CT, US and MRI of Xanthine Urinary Stones: An In-Vitro Analysis

Background: Xanthine urinary stones are a rare entity that may occur in patients with Lesch-Nyhan Syndrome receiving allopurinol. There is little literature describing imaging characteristics of these stones, and the most appropriate approach to imaging these stones is therefore unclear. We performed an in-vitro analysis of xanthine stones using computed tomography (CT) at different energy levels, ultrasound (US), and magnetic resonance imaging (MRI). Methods: Five pure xanthine stones from a boy with Lesch-Nyhan were imaged. CT of the stones was performed at 80kVp, 100kVp, 120kVp and 140kVp and CT numbers of the stones were recorded in Hounseld units (HU). US of the stones was performed and echogenicity, acoustic shadowing and twinkle artifact were assessed. MRI of the stones was performed and included T2-weighted, ultrashort echo-time (UTE)-weighted and T2/T1-weighted 3D bFFE sequences and signal was assessed. Results: On CT, xanthine stones were radiodense and the average attenuation coecient did not differ with varying kVp, measuring 331.0+/-51.7HU at 80kVp, 321.4+/-63.4HU at 100kVp, 329.7+/-54.2HU at 120kVp and 328.4+/-61.1HU at 140kVp. On US, xanthine stones where echogenic with acoustic shadowing and twinkle artifact. On MRI, stones lacked signal on all tested sequences. Conclusion: Xanthine stones demonstrate imaging characteristics typical of most urinary stones: dense on CT, echogenic on US, and lack signal on MRI. Therefore, the approach to imaging xanthine urinary stones should identical to the approach with other urinary stones.


Background
Xanthine urolithiasis is a rare entity, occurring in patients with Lesch-Nyhan Syndrome, who are receiving allopurinol treatment, and in patients with hereditary xanthinuria [1][2][3][4]. While a rare condition, xanthine urolithiasis may cause recurrent symptoms in this group of patients and require frequent medical attention. Children with Lesch-Nyhan Syndrome are developmentally delayed, and often cannot appropriately verbalize their symptoms or localize their pain, making clinical assessment di cult. This often leads to multiple imaging studies over time. Understanding the imaging characteristics of these stones on different imaging modalities is imperative for effective clinical management.
Little is written in the medical literature about the imaging of xanthine stones, and no previous in-vitro studies have described the imaging characteristics of xanthine stones on CT, US or magnetic resonance imaging (MRI). A small number of in-vivo studies have described xanthine stones as radiolucent on radiographs and excretory urograms, as echogenic with posterior shadowing on ultrasound (US) and as having a computed tomography (CT) number ranging from 276-480 HU on conventional single energy CT [1][2][3][4].
Given the small number of previous studies on the topic, we sought to further characterize the imaging features of this rare urinary stone. Utilizing an in-vitro study design we characterized the imaging ndings of xanthine stones on varying CT energy levels (80, 100, 120 and 140 kVp), US and MRI.

Methods
This is a retrospective study, and for this type of study formal consent and an ethics approval by an IRB are not required.
Stones that were previously passed by a 6-year-old boy with Lesch-Nyhan Syndrome on allopurinol therapy were retained and analyzed. Stones' diameters measured 4.2 mm, 3.0 mm, 3.9 mm, 2.2 mm and 2.6 mm.
CT images of the stones were obtained using a GE LightSpeed VCT CT scanner. Stones were placed within saline-containing syringes arranged concentrically in an acrylic PMMA phantom. A 16 cm diameter CTDI phantom was used. CT imaging was performed at 80kVp, 100kVp, 120kVp and 140kVp levels. US images of the stones were obtained using a General Electric (GE) Logiq E9 US machine. Stones were placed one by one in a 0.9% NaCl saline bath on a standoff pad in a round plastic container. Stones were imaged with 7 MHz and 15 MHz transducers. Imaging characteristics were recorded, including echogenicity of the stones, acoustic shadowing and twinkle artifact on color Doppler imaging.
MR images of the stones were obtained on a 3T Philips Achieva MRI scanner with a 32-channel head coil. Stones were rst visualized in air-lled syringes and then in saline-lled syringes. T2-weighted (T2W) turbo spin echo (TSE) sequences, multi-slice balanced eld echo (bFFE, or balanced steady-state free precession) sequences, and 3D stack-of-stars ultra-short-TE(UTE) sequences with radial k-space trajectory acquisition were tested on the phantoms [5]. TSE-based T2W sequences had repetition time After imaging analysis of the stones was complete, chemical analysis of all stones was performed to con rm their composition.

Results
Chemical analysis con rmed that all ve stones where composed of 100% xanthine.  Table 1]. On US all stones were echogenic, demonstrated posterior acoustic shadowing, and twinkle artifact with color Doppler imaging [ Figure 2].
On MRI, stones were only visualized as a signal void when imaged in saline-lled syringes, and were not visualized when imaged in air-lled syringes on all sequences, including TSE based T2W sequences, UTE sequences and T2/T1-weighted 3D bFFE sequences [ Figure 3].

Discussion
To the best of the authors' knowledge, this is the rst in-vitro study describing the imaging characteristics of xanthine stones on CT with multiple different energy levels, US and MRI. A previous in-vivo study of xanthine stones using conventional single energy CT showed CT numbers of stones ranging from 276-480 HU [2]. Previous in-vivo US studies have shown xanthine stones to be echogenic with posterior acoustic shadowing, with features identical to other urinary calculi [3].  [6,8]. This may not be surprising given that xanthine and uric acid are part of the same metabolic pathway. The lower density of xanthine stones likely explains the previous literature describing them as radiolucent on radiographs. The lower density makes them more di cult to appreciate on radiographs than other more dense calculi, and stones were likely radiographically occult rather than truly radiolucent.
On US, all xanthine stones were echogenic, showed posterior acoustic shadowing, and demonstrated twinkle artifact with color Doppler imaging. These features are identical to other types of urinary stones. Previous in-vivo analyses of xanthine stones have also showed them to be indistinguishable from other urinary stones on US [1][2][3]. Based on these ndings, ultrasound is equally suitable to evaluate xanthine stones as any other type of urinary stone.
Xanthine stones showed no signal on all MRI sequences tested, including UTE MRI sequences. Stones are expected to result in signal voids on conventional MRI sequences, but recent studies of UTE imaging have shown signal within other types of urinary calculi on UTE sequences [9,10]. This has led some to suggest that these sequences might be utilized to evaluate urolithiasis. Our analysis suggests that xanthine stones are unlikely to be well visualized when utilizing the described MRI techniques in a clinical setting, including UTE sequences.
Although xanthine urolithiasis is a rare condition, it may cause recurrent symptoms in patients with Lesch-Nyhan Syndrome on allopurinol therapy and in patients with hereditary xanthinuria. Children with Lesch-Nyhan Syndrome are developmentally delayed and are often unable to appropriately verbalize their symptoms, making imaging particularly important in the clinical assessment of these patients. Given the recurrent nature of this condition, multiple imaging studies may be needed over the course of a lifetime. Based on the results of this in-vitro study, xanthine stones are easily detectable on US. Therefore, US should be the rst line imaging test in the evaluation of xanthine stones given its lack of ionizing radiation and ability to visualize these stones. Recent developments in UTE MRI sequences have suggested that MRI may provide an additional imaging modality to assess urinary caluli without ionizing radiation. However, our analysis suggests that xanthine stones are not easily detectable on MRI, including UTE sequences, and MRI is unlikely to be helpful in the evaluation of xanthine urolithiasis. Our analysis suggests that xanthine stones are well visualized on CT. Therefore, judicious use of conventional single energy non-contrast CT may be appropriate in patients with xanthine urolithiasis when ultrasound is inconclusive or insu cient. The risks of radiation exposure should always be considered, especially given the recurrent nature of this condition and the potential need for multiple imaging studies over a lifetime.
A limitation of our study stems from the small size of xanthine stones studied. Stones smaller than 5 mm in diameter tend to demonstrate lower CT numbers regardless of composition secondary to partialvolume effects. CT numbers in our analysis may be lower given the smaller size of the stones studied.
Previous MRI studies that were able to demonstrate signal within urinary stones used stones larger than 1 cm, which is larger than the stones evaluated in this study [7,10,11]. This small size may have contributed to the lack of signal seen on all MRI sequences tested in our study. Future studies could bene t from analyzing larger stones, if available.

Conclusions
Xanthine urinary stones are a rare type of urinary calculus that may cause recurrent symptoms requiring numerous imaging tests over a lifetime. Funding: This research did not receive any speci c grant from funding agencies in the public, commercial, or not-for-pro t sectors. In vitro MRI of xanthine urinary stones A. Coronal T2-weighted MR image shows stones (arrows) as hypointense signal voids within hyperintense saline-lled syringes B. Axial UTE-weighted MR image shows stones (arrows) as hypointense signal voids within hyperintense saline-lled syringes