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.

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.

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.

Cytokine profiles in clinical subtypes of ophthalmic Graves' disease.

PURPOSE: To examine the association of cytokines in the two clinical subtypes of ophthalmic Graves' disease by comparing cytokine expression in the fat and ethmoid tissue of type I and type II patients. METHODS: Patients needing orbital decompression or eyelid surgery were identified and enrolled into a prospective study. Patients were assigned to the type I or type II subclassification, based on the presence of diplopia. Orbital fat, sinus tissue or muscle removed during surgery was evaluated. The mRNA expression profiles of Th1 cytokines (TNF-alpha/beta, IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10) were analyzed using real time PCR. RESULTS: 30 patients were enrolled in the study: 5 type I (80% female), 14 type II (71% female) and 11 controls (73% female). There were 14 decompressions (3 type I and 11 type II), 17 lid procedures (2 type I, 4 type II and 11 controls) and 10 ethmoidectomies (3 type I and 7 type II). The average ages were 45, 56 and 66 in the type I, type II and control groups, respectively. There was more TNF-alpha (p value 0.009) and IL-6 (p value 0.04) in ethmoid sinus cells of type II patients compared to ethmoid sinus cells of type I patients and a trend of higher expression of all cytokines in type II patients. CONCLUSIONS: There is a trend towards greater mRNA expression of both Th1 and Th2 cytokines in both orbital fat and ethmoidal sinus tissue of type II patients compared to type I patients.

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.

Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model.

Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

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.

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.

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.

The genetic control of avascular area in mouse oxygen-induced retinopathy.

PURPOSE: The C57BL/6ByJ and BALB/cByJ inbred strains of mice are, respectively, susceptible and resistant to oxygen-induced retinopathy (OIR). The purpose of this work was to investigate the genetic control of the retinal avascular area in mouse OIR using a mapping cross. METHODS: The central retinal avascular area was measured on postnatal day 16 (P16) in C57BL/6ByJ, BALB/cByJ, 101 (C57BL/6ByJ x BALB/cByJ)F2, and 116 (BALB/cByJ x C57BL/6ByJ)F2 mice that had been subjected to the OIR protocol. A genome-wide scan was performed of selected albino and non-albino mice to determine quantitative trait loci associated with weight and avascular area. RESULTS: C57BL/6ByJ mice had significantly larger avascular areas than BALB/cByJ ones. Albino mice of the F2 generation had smaller avascular areas than the non-albino mice. Genotyping was performed at 856 informative single nucleotide polymorphisms approximately evenly distributed across the genome from each of 85 selected F2 mice. Weight, sex, and the paternal grandmother were found to act as additive covariates associated with the avascular area on P16; mapping analyses that used a model incorporating these covariates found a quantitative trait locus on chromosome 7 related to avascular area. Mapping analyses that used a model that did not incorporate covariates found a quantitative trait locus on chromosome 9 related to avascular area. A quantitative trait locus for bodyweight on P16 was mapped to chromosome 5. CONCLUSIONS: The retinal avascular area in the mouse OIR model is under genetic control. Revascularization in OIR is related to the weight, strain of paternal grandmother, sex, and albinism. Our data support the existence of a quantitative trait locus on chromosome 5 that influences weight after exposure to hyperoxia, as well as quantitative trait loci on chromosomes 7 and 9 that modify susceptibility to OIR.

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.

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.

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.

Self-cleavage of RNA in the replication of small pathogens of plants and animals.

The ability of certain small, circular, pathogenic RNAs of plants and animals to self-cleave at specific sites in vitro in the complete absence of protein most likely plays a central role in their replication in vivo by a rolling circle mechanism. The self-cleavage of an RNA transcript from a satellite DNA of the newt indicates that this reaction is not limited to pathogenic RNAs. Further, the site-specific self-cleavage in trans by two separate RNA molecules suggests that such reactions may be important in gene regulation in normal cells as well as in the genesis of symptom expression on infection by RNA pathogens.

Intravenous bevacizumab causes regression of choroidal neovascularization secondary to diseases other than age-related macular degeneration.

PURPOSE: To investigate the safety, tolerability, and bioactivity of intravenous infusions of bevacizumab in patients with choroidal neovascularization (CNV) attributable to causes other than age-related macular degeneration. DESIGN: Nonrandomized clinical trial. METHODS: Ten patients with CNV received infusions of 5 mg/kg of bevacizumab. The primary efficacy outcome measure was change in visual acuity (VA; Early Treatment Diabetic Retinopathy Study letters read at 4 meters) at 24 weeks and secondary measures were changes from baseline in excess foveal thickness (center subfield thickness), area of fluorescein leakage, and area of CNV. RESULTS: Infusions were well tolerated and there were no ocular or systemic adverse events. At baseline, median VA was 25.5 letters read at 4 meters (20/80) and median foveal thickness was 346 mum. At the primary endpoint (24 weeks), median VA was 48.5 letters (20/32), representing four lines of improvement from baseline (P = .005), median foveal thickness was 248 mum representing a 72% reduction in excess foveal thickness (P = .007). Four of nine patients had complete elimination of fluorescein leakage, three had near complete elimination (reductions of 91%, 88%, and 87%), two had modest reductions, and one had no reduction. All patients except one showed a reduction in area of CNV with a median reduction of 43%. CONCLUSIONS: Despite the small number of patients studied, the marked improvement in VA accompanied by prominent reductions in foveal thickness, fluorescein leakage, and area of CNV suggest a beneficial effect. It may be worthwhile to consider further evaluation of systemic bevacizumab in young patients with CNV.

Common ophthalmic emergencies.

Ophthalmic emergencies are immediate threats to the visual system that can lead to permanent loss of visual function if left untreated. These emergencies should be detected by physicians and immediately treated and referred to an ophthalmologist if necessary. This article reviews the most common ophthalmic emergency room presentations, the history and physical examination for an ophthalmic emergency, and the diagnosis and management of each condition.

Longitudinal outcomes after endovascular repair of abdominal aortic aneurysms.

OBJECTIVE: Endovascular abdominal aneurysm repair (EVAR) is increasingly used, but there is insufficient evaluation of long-term outcomes. METHOD: Retrospective cohort study using the linked Washington State hospital discharge database. RESULT: 3,350 patients underwent elective repair of AAA (1181 EVAR) between 2000 and 2005. EVAR patients were older and had higher comorbidity scores. The 30-day readmission rate after EVAR was 11.6%. The 30-day readmissions included cardiac complications (18.5%) and device complications (10.4%). 46% of the 30-day readmissions after EVAR underwent procedures: abdominal/ iliac angiography (7.4%), angioplasty (8.9%), and device revision (8.2%). Mean time to late interventions was 611 days. CONCLUSION: Readmission, reintervention, and complication rates after EVAR occur more commonly than previously described. Cardiac complications were the most common readmission. Almost half of the 30-day readmissions required a secondary intervention. Long-term complications after EVAR occurred before two years. Population-based assessment may be more reflective of "real world" complication rates after EVAR.