Clinical Utility of Multi-Energy Spectral Photon-Counting Computed Tomography in Crystal Arthritis.

OBJECTIVE: To determine whether novel multi-energy spectral photon-counting computed tomography (SPCCT) imaging can detect and differentiate between monosodium urate (MSU), calcium pyrophosphate (CPP), and hydroxyapatite (HA) crystal deposits ex vivo. METHODS: A finger with a subcutaneous gouty tophus and a calcified knee meniscus excised at the time of surgery were obtained. The finger was imaged using plain x-ray, dual-energy CT (DECT), and multi-energy SPCCT. Plain x-ray and multi-energy SPCCT images of the meniscus were acquired. For validation purposes, samples of the crystals were obtained from the tophus and meniscus, and examined by polarized light microscopy and/or x-ray diffraction. As further validation, synthetic crystal suspensions of MSU, CPP, and HA were scanned using multi-energy SPCCT. RESULTS: Plain x-ray of the gouty finger revealed bone erosions with overhanging edges. DECT and multi-energy SPCCT both showed MSU crystal deposits; SPCCT was able to show finer detail. Plain x-ray of the calcified meniscus showed chondrocalcinosis consistent with CPP, while SPCCT showed and differentiated CPP and HA. CONCLUSION: Multi-energy SPCCT can not only detect, differentiate, and quantify MSU crystal deposits in a gouty finger ex vivo, but also specifically detect, identify, and quantify CPP within an osteoarthritic meniscus, and distinguish them from HA crystal deposits. There is potential for multi-energy SPCCT to become useful in the diagnosis of crystal arthropathies.

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses.

INTRODUCTION: The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. Forms associated with mutations in two of these, CLN5 and CLN6, are being investigated in well-established sheep models. Brain atrophy leading to psychomotor degeneration is among the defining features, as is regional progressive ossification of the inner cranium. Ongoing viral-mediated gene therapy trials in these sheep are yielding encouraging results. In vivo assessment of brain atrophy is integral to the longitudinal monitoring of individual animals and provides robust data for translation to treatments for humans. METHODS: Computed tomography (CT)-based three-dimensional reconstruction of the intracranial volume (ICV) over time reflects the progression of cortical brain atrophy, verifying the use of ICV measurements as a surrogate measure for brain size in ovine NCL. RESULTS: ICVs of NCL-affected sheep increase for the first few months, but then decline progressively between 5 and 13 months in CLN5-/- sheep and 11-15 months in CLN6-/- sheep. Cerebral ventricular volumes are also increased in affected animals. To facilitate ICV measures, the radiodensities of ovine brain tissue and cerebrospinal fluid were identified. Ovine brain tissue exhibited a Hounsfield unit (HU) range of (24; 56) and cerebrospinal fluid a HU range of (-12; 23). CONCLUSIONS: Computed tomography scanning and reconstruction verify that brain atrophy ovine CLN5 NCL originates in the occipital lobes with subsequent propagation throughout the whole cortex and these regional differences are reflected in the ICV loss.

Discrimination Between Calcium Hydroxyapatite and Calcium Oxalate Using Multienergy Spectral Photon-Counting CT.

OBJECTIVE: We aimed to determine whether multienergy spectral photon-counting CT could distinguish between clinically relevant calcium crystals at clinical x-ray energy ranges. Energy thresholds of 15, 22, 29, and 36 keV and tube voltages of 50, 80, and 110 kVp were selected. Images were analyzed to assess differences in linear attenuation coefficients between various concentrations of calcium hydroxyapatite (54.3, 211.7, 808.5, and 1169.3 mg/cm3) and calcium oxalate (2000 mg/cm3). CONCLUSION: The two lower concentrations of hydroxyapatite were distinguishable from oxalate at all energy thresholds and tube voltages, whereas discrimination at higher concentrations depended primarily on the energy thresholds used. Multienergy spectral photon-counting CT shows promise for distinguishing these calcium crystals.

Quantitative imaging of excised osteoarthritic cartilage using spectral CT.

OBJECTIVES: To quantify iodine uptake in articular cartilage as a marker of glycosaminoglycan (GAG) content using multi-energy spectral CT. METHODS: We incubated a 25-mm strip of excised osteoarthritic human tibial plateau in 50 % ionic iodine contrast and imaged it using a small-animal spectral scanner with a cadmium telluride photon-processing detector to quantify the iodine through the thickness of the articular cartilage. We imaged both spectroscopic phantoms and osteoarthritic tibial plateau samples. The iodine distribution as an inverse marker of GAG content was presented in the form of 2D and 3D images after applying a basis material decomposition technique to separate iodine in cartilage from bone. We compared this result with a histological section stained for GAG. RESULTS: The iodine in cartilage could be distinguished from subchondral bone and quantified using multi-energy CT. The articular cartilage showed variation in iodine concentration throughout its thickness which appeared to be inversely related to GAG distribution observed in histological sections. CONCLUSIONS: Multi-energy CT can quantify ionic iodine contrast (as a marker of GAG content) within articular cartilage and distinguish it from bone by exploiting the energy-specific attenuation profiles of the associated materials. KEY POINTS: • Contrast-enhanced articular cartilage and subchondral bone can be distinguished using multi-energy CT. • Iodine as a marker of glycosaminoglycan content is quantifiable with multi-energy CT. • Multi-energy CT could track alterations in GAG content occurring in osteoarthritis.

Energy calibration of the pixels of spectral X-ray detectors.

The energy information acquired using spectral X-ray detectors allows noninvasive identification and characterization of chemical components of a material. To achieve this, it is important that the energy response of the detector is calibrated. The established techniques for energy calibration are not practical for routine use in pre-clinical or clinical research environment. This is due to the requirements of using monochromatic radiation sources such as synchrotron, radio-isotopes, and prohibitively long time needed to set up the equipment and make measurements. To address these limitations, we have developed an automated technique for calibrating the energy response of the pixels in a spectral X-ray detector that runs with minimal user intervention. This technique uses the X-ray tube voltage (kVp) as a reference energy, which is stepped through an energy range of interest. This technique locates the energy threshold where a pixel transitions from not-counting (off) to counting (on). Similarly, we have developed a technique for calibrating the energy response of individual pixels using X-ray fluorescence generated by metallic targets directly irradiated with polychromatic X-rays, and additionally γ-rays from (241)Am. This technique was used to measure the energy response of individual pixels in CdTe-Medipix3RX by characterizing noise performance, threshold dispersion, gain variation and spectral resolution. The comparison of these two techniques shows the energy difference of 1 keV at 59.5 keV which is less than the spectral resolution of the detector (full-width at half-maximum of 8 keV at 59.5 keV). Both techniques can be used as quality control tools in a pre-clinical multi-energy CT scanner using spectral X-ray detectors.

Clinical applications of spectral molecular imaging: potential and challenges.

Spectral molecular imaging is a new X-ray-based imaging technology providing highly specific 3D imaging at high spatial resolution that has the potential to measure disease activity and response to treatment noninvasively. The ability to identify and quantify components of tissue and biomarkers of disease activity derive from the properties of the photon-processing detector. Multiple narrow sections of the energy spectrum are sampled simultaneously, providing a range of energy dependent Hounsfield units. As each material has a specific measurable X-ray spectrum, spectroscopic imaging allows for multiple materials to be quantified and differentiated from each other simultaneously. The technology, currently in its infancy, is set to grow rapidly, much as magnetic resonance did. The critical clinical applications have not yet been established, but it is likely to play a major role in identifying and directing treatment for unstable atherosclerotic plaque, assessing activity and response to treatment of a range of inflammatory diseases, and monitoring biomarkers of cancer and its treatment. If combined with Positron-emission tomography (PET), spectral molecular imaging could have a far greater effective role in cancer diagnosis and treatment monitoring than PET-CT does at present. It is currently used for small animal and specimen imaging. There are many challenges to be overcome before spectral imaging can be introduced into clinical medicine - these include technological improvements to detector design, bonding to the semiconductor layer, image reconstruction and display software, identifying which biomarkers are of most relevance to the disease in question, and accelerating drug discovery enabled by the new capabilities provided by spectral imaging.

Toward quantifying the composition of soft tissues by spectral CT with Medipix3.

PURPOSE: To determine the potential of spectral computed tomography (CT) with Medipix3 for quantifying fat, calcium, and iron in soft tissues within small animal models and surgical specimens of diseases such as fatty liver (metabolic syndrome) and unstable atherosclerosis. METHODS: The spectroscopic method was applied to tomographic data acquired using a micro-CT system incorporating a Medipix3 detector array with silicon sensor layer and microfocus x-ray tube operating at 50 kVp. A 10 mm diameter perspex phantom containing a fat surrogate (sunflower oil) and aqueous solutions of ferric nitrate, calcium chloride, and iodine was imaged with multiple energy bins. The authors used the spectroscopic characteristics of the CT number to establish a basis for the decomposition of soft tissue components. The potential of the method of constrained least squares for quantifying different sets of materials was evaluated in terms of information entropy and degrees of freedom, with and without the use of a volume conservation constraint. The measurement performance was evaluated quantitatively using atheroma and mouse equivalent phantoms. Finally the decomposition method was assessed qualitatively using a euthanized mouse and an excised human atherosclerotic plaque. RESULTS: Spectral CT measurements of a phantom containing tissue surrogates confirmed the ability to distinguish these materials by the spectroscopic characteristics of their CT number. The assessment of performance potential in terms of information entropy and degrees of freedom indicated that certain sets of up to three materials could be decomposed by the method of constrained least squares. However, there was insufficient information within the data set to distinguish calcium from iron within soft tissues. The quantification of calcium concentration and fat mass fraction within atheroma and mouse equivalent phantoms by spectral CT correlated well with the nominal values (R(2) = 0.990 and R(2) = 0.985, respectively). In the euthanized mouse and excised human atherosclerotic plaque, regions of calcium and fat were appropriately decomposed according to their spectroscopic characteristics. CONCLUSIONS: Spectral CT, using the Medipix3 detector and silicon sensor layer, can quantify certain sets of up to three materials using the proposed method of constrained least squares. The system has some ability to independently distinguish calcium, fat, and water, and these have been quantified within phantom equivalents of fatty liver and atheroma. In this configuration, spectral CT cannot distinguish iron from calcium within soft tissues.

Distal ureteral calculi: US follow-up.

PURPOSE: To assess accuracy of ultrasonographic (US) follow-up of distal ureteral calculi by using computed tomography (CT) and conventional radiography (kidneys, ureters, and bladder) as reference standards. MATERIALS AND METHODS: The study was approved by the Regional Ethics Committee, and written informed consent was obtained. One hundred fifty-eight patients with CT-diagnosed symptomatic ureteral calculi, for whom follow-up imaging was ordered, were enrolled from February 2006 to December 2008. Six were excluded, having not met study entry criteria, with 121 men (mean age, 49 years; range, 20-91 years) and 31 women (mean age, 44 years; range, 34-77 years) completing the protocol with adequate reference standard imaging. Targeted transabdominal US occurred coincidently with follow-up CT (n = 92) or radiography (n = 60), with US evaluation prospectively compared considering sensitivity and specificity. Statistical analysis was performed with a χ(2) test, t test, or paired t test, as appropriate. RESULTS: Results of nine US examinations were nondiagnostic because of inadequate ureteral visualization, and among these, two cases showed residual distal calculi. Of the remaining 143 patients, 33 had residual distal calculi, all visualized with US. There was a single false-positive study, giving sensitivity, including nondiagnostic US examinations, of 94.3% (95% confidence interval [CI]: 80.8%, 99.3%) and specificity of 99.1% (95% CI: 95.3%, 100%). All calculi appeared hyperechoic with posterior acoustic shadowing. Additional diagnostic features included presence of a hypoechoic rim and Doppler twinkle artifact. Mean stone length was 7.2 mm ± 2.6 (standard deviation) (range, 4-18 mm). Mean ureteral length visualized was 36.4 mm (range, 12-77 mm), with calculi positioned at a mean of 13.1 mm ± 11.2 (range, 0-40 mm) from the ureterovesical junction (UVJ). Nondiagnostic results were more likely with bladder volume of 110 mL or less (eight [16%] of 50 vs one [1%] of 102, P = .0009). CONCLUSION: Ureteral calculi within 35 mm of the UVJ can be accurately followed-up by using transabdominal US, which substantially reduces patient radiation burden.

Management in children of mild postnatal renal dilatation but without vesicoureteral reflux.

Infants with mild postnatal renal dilatation but without vesicoureteral reflux pose a challenge. For how long and in what way should they be followed? From May 1989 to December 2006, we prospectively followed 1,795 pregnancies in which the foetal renal pelvis measured 4 mm or greater. Voiding cystourethrography (VCUG) and renal ultrasound were performed on 1,315 infants at 6 weeks of age. Our study group comprised 208 (167 male) infants with normal VCUG findings who had a renal pelvis of 6-11 mm. We followed them for 1-17 years (mean 11 years). Medical and radiological records were reviewed to determine any urinary symptoms and final outcome. They underwent, on average, four further imaging tests. The renal dilatation had resolved by 24 months in approximately 70%. Urinary tract infection (UTI) developed in 16 (8%). Calyceal dilatation was more likely in those developing UTI (P=0.02). Twenty-two (10.6%) had a radiologically demonstrated urinary tract abnormality. Of the five who had renal scarring or severe obstruction, four became symptomatic. Most infants with mild postnatal renal dilatation can be investigated with only one further sonogram at 24 months of age. Mild postnatal renal dilatation is associated with subsequent UTI or renal tract abnormality in 18%. Severe renal abnormality occurred in 2.4%.

Sonographic appearances of the endometrium after termination of pregnancy in asymptomatic versus symptomatic women.

OBJECTIVE: The purpose of this study was to describe normal sonographic appearances of the endometrium in asymptomatic women after elective termination of pregnancy (TOP) and to determine whether sonographic findings are discriminatory in symptomatic women after TOP. METHODS: Sonographic parameters were compared in prospectively recruited women after elective TOP. The first 38 were asymptomatic. In a later group, 105 had symptoms suggestive of retained products of conception (RPOC). Endometrial thickness, cavity irregularity, echogenicity of cavity contents, color Doppler flow, and resistive indices (RIs) were assessed. In the symptomatic group, sonographic findings were correlated with symptoms and histologic results. RESULTS: There was a marked overlap in sonographic appearances between the groups. The endometrial cavity is commonly irregular and thickened and may show prominent color Doppler flow in women with an uneventful course as well as in women with histologically proven RPOC. Differences between asymptomatic and symptomatic women were only seen for: endometrial thickness (10.8 mm [range, 1-29 mm] versus 15.3 mm [range, 1.8-34 mm]; P = .0005), and cavity irregularity was greater in symptomatic women (P = .001). Color Doppler flow mean RIs were similar. Symptoms were similar in women proceeding to curettage versus no curettage; no significant relationship was found between individual symptoms and sonographic parameters. Chorionic villi were seen in 47 of 56 women (84%) with positive histologic results. CONCLUSIONS: Sonographic appearances and symptoms correlate poorly with each other and with histologic results. Sonography has limited benefits in triaging women with suspected RPOC after TOP in the first trimester. Our findings support a more conservative approach to suspected RPOC after TOP.

Detection of impaired growth of the corpus callosum in premature infants.

OBJECTIVE: There is an urgent need for a bedside method to assess the effectiveness of neonatal therapies designed to improve cerebral development in very low birth-weight infants. The aim of this study was to assess the impact of preterm birth on the serial growth of the corpus callosum and how soon it could be detected after birth with cranial ultrasound. METHODS: We recruited 61 very low birth-weight infants admitted to a single regional level III NICU from 1998 to 2000. Study infants had 2 cranial sonograms > or = 7 days apart in the first 2 weeks of life and further sonograms at 6 weeks and at term equivalent. At each time point, the length of the corpus callosum and cerebellar vermis was measured on midline sagittal images, with growth rates calculated in millimeters per day. We compared growth of corpus callosum and cerebellar vermis in individuals, between birth age groups, and with corrected gestational age. We used antenatal growth rate of the corpus callosum of 0.2 to 0.27 mm/day as a reference. Relationships between corpus callosum growth rates and neurodevelopmental outcome at 2 years of age (corrected) were also examined. RESULTS: Growth of the corpus callosum was normal in most infants during the first 2 weeks of life but slowed after this (0.21 mm/day from 0-2 weeks vs 0.11 mm/day for weeks 2-6). Slowing of corpus callosum growth below expected reference range was consistently detectable by age 6 weeks for 96% of infants born between 23 and 33 weeks' gestation. Although some improvement in growth rate was observed for 15% of infants after 6 weeks, this was confined to infants born after 28 weeks. Vermis length correlated strongly with corpus callosum length. By 2 years of age, serious motor delay and cerebral palsy were associated with poorer growth of the length of the corpus callosum between 2 and 6 weeks after birth. CONCLUSIONS: The effect of preterm birth on growth of the corpus callosum is detectable by 6 weeks after delivery in preterm infants born at gestations of 23 to 33 weeks. Reduced growth of the corpus callosum in weeks 2 to 6, places these infants at elevated risks of later psychomotor delay and cerebral palsy.

Growth rate of corpus callosum in very premature infants.

BACKGROUND AND PURPOSE: It is desirable to develop a bedside method for assessing cerebral development in the very premature infant to monitor the effectiveness of interventions aimed at improving cerebral development. Our aim was to describe the growth trajectory of the corpus callosum (CC) on cranial sonography in very premature infants. METHODS: We recruited 100 very-low-birth-weight infants admitted to a single regional level III neonatal intensive care unit from November 1998 to November 2000. Cranial sonography images of the CC were obtained for 64 (32 boys) infants (mean gestational age, 28 weeks; range, 23-33 weeks) in the first week of life and at term equivalency. The growth rate of the CC was compared in the 64 study infants to the expected growth rate of 0.20-0.27 mm/day from antenatal data and correlated with clinical outcome at 2 years of age by using Mental Development Index (MDI) and Psychomotor Development Index (PDI). RESULTS: The average growth rate of the CC was half of that expected from antenatal data. Mean growth rates were similar for all gestational ages (mean, 0.11 mm/day; range, 0.05-0.29; P = .4). The CC at term equivalency was longer for those in MDI class 2 (mean, 44.3 mm) compared with MDI class 3 (mean 40.2 mm; P = .003) as well as for PDI class 2 versus 3 (P = .017). CONCLUSION: Measurement of the length of the CC at cranial sonography is reproducible. Those with poorer neurodevelopmental outcomes have a shorter CC at term equivalency. The CC grows at a much lower rate postnatally than in utero among very premature infants.

Fluctuating fetal or neonatal renal pelvis: marker of high-grade vesicoureteral reflux.

Fetal renal pelvic dilatation is a predictor of vesicoureteral reflux (VUR), but has low specificity. The aim of this study was to determine the clinical significance of fluctuating size of the renal pelvis on sonography, particularly in relationship to VUR. We prospectively recorded fetal renal pelvic diameter >/=4 mm in 1,092 fetuses (692 boys), from May 1989 to December 1995, with a minimum follow-up of 7 years. Fluctuation, defined as size of renal pelvis changing by more than 4 mm during the course of obstetric (23), postnatal (128), and both pre- and postnatal (7) renal sonograms, was recorded prospectively in 159 (117 boys). Of the 1,092, 849 (593 boys) had a voiding cystourethrogram at a mean age of 7 weeks (range 3-20 weeks). Of the 31 (16 girls) with high-grade VUR, fluctuation was observed in 20 (9 girls). Fluctuation was strongly associated with high-grade VUR (odds ratio 11.1, P=0.0000003) and with renal damage (sensitivity 61%, positive predictive value 31%). Primary high-grade VUR was persistent, seen equally in boys and girls, and required surgery in the majority. Fluctuation was associated with renal duplication anomalies ( P=0.00009) and megaureter ( P<0.00000001). Fluctuation of the renal pelvis on sonography is a marker for persistent high-grade VUR and renal damage in girls and boys.

A limited range of measures of 2-D ultrasound correlate with 3-D MRI cerebral volumes in the premature infant at term.

Two-dimensional (2-D) cranial ultrasound (US) is the principal method for the detection of cerebral injury in the newborn. The aim of this study was to compare 2-D sonographic methods with more advanced 3-D magnetic resonance imaging (MRI) for assessing brain structure. From July 1998 to November 2000, we conducted a prospective methodological study comparing 2-D cranial sonographic measurements with volumes of cerebrospinal fluid (CSF), white matter, grey matter and total volume of brain obtained using 3-D MRI. The study group comprised 63 infants (33 boys), mean gestational age 28 weeks (range 23 to 33 weeks), with imaging studies within 15 days of term equivalent. The highest correlations were between the occipital horn length and total brain volume (R2 = 0.30), the subarachnoid space and both CSF volume (R2 = 0.46) and relative intracranial space occupied by brain tissue (R2 = 0.48). Only 8 (30%) of the 2-D cranial US measures demonstrated good reproducibility. 2-D sonographic measures are limited in reflecting variations in overall cerebral structure, although certain measures, such as subarachnoid space and occipital lobe measures, may be useful in better defining cerebral parenchymal and CSF volumes.

Fetal renal pelvic dilatation--poor predictor of familial vesicoureteral reflux.

The sensitivity and positive predictive value (PPV) of fetal renal pelvic dilatation for detecting vesicoureteral reflux (VUR) can only be determined by performing voiding cystourethrography (VCUG) on all newborns in a study population. We sought to determine this for infants with a family history of reflux. From June 1989 to September 1996, 157 children (80 males) under 2 years with a family history of primary VUR in a first-degree relative had VCUG. VCUG results were compared with the fetal renal pelvic diameter on obstetric sonogram performed after 16 weeks gestation. Of the 157 infants, 33 (11 boys) had primary VUR. In those with a parent as the index case, the prevalence of reflux was 5% in boys and 35% in girls ( P=0.03). The largest renal pelvic diameter after 16 weeks was not discriminatory for VUR, but after 30 weeks gestation a 4 mm renal pelvis had a sensitivity of 33% and a PPV of 32%. The sensitivity was higher for grades 4 and 5 (75%) than for grades 1-3 reflux (17%), ( P=0.04). In conclusion, fetal renal pelvic diameter has a low sensitivity and poor predictive value for detecting VUR, but this improves a little after 30 weeks gestation.

Comparison of echo-enhanced ultrasound with fluoroscopic MCU for the detection of vesicoureteral reflux in neonates.

BACKGROUND: Fluoroscopic micturating cystourethrography (MCU) is used for screening and grading of vesicoureteral reflux (VUR). It involves ionizing radiation. This study was designed to assess the efficacy of contrast-enhanced sonography in predicting the presence or absence of VUR. OBJECTIVE: To compare an ultrasound contrast agent for detection of VUR in at-risk infants, and to compare these findings with fluoroscopic MCU with the aim of determining whether echo-enhanced sonography could be used instead of fluoroscopic MCU to identify neonates who do not have VUR, thus avoiding the use of radiation in this group. MATERIALS AND METHODS: From August 1999 to August 2000, 97 neonates (69 male, 31 female), aged 28-90 days (mean 48 days), referred for MCU and renal ultrasonography for investigation of VUR were recruited consecutively. Echo-enhanced sonography using stabilized microbubbles was followed immediately by fluoroscopic MCU. VUR was diagnosed if transient hyperechogenicity appeared within the pelvicalyceal system or ureter. The mean number of micturitions was 2.7 (range 1-6). RESULTS: Reflux was detected in 19 kidneys (14 babies) by one or other technique. The findings were concordant in 181 kidneys (94.2%). Echo-enhanced sonography had a sensitivity of 64% (95% CI 35-87%), a specificity of 100% (95-100%), a positive predictive value of 100% (66-100%), and a negative predictive value of 94% (87-98%). CONCLUSIONS: The role of echo-enhanced sonography is limited at present in our neonatal population as a screening examination. Its ability to detect cases of high-grade reflux may make it an attractive alternative in follow-up of known cases of VUR, and may help to reduce radiation exposure in this group.