quantitatively after first percutaneous interventional treatment of VM and AVM with TIC analyses in CEUS.

2 Material and mthods

This pilot study is a retrospective analysis of 29 patients (10 males, 19 females) between 6 and 63 years (mean 28.1 ± 17.2 years) with 12 arterio-venous and 17 venous malformations, who had undergone a percutaneous treatment for vascular malformations for the first time (see Table 1). The patients presented to our interdisciplinary vascular anomalies centre because of painful complaints. These patients received CEUS before and 24 hours after the percutaneous treatment. Diagnosis was formed on anamnesis, clinical and imaging findings. Indication for treatment was based on clinical findings in an interdisciplinary consensus. Before the procedure the patients were adequately informed about the CEUS procedure and the percutaneous intervention. Written informed consent was obtained from each patient before entry into the study. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki as reflected in an a priori approval by the institutional ethical board of the Medical Faculty of the University Regensburg.

2.1 Method US/CEUS

The sonographic examination was performed by an experienced examiner (>3000 examinations/ year, >10 years) using a high-end ultrasound machine (LOGIQ E9, GE Milwaukee, WI, USA), and a multifrequency transducer (6–9 MHz, GE).

All patients underwent detailed B-scan ultrasound (US) combined with power Doppler and color-coded Doppler sonography (CCDS) to delineate the malformation. CEUS was performed with a low mechanical index (MI 0.1–0.16) using the technique of pulse inversion harmonic imaging (PIHI) [1]. As ultrasonic second generation contrast agents, sulphur hexafluoride microbubbles (SonoVue^®, Bracco, Italy) were used. An intravenous bolus of 1–2.4 ml SonoVue^® was applied followed by a bolus of 10 ml saline injected through a 20–18 G peripheral cubital cannula.

Digital sequences were recorded as DICOM. In the centre of the lesion cine sequences were documented digitally trying to avoid motion artefacts. Afterwards cine-sequences of CEUS were performed of the whole malformation. Digitally stored cine-sequences of CEUS were evaluated using TIC analyses.

For follow up another CEUS examination was performed at the nidus of the peripheral malformation 24 hours after the percutaneous intervention. CEUS was performed in the same way as explained above. Post-interventional TTP and AUC were calculated.

2.2 Method TIC analysis

TIC analysis is an integrated software (LOGIQ WORKS, LOGIQ E9, GE) for quantification of tissue perfusion. It calculates the average signal intensity as a function of time in a defined region of interest (ROI). Regions of interest (ROI, 30 mm×10 mm) were manually placed in the centre, and the margins of the malformation, as well as in the surrounding healthy tissue. Time to peak (TTP, in sec), which represents the time of arrival of the contrast media to its maximum, and Area under the Curve (AUC in rU = relative units) were calculated (5). Cine-sequences before and after percutaneous intervention were compared.

2.3 Statistics

Besides descriptive analysis a Kruskal-Wallis test was used to compare perfusion parameters as well as Tukey procedure as post-hoc-test. If a difference was found, and to exclude the effect of multiple testing, Tukey tests were performed to determine which measurement had the most influence. Changes were considered to be significant for probabilities p less than 0.05.

3 Results

Ten male and 19 female patients between 6 and 63 years (mean 28.1 ± 17.2 years) with 12 arterio-venous and 17 venous malformations, who had undergone a percutaneous treatment for vascular malformations for the first time (see Table 1) were included. Most of the vascular malformations were located at the lower extremity (n = 20), 5 at the upper extremity and 2 in the face/neck, and torso each (see Table 2).

For the 12 AVM the pre-interventional TTP in the centre ranged between 7.25–36.79 sec (mean 16.9 ± 8.5 sec), at the margins between 6.33–48.42 sec (mean 18.9 ± 13.0 sec), and in the surrounding tissue between 6.79–44.16 sec (mean 22.2 ± 12.1 sec). The AUC in the centre was between 67.14–1279.08 rU (mean 514.6 ± 351.9 rU). At the margins between 17.94 und 1218.99 rU (mean 480.2 ± 365.2 rU), and in the healthy tissue between –11.68 und 814.93 rU (mean 273.5 ± 261.8 rU).

After the percutaneous treatment TTP for arterio-venous malformations in the centre was between 8.87 and 46.58 sec (mean 20.9 ± 12.5 sec), at the margins between 12.08 and 40.37 sec (mean 22.2 ± 9.6 sec) and in the surroundings between 9.09 and 53.36 sec (mean 25.4 ± 13.4). The AUC in the centre ranged between 39.29 and 1357.58 rU (mean 507.8 ± 407.4), at the margins 93.49 and 1077.12 rU (mean 470.7 ± 311.3 rU), and in the healthy tissue between 1.22 and 904.52 rU (mean 194.1 ± 245.8 rU) (see Table 3).

For the venous malformations TTP lay between 6.21 and 41.57 sec (mean 19.1 ± 10.7 sec) pre-interventionally, at the margins between 2.65 and 44.74 sec (mean 19.9 ± 11.6 sec) and in the surroundings between 4.60 and 55.98 sec (mean 26.5 ± 15.3 sec). AUC in the centre ranged between 73,81 and 943.60 rU (mean 323.1 ± 273.1 rU), at the margins between 59.62 and 525.47 rU (mean 217.8 ± 139.8 rU) and in the healthy tissue between –46.67 and 331.43 rU (mean 130.4 ± 97.9 rU).

After the intervention TTP in the centre was between 7.89 and 61.29 sec (mean 25.7 ± 16.9 sec), at the margins 7.13 and 52.44 sec (mean 27.1 ± 14.7 sec) and in the surroundings between 1.38 and 51.98 sec (mean 23.5 ± 14.3 sec). AUC in the centre was between 47.74 and 899.31 rU (mean 331.0 ± 213.7 rU), at the margins between 69.28 and 516.03 rU (mean 272.9 ± 131.0 rU) and in the healthy tissue between –18.66 and 319.68 rU (mean 106.9 ± 95.6 rU) (see Table 4).

For venous malformations there was a significant difference (p < 0.05) for AUC between the centre and the surroundings before the percutaneous treatment (mean 323.1 ± 273.1 rU vs. 130.4 ± 97.9 rU). However there was no significant difference, neither between centre and margins (mean 323.1 ± 273.1 rU vs. 217.8 ± 139.8 rU) nor between margins and the healthy tissue. After the intervention there was a significant difference (p < 0.05) concerning AUC for venous malformations between centre and surroundings (mean 331.0 ± 213.7 rU vs. 106.9 ± 95.6 rU) and margins compared to periphery (mean 273.0 ± 131.1 rU vs. 106.9 ± 95.6 rU).

Concerning TTP there was no significant difference, neither before (mean 19.1 ± 10.7 vs. 19.9 ± 11.6 vs. 26.5 ± 15.3 sec) nor after the intervention (mean 25.7 ± 16.9 vs. 27.1 ± 14.7 vs. 23.5 ± 14.3 sec) between the three ROIs (see Table 4).

Analogous there was a significant difference in AUC (p < 0.05) for arterio-venous malformations after the intervention between margin and surrounding tissue (470.7 ± 311.3 rU vs. 194.1 ± 245.8 rU) as well as between centre and periphery (507.8 ± 407.4 rU vs. 194.1 ± 245.8). Before the intervention there was no significant difference for the three ROIs, however AUC was lower in the healthy tissue (mean 273.5 ± 261.8 rU) than in the centre (mean 514.6 ± 351.9 rU) before the intervention. There was a tendency that TTP in AVM was lower in the centre than in the surroundings (mean 16.9 ± 8.5 sec vs. 22.2 ± 12.1 sec). After the percutaneous treatment there was a decrease of AUC in the centre, the margin and the surroundings for the AVM compared to AUC before the treatment (see Table 3). There was an increase in TTP, however TTP in the centre of AVM remained lower than in the healthy tissue (mean 20.9 ± 12.5 sec vs. 25.4 ± 13.4 sec).

4 Discussion

Contrast-enhanced ultrasound is not yet a standardized examination in evaluation of vascular malformations. However, it has a proven role in clinical routine e.g. for differential diagnosis of focal liver lesion [2] and for follow-up after liver transplantation [13], as well as for analysis of paratoid gland tumors [11]. By using TIC analysis capillary micro-vascularisation can be detected. There is only strictly intravascular dispersion of contrast media in CEUS [9]. For the first time, TIC analyses that have already been used for postoperative control of tissue transplants [6, 7] were used in the vascular malformations before and after the initial treatment (Figs. 1–5).

The CEUS procedures show a significant difference in the perfusion patterns between the centre and the surrounding healthy tissue for VM and AVM. There is a drop in the AUC for AVM when pre-interventional curves are compared with post-interventional curves. TTP is lower in the centre of the AVM because there is a faster enhancement due to the arterial part of the vascular malformation as compared to the surrounding tissue. Analogous TTP increases after the intervention for AVM because the pathological arterial flow in the lesion due to multiple arterio-venous fistulas was reduced by the embolisation. For venous malformations TTP is equal for the centre and the margins of the lesion, however it is still lower than TTP of the surrounding healthy tissue. This difference is nullified after the percutaneous treatment.

A limitation of this study is the small scanning area as compared to the size of the lesion. For further analyses more patients need to be evaluated, since this study only represents a small sample size at only one centre. Comparison of perfusion parameters before and after treatment depend on the identical location of the analysed area.

5 Conclusion

The study revealed a therapy-induced decrease of the perfusion in malformations. However the blood supply cannot be stopped completely at once because of necrosis. According to our clinical impression there is a certain pain-relieve from the malformation, however more sessions are needed for complete healing.

Baseline evaluations prior therapy of vascular malformations by a colour-coded perfusion software showed similar results for perfusion values evaluated by CEUS. However, the AUC and TTP were not equal to values measured in the surrounding healthy tissue. This implies that in many of the patients additional interventions may be warranted. This correlates with the clinical findings that sclerotherapy in VM and embolization in AVM have to be repeated in most patients.

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