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Francisco José Muñoz Negrete,1 Hans G Lemij,2 Carl Erb3 1Ophthalmology Service, Hospital Ramón y Cajal, Madrid, Spain; 2Glaucoma Service, Rotterdam Eye Hospital, Rotterdam, the Netherlands; 3Augenklinik Wittenbergplatz, Berlin, Germany Abstract: Patient satisfaction with glaucoma treatment has been poorly studied to date. Because glaucoma is a chronic condition in which the therapeutic response is dependent on adherence to treatment, patient acceptability is an important factor in achieving satisfactory outcomes. This multicenter, international (Belgium, the Netherlands, and Spain), epidemiological convenience sample survey among patients commencing treatment with preservative-free latanoprost collected data on patient satisfaction with particular regard to tolerability. A total of 1,541 patients were recruited who were predominantly elderly (74% were over 60 years of age) and female (61%). Most of the patients had previously received preserved topical glaucoma medication (69%), 6.7% had previously received preservative-free medication, whereas 24% had not previously been treated for glaucoma. The great majority of patients (>95%) were satisfied with the preservative-free latanoprost treatment. Among the patients who had previously received preserved medication, 73% of patients found preservative-free latanoprost to be better tolerated and 89% found it at least as easy to use as their prior treatment. Patient satisfaction (determined by a 0–100 mm visual analog scale) was improved by 47% on a switch from preserved treatment to preservative-free latanoprost. Intraocular pressure was similar in patients who had previously received preserved (18.3 mmHg), preservative-free (17.8 mmHg) glaucoma medication or who were naïve to treatment (20.3 mmHg). Preservative-free latanoprost provided effective reduction of intraocular pressure with better tolerability and patient satisfaction than preserved glaucoma medication. This tolerability profile can be expected to improve adherence to treatment in glaucoma patients. Keywords: prostaglandins analogs, glaucoma therapy, preservative, patient satisfaction, tolerability, persistence, tear substitutes

Hans G Lemij,1 Juliette GMM Hoevenaars,2 Cees van der Windt,3 Christophe Baudouin4 On behalf of the GOAL Study Investigators 1Glaucoma Service, Rotterdam Eye Hospital, Rotterdam, 2VieCuri Medisch Centrum, Venlo, 3Ziekenhuis Rivierenland, Tiel, the Netherlands; 4Quinze-Vingts National Hospital and Vision Institute, Paris, France Abstract: While safe and effective treatments for glaucoma exist, their effectiveness is compromised by poor compliance. Patients who have problems with their topical glaucoma medication are acknowledged to be at higher risk for poor compliance, frequent medication switching, and surgery. Patient satisfaction with therapy and its associated benefits have until recently taken second place to efficacy. The present study is a transverse cross-sectional epidemiological survey among glaucoma patients receiving therapy with prostaglandin analogs. The primary objective was to determine and characterize patient satisfaction with glaucoma therapy, and the secondary objective was to identify factors that may contribute to poor patient satisfaction. Ophthalmologists in the Netherlands included 199 patients and 164 were analyzed. Patients were predominantly elderly with early, primary, open angle glaucoma. Eighty-nine percent of them stated they were satisfied or very satisfied with their treatment. However, signs of ocular surface disorder on ophthalmological examination were evident in 44% of patients, corneal fluorescein staining was positive in 28% of patients, and 38% of patients were using tear substitutes. The prevalence of blepharitis/meibomian gland dysfunction and dry eye was more than twice as high after the commencement of therapy compared with before therapy. Univariate analysis revealed that patient dissatisfaction with their glaucoma therapy was statistically significantly (P

Eye movement perimetry (EMP) expresses the decline in visual field (VF) responsiveness based on the deviation in saccadic reaction times (SRTs) from their expected age-similar responses (normative database). Since ethnic dissimilarities tend to affect saccade parameters, we evaluated the effect of such a factor on SRT and its interaction with age, stimulus eccentricity, and intensity. 149 healthy adults, spread into five age groups, drawn from Indian and Dutch ethnicities underwent a customized EMP protocol integrated with a saccade task from which the SRTs to 'seen' visual stimuli were computed. The EMP test had a total of 54 coordinates (five stimulus eccentricities) tested using Goldmann size III visual stimuli presented at four stimulus intensity (SI) levels against a constant background. Considering SRT as a dependent variable, a Generalized Linear Mixed Model analysis was conducted that revealed a statistically significant (p < 0.001) influence of ethnicity and interaction between the tested factors (ethnicity × age × stimulus eccentricity × intensity). However, during the post hoc analysis, out of the 100 possible pair-wise comparisons, only 6% (minor proportion) of the estimates showed statistical significance. Hence, the ethnic-specific differences need not be accounted for while implementing EMP in a diverse set of populations instead a collective database might serve the purpose., (© 2024. The Author(s).)

The early detection of glaucoma is essential in preventing visual impairment. Artificial intelligence (AI) can be used to analyze color fundus photographs (CFPs) in a cost-effective manner, making glaucoma screening more accessible. While AI models for glaucoma screening from CFPs have shown promising results in laboratory settings, their performance decreases significantly in real-world scenarios due to the presence of out-of-distribution and low-quality images. To address this issue, we propose the Artificial Intelligence for Robust Glaucoma Screening (AIROGS) challenge. This challenge includes a large dataset of around 113,000 images from about 60,000 patients and 500 different screening centers, and encourages the development of algorithms that are robust to ungradable and unexpected input data. We evaluated solutions from 14 teams in this paper and found that the best teams performed similarly to a set of 20 expert ophthalmologists and optometrists. The highest-scoring team achieved an area under the receiver operating characteristic curve of 0.99 (95% CI: 0.98-0.99) for detecting ungradable images on-the-fly. Additionally, many of the algorithms showed robust performance when tested on three other publicly available datasets. These results demonstrate the feasibility of robust AI-enabled glaucoma screening.

Purpose: Significant visual impairment due to glaucoma is largely caused by the disease being detected too late., Objective: To build a labeled data set for training artificial intelligence (AI) algorithms for glaucoma screening by fundus photography, to assess the accuracy of the graders, and to characterize the features of all eyes with referable glaucoma (RG)., Design: Cross-sectional study., Subjects: Color fundus photographs (CFPs) of 113 893 eyes of 60 357 individuals were obtained from EyePACS, California, United States, from a population screening program for diabetic retinopathy., Methods: Carefully selected graders (ophthalmologists and optometrists) graded the images. To qualify, they had to pass the European Optic Disc Assessment Trial optic disc assessment with ≥ 85% accuracy and 92% specificity. Of 90 candidates, 30 passed. Each image of the EyePACS set was then scored by varying random pairs of graders as "RG," "no referable glaucoma (NRG)," or "ungradable (UG)." In case of disagreement, a glaucoma specialist made the final grading. Referable glaucoma was scored if visual field damage was expected. In case of RG, graders were instructed to mark up to 10 relevant glaucomatous features., Main Outcome Measures: Qualitative features in eyes with RG., Results: The performance of each grader was monitored; if the sensitivity and specificity dropped below 80% and 95%, respectively (the final grade served as reference), they exited the study and their gradings were redone by other graders. In all, 20 graders qualified; their mean sensitivity and specificity (standard deviation [SD]) were 85.6% (5.7) and 96.1% (2.8), respectively. The 2 graders agreed in 92.45% of the images (Gwet's AC2, expressing the inter-rater reliability, was 0.917). Of all gradings, the sensitivity and specificity (95% confidence interval) were 86.0 (85.2-86.7)% and 96.4 (96.3-96.5)%, respectively. Of all gradable eyes ( n  = 111 183; 97.62%) the prevalence of RG was 4.38%. The most common features of RG were the appearance of the neuroretinal rim (NRR) inferiorly and superiorly., Conclusions: A large data set of CFPs was put together of sufficient quality to develop AI screening solutions for glaucoma. The most common features of RG were the appearance of the NRR inferiorly and superiorly. Disc hemorrhages were a rare feature of RG., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Purpose: To assess if ocular motility impairment, and the ensuing diplopia, after Baerveldt Glaucoma device (BGI) implantation, is related to the presence of a large fluid reservoir (bleb), using Magnetic Resonance Imaging (MRI)., Methods: In a masked observational study (CCMO-registry number: NL65633.058.18), the eyes of 30 glaucoma patients with (n = 12) or without diplopia (n = 18) who had previously undergone BGI implantation were scanned with a 7 Tesla MRI-scanner. The substructures of the BGI-complex, including both blebs and plate, were segmented in 3D. Primary outcomes were a comparison of volume and height of the BGI-complex between patients with and without diplopia. Comparisons were performed by using an unpaired t-test, Fisher's Exact or Mann-Whitney test. Correlations were determined by using Spearman correlation., Results: The median volume and height of the BGI-complex was significantly higher in patients with compared to patients without diplopia (p = 0.007 and p = 0.025, respectively). Six patients had an excessively large total bleb volume (median of 1736.5mm3, interquartile range 1486.3-1933.9mm3), four of whom experienced diplopia (33% of the diplopia patients). Fibrotic strands through the BGI plate, intended to limit the height of the bleb, could be visualized but were not related to diplopia (75% versus 88%; p = 0.28)., Conclusions: With MRI, we show that in a significant number of diplopia cases a large bleb is present in the orbit. Given the large volume of these blebs, they are a likely explanation of the development of diplopia in at least some of the patients with diplopia after BGI implantation. Additionally, the MR-images confirm the presence of fibrotic strands. As these strands are also visible in patients with a large bleb, they are apparently not sufficient to restrict the bleb height., Competing Interests: J.W.B. reports research support from Philips Healthcare during the conduct of the study. All other authors declare that no competing interests exists. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Corneal guttae, which are the abnormal growth of extracellular matrix in the corneal endothelium, are observed in specular images as black droplets that occlude the endothelial cells. To estimate the corneal parameters (endothelial cell density [ECD], coefficient of variation [CV], and hexagonality [HEX]), we propose a new deep learning method that includes a novel attention mechanism (named fNLA), which helps to infer the cell edges in the occluded areas. The approach first derives the cell edges, then infers the well-detected cells, and finally employs a postprocessing method to fix mistakes. This results in a binary segmentation from which the corneal parameters are estimated. We analyzed 1203 images (500 contained guttae) obtained with a Topcon SP-1P microscope. To generate the ground truth, we performed manual segmentation in all images. Several networks were evaluated (UNet, ResUNeXt, DenseUNets, UNet++, etc.) and we found that DenseUNets with fNLA provided the lowest error: a mean absolute error of 23.16 [cells/mm[Formula: see text]] in ECD, 1.28 [%] in CV, and 3.13 [%] in HEX. Compared with Topcon's built-in software, our error was 3-6 times smaller. Overall, our approach handled notably well the cells affected by guttae, detecting cell edges partially occluded by small guttae and discarding large areas covered by extensive guttae., (© 2022. The Author(s).)

Purpose: Accurate assessment of visual field (VF) trend may help clinicians devise the optimum treatment regimen. This study was conducted to investigate the behavior of VF sequences using pointwise and region-wise linear, exponential, and sigmoid regression models., Materials and Methods: In a retrospective cohort study, 277 eyes of 139 patients with glaucoma who had been followed for at least 7 years were investigated. Linear, exponential, and sigmoid regression models were fitted for each VF test location and Glaucoma Hemifield Test (GHT) region to model the trend of VF loss. The model with the lowest root mean square error (RMSE) was selected as the best fit., Results: The mean age (standard deviation [SD]) of the patients was 59.9 years (9.8) with a mean follow-up time of 9.3 (0.7) years. The exponential regression had the best fit based on pointwise and region-wise approaches in 39.3% and 38.1% of eyes, respectively. The results showed a better performance based on sigmoid regression in patients with initial VF sensitivity threshold greater than 22 dB (71.6% in pointwise and 62.2% in region-wise approaches). The overall RMSE of the region-wise regression model was lower than the overall RMSE of the pointwise model., Conclusions: In the current study, nonlinear regression models showed a better fit compared to the linear regression models in tracking VF loss behavior. Moreover, findings suggest region-wise analysis may provide a more appropriate approach for assessing VF deterioration., Translational Relevance: Findings may confirm a nonlinear progression of VF deterioration in patients with glaucoma.

Purpose: To determine the sensitivity of optical coherence tomography (OCT) and standard automated perimetry (SAP) for detecting glaucomatous progression in the superior and inferior hemiretina., Methods: We calculated contrast-to-noise ratios (CNRs) for OCT retinal nerve fiber layer (RNFL) thickness of hemiretinas and for SAP mean total deviation (MTD) of the corresponding hemifields from longitudinal data (205 eyes, 125 participants). The glaucoma stage for each hemiretina was based on the corresponding hemifield's MTD. Contrast was defined as the difference of the parameter between two consecutive glaucoma stages, whereas noise was the measurement variability of the parameter in those stages. The higher the CNR of a parameter, the more sensitive it is to detecting progression in the transition between successive stages., Results: There were no statistically significant differences for the RNFL CNR and MTD CNR between superior and inferior hemiretinas. As the glaucoma stage of the opposite hemiretina worsened, the MTD CNR in the transition from moderate to advanced glaucoma significantly increased. The RNFL CNR in the transition from mild to moderate glaucoma significantly decreased in case of advanced glaucoma in the opposite hemiretina., Conclusions: Similar to full retinas, detecting conversion to glaucoma in hemiretinas is more sensitive with OCT than SAP, whereas with more advanced disease, SAP is more sensitive for detecting progression. More importantly, the sensitivity for detecting progression in one hemiretina with either technique depends on the glaucoma severity in the opposite hemiretina., Translational Relevance: Monitoring glaucomatous progression with either OCT or SAP partly depends on the glaucoma severity in the opposite hemiretina.

Purpose: To determine whether the postoperative corneal endothelial cell density (ECD) differs between glaucoma patients who underwent Baerveldt implant (BGI) surgery and patients who underwent a trabeculectomy (TE) over 5 years ago., Methods: Cross-sectional, observational study including 34 patients who underwent TE and 36 patients who underwent BGI surgery 5-11 years ago, as part of a randomized clinical trial. None of the patients had a history of intraocular surgery prior to their glaucoma surgery. Central and peripheral ECD was measured by using a non-contact specular microscope., Results: Central and peripheral ECD in the TE group was 2285 ± 371 cells/mm 2 (mean ± SD) and 2463 ± 476 cells/mm 2 , respectively. Central and peripheral ECD in the BGI group was 1813 ± 745 cells/mm 2 and 1876 ± 764 cells/mm 2 , respectively. The central and peripheral ECD was statistically significantly higher in the TE group than in the BGI group (p = 0.001 for both). Additional intraocular surgical interventions were more prevalent in the BGI group (23) than in the TE group (5) (p < 0.001). In a subanalysis, without eyes that had undergone additional surgical interventions, only the peripheral ECD was statistically significantly higher in the TE group compared with the BGI group (p = 0.011). For the BGI group, a longer postoperative period resulted in a lower central ECD (r = -0.614, p = 0.004)., Conclusion: Long-term ECD in eyes that underwent a BGI was considerably lower compared with eyes that underwent a TE, mainly in the peripheral cornea. This suggests that BGI causes a larger decrease of ECD than TE. Additionally, the decrease after BGI appears to continue for a longer period than after TE., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Primary open-angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe., Methods: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA)., Results: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p < 0.001); visual acuity in the worse eye: 1.78, 1.78, 0.3, 0.3 LogMAR (p < 0.001); maximum intraocular pressure of both eyes: 36, 34, 29, 29 mmHg (p anova  < 0.001); maximum vertical cup to disc ratio (VCDR) of both eyes: 0.90, 0.90, 0.84, 0.83 (p < 0.001); mean central corneal thickness: 506, 487, 511, 528 μm (p < 0.001). Fourteen percent of Tanzanian patients presented with blindness (<3/60 Snellen) in the better eye in contrast to only 1% in the Dutch., Conclusion: In this multi-ethnic comparative study, Sub-Saharan Africans present at a younger age with lower visual acuity, higher IOP, larger VCDR, than SAC and Dutch participants. This indicates the more progressive and destructive course in Sub-Saharan Africans., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To investigate the effect of two surgical techniques in primary Baerveldt glaucoma implant (BGI) surgery, that is the sutured technique and the unsutured (free) plate technique, on the ocular motility and prevalence of diplopia. We hypothesize that the free plate technique results in a lower diplopia prevalence., Methods: We performed a prospective study of patients who underwent BGI surgery with the free plate technique and compared them with patients from a previous study who had undergone BGI surgery with the sutured technique. Their ductions, ocular alignment and fusion range and the prevalence of diplopia were measured before surgery and at 3 months, 6 months and 1 year postoperatively., Results: We analysed 57 free plate and 51 sutured plate patients. One year postoperatively, we found no statistically significant difference in the prevalence of diplopia between the two techniques. All duction changes between baseline and 1-year follow-up were restrictions and occurred statistically significantly more frequently in the free plate than in the sutured plate group (p = 0.03; 60% versus 34%). About the ocular alignment, in the horizontal direction, a change in exodirection was more common in both groups, while in the vertical direction, a hyperdeviation of the operated eye was more common. The vertical ocular alignment change was smaller in the free plate group than in the sutured plate group (p = 0.04 at near and p = 0.02 at distance)., Conclusions: One year postoperatively, the prevalence of diplopia was not significantly different between patients with the sutured plate and patients with the free plate technique. Both surgical techniques induce diplopia and changes in ocular motility and/or in ocular alignment., (© 2021 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: In eye movement perimetry, peripheral stimuli are confirmed by goal-directed eye movements toward the stimulus. The saccadic reaction time (SRT) is regarded as an index of visual field responsiveness, whereas in standard automated perimetry (SAP), the visual field sensitivity is tested. We investigated the relation between visual field sensitivity and responsiveness in corresponding locations of the visual field in healthy controls and in patients with mild, moderate and advanced glaucoma. Materials and Methods: Thirty-four healthy control subjects and 42 glaucoma patients underwent a 54-point protocol in eye movement perimetry (EMP) and a 24-2 SITA standard protocol in a Humphrey Field Analyzer. The visual field points were stratified by total deviation sensitivity loss in SAP into 6 strata. A generalized linear mixed model was applied to determine the influence of the various factors. Results: The generalized linear mixed model showed that the mean SRT increased with increasing glaucoma severity, from 479 ms in the control eyes to 678 ms in the eyes of patients with advanced glaucoma ( p < 0.001). Mean SRTs significantly increased with increasing SAP sensitivity loss. Even at the locations where no sensitivity loss was detected by SAP (total deviation values greater or equal than 0 dB), we found lengthened SRTs in mild, moderate and advanced glaucoma compared to healthy controls ( p < 0.05) and in moderate and advanced glaucoma compared to mild glaucoma ( p < 0.05). At locations with total deviation values between 0 and -3 dB, -3 and -6 dB and -6 and -12 dB, we found similar differences. Conclusions: The lengthened SRT in areas with normal retinal sensitivities in glaucomatous eyes, i.e., planning and execution of saccades to specific locations, precede altered sensory perception as assessed with SAP. Better understanding of altered sensory processing in glaucoma might allow earlier diagnosis of emerging glaucoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thepass, Lemij, Vermeer, van der Steen and Pel.)

Background: Patient-reported outcome measures (PROMs) are valuable supplements in regular care to facilitate routine monitoring of quality of life from the patient's perspective. The 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) is a widely used PROM in ophthalmology. However, the NEI-VFQ-25 is too time-consuming and cumbersome for routine evaluations in regular care. The aim of this study is to construct a 7-item questionnaire of which only 3 items are presented to the patient, by means of routing. This VFQ 3 out of 7 (VFQ-3oo7) should have a minimal loss of information compared with the NEI-VFQ-25., Methods: An historical database including 3293 administrations of the NEI-VFQ-25 was constructed involving patients with retinal detachment, cataract, corneal diseases, glaucoma, macular degeneration, uveal melanoma and a normal population sample. The data were subjected to Rasch analyses, in particular a generalized partial credit model. Items were sorted on the latent trait and divided into seven categories. From each category, the item with the highest discriminative value was selected. Through routing, only three out of the seven remaining questions are used, where the answers navigate patients to a fitting trait level., Results: A one-dimensional structure was considered fitting. The VFQ-3oo7 showed a small loss of information compared with the total score of the NEI-VFQ-25: correlation 0.927 and a relative precision of 0.868., Conclusion: The very short, but valid, VFQ-3oo7 can be applied to evaluate the patient's perceived vision-related health status in routine evaluations of treatments in regular care, with a small burden for patients., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To present a fully automatic method to estimate the corneal endothelium parameters from specular microscopy images and to use it to study a one-year follow-up after ultrathin Descemet stripping automated endothelial keratoplasty., Methods: We analyzed 383 post ultrathin Descemet stripping automated endothelial keratoplasty images from 41 eyes acquired with a Topcon SP-1P specular microscope at 1, 3, 6, and 12 months after surgery. The estimated parameters were endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX). Manual segmentation was performed in all images., Results: Our method provided an estimate for ECD, CV, and HEX in 98.4% of the images, whereas Topcon's software had a success rate of 71.5% for ECD/CV and 30.5% for HEX. For the images with estimates, the percentage error in our method was 2.5% for ECD, 5.7% for CV, and 5.7% for HEX, whereas Topcon's software provided an error of 7.5% for ECD, 17.5% for CV, and 18.3% for HEX. Our method was significantly better than Topcon's ( P < 0.0001) and was not statistically significantly different from the manual assessments ( P > 0.05). At month 12, the subjects presented an average ECD = 1377 ± 483 [cells/mm 2 ], CV = 26.1 ± 5.7 [%], and HEX = 58.1 ± 7.1 [%]., Conclusions: The proposed method obtains reliable and accurate estimations even in challenging specular images of pathologic corneas., Translational Relevance: CV and HEX, not currently used in the clinic owing to a lack of reliability in automatic methods, are useful biomarkers to analyze the postoperative healing process. Our accurate estimations allow now for their clinical use., Competing Interests: Disclosure: J.P. Vigueras-Guillén, None; J. van Rooij, None; A. Engel, None; H.G. Lemij, None; L.J. van Vliet, None; K.A. Vermeer, None, (Copyright 2020 The Authors.)

Objectives: To evaluate the performance of a deep learning based Artificial Intelligence (AI) software for detection of glaucoma from stereoscopic optic disc photographs, and to compare this performance to the performance of a large cohort of ophthalmologists and optometrists., Methods: A retrospective study evaluating the diagnostic performance of an AI software (Pegasus v1.0, Visulytix Ltd., London UK) and comparing it with that of 243 European ophthalmologists and 208 British optometrists, as determined in previous studies, for the detection of glaucomatous optic neuropathy from 94 scanned stereoscopic photographic slides scanned into digital format., Results: Pegasus was able to detect glaucomatous optic neuropathy with an accuracy of 83.4% (95% CI: 77.5-89.2). This is comparable to an average ophthalmologist accuracy of 80.5% (95% CI: 67.2-93.8) and average optometrist accuracy of 80% (95% CI: 67-88) on the same images. In addition, the AI system had an intra-observer agreement (Cohen's Kappa, κ) of 0.74 (95% CI: 0.63-0.85), compared with 0.70 (range: -0.13-1.00; 95% CI: 0.67-0.73) and 0.71 (range: 0.08-1.00) for ophthalmologists and optometrists, respectively. There was no statistically significant difference between the performance of the deep learning system and ophthalmologists or optometrists., Conclusion: The AI system obtained a diagnostic performance and repeatability comparable to that of the ophthalmologists and optometrists. We conclude that deep learning based AI systems, such as Pegasus, demonstrate significant promise in the assisted detection of glaucomatous optic neuropathy.

Purpose: We determine the contrast-to-noise ratios (CNRs) of structural and functional measurements to assess their sensitivity to detect progression in the various stages of glaucoma., Methods: We calculated the CNRs for the mean peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral domain optical coherence tomography, and the mean deviation (MD) and visual field index (VFI) determined by standard automated perimetry for the transitions between five stages. Longitudinal data from healthy and glaucomatous eyes from a prospective study were used. Contrast was defined as the change in the mean value of the parameter between two successive stages. Noise was defined as the variability of the parameter and calculated from the residuals of linear regression on the data from five subsequent visits per eye., Results: We studied 205 eyes from 125 participants (46% men, 54% women). CNRs for different parameters varied considerably across the range of disease severity (0.8-12.2). The RNFL thickness had a higher CNR in the transition from normal to mild glaucoma (12.2) compared to the CNRs of the functional measures (MD 4.1, VFI 4.5). The CNRs for the functional measures were higher in the transition from moderate to advanced (MD 5.2, VFI 5.8) and advanced to severe glaucoma (MD 7.2, VFI 5.8) compared to the RNFL thickness (CNR 0.8 and 3.2, respectively)., Conclusions: The RNFL thickness is more sensitive for detecting glaucomatous progression at the onset of glaucoma compared to the functional measures, while the latter are more sensitive for detecting progression in the later stages of glaucoma., Translational Relevance: The CNR method can be used to determine which measurement is most sensitive for detecting progression in glaucoma, differentiated for the severity of the disease. Furthermore, it creates a basic toolset for determining the most sensitive measurement in detecting progression not only in glaucoma, but other (ophthalmic) diseases as well.

Background: Corneal endothelium (CE) images provide valuable clinical information regarding the health state of the cornea. Computation of the clinical morphometric parameters requires the segmentation of endothelial cell images. Current techniques to image the endothelium in vivo deliver low quality images, which makes automatic segmentation a complicated task. Here, we present two convolutional neural networks (CNN) to segment CE images: a global fully convolutional approach based on U-net, and a local sliding-window network (SW-net). We propose to use probabilistic labels instead of binary, we evaluate a preprocessing method to enhance the contrast of images, and we introduce a postprocessing method based on Fourier analysis and watershed to convert the CNN output images into the final cell segmentation. Both methods are applied to 50 images acquired with an SP-1P Topcon specular microscope. Estimates are compared against a manual delineation made by a trained observer., Results: U-net (AUC=0.9938) yields slightly sharper, clearer images than SW-net (AUC=0.9921). After postprocessing, U-net obtains a DICE=0.981 and a MHD=0.22 (modified Hausdorff distance), whereas SW-net yields a DICE=0.978 and a MHD=0.30. U-net generates a wrong cell segmentation in only 0.48% of the cells, versus 0.92% for the SW-net. U-net achieves statistically significant better precision and accuracy than both, Topcon and SW-net, for the estimates of three clinical parameters: cell density (ECD), polymegethism (CV), and pleomorphism (HEX). The mean relative error in U-net for the parameters is 0.4% in ECD, 2.8% in CV, and 1.3% in HEX. The computation time to segment an image and estimate the parameters is barely a few seconds., Conclusions: Both methods presented here provide a statistically significant improvement over the state of the art. U-net has reached the smallest error rate. We suggest a segmentation refinement based on our previous work to further improve the performance., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2019.)

Purpose: To study whether a clinically significant increase in intraocular pressure (IOP) occurs during simulated sleep conditions with the subject's head turned comfortably into a pillow (the simulated sleep position) and the effect of protective glasses on any such IOP rise., Methods: A specially developed electronic epipalpebral pressure (EPP) sensor was attached to an eyelid of the right eye of all participants: 11 patients with primary open-angle glaucoma and 11 healthy volunteers. During calibration, mechanical pressure was applied to the EPP sensor taped to the lower eyelid and the IOP was measured simultaneously at the slit lamp by Goldmann applanation tonometry. The EPP was increased in a stepwise fashion to assess the relationship between EPP and IOP for each individual eye. Thereafter, EPP (with the sensor now taped to the upper eyelid) measurements were performed in the simulated sleep position, both with and without protective glasses. The EPP was determined in each individual eye, and the estimated IOP was then inferred from the established EPP/IOP relationship., Results: In the simulated sleep position, the mean IOP increased by an estimated 19.6 mmHg (SD: 7.5; range 11.6-32.8; p < 0.0001) in the patient group and 28.0 mmHg (SD: 9.6; range 12.3-41.1); p < 0.0001) in the control group. When the subjects wore protective glasses, the mean estimated IOP decreased again by 16.3 mmHg (SD: 5.6; range 9.8-28.1; p < 0.0001) in the patient group and 25.1 mmHg (SD: 8.2; range 11.7-38.3; p = <0.0001) in the control group., Conclusion: Turning the head into a pillow gave a large and clinically significant increase in the estimated IOP in the simulated sleep position. With protective glasses, however, the increase in estimated IOP was almost absent. Therefore, protective shielding of the eyes during sleep may be a treatment option in glaucoma., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Corneal endothelium images obtained by in vivo specular microscopy provide important information to assess the health status of the cornea. Estimation of clinical parameters, such as cell density, polymegethism, and pleomorphism, requires accurate cell segmentation. State-of-the-art techniques to automatically segment the endothelium are error-prone when applied to images with low contrast and/or large variation in cell size. Here, we propose an automatic method to segment the endothelium. Starting with an oversegmented image comprised of superpixels obtained from a stochastic watershed segmentation, the proposed method uses intensity and shape information of the superpixels to identify and merge those that constitute a cell, using support vector machines. We evaluated the automatic segmentation on a data set of in vivo specular microscopy images (Topcon SP-1P), obtaining 95.8% correctly merged cells and 2.0% undersegmented cells. We also evaluated the parameter estimation against the results of the vendor's built-in software, obtaining a statistically significant better precision in all parameters and a similar or better accuracy. The parameter estimation was also evaluated on three other data sets from different imaging modalities (confocal microscopy, phase-contrast microscopy, and fluorescence confocal microscopy) and tissue types (ex vivo corneal endothelium and retinal pigment epithelium). In comparison with the estimates of the data sets' authors, we achieved statistically significant better accuracy and precision in all parameters except pleomorphism, where a similar accuracy and precision were obtained.

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR [T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10 -5 ). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR [A] 0.48; P = 3.75 × 10 -8 ), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Purpose: The purpose of this study was to quantify any diplopia and motility changes after the implantation of a Baerveldt glaucoma implant (BGI) or after trabeculectomy (TE)., Methods: We analyzed 51 patients with a BGI and 52 patients with a TE from a prospective cohort study. To quantify any diplopia, we asked patients about the presence of diplopia at 1 year after surgery. To quantify any ocular motility changes, we measured ductions in eight gaze directions, the patients' ocular alignment and their fusion range before and 1 year after surgery., Results: In the BGI group, 14 patients (28%) experienced diplopia compared with one patient (2%) in the TE group ( P < 0.001). Duction changes were more commonly observed in the BGI group (35%) than in the TE group (19%). In the BGI group, ductions were mostly restricted in elevation (13%; P < 0.001), in abduction (13%), in elevation in 25° adduction (13%; P = 0.044), and in elevation in 25° abduction (25%; P < 0.001). In 32% of the patients, their near horizontal ocular alignment shifted, notably in exodirection ( P = 0.04). The fusion range decreased significantly in the horizontal direction (-12.6° ± 10.3°, mean ± standard deviation; P = 0.01)., Conclusions: BGI surgery was significantly associated with postoperative diplopia and impaired eye motility (reduced ductions), mostly present in abduction, elevation, elevation in 25° adduction, and elevation in 25° abduction. Even without impaired ductions, diplopia could come about., Translational Relevance: By studying diplopia across glaucoma patients prospectively with diplopia questionnaires and extensive orthoptic measurements, we gain better insight into its occurrence.

Purpose: To unravel the relationship between African ancestry, central corneal thickness (CCT), and intraocular pressure (IOP) by estimating the genetic African ancestry (GAA) proportion in primary open-angle glaucoma (POAG) patients and controls from an admixed South African Colored (SAC) and a South African Black (SAB) population., Methods: In this case-control study, 268 POAG patients and 137 controls were recruited from a university clinic in Cape Town, South Africa. All participants were genotyped on the Illumina HumanOmniExpress beadchip or HumanOmni2.5Exome beadchip. ADMIXTURE was used to infer participant's GAA among 86,632 SNPs. Linear and logistic regression models were used to assess the relation between GAA, POAG, CCT, and IOP., Results: The median proportion of GAA was 60% in the study population. GAA was significantly associated with thinner CCT (P < 0.001) and IOP (P = 0.034) in POAG patients. The effect of GAA on CCT was marginally different among POAG patients versus controls (P = 0.066). In POAG patients, the CCT was significantly thinner compared to controls after adjusting for age and sex (P = 0.016). In a stratified analysis in participants with >60% GAA, CCT was not associated with POAG (P = 0.550)., Conclusions: This study demonstrated that a higher proportion of GAA was associated with a thinner CCT and a higher IOP in POAG patients. Remarkably, at higher proportions of GAA, the difference in CCT between POAG and controls was reduced. This suggests that thinner CCT is not associated with POAG in Africans.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)