Validation of an automated method for studying retinal capillary blood flow.

Two major approaches for tracking cellular motion across a range of biological tissues are the manual labelling of cells, and automated analysis of spatiotemporal information represented in a kymograph. Here we compare these two approaches for the measurement of retinal capillary flow, a particularly noisy application due to the low intrinsic contrast of single red blood cells (erythrocytes). Image data were obtained using a flood-illuminated adaptive optics ophthalmoscope at 750 nm, allowing the acquisition of flow information over several cardiac cycles which provided key information in evaluating tracking accuracy. Our results show that in addition to being much faster, the automated method is more accurate in the face of rapid flow and reduced image contrast. This study represents the first validation of commonly used kymograph approaches to capillary flow analysis.

Mapping the human parafoveal vascular network to understand flow variability in capillaries.

Capillary flow is known to be non-homogenous between vessels and variable over time, for reasons that are poorly understood. The local properties of individual vessels have been shown to have limited explanatory power in this regard. This exploratory study investigates the association of network-level properties such as vessel depth, branch order, and distance from the feeding arteriole with capillary flow. Detailed network connectivity analysis was undertaken in 3 healthy young subjects using flood-illuminated adaptive optics retinal imaging, with axial depth of vessels determined via optical coherence tomography angiography. Forty-one out of 70 vessels studied were of terminal capillary type, i.e. fed from an arterial junction and drained by a venous junction. Approximately half of vessel junctions were amenable to fitting with a model of relative branch diameters, with only a few adhering to Murray's Law. A key parameter of the model (the junction exponent) was found to be inversely related to the average velocity (r = -0.59, p = 0.015) and trough velocity (r = -0.67, p = 0.004) in downstream vessels. Aspects of cellular flow, such as the minimum velocity, were also moderately correlated (r = 0.46, p = 0.009) with distance to the upstream feeding arteriole. Overall, this study shows that capillary network topology contributes significantly to the flow variability in retinal capillaries in human eyes. Understanding the heterogeneity in capillary flow is an important first step before pathological flow states can be properly understood. These results show that flow within capillary vessels is not affected by vessel depths but significantly influenced by the upstream feeder distance as well as the downstream vessel junction exponents, but there remains much to be uncovered regarding healthy capillary flow.

Performance of Automated ASPECTS Software and Value as a Computer-Aided Detection Tool.

BACKGROUND AND PURPOSE: ASPECTS quantifies early ischemic changes in anterior circulation stroke on NCCT but has interrater variability. We examined the agreement of conventional and automated ASPECTS and studied the value of computer-aided detection. MATERIALS AND METHODS: We retrospectively collected imaging data from consecutive patients with acute ischemic stroke with large-vessel occlusion undergoing thrombectomy. Five raters scored conventional ASPECTS on baseline NCCTs, which were also processed by RAPID software. Conventional and automated ASPECTS were compared with a consensus criterion standard. We determined the agreement over the full ASPECTS range as well as dichotomized, reflecting thrombectomy eligibility according to the guidelines (ASPECTS 0-5 versus 6-10). Raters subsequently scored ASPECTS on the same NCCTs with assistance of the automated ASPECTS outputs, and agreement was obtained. RESULTS: For the total of 175 cases, agreement among raters individually and the criterion standard varied from fair to good (weighted κ = between 0.38 and 0.76) and was moderate (weighted κ = 0.59) for the automated ASPECTS. The agreement of all raters individually versus the criterion standard improved with software assistance, as did the interrater agreement (overall Fleiss κ = 0.15-0.23; P < .001 and .39 to .55; P = .01 for the dichotomized ASPECTS). CONCLUSIONS: Automated ASPECTS had agreement with the criterion standard similar to that of conventional ASPECTS. However, including automated ASPECTS during the evaluation of NCCT in acute stroke improved the agreement with the criterion standard and improved interrater agreement, which could, therefore, result in more uniform scoring in clinical practice.

Flow Heterogeneity and Factors Contributing to the Variability in Retinal Capillary Blood Flow.

Purpose: Capillary flow plays an important role in the nourishment and maintenance of healthy neural tissue and can be observed directly and non-invasively in the living human retina. Despite their importance, patterns of normal capillary flow are not well understood due to limitations in spatial and temporal resolution of imaging data. Methods: Capillary flow characteristics were studied in the retina of three healthy young individuals using a high-resolution adaptive optics ophthalmoscope. Imaging with frame rates of 200 to 300 frames per second was sufficient to capture details of the single-file flow of red blood cells in capillaries over the course of about 3 seconds. Results: Erythrocyte velocities were measured from 72 neighboring vessels of the parafoveal capillary network for each subject. We observed strong variability among vessels within a given subject, and even within a given imaged field, across a range of capillary flow parameters including maximum and minimum velocities, pulsatility, abruptness of the systolic peak, and phase of the cardiac cycle. The observed variability was not well explained by "local" factors such as the vessel diameter, tortuosity, length, linear cell density, or hematocrit of the vessel. Within a vessel, a moderate relation between the velocities and hematocrit was noted, suggesting a redistribution of plasma between cells with changes in flow. Conclusions: These observations advance our fundamental understanding of normal capillary physiology and raise questions regarding the potential role of network-level effects in explaining the observed flow heterogeneity.

A comparison of macular ganglion cell and retinal nerve fibre layer optical coherence tomographic parameters as predictors of visual outcomes of surgery for pituitary tumours.

PURPOSE: The prognostic value of optical coherence tomography (OCT) of the macular ganglion cell layer (mGGL) versus peripapillary retinal nerve fibre layers (pRNFL) following chiasmal decompression is unclear. This study is the largest comparison of the two parameters to date and aims to clarify how their performance as covariates compare in predictive models of long-term visual outcomes following pituitary or parasellar tumour surgical resection. METHODS: This was a prospective, two-year, longitudinal cohort study in a single centre tertiary hospital setting. Participants with MRI evidence of pituitary or parasellar tumour compression of the optic chiasm who underwent surgical decompression, were enrolled. Associations between pre-operative OCT parameters and long-term visual outcomes were assessed using multivariable generalised linear mixed models and an age matched normative database. RESULTS: Final analysis included 216 eyes of 108 participants with a mean age (standard deviation) of 51.6 (17.04) years, of whom 58 (49%) were female. The superior inner mGCL was the best predictor of long-term visual field recovery, with an area under the curve of 0.90, a sensitivity of 80%, specificity of 88%, positive predictive value of 86%, and negative predictive value of 83%. CONCLUSION: mGCL performed better in predicting long-term visual field recovery post-pituitary or parasellar surgical resection. The superior inner mGCL was the best specific measure which may provide clinical utility in pre-operative counselling. In this study we clarify previously variable comparisons of mGCL and pRNFL parameters in post-operative predictive modelling.

Temporal patterns of visual recovery following pituitary tumor resection: A prospective cohort study.

Significant restoration of visual function can occur following pituitary tumor resection, although the time course of visual recovery remains poorly understood. This single-centre, two-year, prospective cohort study investigated the temporal patterns of visual recovery in consecutive patients undergoing pituitary tumor resection, between 2009 and 2018. Eyes were stratified based on pre-operative optical coherence tomography (OCT) retinal nerve fibre layer (RNFL) thickness measurements, with thin RNFL being defined as those within the fifth-percentile of age-matched normative values, and normal RNFL as those above the fifth-percentile. Visual function and OCT parameters were assessed pre-operatively, and at 6 weeks, 6 months, and 2 years post-operatively. 456 eyes of 228 patients (mean ± SD age, 53 ± 15 years) were included, of which 114 (25%) eyes had thin RNFL pre-operatively. Visual field recovery was observed in both groups during the first 6 weeks post-operatively (all Q ≤ 0.02), although improvements in visual field parameters between 6 weeks to 6 months were limited to eyes with thin RNFL (both Q < 0.05). No further improvements in visual function were detected beyond 6 months in both groups (both Q > 0.50). Similar trends were observed in linear regression analysis according to baseline visual function in both groups. In summary, eyes with normal RNFL thickness at baseline experienced most of their recovery within the first six weeks following surgery, while eyes with thin RNFL exhibited gradual improvements during the first six months. These findings have important implications when providing patient counselling and prognostication in the pre-operative setting.

ASYMMETRIC HYDROXYCHLOROQUINE MACULAR TOXICITY WITH APHAKIC FELLOW EYE.

BACKGROUND/PURPOSE: Retinal toxicity associated with antimalarial drug use in inflammatory conditions is well described and may be more common than previously recognized. Antimalarial drugs bind to melanin in ocular tissues, particularly the retinal pigment epithelium, but the mechanism of toxicity and its relation to light is unclear. METHODS: Case report. RESULTS: A 62-year-old white woman with erosive rheumatoid arthritis developed hydroxychloroquine toxicity in her phakic eye, with her aphakic fellow eye only mildly affected. CONCLUSION: We report the clinical evaluation of this rare case of asymmetrical hydroxychloroquine retinopathy and present a hypothesis regarding the mechanism of drug toxicity.

Myocardial T1 mapping and extracellular volume quantification as novel biomarkers in risk stratification of patients with systemic sclerosis.

AIM: To study the prognostic value of myocardial native T1 and extracellular volume (ECV), measured by cardiovascular magnetic resonance (CMR), in patients with systemic sclerosis (SSc). MATERIALS AND METHODS: Thirty-three SSc patients (16/33 male, 48.5%) were studied using multiparametric CMR including native T1 mapping with ECV calculation, T2 mapping, and late gadolinium enhancement (LGE). Patients were followed-up for cardiac death, haemodynamically significant arrhythmia, or heart failure. Results were compared with 33 age- and gender-matched healthy controls. RESULTS: When compared with controls, SSc patients had higher myocardial native T1 (1,058.9±71 versus 989.4±21.4 ms, p<0.001), higher T2 (54.9±5.7 versus 50±2.5 ms, p<0.001), and ECV values (27.9±5.4% versus 24.8±2%, p<0.004). LGE was present in eight patients (24%), two subendocardial, five midwall, and four subepicardial. LGE, native T1, and ECV were significantly associated with adverse events during follow-up in multivariate Cox regression analysis. Kaplan-Meier analysis demonstrated significant divergence of the survival curves based on the presence of elevated native T1 (≥1,069 ms) or ECV (≥31.4%) values. CONCLUSION: Cardiac involvement is frequent in SSc. Both native T1 mapping and ECV represent novel non-invasive markers of myocardial fibrosis and could be used in the risk stratification of patients with SSc. CMR mapping may provide a novel biomarker for disease monitoring and study of therapies aiming to reduce myocardial fibrosis in SSc.

Prognostic Utility of Optical Coherence Tomography for Long-Term Visual Recovery Following Pituitary Tumor Surgery.

PURPOSE: To investigate the association between optical coherence tomography (OCT) parameters and long-term visual recovery following optic chiasm decompression surgery. DESIGN: Prospective cohort study. METHODS: Consecutive patients who underwent pituitary or parasellar tumor resection between January 2009 to December 2018 were recruited in a single-center, 2-year prospective, longitudinal cohort study. Best-corrected visual acuity, visual fields, and OCT retinal nerve fiber layer (RNFL) thickness, macular thickness and volume were assessed preoperatively, and at 6 weeks, 6 months, and 2 years postoperatively. Long-term visual field recovery and maintenance were defined as a mean deviation of >-3 at 24 months, and visual acuity recovery and maintenance were defined as a logarithm of minimal angle of resolution (logMAR) of 0 (Snellen 20/20) or better at 24 months. RESULTS: A total of 239 patients (129 men, 110 women; mean ± SD age: 52 ± 16 years) were included. Multiple logistic regression analysis demonstrated that increased inferior RNFL thickness (per 10 µm) was associated with higher odds of long-term visual field recovery and maintenance (odds ratio [OR]: 1.26; 95% confidence interval [CI]: 1.12-1.41; Q < 0.001), and greater superior RNFL thickness (per 10 µm) was associated with higher odds of visual acuity recovery and maintenance (OR: 1.13; 95% CI: 1.03-1.27; Q = 0.031). A multivariable risk prediction model developed for long-term visual field recovery and maintenance that incorporated age, preoperative visual function, and RNFL thickness demonstrated C-statistics of 0.83 (95% CI: 0.72-0.94). CONCLUSION: Preoperative RNFL thickness was associated with long-term visual recovery and maintenance following chiasmal decompression. The multivariable risk prediction model developed in the present study may assist with preoperative patient counseling and prognosis.

Optical coherence tomography analysis of patients with untreated diabetic macular edema.

PURPOSE: Diabetic macular edema (DME) is a major cause of vision loss. Diabetes patients with mild macular edema and good visual acuity are often observed carefully so that treatment can be instituted when central vision is threatened. Optimal frequency of monitoring of these patients is unknown. Our study aimed to gather more information to determine a safe interval for monitoring of patients with eyes that were not undergoing active treatment for DME and to correlate outcomes with clinical risk factors. METHODS: Study population: Ninety-seven eyes with optical coherence tomography (OCT) evidence of DME of 97 patients with diabetes. Study procedures: Retrospective review of medical records and macular OCT scans at a 6-12-month interval. Primary outcomes: Change in visual acuity and change in central subfield thickness (CSFT) between the initial and follow-up OCT scans. RESULTS: There was no significant change from median baseline visual acuity 6/9 (inter-quartile range 6/6-6/12) or from median baseline CSFT (290 µm, inter-quartile range 270-312 µm) over a median duration of 8 months (inter-quartile range 7-10 months). The numbers of eyes where CSFT had increased ≥ 25 µm, reduced ≥ 25 µm, or remained unchanged were 16 (16%), 6 (6%), and 74 (76%), respectively. Patients with hemoglobin A1c ≥ 8.5% were 5.7 times more likely to develop central subfield thickening (95% CI 1.1-30.1, P = 0.038). CONCLUSIONS: Majority of eyes with DME on OCT had stable CSFT without treatment over a median duration of 8 months. Hemoglobin A1c may be useful for risk stratification.

Bull's eye maculopathy and subfoveal deposition in two mucopolysaccharidosis type I patients on long-term enzyme replacement therapy.

PURPOSE: To report retinal findings in two patients with mucopolysaccharidosis type I (MPS I) receiving human recombinant alpha-l-iduronidase (Laronidase) as enzyme replacement therapy. OBSERVATIONS: Patient 1 had visual acuity 20/20 right eye, 20/25 left eye and unremarkable anterior segment and retinal examination. Optical coherence tomography (OCT) scanning demonstrated parafoveal thinning and subfoveal hyperreflectant material. Patient 2 had visual acuity 20/20 both eyes, with dense nuclear cataract both eyes. Retinal examination demonstrated bull's eye maculopathy both eyes. OCT scanning confirmed parafoveal atrophy and demonstrated similar appearing subfoveal hyperreflectant material, more prominent than in case 1. CONCLUSIONS AND IMPORTANCE: These two patients with MPS I receiving Laronidase treatment have developed bull's eye maculopathy changes and subfoveal deposition of hyperreflectant material despite excellent compliance and good tolerance of the standard dose of enzyme therapy for this disorder. Further studies are required to determine the nature of the material, the incidence and the effect of enzyme replacement therapy on these findings in patients with MPS I.

Child road traffic injury mortality in Victoria, Australia (0-14 years), the need for targeted action.

INTRODUCTION: Extensive efforts to reduce unintentional injury were enacted in the last three decades of the 20th century. Examination of road traffic injury mortality indicates the extent of fatal, unintentional child injuries (0-14 years) future interventions must address. AIMS: (1) describe in-depth child road traffic injury (RTI) deaths 2001-2012 in Victoria, Australia (2) identify the potential preventability of the RTI causes by currently available countermeasures and scope for enhanced implementation and novel solutions. METHOD: Fatal Victorian child injury data were extracted from the National Coronial Information System (NCIS) for the 12 year period January 2001-December 2012. All on-road data was analysed. Data for passenger and pedestrian deaths was examined in depth. Associated factors were determined using univariate and pairwise analysis of factors. Published WHO key prevention strategies, and the recent literature were reviewed, focusing on the identified fatalities among children 0-14 years. RESULTS: For 172 RTI deaths, head injury was the leading medical cause of death (68%). Significantly, the most vulnerable age group for both passengers and pedestrians was 0-4 years. Rural children were over-represented with children aged 0-4 years at greatest risk. Common factors for occupants were loss of control and veering to the incorrect side. For pedestrians the major factors related to rural residence and supervision. DISCUSSION AND CONCLUSIONS: This study confirms that RTIs are complex and follow chains of events. Numerous promising interventions were identified. Wider implementation of these advanced engineering, education and enforcement strategies may further improve mortality rates in Victoria. Feasible solutions for aspects of the child pedestrian problem remain elusive. This study describes the RTI problem in greater depth than previous studies and reveals that some existing measures are not fully implemented. The need for targeted action in: 0-4 year olds; head injury; and rural regions of Victoria is highlighted. The need for a safe systems approach is paramount.

Photon-Counting CT of the Brain: In Vivo Human Results and Image-Quality Assessment.

BACKGROUND AND PURPOSE: Photon-counting detectors offer the potential for improved image quality for brain CT but have not yet been evaluated in vivo. The purpose of this study was to compare photon-counting detector CT with conventional energy-integrating detector CT for human brains. MATERIALS AND METHODS: Radiation dose-matched energy-integrating detector and photon-counting detector head CT scans were acquired with standardized protocols (tube voltage/current, 120 kV(peak)/370 mAs) in both an anthropomorphic head phantom and 21 human asymptomatic volunteers (mean age, 58.9 ± 8.5 years). Photon-counting detector thresholds were 22 and 52 keV (low-energy bin, 22-52 keV; high-energy bin, 52-120 keV). Image noise, gray matter, and white matter signal-to-noise ratios and GM-WM contrast and contrast-to-noise ratios were measured. Image quality was scored by 2 neuroradiologists blinded to the CT detector type. Reproducibility was assessed with the intraclass correlation coefficient. Energy-integrating detector and photon-counting detector CT images were compared using a paired t test and the Wilcoxon signed rank test. RESULTS: Photon-counting detector CT images received higher reader scores for GM-WM differentiation with lower image noise (all P < .001). Intrareader and interreader reproducibility was excellent (intraclass correlation coefficient, ≥0.86 and 0.79, respectively). Quantitative analysis showed 12.8%-20.6% less image noise for photon-counting detector CT. The SNR of photon-counting detector CT was 19.0%-20.0% higher than of energy-integrating detector CT for GM and WM. The contrast-to-noise ratio of photon-counting detector CT was 15.7% higher for GM-WM contrast and 33.3% higher for GM-WM contrast-to-noise ratio. CONCLUSIONS: Photon-counting detector brain CT scans demonstrated greater gray-white matter contrast compared with conventional CT. This was due to both higher soft-tissue contrast and lower image noise for photon-counting CT.

Retinal disease in the C3 glomerulopathies and the risk of impaired vision.

BACKGROUND: Dense deposit disease and atypical hemolytic uremic syndrome are often caused by Complement Factor H (CFH) mutations. This study describes the retinal abnormalities in dense deposit disease and, for the first time, atypical haemolytic uremic syndrome. It also reviews our understanding of drusen pathogenesis and their relevance for glomerular disease. METHODS: Six individuals with dense deposit disease and one with atypical haemolytic uremic syndrome were studied from 2 to 40 years after presentation. Five had renal transplants. All four who had genetic testing had CFH mutations. Individuals underwent ophthalmological review and retinal photography, and in some cases, optical coherence tomography, and further tests of retinal function. RESULTS: All subjects with dense deposit disease had impaired night vision and retinal drusen or whitish-yellow deposits. Retinal atrophy, pigmentation, and hemorrhage were common. In late disease, peripheral vision was restricted, central vision was distorted, and there were scotoma from sub-retinal choroidal neovascular membranes and atypical serous retinopathy. Drusen were present but less prominent in the young person with atypical uremic syndrome due to a heterozygous CFH mutation. CONCLUSIONS: Drusen are common in forms of C3 glomerulopathy caused by compound heterozygous or heterozygous CFH mutations. They are useful diagnostically but also impair vision. Drusen have an identical composition to glomerular deposits. They are also identical to the drusen of age-related macular degeneration, and may respond to the same treatments. Individuals with a C3 glomerulopathy should be assessed ophthalmologically at diagnosis, and monitored regularly for vision-threatening complications.

Incidence and clinical predictors of ocular candidiasis in patients with Candida fungemia.

Purpose. The aim of this study is to determine the incidence and the predictors of ocular candidiasis among patient with Candida fungemia. Methods. We retrospectively reviewed the charts of all patients diagnosed with candidemia at the University of Kansas Medical Center during February 2000-March 2010. Data regarding patients' demographics, clinical characteristics, laboratory results, and ophthalmology examination findings were collected. Results. A total of 283 patients with candidemia were enrolled. The mean age (± standard deviation) was 55 ± 18 years; 66% were male. The most commonly isolated Candida species were C. albicans (54%), C. parapsilosis (20%), C. glabrata (13%), and C. tropicalis (8%). Only 144 (51%) patients were evaluated by ophthalmology; however, the proportion of patients who were formally evaluated by an ophthalmologist increased during the study period (9%in 2000 up to 73%in 2010; P < 0.0001). Evidence of ocular candidiasis was present in 18 (12.5%) patients. Visual symptoms were reported by 5 of 18 (28%) patients. In multivariable analysis, no predictors of ocular candidiasis were identified. Conclusions. The incidence of ocular candidiasis among patients with fungemia remains elevated. Most patients are asymptomatic and therefore all patients with candidemia should undergo fundoscopic examination to rule out ocular involvement.

Bilateral retrobulbar optic neuropathy in the setting of interferon alpha-2a therapy.

The development of biopharmaceutical agents, including the interferons (IFN), offers new treatment options for a wide range of medical conditions. Such advancements, however, have not come without risk to patients. Optic neuropathy in the setting of IFN therapy has been previously documented and is usually attributed to anterior ischaemic optic neuropathy; however, the pathophysiology remains poorly understood. Retrobulbar optic neuropathy associated with IFN treatment has not been described in the medical literature to date. We report the case of a 38-year-old Caucasian female with refractory acute myeloid leukaemia who developed painless bilateral blurred vision within 2 weeks of commencing a course of IFN alpha-2a. Extensive clinical workup demonstrated bilateral retrobulbar optic neuropathy. We report the clinical evaluation of this first documented case and discuss the possible aetiologies of her presentation.