Treatment of AICA ribosiduria by suppression of de novo purine synthesis.

AICA ribosiduria is an ultra-rare disorder of de novo purine biosynthesis associated with developmental delay of varying severity, seizures, and varying degrees of visual impairment due to chorioretinal atrophy. Caused by biallelic pathogenic variants in ATIC, accumulation of AICA-riboside is the biochemical hallmark and presumed pathomechanism of the condition. In this study, we report the case of a teenage patient compound-heterozygous for the variants c.1277 A > G (p.K426R) and c.642G > C (p.Q214H) in ATIC, with the latter not previously reported. Excessive secretion of AICA-riboside and succinyladenosine was significantly reduced following the introduction of a purine-enriched diet. By suppressing de novo purine biosynthesis in favour of purine salvage, exogenous purine substitution represents a promising treatment approach for AICA ribosiduria. SYNOPSIS: Suppression of de novo purine biosynthesis by increased exogeneous purine supply leads to decreased accumulation of AICA-riboside and succinyl-adenosine and thus is a promising treatment approach for AICA ribosiduria.

Open-Source Automatic Biomarker Measurement on Slit-Lamp Photography to Estimate Visual Acuity in Microbial Keratitis.

Purpose: To assess clinical applicability of automatic image analysis in microbial keratitis (MK) by evaluating the relationship between biomarker measurements on slit-lamp photography (SLP) and best-corrected visual acuity (BCVA). Methods: Seventy-six patients with MK with SLP images and same-day logarithm of the minimum angle of resolution (logMAR) BCVA were evaluated. MK biomarkers (stromal infiltrate, white blood cell infiltration, corneal edema, hypopyon, epithelial defect) were segmented manually by ophthalmologists and automatically by a novel, open-source, deep learning-based segmentation algorithm. Five measurements (presence, maximum width, total area, proportion of the corneal limbus area affected, centrality) were calculated. Correlations between the measurements and BCVA were calculated. An automatic regression model estimated BCVA from the measurements. Differences in performance between using manual and automatic measurements were evaluated using William's test (for correlation) and the paired-sample t-test (for absolute error). Results: Measurements had high correlations of 0.86 (manual) and 0.84 (automatic) with true BCVA. Estimated BCVA had average (mean ± SD) absolute errors of 0.39 ± 0.27 logMAR (manual, median: 0.30) and 0.35 ± 0.28 logMAR (automatic, median: 0.30) and high correlations of 0.76 (manual) and 0.80 (automatic) with true BCVA. Differences between using manual and automatic measurements were not statistically significant for correlations of measurements with true BCVA (P = .66), absolute errors of estimated BCVA (P = .15), or correlations of estimated BCVA with true BCVA (P = .60). Conclusions: The proposed algorithm measured MK biomarkers as accurately as ophthalmologists. Measurements were highly correlated with and estimative of visual acuity. Translational Relevance: This study demonstrates the potential of developing fully automatic objective and standardized strategies to aid ophthalmologists in the clinical assessment of MK.

Open-Source Automatic Segmentation of Ocular Structures and Biomarkers of Microbial Keratitis on Slit-Lamp Photography Images Using Deep Learning.

We propose a fully-automatic deep learning-based algorithm for segmentation of ocular structures and microbial keratitis (MK) biomarkers on slit-lamp photography (SLP) images. The dataset consisted of SLP images from 133 eyes with manual annotations by a physician, P1. A modified region-based convolutional neural network, SLIT-Net, was developed and trained using P1's annotations to identify and segment four pathological regions of interest (ROIs) on diffuse white light images (stromal infiltrate (SI), hypopyon, white blood cell (WBC) border, corneal edema border), one pathological ROI on diffuse blue light images (epithelial defect (ED)), and two non-pathological ROIs on all images (corneal limbus, light reflexes). To assess inter-reader variability, 75 eyes were manually annotated for pathological ROIs by a second physician, P2. Performance was evaluated using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). Using seven-fold cross-validation, the DSC of the algorithm (as compared to P1) for all ROIs was good (range: 0.62-0.95) on all 133 eyes. For the subset of 75 eyes with manual annotations by P2, the DSC for pathological ROIs ranged from 0.69-0.85 (SLIT-Net) vs. 0.37-0.92 (P2). DSCs for SLIT-Net were not significantly different than P2 for segmenting hypopyons (p > 0.05) and higher than P2 for WBCs (p < 0.001) and edema (p < 0.001). DSCs were higher for P2 for segmenting SIs (p < 0.001) and EDs (p < 0.001). HDs were lower for P2 for segmenting SIs (p = 0.005) and EDs (p < 0.001) and not significantly different for hypopyons (p > 0.05), WBCs (p > 0.05), and edema (p > 0.05). This prototype fully-automatic algorithm to segment MK biomarkers on SLP images performed to expectations on an exploratory dataset and holds promise for quantification of corneal physiology and pathology.

Measurement Reliability for Keratitis Morphology.

PURPOSE: To evaluate the reliability of manual annotation when quantifying cornea anatomical and microbial keratitis (MK) morphological features on slit-lamp photography (SLP) images. METHODS: Prospectively enrolled patients with MK underwent SLP at initial encounter at 2 academic eye hospitals. Patients who presented with an epithelial defect (ED) were eligible for analysis. Features, which included ED, corneal limbus (L), pupil (P), stromal infiltrate (SI), white blood cell (WBC) infiltration at the SI edge, and hypopyon (H), were annotated independently by 2 physicians on SLP images. Intraclass correlation coefficients (ICCs) were applied for reliability assessment; dice similarity coefficients (DSCs) were used to investigate the area overlap between readers. RESULTS: Seventy-five MK patients with an ED received SLP. DSCs indicate good to fair annotation overlap between graders (L = 0.97, P = 0.80, ED = 0.94, SI = 0.82, H = 0.82, WBC = 0.83) and between repeat annotations by the same grader (L = 0.97, P = 0.81, ED = 0.94, SI = 0.85, H = 0.84, WBC = 0.82). ICC scores showed good intergrader (L = 0.98, P = 0.78, ED = 1.00, SI = 0.67, H = 0.97, WBC = 0.86) and intragrader (L = 0.99, P = 0.92, ED = 0.99, SI = 0.94, H = 0.99, WBC = 0.92) reliabilities. When reliability statistics were recalculated for annotated SI area in the subset of cases where both graders agreed WBC infiltration was present/absent, intergrader ICC improved to 0.91 and DSC improved to 0.86 and intragrader ICC remained the same, whereas DSC improved to 0.87. CONCLUSIONS: Manual annotation indicates usefulness of area quantification in the evaluation of MK. However, variability is intrinsic to the task. Thus, there is a need for optimization of annotation protocols. Future directions may include using multiple annotators per image or automated annotation software.

Algorithm Variability in Quantification of Epithelial Defect Size in Microbial Keratitis Images.

PURPOSE: To investigate the sources of measurement variability when quantifying the morphology of microbial keratitis (MK) from slit-lamp photography (SLP) images using a semiautomated, image-analysis algorithm. METHODS: Prospectively enrolled patients with MK underwent SLP to obtain images of their epithelial defects (ED). Eyes were stained with fluorescein and imaged multiple times under blue light, at low and high magnifications. A masked research assistant chose the 3 best images and annotated each 3 times to provide seed regions corresponding to ED and healthy cornea. The algorithm returned the ED area for each seeded image. Eyes without EDs and algorithm failures were excluded. Variance components were estimated with a random effects model and intraclass correlation coefficients estimated with intragrader reliability. RESULTS: A total of 42 eyes from 42 MK participants were photographed. After excluding poor quality images, eyes with no EDs, and algorithm failures, 34 patients with 92 images and 274 seeds were analyzed. No significant differences in the average ED area were found between seedings or high- versus low-SLP magnifications (all P > 0.5, paired t tests). Minimal measurement variability was because of image (0.9%), magnification (0.2%), or seed (0.1%). Most variability was attributable to differences in ED sizes between patients (85.2%). 13.7% of variability was unexplained. Multiple iterations of the algorithm on the same image showed good consistency (intraclass correlation coefficient = 0.98, 95% confidence interval, 0.97-0.99). CONCLUSIONS: Image-analysis algorithms showed good reliability for measuring the ED area from SLP images. Most measurement variability was because of between-patient differences, not imaging settings or application of the algorithm by the user.

Influence of Inflammation in Uveitis on Confocal Scanning Laser Tomography and Optical Coherence Tomography Measurements.

PURPOSE: To evaluate the influence of active inflammation in uveitis on confocal scanning laser tomography (CSLT) and optical coherence tomography (OCT) measurements. METHODS: Prospective enrollment of patients (64 eyes) with non-infectious uveitis. Retinal nerve fiber layer (RNFL), rim-area and -volume for CSLT and Bruch's-membrane-opening minimum-rim-width (BMO-MRW) and retinal nerve fiber layer thickness (RNFL-O) for OCT were recorded. RESULTS: No significant differences between eyes with active inflammation (31) vs no inflammation (33) were observed for all investigated CSLT parameters and BMO-MRW. The RNFL-O in OCT was significantly increased (1st p = .0439, 2nd p = .0327, 3rd p = .0313) while actively inflamed. CSLT did not show a significant difference between glaucomatous and non-glaucomatous eyes albeit all OCT derived parameters did. CONCLUSION: CSLT measurements were not affected by inflammation but unreliable in glaucomatous eyes. RNFL-O was significantly influenced by inflammation while BMO-MRW was not. BMO-MRW seems to be the best approach in uveitic eyes.

Influence of uveitis on Bruch's membrane opening minimum rim width and retinal nerve fibre layer thickness measurements.

BACKGROUND/AIMS: To assess the impact of papillary leakage and active inflammation on optical coherence tomography (OCT)-based retinal nerve fibre layer thickness (RNFLT) and Bruch's membrane opening minimum rim width (BMO-MRW) measurements in uveitic eyes with and without secondary glaucoma. METHODS: Prospective, single-centre analysis of patients with uveitis. All patients included received a fluorescein angiography examination and an OCT scan measuring the BMO-MRW and the RNFLT in three concentric peripapillary ring scans. RESULTS: Overall, 95 eyes of 56 patients were enrolled. Papillary leakage and active inflammation were present in 39 (41%) and 57 (60%) eyes, respectively. Twenty-one eyes were classified as glaucomatous; 10 of those glaucomatous eyes showed papillary leakage. Both BMO-MRW and RNFLT measurements were significantly increased in eyes with papillary leakage (BMO-MRW: p=0.0001; RNFLT: first to third ring (p<0.0001)). Active inflammation led to a significantly thickened RNFLT (first ring: p=0.0026; second ring: p=0.0009; third ring: p=0.0002) while only a trend towards increased values could be observed in the BMO-MRW measurements (p=0.3063). Glaucomatous eyes with papillary leakage demonstrated significantly higher values on both BMO-MRW and RNFLT measurements than glaucomatous eyes without leakage (BMO-MRW: p=0.0159; RNFLT: first ring: p=0.0062; second ring: p=0.0037; third ring: p=0.0197). No significant difference could be observed between glaucomatous eyes with leakage and non-glaucomatous eyes without leakage (BMO-MRW: p=0.4132; RNFLT: first ring: p=0.5412; second ring: p=0.3208; third ring: p=0.1164). CONCLUSIONS: The OCT scanning parameters BMO-MRW and RNFLT were significantly influenced by papillary leakage in uveitic eyes with and without glaucoma. RNFLT values were also significantly increased while active inflammation was present. In patients with uveitis, these OCT-based imaging tools should be interpreted with caution, especially in those with papillary leakage or active inflammation.

Distribution, determinants, and normal reference values of thoracic and abdominal aortic diameters by computed tomography (from the Framingham Heart Study).

Current screening and detection of asymptomatic aortic aneurysms is based largely on uniform cut-point diameters. The aims of this study were to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease. Measurements of the diameters of the ascending thoracic aorta (AA), descending thoracic aorta (DTA), infrarenal abdominal aorta (IRA), and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study (FHS) participants. Mean diameters were stratified by gender, age, and body surface area. Univariate associations with risk factor levels were examined, and multivariate linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameters were 34.1 mm for the AA, 25.8 mm for the DTA, 19.3 mm for the IRA, and 18.7 mm for the LAA. For women, the average diameters were 31.9 mm for the AA, 23.1 mm for the DTA, 16.7 mm for the IRA, and 16.0 mm for the LAA. The mean aortic diameters were strongly correlated (p <0.0001) with age and body surface area in age-adjusted analyses, and these relations remained significant in multivariate regression analyses. Positive associations of diastolic blood pressure with AA and DTA diameters in both genders and pack-years of cigarette smoking with DTA diameter in women and IRA diameter in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by computed tomography are larger in men compared with women, vary significantly with age and body surface area, and are associated with modifiable cardiovascular disease risk factors, including diastolic blood pressure and cigarette smoking.

The napkin-ring sign indicates advanced atherosclerotic lesions in coronary CT angiography.

OBJECTIVES: This study sought to determine the accuracy of plaque pattern assessment by coronary computed tomography angiography (CCTA) to differentiate between early and advanced atherosclerotic lesions as defined by histology. BACKGROUND: A ringlike attenuation pattern of coronary atherosclerotic plaques termed as napkin-ring sign (NRS) was described in CCTA of patients who had acute coronary syndrome. METHODS: All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local ethics committees was obtained. We investigated 21 coronary arteries of 7 donor hearts. Overall, 611 histological sections were obtained and coregistered with CCTA images. The CCTA cross sections were read in random order for conventional plaque categories (noncalcified [NCP], mixed [MP], calcified [CP]) and plaque patterns (homogenous, heterogeneous with no napkin-ring sign [non-NRS], and heterogeneous with NRS). RESULTS: No plaque was detected in 134 (21.9%), NCP in 254 (41.6%), MP in 191 (31.3%), and CP in 32 (5.2%) CCTA cross sections. The NCP and MP were further classified into homogenous plaques (n = 207, 46.5%), non-NRS plaques (n = 200, 44.9%), and NRS plaques (n = 38, 8.6%). The specificities of NCP and MP to identify advanced lesions were moderate (57.9%, 95% confidence interval [CI]: 50.1% to 65.6%, and 72.1%, 95% CI: 64.7% to 79.4%, respectively), which were similar to the homogenous and heterogeneous plaques (62.6%, 95% CI: 54.8% to 70.3%, and 67.3%, 95% CI: 58.6% to 76.1%, respectively). In contrast, the specificity of the NRS to identify advanced lesions was excellent (98.9%, 95% CI: 97.6% to 100%). The diagnostic performance of the pattern-based scheme to identify advanced lesions was significantly better than that of the conventional plaque scheme (area under the curve: 0.761 vs. 0.678, respectively; p = 0.001). CONCLUSIONS: The assessment of the plaque pattern improves diagnostic accuracy of CCTA to identify advanced atherosclerotic lesions. The CCTA finding of NRS has a high specificity and high positive predictive value for the presence of advanced lesions.

Orbitofrontal and insular epilepsy.

PURPOSE: Orbitofrontal and insular epilepsy are difficult to recognize because clinical presentations are variable and surgical approaches remain difficult. METHODS: Literature review and review of our own case series including selected cases regarding the clinical manifestation and diagnostic utility of diagnostic tests in orbitofrontal and insular epilepsy. RESULTS: Orbitofrontal epilepsy presents with either frontal lobe type seizures with hypermotor automatism or temporal lobe type seizures with oroalimentary and manual automatisms depending on the spread pattern. Ictal single photon emission computed tomography (SPECT) and other functional imaging can be helpful, but intracranial electroencephalograms (EEGs) are still required to identify orbitofrontal seizure onset. Insular epilepsy presents with throat constriction and unilateral paresthesias. Preoperative functional imaging methods can be helpful, but exploration of the insula is required to identify unequivocal insular onset. Intracranial EEG in the insula can be performed safely and should be considered in atypical temporal lobe cases. CONCLUSIONS: Intracranial EEG remains the main diagnostic modality to identify orbitofrontal and insular epilepsy. Newer diagnostic modalities such as high-frequency oscillations, EEG, functional magnetic resonance imaging (fMRI), magnet resonance spectroscopy, and magnet source imaging need to be examined further to establish their diagnostic utility.

Differentiation of early from advanced coronary atherosclerotic lesions: systematic comparison of CT, intravascular US, and optical frequency domain imaging with histopathologic examination in ex vivo human hearts.

PURPOSE: To establish an ex vivo experimental setup for imaging coronary atherosclerosis with coronary computed tomographic (CT) angiography, intravascular ultrasonography (US), and optical frequency domain imaging (OFDI) and to investigate their ability to help differentiate early from advanced coronary plaques. MATERIALS AND METHODS: All procedures were performed in accordance with local and federal regulations and the Declaration of Helsinki. Approval of the local Ethics Committee was obtained. Overall, 379 histologic cuts from nine coronary arteries from three donor hearts were acquired, coregistered among modalities, and assessed for the presence and composition of atherosclerotic plaque. To assess the discriminatory capacity of the different modalities in the detection of advanced lesions, c statistic analysis was used. Interobserver agreement was assessed with the Cohen κ statistic. RESULTS: Cross sections without plaque at coronary CT angiography and with fibrous plaque at OFDI almost never showed advanced lesions at histopathologic examination (odds ratio [OR]: 0.02 and 0.06, respectively; both P<.0001), while mixed plaque at coronary CT angiography, calcified plaque at intravascular US, and lipid-rich plaque at OFDI were associated with advanced lesions (OR: 2.49, P=.0003; OR: 2.60, P=.002; and OR: 31.2, P<.0001, respectively). OFDI had higher accuracy for discriminating early from advanced lesions than intravascular US and coronary CT angiography (area under the receiver operating characteristic curve: 0.858 [95% confidence interval {CI}: 0.802, 0.913], 0.631 [95% CI: 0.554, 0.709], and 0.679 [95% CI: 0.618, 0.740]; respectively, P<.0001). Interobserver agreement was excellent for OFDI and coronary CT angiography (κ=0.87 and 0.85, respectively) and was good for intravascular US (κ=0.66). CONCLUSION: Systematic and standardized comparison between invasive and noninvasive modalities for coronary plaque characterization in ex vivo specimens demonstrated that coronary CT angiography and intravascular US are reasonably associated with plaque composition and lesion grading according to histopathologic findings, while OFDI was strongly associated. These data may help to develop initial concepts of sequential imaging strategies to identify patients with advanced coronary plaques.

Association of pericardial fat and coronary high-risk lesions as determined by cardiac CT.

OBJECTIVE: Pericardial adipose tissue (PAT) is a pathogenic fat depot associated with coronary atherosclerosis and cardiovascular events. We hypothesized that higher PAT is associated with coronary high-risk lesions as determined by cardiac CT. METHODS: We included 358 patients (38% female; median age 51 years) who were admitted to the ED with acute chest pain and underwent 64-slice CT angiography. The cardiac CT data sets were assessed for presence and morphology of CAD and PAT. Coronary high-risk lesions were defined as >50% luminal narrowing and at least two of the following characteristics: positive remodeling, low-density plaque, and spotty calcification. PAT was defined as any pixel with CT attenuation of -190 to -30 HU within the pericardial sac. RESULTS: Based on cardiac CT, 50% of the patients (n=180) had no CAD, 46% (n=165) had CAD without high-risk lesions, and 13 patients had CAD with high-risk lesions. The median PAT in patients with high-risk lesions was significantly higher compared to patients without high-risk lesions and without any CAD (151.9 [109.0-179.4]cm(3) vs. 110.0 [81.5-137.4]cm(3), vs. 74.8 [58.2-111.7]cm(3), respectively p=0.04 and p<0.0001). These differences remained significant after adjusting for traditional risk factors including BMI (all p<0.05). The area under the ROC curve for the identification of high-risk lesions was 0.756 in a logistic regression model with PAT as a continuous predictor. CONCLUSION: PAT volume is nearly twice as high in patients with high-risk coronary lesions as compared to those without CAD. PAT volume is significantly associated with high risk coronary lesion morphology independent of clinical characteristics and general obesity.

Reference values for normal pulmonary artery dimensions by noncontrast cardiac computed tomography: the Framingham Heart Study.

BACKGROUND: Main pulmonary artery diameter (mPA) and ratio of mPA to ascending aorta diameter (ratio PA) derived from chest CT are commonly reported in clinical practice. We determined the age- and sex-specific distribution and normal reference values for mPA and ratio PA by CT in an asymptomatic community-based population. METHODS AND RESULTS: In 3171 men and women (mean age, 51±10 years; 51% men) from the Framingham Heart Study, a noncontrast, ECG-gated, 8-slice cardiac multidetector CT was performed. We measured the mPA and transverse axial diameter of the ascending aorta at the level of the bifurcation of the right pulmonary artery and calculated the ratio PA. We defined the healthy referent cohort (n=706) as those without obesity, hypertension, current and past smokers, chronic obstructive pulmonary disease, history of pulmonary embolism, diabetics, cardiovascular disease, and heart valve surgery. The mean mPA diameter in the overall cohort was 25.1±2.8 mm and mean ratio PA was 0.77±0.09. The sex-specific 90th percentile cutoff value for mPA diameter was 28.9 mm in men and 26.9 mm in women and was associated with increase risk for self-reported dyspnea (adjusted odds ratio, 1.31; P=0.02). The 90th percentile cutoff value for ratio PA of the healthy referent group was 0.91, similar between sexes but decreased with increasing age (range, 0.82-0.94), though not associated with dyspnea. CONCLUSIONS: For simplicity, we established 29 mm in men and 27 mm in women as sex-specific normative reference values for mPA and 0.9 for ratio PA.

Assessment of coronary plaque progression in coronary computed tomography angiography using a semiquantitative score.

OBJECTIVES: We sought to describe the progression of coronary atherosclerotic plaque over time by computed tomography (CT) angiography stratified by plaque composition and its association with cardiovascular risk profiles. BACKGROUND: Data on the progression of atherosclerosis stratified by plaque composition with the use of noninvasive assessment by CT are limited and hampered by high measurement variability. METHODS: This analysis included patients who presented with acute chest pain to the emergency department but initially showed no evidence of acute coronary syndromes. All patients underwent contrast-enhanced 64-slice CT at baseline and after 2 years with the use of a similar protocol. CT datasets were coregistered and assessed for the presence of calcified and noncalcified plaque at 1 mm cross sections of the proximal 40 mm of each major coronary artery. Plaque progression over time and its association with risk factors were determined. Measurement reproducibility and correlation to plaque volume was performed in a subset of patients. RESULTS: We included 69 patients (mean age 55 +/- 12 years, 59% male patients) and compared 8,311 coregistered cross sections at baseline and follow-up. At baseline, any plaque, calcified plaque, and noncalcified were detected in 12.5%, 10.1%, and 2.4% of cross sections per patient, respectively. There was significant progression in the mean number of cross sections containing any plaque (16.5 +/- 25.3 vs. 18.6 +/- 25.5, p = 0.01) and noncalcified plaque (3.1 +/- 5.8 vs. 4.4 +/- 7.0, p = 0.04) but not calcified plaque (13.3 +/- 23.1 vs. 14.2 +/- 22.0, p = 0.2). In longitudinal regression analysis, the presence of baseline plaque, number of cardiovascular risk factors, and smoking were independently associated with plaque progression after adjustment for age, sex, and follow-up time interval. The semiquantitative score based on cross sections correlated closely with plaque volume progression (r = 0.75, p < 0.0001) and demonstrated an excellent intraobserver and interobserver agreement (kappa = 0.95 and kappa = 0.93, respectively). CONCLUSIONS: Coronary plaque burden of patients with acute chest pain significantly increases during the course of 2 years. Progression over time is dependent on plaque composition and cardiovascular risk profile. Larger studies are needed to confirm these results and to determine the effect of medical treatment on progression.