The Current Burden and Future Solutions for Preoperative Cataract-Refractive Evaluation Diagnostic Devices: A Modified Delphi Study.

Purpose: To obtain consensus on the key areas of burden associated with existing devices and to understand the requirements for a comprehensive next-generation diagnostic device to be able to solve current challenges and provide more accurate prediction of intraocular lens (IOL) power and presbyopia correction IOL success. Patients and Methods: Thirteen expert refractive cataract surgeons including three steering committee (SC) members constituted the voting panel. Three rounds of voting included a Round 1 structured electronic questionnaire, Round 2 virtual face-to-face meeting, and Round 3 electronic questionnaire to obtain consensus on topics related to current limitations and future solutions for preoperative cataract-refractive diagnostic devices. Results: Forty statements reached consensus including current limitations (n = 17) and potential solutions (n = 23) associated with preoperative diagnostic devices. Consistent with existing evidence, the panel reported unmet needs in measurement accuracy and validation, IOL power prediction, workflow, training, and surgical planning. A device that facilitates more accurate corneal measurement, effective IOL power prediction formulas for atypical eyes, simplified staff training, and improved decision-making process for surgeons regarding IOL selection is expected to help alleviate current burdens. Conclusion: Using a modified Delphi process, consensus was achieved on key unmet needs of existing preoperative diagnostic devices and requirements for a comprehensive next-generation device to provide better objective and subjective outcomes for surgeons, technicians, and patients.

Role of vasorin, an anti-apoptotic, anti-TGF-ß and hypoxia-induced glycoprotein in the trabecular meshwork cells and glaucoma.

Glaucoma, one of the leading causes of irreversible blindness, is commonly associated with elevated intraocular pressure due to impaired aqueous humour (AH) drainage through the trabecular meshwork. The aetiological mechanisms contributing to impaired AH outflow, however, are poorly understood. Here, we identified the secreted form of vasorin, a transmembrane glycoprotein, as a common constituent of human AH by mass spectrometry and immunoblotting analysis. ELISA assay revealed a significant but marginal decrease in vasorin levels in the AH of primary open-angle glaucoma patients compared to non-glaucoma cataract patients. Human trabecular meshwork (HTM) cells were confirmed to express vasorin, which has been shown to possess anti-apoptotic and anti-TGF-ß activities. Treatment of HTM cells with vasorin induced actin stress fibres and focal adhesions and suppressed TGF-ß2-induced SMAD2/3 activation in HTM cells. Additionally, cobalt chloride-induced hypoxia stimulated a robust elevation in vasorin expression, and vasorin suppressed TNF-α-induced cell death in HTM cells. Taken together, these findings reveal the importance of vasorin in maintenance of cell survival, inhibition of TGF-ß induced biological responses in TM cells, and the decreasing trend in vasorin levels in the AH of glaucoma patients suggests a plausible role for vasorin in the pathobiology of ocular hypertension and glaucoma.

Elevated Levels of Growth/Differentiation Factor-15 in the Aqueous Humor and Serum of Glaucoma Patients.

Dysregulated levels of growth/differentiation factor-15 (GDF15), a divergent member of the transforming growth factor-beta super family, have been found to be associated with the pathology of various diseases. In this study, we evaluated the levels of GDF15 in aqueous humor (AH) and serum samples derived from primary open-angle glaucoma (POAG) and age- and gender-matched non-glaucoma (cataract) patients to assess the plausible association between GDF15 and POAG. GDF15 levels were determined using an enzyme-linked immunosorbent assay, and data analysis was performed using the Wilcoxon rank sum test, or the Kruskal-Wallis test and linear regression. GDF15 levels in the AH (n = 105) of POAG patients were significantly elevated (by 7.4-fold) compared to cataract patients (n = 117). Serum samples obtained from a subgroup of POAG patients (n = 41) also showed a significant increase in GDF15 levels (by 50%) compared to cataract patients. GDF15 levels were elevated in male, female, African American, and Caucasian POAG patients. This study reveals a significant and marked elevation of GDF15 levels in the AH of POAG patients compared to non-glaucoma cataract control patients. Although serum GDF15 levels were also elevated in POAG patients, the magnitude of difference was much smaller relative to that found in the AH.

QUANTITATIVE TOPOGRAPHIC CURVATURE MAPS OF THE POSTERIOR EYE UTILIZING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: Deformations of the retina such as staphylomas in myopia or scleral flattening in high intracranial pressure can be challenging to quantify with en face imaging. We describe an optical coherence tomography-based method for the generation of quantitative posterior eye topography maps in normal and pathologic eyes. METHODS: Using "whole eye" optical coherence tomography, we corrected for subjects' optical distortions to generate spatially accurate posterior eye optical coherence tomography volumes and created local curvature (KM, mm-1) topography maps for each consented subject. We imaged nine subjects, three normal, two with myopic degeneration, and four with papilledema including one that was imaged longitudinally. RESULTS: Normal subjects mean temporal KM was 0.0923 mm-1, nasal KM was 0.0927 mm-1, and KM local variability was 0.0162 mm-1. In myopic degeneration, subjects KM local variability was higher at 0.0836 mm-1. In papilledema subjects nasal KM was flatter compared with temporal KM (0.0709 vs. 0.0885 mm-1). Mean intrasession KM repeatability for all subjects was 0.0036 mm-1. CONCLUSION: We have developed an optical coherence tomography based method for quantitative posterior eye topography that offers the ability to analyze local curvature with micron scale resolution and offers the potential to help clinicians and researchers characterize subtle, local retinal deformations earlier in patients and follow their development over time.

Impact of Preoperative Video Education for Cataract Surgery on Patient Learning Outcomes.

PURPOSE: To assess the effect of an educational video on 1) patient knowledge about cataract surgery, 2) patient perception of preoperative assessment visit quality, 3) face-to-face time with the surgeon, and 4) choices regarding premium intraocular lenses (IOLs) or laser-assisted cataract surgery (LACS). SETTING: Eye clinic in an academic medical center. DESIGN: Prospective survey of patients who randomly viewed or did not view an educational video. METHODS: Patients of three cataract surgeons completed a survey during cataract surgery preoperative visits. One group viewed an educational video about cataract surgery, while the other did not. All patients received their surgeon's typical preoperative counseling. RESULTS: A total of 101 patients were surveyed. Out of 101 patients, 58 viewed the educational video. Patients who viewed the video exhibited stronger learning outcomes; in particular, patients who viewed the video scored higher on cataract surgery educational assessments than those who did not (83% vs 76%, p=0.032), particularly on the assessment of postoperative visual expectations (98% vs 80%, p=0.003). Differences in educational assessment scores between groups were not affected by which surgeon patients saw (p=0.807). Patients who watched the video were more likely to agree their surgeon provided quality explanations (93% vs 74% strongly agreed, p=0.025) and trended toward greater perception the surgeon spent enough time with them (p=0.067). Video education did not affect face-to-face surgeon time with patients (p=0.212) or choices of multifocal IOLs (p=0.795), toric IOLs (p=0.321), or LACS (p=0.940). CONCLUSION: Video education during preoperative cataract surgery assessments improved patient understanding of cataract surgery and perception of preoperative visits. Video education is easily integrated into preoperative visits and can enhance the preoperative experience.

Intraoperative aberrometry vs modern preoperative formulas in predicting intraocular lens power.

PURPOSE: To compare the outcomes of an intraoperative aberrometer (ORA) to the Barrett Universal II (Barrett II) and Hill-RBF 2.0 (Hill-RBF) intraocular lens (IOL) power calculation formulas. SETTING: Duke University Eye Center, Durham, North Carolina, USA. DESIGN: Retrospective study. METHODS: Patients without history of refractive corneal surgery who had an uneventful cataract surgery from April 2016 to June 2018 were enrolled. Refractive prediction error was calculated with the Barrett II formula, the Hill-RBF formula, and the ORA intraoperative aberrometer (OIA) and was stratified by axial length, IOL type, and the percentage of eyes within a diopteric range of target refraction. RESULTS: Nine-hundred forty-nine eyes were included. The mean and median absolute predictive errors were 0.29 diopters (D) and 0.23 D (Barrett II), 0.31 D and 0.24 D (Hill-RBF), and 0.31 D and 0.25 D (intraoperative aberrometry), respectively (P > .05). Axial length stratification did not influence statistical difference in the IOL prediction methods. Barrett II outperformed the OIA toric multifocal (P = .011) group. Postoperative refraction was within 0.50 D of target in 84% (Barrett II), 83% (Hill-RBF), and 82% (OIA) of eyes (P > .05). CONCLUSIONS: Comparing the OIA to the Barrett II and Hill-RBF calculators, there was minimal clinical difference in the toric multifocal group. Regarding postoperative predicted spherical equivalent, for patients without a history of refractive surgery and good potential visual acuity, refractive outcome was not improved by utilizing the OIA.

Role of the autotaxin-lysophosphatidic acid axis in glaucoma, aqueous humor drainage and fibrogenic activity.

Ocular hypertension due to impaired aqueous humor (AH) drainage through the trabecular meshwork (TM) is a major risk factor for glaucoma, a leading cause of irreversible blindness. However, the etiology of ocular hypertension remains unclear. Although autotaxin, a secreted lysophospholipase D and its catalytic product lysophosphatidic acid (LPA) have been shown to modulate AH drainage through TM, we do not have a complete understanding of their role and regulation in glaucoma patients, TM and AH outflow. This study reports a significant increase in the levels of autotaxin, lysophosphatidylcholine (LPC), LPA and connective tissue growth factor (CTGF) in the AH of Caucasian and African American open angle glaucoma patients relative to age-matched non-glaucoma patients. Treatment of human TM cells with dexamethasone, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) increased the levels of autotaxin protein, a response that was mitigated by inhibitors of glucocorticoid receptor, NF-kB and SMAD3. Dexamethasone, TNF-α, IL-1ß and LPC treatment of TM cells also led to an increase in the levels of CTGF, fibronectin and collagen type 1 in an autotaxin dependent manner. Additionally, in perfused enucleated mouse eyes, autotaxin and LPC were noted to decrease, while inhibition of autotaxin was increased aqueous outflow through the TM. Taken together, these results provide additional evidence for dysregulation of the autotaxin-LPA axis in the AH of glaucoma patients, reveal molecular insights into the regulation of autotaxin expression in TM cells and the consequences of autotaxin inhibitors in suppressing the fibrogenic response and resistance to AH outflow through the TM.

Influence of corneal diameter on surgically induced astigmatism in small-incision cataract surgery.

OBJECTIVE: Clear corneal incisions (CCI) in cataract surgery create a variable amount of surgically induced astigmatism (SIA). As refractive outcomes become increasingly important, it is necessary to understand factors that impact SIA and refractive surprises. In this study, we evaluate the effect of horizontal corneal diameter (white-to-white, WTW) on SIA in 2.2 mm small-incision cataract surgery. DESIGN: Prospective study at an academic-university-based outpatient clinic (Duke Eye Center). PARTICIPANTS: We enrolled adults ≥18 years of age without prior corneal surgery or corneal pathology undergoing cataract surgery with a single surgeon (R.R.V.). METHODS: All surgeries were uncomplicated and performed through a manually constructed, limbal, temporal, or superotemporal 2.2 mm CCI. Enrolled participants received standard-of-care evaluations and postoperative management. SIA was calculated at the first postoperative month using the Jaffe and Clayman vector analysis equation. RESULTS: We enrolled 43 subjects (55 eyes) with a mean age of 71 years with WTW corneal diameter values ranging from 11.34 to 12.99 mm obtained from Lenstar® (Haag-Streit Group, Koeniz, Switzerland). Postoperative SIA ranged from 0.072 to 1.6 D (mean 0.47 D, standard deviation 0.33 D). SIA was plotted against WTW and best fit to a linear regression model with a slope of -0.056 and an R2 value of 0.006. CONCLUSIONS: In this prospective study, WTW diameter had minimal effects on the SIA in uncomplicated small-incisional cataract surgery through a 2.2 mm temporal or superotemporal CCI with a single surgeon. Our findings suggest that corneal diameter does not play a clinically significant role in this population undergoing small-incisional cataract surgery.

Wide-field whole eye OCT system with demonstration of quantitative retinal curvature estimation.

Current conventional clinical OCT systems image either only the anterior or the posterior eye during a single acquisition. This localized imaging limits conventional OCT's use for characterizing global ocular morphometry and biometry, which requires knowledge of spatial relationships across the entire eye. We developed a "whole eye" optical coherence tomography system that simultaneously acquires volumes with a wide field-of-view for both the anterior chamber (14 x 14 mm) and retina (55°) using a single source and detector. This system was used to measure retinal curvature in a pilot population and compared against curvature of the same eyes measured with magnetic resonance imaging.

Preclinical evaluation and intraoperative human retinal imaging with a high-resolution microscope-integrated spectral domain optical coherence tomography device.

PURPOSE: The authors have recently developed a high-resolution microscope-integrated spectral domain optical coherence tomography (MIOCT) device designed to enable OCT acquisition simultaneous with surgical maneuvers. The purpose of this report is to describe translation of this device from preclinical testing into human intraoperative imaging. METHODS: Before human imaging, surgical conditions were fully simulated for extensive preclinical MIOCT evaluation in a custom model eye system. Microscope-integrated spectral domain OCT images were then acquired in normal human volunteers and during vitreoretinal surgery in patients who consented to participate in a prospective institutional review board-approved study. Microscope-integrated spectral domain OCT images were obtained before and at pauses in surgical maneuvers and were compared based on predetermined diagnostic criteria to images obtained with a high-resolution spectral domain research handheld OCT system (HHOCT; Bioptigen, Inc) at the same time point. Cohorts of five consecutive patients were imaged. Successful end points were predefined, including ≥80% correlation in identification of pathology between MIOCT and HHOCT in ≥80% of the patients. RESULTS: Microscope-integrated spectral domain OCT was favorably evaluated by study surgeons and scrub nurses, all of whom responded that they would consider participating in human intraoperative imaging trials. The preclinical evaluation identified significant improvements that were made before MIOCT use during human surgery. The MIOCT transition into clinical human research was smooth. Microscope-integrated spectral domain OCT imaging in normal human volunteers demonstrated high resolution comparable to tabletop scanners. In the operating room, after an initial learning curve, surgeons successfully acquired human macular MIOCT images before and after surgical maneuvers. Microscope-integrated spectral domain OCT imaging confirmed preoperative diagnoses, such as full-thickness macular hole and vitreomacular traction, and demonstrated postsurgical changes in retinal morphology. Two cohorts of five patients were imaged. In the second cohort, the predefined end points were exceeded with ≥80% correlation between microscope-mounted OCT and HHOCT imaging in 100% of the patients. CONCLUSION: This report describes high-resolution MIOCT imaging using the prototype device in human eyes during vitreoretinal surgery, with successful achievement of predefined end points for imaging. Further refinements and investigations will be directed toward fully integrating MIOCT with vitreoretinal and other ocular surgery to image surgical maneuvers in real time.

Prospective multicenter study of toric IOL outcomes when dual zone automated keratometry is used for astigmatism planning.

PURPOSE: To evaluate clinical outcomes when toric intraocular lens (IOL) calculations are based on the keratometric output from the Lenstar LS-900 dual zone automated keratometer (Haag-Streit AG, Koeniz, Switzerland). METHODS: Eligible subjects presenting for toric IOL implantation at five sites were measured with a dual-zone automated keratometer. The data were used to plan the power and angle of the toric IOL to be implanted. Refractive and visual acuity status were checked at 1 and 3 months postoperatively. RESULTS: A total of 102 eyes had relevant data for analysis. More than 76% of eyes had 0.50 diopter or less of refractive astigmatism at 1 and 3 months, with no difference by level of astigmatism corrected. More than half of the eyes had uncorrected distance visual acuity of 20/20 or better and 78% were 20/25 or better. A new measure of effectiveness of toric correction power is described that suggested lens selection was appropriate. Results appeared better than those obtained in previous studies when the IOL cylinder power and alignment were calculated using manual keratometry. CONCLUSIONS: In this series of eyes from multiple centers, the calculation of toric IOL power using dual-zone automated keratometry measurements produced clinical results that were better than results in the literature where manual keratometry was used.

Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure.

Primary open-angle glaucoma is the second leading cause of blindness in the United States and is commonly associated with elevated intraocular pressure (IOP) resulting from diminished aqueous humor (AH) drainage through the trabecular pathway. Developing effective therapies for increased IOP in glaucoma patients requires identification and characterization of molecular mechanisms that regulate IOP and AH outflow. This study describes the identification and role of autotaxin (ATX), a secretory protein and a major source for extracellular lysophosphatidic acid (LPA), in regulation of IOP in a rabbit model. Quantitative proteomics analysis identified ATX as an abundant protein in both human AH derived from non-glaucoma subjects and in AH from different animal species. The lysophospholipase D (LysoPLD) activity of ATX was found to be significantly elevated (by ∼1.8 fold; n=20) in AH derived from human primary open angle glaucoma patients as compared to AH derived from age-matched cataract control patients. Immunoblotting analysis of conditioned media derived from primary cultures of human trabecular meshwork (HTM) cells has confirmed secretion of ATX and the ability of cyclic mechanical stretch of TM cells to increase the levels of secreted ATX. Topical application of a small molecular chemical inhibitor of ATX (S32826), which inhibited AH LysoPLD activity in vitro (by >90%), led to a dose-dependent and significant decrease of IOP in Dutch-Belted rabbits. Single intracameral injection of S32826 (∼2 µM) led to significant reduction of IOP in rabbits, with the ocular hypotensive response lasting for more than 48 hrs. Suppression of ATX expression in HTM cells using small-interfering RNA (siRNA) caused a decrease in actin stress fibers and myosin light chain phosphorylation. Collectively, these observations indicate that the ATX-LPA axis represents a potential therapeutic target for lowering IOP in glaucoma patients.

Bilateral intraocular hemorrhage from vascularization of cataract wounds.

We report a case of bilateral intraocular hemorrhage from vascularization of cataract wounds. The patient experienced decreased vision following an episode of vomiting more than 2.5 years after phacoemulsification through a scleral tunnel incision in the right eye and combined trabeculectomy and extracapsular cataract extraction in the left eye. Gonioscopy demonstrated abnormal vessels in the region of the cataract wound superiorly and small hyphemas inferiorly in both eyes. The hemorrhages and elevated intraocular pressure normalized over weeks. The left eye had a recurrent hemorrhage 5 months later, which was successfully treated with argon laser goniophotocoagulation.

Analysis of LOXL1 polymorphisms in a United States population with pseudoexfoliation glaucoma.

PURPOSE: To identify if recently described LOXL1 (lysyl oxidase-like 1) polymorphisms are associated with pseudoexfoliation glaucoma (XFG) in a United States (U.S.) Caucasian patient population. METHODS: Individuals with XFG were identified using standard clinical examination techniques. TaqMan allelic discrimination assays were used to genotype 13 single nucleotide polymorphisms (SNPs) that tag LOXL1 in Caucasian individuals. The coding region of exon 1 that includes the previously associated SNP, rs1048661, was sequenced. Allele and genotype frequencies were compared between cases and unrelated controls. RESULTS: Fifty affected individuals and 235 control individuals were recruited into this study. We replicated the previously reported association of three SNPs (rs1048661, rs2165241, and rs3825942) in our independent XFG population (single SNP p-values were 0.001-0.02). The risk alleles at these three and several other intragenic SNPs are part of an extended XFG-associated LOXL1 haplotype with a frequency of 32.0% in XFG patients and 21.6% in controls. CONCLUSIONS: We have performed an analysis of LOXL1 and XFG in a United States patient population and have confirmed the strong association previously reported for Icelandic and Swedish samples. However, due to the high frequency of risk alleles in non-XFG individuals, this association should not form the basis of a diagnostic test for XFG. It is likely that additional genetic or environmental factors modulate the penetrance of LOXL1 susceptibility alleles.