Large-scale machine-learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology.

Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10-8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

Diagnostic ability of the combination of retinal microvasculature evaluation and static automated perimetry for early primary open-angle glaucoma.

PURPOSE: To investigate the diagnostic ability of retinal superficial vasculature evaluation by optic coherence tomography angiography (OCTA) combined with visual field (VF) testing for early primary open-angle glaucoma (POAG). PATIENTS AND METHODS: In this cross-sectional study, 84 participants were included, including 11 in the ocular hypertension (OHT) group, 11 in the preperimetric POAG (pre-POAG) group, 29 in the early POAG group and 33 in the control group. All participants underwent 6 × 6 mm2 scans of macula and optic nerved head by optic coherence tomography (OCT) and OCTA, along with white-on-white and blue-on-yellow VF testing by static automated perimetry. The ability of diagnosing early glaucoma by either various examinations separately or combination of examinations in both terms of function and structure was studied using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). RESULTS: The superficial retinal vessel densities (VD) in peri-nasal, para-temporal, peri-temporal and peri-inferior regions around the macula, as well as vessel area densities (VAD) in all peripapillary regions, were significantly different among the four groups, with lower VD or VAD in the early POAG patients compared to the normal individuals. The diagnostic ability of peripapillary superficial retinal VAD alone or VF testing alone was limited for early POAG only. However, the combination of these two was more effective in distinguishing normal individuals from OHT subjects or pre-POAG patients without VF defects, with better performance than the combination of peripapillary retinal nerve fiber layer (RNFL) thickness and VF indicators. CONCLUSIONS: Peripapillary retinal vessel densities were generally lower in early POAG patients compared to normal individuals. The combination of peripapillary superficial retinal VAD by OCTA with white-on-white VF testing improved the ability to distinguish POAG patients at early stage without function impairment, which may help in providing reference and guidance for the following-up and treatment of suspected POAG patients.

The Agreement of the Nomogram Tool and Ultrasound Biomicroscopy Images in Calculating Ultrasound Cycloplasty Probe Model in Chinese Patients.

PURPOSE: The aim of the study was to compare and explore the agreement between the nomogram tool and ultrasound biomicroscopy (UBM) images method to calculate the ultrasound cycloplasty (UCP) probe model in Chinese glaucoma patients. METHODS: Retrospective analysis of Chinese glaucoma patients who visited Zhongshan Ophthalmic Center in Guangzhou from January to December 2019 and were eligible for UCP surgery. Visual acuity, intraocular pressure (IOP), ocular axial length (AL), and horizontal corneal diameter (white to white [WTW]) were measured. UBM images with clear ciliary body imaging and AL and WTW data were sent to trained personnel for probe model measurements. The data calculated by both methods were analyzed using unweighted and weighted κ statistics. The level of agreement refers to Landis and Koch's guideline for the strength of agreement indicated with weighted κ values. RESULTS: 1,061 eyes of 642 patients were involved, with a mean age of 61.66 ± 11.66 years. Their best-corrected visual acuity converted to logarithm of minimal-angle-of-resolution (logMAR) scores of -0.18-3.00 with a mean value of 0.69 ± 0.77. IOP was 22.0-60.0 mm Hg with a mean of 27.97 ± 5.66 mm Hg. The mean AL and WTW were 22.88 ± 1.33 (19.15-32.14) mm and 11.52 ± 0.49 (10.00-12.90) mm, respectively. The agreement between the two methods was fair (weighted κ = 0.299), matching in 62.86% of eyes (weighted κ = 0.299, κ = 0.264). The agreement in primary open angle glaucoma, acute primary angle-closure glaucoma, chronic primary angle-closure glaucoma, and secondary glaucoma patients was 60.85% (weighted κ = 0.336, κ = 0.301), 65.06% (weighted κ = 0.146, κ = 0.127), 62.26% (weighted κ = 0.204, κ = 0.184), and 57.97% (weighted κ = 0.332, κ = 0.280) of eyes, respectively. CONCLUSION: The agreement between UBM images and the nomogram tool to calculate the UCP probe model of Chinese patients is at a fair level. The nomogram tool prefers to use larger probes. Improvements to the nomogram tool, such as including data from more ethnic groups and being able to calculate separately for different types of glaucoma, are needed to improve accuracy. The inclusion of parameters or images from more directions of the eye may help measure probe models more accurately for both the nomogram tool and the UBM image measurement.

Usability of Real-Time Elastography for the Diagnosis of Primary Open Angle and Pseudoexfoliation Glaucoma.

OBJECTIVES: This study aims to investigate real-time elastography (RTE) use in the evaluation of the optic nerve head (ONH) and peripapillary structures for the diagnosis of primary open angle (POAG) and pseudoexfoliation (PEX) glaucoma. METHODS: This case-controlled study included 30 patients with POAG, 30 patients with PEX glaucoma, and 30 age-matched control subjects. All of the participants underwent comprehensive ophthalmological examinations covering vessel density of optic nerve and retinal nerve fiber layer (RNFL) thickness measurements with optical cohorence tomography angiography and mean deviation (MD) measurements with Humphrey II Perimetry Visual Field Analyzer. In vivo evaluation of the biomechanical properties of the ONH and peripapillary structures were performed with RTE in all participants. RESULTS: We observed higher ratios of orbital fat to optic nerve head (ROFON) values (P = .008) and strain ratios of orbital fat to scleral-choroidal-retinal complex (ROFSCR) values (P = .004) in the POAG group compared with PEX glaucoma group and higher ROFON (P = .012) and ROFSCR values (P = .004) in PEX glaucoma group than the control group. ROFON and ROFSCR values were positively correlated with glaucoma duration and negatively correlated with MD, radial peripapillary vessel density (RPCVD), and inside disc vessel density in both glaucoma groups (P < .005; only in the PEX glaucoma group for MD and ROFSCR, P = .445). CONCLUSION: Determining the biomechanical properties of ONH and peripapillary structures with RTE in glaucomatous eyes may offer a new perspective on the diagnosis and follow-up of the progression of the disease.

Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic etiology of ocular diseases.

Corneal hysteresis and corneal resistance factor are parameters that reflect the dynamic biomechanical properties of the cornea and have been shown to be biomarkers of corneal disease. In this genome-wide association study of over 100 000 participants, we identified over 200 genetic loci, all but eight novel, significantly associated with either one or both of these traits. In addition to providing key insights into the genetic architecture underlying normal corneal function, these results identify many candidate loci in the study of corneal diseases that lead to severe visual impairment. Additionally, using Mendelian randomization, we were able to identify causal relationships between corneal biomechanics and intraocular pressure measurements, which help elucidate the relationship between corneal properties and glaucoma.

Multimodal Machine Learning Using Visual Fields and Peripapillary Circular OCT Scans in Detection of Glaucomatous Optic Neuropathy.

PURPOSE: To develop and validate a multimodal artificial intelligence algorithm, FusionNet, using the pattern deviation probability plots from visual field (VF) reports and circular peripapillary OCT scans to detect glaucomatous optic neuropathy (GON). DESIGN: Cross-sectional study. SUBJECTS: Two thousand four hundred sixty-three pairs of VF and OCT images from 1083 patients. METHODS: FusionNet based on bimodal input of VF and OCT paired data was developed to detect GON. Visual field data were collected using the Humphrey Field Analyzer (HFA). OCT images were collected from 3 types of devices (DRI-OCT, Cirrus OCT, and Spectralis). Two thousand four hundred sixty-three pairs of VF and OCT images were divided into 4 datasets: 1567 for training (HFA and DRI-OCT), 441 for primary validation (HFA and DRI-OCT), 255 for the internal test (HFA and Cirrus OCT), and 200 for the external test set (HFA and Spectralis). GON was defined as retinal nerve fiber layer thinning with corresponding VF defects. MAIN OUTCOME MEASURES: Diagnostic performance of FusionNet compared with that of VFNet (with VF data as input) and OCTNet (with OCT data as input). RESULTS: FusionNet achieved an area under the receiver operating characteristic curve (AUC) of 0.950 (0.931-0.968) and outperformed VFNet (AUC, 0.868 [95% confidence interval (CI), 0.834-0.902]), OCTNet (AUC, 0.809 [95% CI, 0.768-0.850]), and 2 glaucoma specialists (glaucoma specialist 1: AUC, 0.882 [95% CI, 0.847-0.917]; glaucoma specialist 2: AUC, 0.883 [95% CI, 0.849-0.918]) in the primary validation set. In the internal and external test sets, the performances of FusionNet were also superior to VFNet and OCTNet (FusionNet vs VFNet vs OCTNet: internal test set 0.917 vs 0.854 vs 0.811; external test set 0.873 vs 0.772 vs 0.785). No significant difference was found between the 2 glaucoma specialists and FusionNet in the internal and external test sets, except for glaucoma specialist 2 (AUC, 0.858 [95% CI, 0.805-0.912]) in the internal test set. CONCLUSIONS: FusionNet, developed using paired VF and OCT data, demonstrated superior performance to both VFNet and OCTNet in detecting GON, suggesting that multimodal machine learning models are valuable in detecting GON.

Open-source deep learning-based automatic segmentation of mouse Schlemm's canal in optical coherence tomography images.

The purpose of this study was to develop an automatic deep learning-based approach and corresponding free, open-source software to perform segmentation of the Schlemm's canal (SC) lumen in optical coherence tomography (OCT) scans of living mouse eyes. A novel convolutional neural network (CNN) for semantic segmentation grounded in a U-Net architecture was developed by incorporating a late fusion scheme, multi-scale input image pyramid, dilated residual convolution blocks, and attention-gating. 163 pairs of intensity and speckle variance (SV) OCT B-scans acquired from 32 living mouse eyes were used for training, validation, and testing of this CNN model for segmentation of the SC lumen. The proposed model achieved a mean Dice Similarity Coefficient (DSC) of 0.694 ± 0.256 and median DSC of 0.791, while manual segmentation performed by a second expert grader achieved a mean and median DSC of 0.713 ± 0.209 and 0.763, respectively. This work presents the first automatic method for segmentation of the SC lumen in OCT images of living mouse eyes. The performance of the proposed model is comparable to the performance of a second human grader. Open-source automatic software for segmentation of the SC lumen is expected to accelerate experiments for studying treatment efficacy of new drugs affecting intraocular pressure and related diseases such as glaucoma, which present as changes in the SC area.

Correlation of Measurements From Doppler Ultrasound and Optical Coherence Tomography in Glaucoma.

OBJECTIVES: To relate the changes in ocular structure and hemodynamic response in primary open-angle glaucoma (POAG). METHODS: Patients with POAG (n = 46) and control subjects (n = 53) were recruited. Retinal nerve fiber layer and ganglion cell complex were evaluated using optical coherence tomography (OCT). Blood flow was characterized in ophthalmic artery (OA) and central retinal artery (CRA) using color Doppler ultrasonography (CDU), and resistivity index (RI) was calculated. Measurements from CDU and OCT were statistically correlated and the degree of the association was examined. Receiver operating characteristics was produced based on RI and optimal threshold was determined. RESULTS: In POAG patients, OCT revealed neuronal damage and CDU indicated increased resistance to arterial flow. Flow dynamics correlated negatively with the ocular tissue dimensions, sufficiently establishing an association between the ocular structure and its hemodynamic response. Based on the possibility of indirect POAG diagnosis with CDU, threshold 0.7 for RI of OA yielded 73.9% sensitivity and 77.4% specificity in distinguishing the cases of POAG from the controls. Threshold of 0.66 for RI of CRA, had higher specificity of 83%, but lower sensitivity of 52.1%. CONCLUSIONS: Ocular flow exhibits different characteristics in individuals with POAG than normal. The changes associated with the underlying neuronal structure, suggesting the possibility of a potential new diagnostic biomarker for POAG. This justifies further studies with a larger cohort, examining the ocular flow with CDU in POAG and comparing it against OCT findings for establishing the power of CDU in differential diagnosis or glaucoma progression.

Relationship between Three-Dimensional Magnetic Resonance Imaging Eyeball Shape and Optic Nerve Head Morphology.

PURPOSE: To determine if the 3-dimensional (3D) eyeball shape is associated with the positions of the central retinal vascular trunk (CRVT) and the externally oblique border (EOB) in the optic nerve head (ONH). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Fifty-six subjects (112 eyes) with a diagnosis of glaucoma or glaucoma suspect. METHODS: The eyeball shape on 3D magnetic resonance imaging (MRI) scans was classified according to the dimension of the longest diameter: axial dimension (prolate sphere), group 1; horizontal dimension (horizontally oblate sphere), group 2; and vertical dimension (vertically oblate sphere), group 3. The deviation of the CRVT, as a surrogate of lamina cribrosa (LC) shift, was measured from the center of the Bruch's membrane opening (BMO) demarcated by OCT imaging, with the horizontal midline as 0° and the superior location as a positive value. The angular location of the longest EOB was also measured. MAIN OUTCOME MEASURE: Positions of CRVT and EOB according to the 3D eyeball shape. RESULTS: Among 112 eyes, 54 (48%) had a prolate shape (group 1), 23 (21%) had a horizontally oblate shape (group 2), and 35 (31%) had a vertically oblate shape (group 3). The angular deviation of the CRVT differed among the groups: to the nasal side in group 1, to the temporal side in group 2, and along the vertical meridian in group 3. In cases of asymmetric eyeball shape, the CRVT was deviated toward the undergrown side from the overgrown side, regardless of grouping. The angular location of the longest EOB was in the direction opposite to the CRVT position (P < 0.001). A generalized estimating equation analysis revealed that the temporal location of the CRVT was associated with older age (P = 0.001), nasal location of the longest EOB (P < 0.001), and oblate shape of the eyeball (P < 0.001, group 2; P = 0.007, group 3). CONCLUSIONS: The position of the CRVT and EOB were associated with the 3D eyeball shape. Considering that infant ONH morphology is highly uniform, various modes of eyeball expansion during growth can result in diverse directionalities of offset between the LC and the BMO in adults.

Interpreting Retinal Nerve Fiber Layer Reflectance Defects Based on Presence of Retinal Nerve Fiber Bundles.

SIGNIFICANCE: Adaptive-optics scanning-laser-ophthalmoscopy (AOSLO) retinal imaging of the retinal nerve fiber layer (RNFL) helps predict the severity of perimetric damage based on absence of fibers and projection of the defects in en face images of the RNFL from spectral-domain optical coherence tomography (SD-OCT). PURPOSE: En face images of the RNFL reveal reflectance defects in patients with glaucoma and predict locations of perimetric defects. These defects could arise from either loss of retinal nerve fiber bundles or reduced bundle reflectance. This study used AOSLO to assess presence of bundles in areas with RNFL reflectance defects on SD-OCT. METHODS: Adaptive-optics scanning laser ophthalmoscopy was used to image a vertical strip of RNFL measuring approximately 30 × 3° between the optic disc and the fovea. Fifteen patients with glaucoma who had SD-OCT reflectance defects that passed through this region were chosen. Four patients had reflectance defects in both superior and inferior hemifields, so presence of bundles on AOSLO was assessed for 19 hemifields. Where bundles were present, the hemifield was scored for whether bundles seemed unusual (low contrast and/or low density). Perimetric defects were considered deep when sensitivity was below 15 dB. RESULTS: Ten hemifields had a region with no fibers present on AOSLO; all had a corresponding deep perimetric defect. The other nine hemifields had no region in the AOSLO image without fibers: four with normal fibers and five with unusual fibers. The only one of these nine hemifields with a deep perimetric defect was one with low-contrast fibers and overall thin RNFL. CONCLUSIONS: Retinal nerve fiber layer reflectance defects, which were associated with deep perimetric defects, usually had a region with absence of fibers on AOSLO images of RNFL. Ability to predict severity of perimetric damage from en face SD-OCT RNFL reflectance images could benefit from quantification that differentiated between absence of fibers and unusual fibers.

Detecting Progression in Advanced Glaucoma: Are Optical Coherence Tomography Global Metrics Viable Measures?

SIGNIFICANCE: Optical coherence tomography (OCT) summary measures have been suggested as a way to detect progression in eyes with advanced glaucoma. Here, we show that these measures have serious flaws largely due to segmentation errors. However, inspection of the images and thickness maps can be clinically useful. PURPOSE: This study aimed to test the hypothesis that recently suggested global OCT measures for detecting progression in eyes with advanced progression are seriously affected by segmentation mistakes and other errors that limit their clinical utility. METHODS: Forty-five eyes of 38 patients with a 24-2 mean deviation worse than -12 dB had at least two spectral domain OCT sessions (0.8 to 4.4 years apart) with 3.5-mm circle scans of the disc and cube scans centered on the fovea. Average (global) circumpapillary retinal nerve fiber layer thickness, GcRNFL, and ganglion cell plus inner plexiform layer thickness, GGCLP, were obtained from the circle and cube scan, respectively. To evaluate progression, ΔGcRNFL was calculated for each eye as the GcRNFL value at time 2 minus the value at time 1, and ΔGGCLP was calculated in a similar manner. The b-scans of the six eyes with the highest and lowest ΔGcRNFL and ΔGGCLP values were examined for progression as well as segmentation, alignment, and centering errors. RESULTS: Progression was a major factor in only 7 of the 12 eyes with the most negative values of either ΔGcRNFL or ΔGGCLP, whereas segmentation played a role in 8 eyes and was the major factor in all 12 eyes with the largest positive values. In addition, alignment (one eye) and other (three eyes) errors played a secondary role in four of the six eyes with the most negative ΔGcRNFL values. CONCLUSIONS: For detecting the progression of advanced glaucoma, common summary metrics have serious flaws largely due to segmentation errors, which limit their utility in clinical and research settings.

Glaucoma phenotype in a large Chinese family with myocilin Val251Ala mutation.

Family study is an effective way to identify disease-causing mutations (DCMs) and characterize the clinical phenotype of genetic diseases. In this study we recruited a Chinese primary open-angle glaucoma (POAG) family spanning six generations and consisting 112 individuals, in which 63 were participated in. Targeted exome sequencing on the proband identified a heterozygous mutation (c.752T>C, p.Val251Ala) in MYOC gene. Sanger sequencing performed on all participants found that fourteen family members carried this mutation. Ten (71.4%) of them were diagnosed with POAG, two (14.3%) with ocular hypertension (OHT) and two (14.3%) without manifestations of glaucoma. According to the results of ophthalmic examinations of the family members and their medical history, we found that the Val251Ala mutation was associated with clinical phenotype including intermediate penetrance, high intraocular pressure (IOP), severe visual defects and requirement of surgery.

[Application of Ultrasound Biomicroscopy in Longterm Follow-up Post Modified CO2 Laser-assisted Sclerectomy Surgery].

Objective To observe the role of ultrasound biomicroscopy(UBM)in two-year post-operative follow-up for primary open-angle glaucoma patients with modified CO2 laser-assisted sclerectomy surgery(CLASS).Methods This was a case series study.A combination of modified CLASS and preoperative laser iris management was administered to 28 eyes.Visual acuity,intraocular pressure(IOP),and slit-lamp examinations,visual field testing,and gonioscopy were carried out at baseline and until 24 months postoperatively.UBM examination was performed at 1,3,12 and 24 months postoperatively.Results Compared with the mean preoperative IOP [(30.61±10.59)mmHg],the IOP at each time point after operation was significantly lowered [(15.15±5.87),(12.56±3.24),(13.15±2.73),(13.75±2.55)and(13.75±2.46)mmHg at 1,3,6,12 and 24 months,respectively;all P<0.001].Complete success rates and qualified success rates at 12 months and 24 months were 60.71%,89.29% and 53.57%,85.71%,respectively.UBM images can present "dolphin head sign" after successful CLASS.The thickness of trabeculo-Descemet's window was(0.13±0.03)mm,which had no significant correlation with postoperative IOP at 12(r=-0.278,P=0.144)and 24 months(r=0.026,P=0.895).UBM examination revealed a severe scleral lake diminution(a change > 50%)in 1 eye(3.57%)at 12 months and 3 eyes(10.71%)at 24 months.There was no statistical significance detected between the size of the scleral lake and IOP after CLASS.Non-founctional blebs were found in 16 eyes(57.14%)at 12 months and 25 eyes(89.28%)at 24 months.Two eyes(7.14%)demonstrated severe peripheral anterior synechiae at 24 months,requiring surgical intervention.Conclusions UBM can effectively observe the morphology of the scleral lake,anterior chamber angle and filtering blebs in post-operative follow-up after modified CLASS,and give early warning of complications.It plays an important role in ensuring the success of CLASS.

[Sub-foveal choroidal thickness in both eyes of patients with unilateral primary open-angle glaucoma and related influencing factors].

Objective: To investigate and compare the sub-foveal choroidal thickness (SFCT) in both eyes of patients with unilateral primary open-angle glaucoma (POAG) and healthy controls. Methods: Cross-sectional study. Patients with unilateral POAG and healthy controls were recruited from September 2018 to September 2019 in the Beijing Tongren Hospital. All subjects underwent enhanced depth imaging optical coherence tomography. The SFCT was measured at the fovea, and at 500 µm, 1 000 µm and 2 000 µm nasal and temporal to the fovea. Paired t test was conducted to compare the choroidal thickness between affected POAG eyes and unaffected fellow eyes. Analysis of covariance was conducted to compare the choroidal thicknesses between POAG eyes and controls. Multiple regression analysis determined the association between choroidal thickness and age, gender, spherical equivalent and mean deviation. Results: Seventy-five patients with unilateral POAG (mean age, 46 years; 48 males, 27 females) and 61 healthy controls (mean age, 44 years; 34 males, 27 females) were included in this study. The SFCT of POAG eyes was (244.41±83.18) µm, which was not significantly different from their unaffected fellow eyes [(254.28±88.92) µm, P>0.05] and controls (right eyes) [(272.98±55.87) µm, P>0.05]. Choroidal thickness at 2 000 µm nasal to the fovea was significantly decreased in the glaucomatous eyes compared with the unaffected fellow eyes [(167.84±70.44) vs. (188.84±89.06) µm, t=-3.55; P<0.01]. There were no significant differences among the glaucomatous eyes, unaffected fellow eyes and healthy controls in choroidal thickness at 500 µm and 1 000 µm nasal and temporal to the fovea, as well as at 2 000 µm temporal to the fovea (all P>0.05). The SFCT of POAG eyes was associated with mean deviation (ß=14.66, P<0.05) and spherical equivalent (ß=14.95, P<0.01) but not with age and gender (both P>0.05). Conclusions: The SFCT of affected eyes in patients with unilateral POAG has no significant difference from unaffected fellow eyes and healthy controls. However, the choroidal thickness at 2 000 µm nasal to the fovea is thinner in the POAG eyes as compared with the fellow eyes. A thinner SFCT is correlated with the loss of visual field and a higher spherical equivalent in myopia. This may suggest a contributing role of the perfusion of the choroid in the pathogenesis of glaucoma. (Chin J Ophthalmol, 2021, 57: 194-200).

Measuring Glaucomatous Focal Perfusion Loss in the Peripapillary Retina Using OCT Angiography.

PURPOSE: To measure low perfusion areas (LPAs) and focal perfusion loss (FPL) in the peripapillary retina using OCT angiography (OCTA) in glaucoma. DESIGN: Prospective, observational study. PARTICIPANTS: A total of 47 patients with primary open-angle glaucoma (POAG) and 36 normal participants were analyzed. METHODS: One eye of each subject was scanned using an AngioVue (Optovue, Fremont, CA) 4.5-mm OCTA scan centered on the disc. En face nerve fiber layer (NFL) plexus angiogram was generated. With the use of custom software, a capillary density map was obtained by computing the fraction of area occupied by flow pixels after low-pass filtering by local averaging 21×21 pixels. The low-perfusion map is defined by local capillary density below 0.5 percentile over a contiguous area above 98.5 percentile of the normal reference population. The LPA parameter is the cumulative area, and the FPL is the percent capillary density loss (relative to normal mean) integrated over the LPA. MAIN OUTCOME MEASURES: Peripapillary retinal LPA and FPL. RESULTS: Among patients with POAG, 3 had preperimetric glaucoma and 44 had perimetric glaucoma, with visual field (VF) mean deviation (MD) of -5.14±4.25 decibels (dB). The LPA was 3.40±2.29 mm2 in those with POAG and 0.11±0.18 mm2 in normal subjects (P < 0.001). The FPL was 21.8%±17.0% in those with POAG and 0.3%±0.7% in normal subjects (P < 0.001). The diagnostic accuracy as measured by the area under the receiver operating curve was 0.965 for both LPA and FPL, with a sensitivity of 93.7% at 95% specificity. The repeatability as measured by intraclass correlation coefficient was 0.977 for LPA and 0.958 for FPL. The FPL had excellent correlation with VF MD (Spearman's rho = -0.843), which was significantly (P = 0.008) better than the correlation between NFL thickness and VF MD (rho = 0.760). The hemispheric difference correlation between FPL and VF (Spearman's rho = 0.770) was significantly (P < 0.001) higher than the hemispheric difference correlation between LPA and VF (rho = 0.595). CONCLUSIONS: The low-perfusion map and LPA and FPL parameters are able to assess the location and severity of focal glaucoma damage with good agreement with VF.

Structure-function correlation of localized visual field defects and macular microvascular damage in primary open-angle glaucoma.

PURPOSE: To investigate regional alterations of macular microvasculature in primary open-angle glaucoma (POAG), and to determine the structure-function correlation between localized visual field defects and macular microvascular damage in matching sectors. METHODS: Fifty-eight patients with POAG and 27 normal controls were recruited for this study. Optical coherence tomography angiography (OCTA) was used to measure retinal vascular microcirculation of the macula in superior, inferior, temporal, and nasal sectors. Visual field (VF) was tested using automated perimeter. Sensitivities of 16 central points of the VF were selected and divided into the 4 previously mentioned sectors. Structure-function correlation analysis was performed between localized visual field defects and the matching macular microvasculature damage. The relationship was also assessed using a previously described model. RESULTS: The temporal vascular density was thinner than those of the superior and inferior positions of parafovea in the control group (P < 0.05). Vascular densities in all sectors were decreased in the POAG group compared with the normal control group (P < 0.05). The structure-function correlation coefficients between sectors of VF sensitivity and the matched vascular densities ranged from 0.295 to 0.433 (P < 0.01). The coefficient of determination between OCT derived vascular density measurements and the estimates using the previous model ranged from 0.08 to 0.19. The best fit was in the inferior sector. CONCLUSIONS: Compared with age-matched control subjects, vascular density of the parafoveal retina decreased in the POAG subjects. There is a moderate structure-function correlation between visual field sensitivity thresholds measured with automated perimeter and macular vascular density assessed by OCT.

The Relationship Between Corneal Hysteresis and Retinal Ganglion Cells - A Step Forward in Early Glaucoma Diagnosis.

BACKGROUND Glaucoma is a major cause of irreversible visual field (VF) loss across the world. Many studies have assessed the accuracy of glaucoma diagnostic tests for a more precise diagnosis to quickly identify patients with higher risk of progression. MATERIAL AND METHODS We conducted a study that included 214 eyes divided into 3 groups: 79 eyes from patients diagnosed with primary open-angle glaucoma (POAG), 68 eyes from patients diagnosed with ocular hypertension (OH), and 67 eyes from normal individuals (normal eyes, NE). All patients included in the study received a complete checkup. RESULTS In POAG patients, means of central corneal thickness (CCT), corneal hysteresis (CH), corneal resistance factor (CRF), mean defect (MD), visual field index (VFI), peripapillary retinal nerve fiber layer (pRNFL), and ganglion cell complex (GCC) are lower than in OH patients, and in NE are higher than in both groups. Also, we found a statistically significant direct correlation between CH and GCC thickness. Further statistical analysis revealed that both pRNFL thickness and GCC thickness are significantly influenced by CH value in a precise manner. CONCLUSIONS The first cell type affected in glaucoma is the retinal ganglion cell. We found a positive correlation between GCC thickness and CH, suggesting that CH might be a parameter to consider in the evaluation of all glaucoma patients from their first examination. Moreover, both pRNFL thickness and GCC thickness are influenced by CH, suggesting the utility of monitoring the value of CH at every checkup to detect its decrease in glaucoma patients.

Case Report: Glaucoma-associated Peripapillary Retinoschisis with Corresponding Lamina Cribrosa Defect.

SIGNIFICANCE: Peripapillary retinoschisis is associated with primary and secondary glaucoma. It is important that clinicians are familiar with the presentation and management of peripapillary retinoschisis to understand its effects on the patient's glaucoma and to avoid unnecessary referral when the macula is not involved. PURPOSE: We present a case of peripapillary retinoschisis found incidentally on routine optical coherence tomographic (OCT) surveillance of primary open-angle glaucoma. CASE REPORT: A 70-year-old man presented for his annual diabetic eye examination. Surveillance with OCT revealed a splitting of the inner peripapillary retina corresponding to a previously noted notch in the right optic nerve. Further imaging of the right eye using enhanced depth imaging OCT revealed a defect in the lamina cribrosa that may have contributed to the formation and persistence of peripapillary retinoschisis. Retinal nerve fiber layer analysis showed a 5-year history of progressive temporal and inferotemporal thickening in the right eye. The patient was managed conservatively with instruction on regular Amsler grid testing. CONCLUSIONS: As seen in this case, peripapillary retinoschisis typically alters retinal nerve fiber layer thickness on OCT and can be mistakenly attributed to glaucomatous change. Glaucoma-associated peripapillary retinoschisis is usually not vision threatening and can be managed conservatively; in rare cases of progression to macular involvement, patients should be referred to a retina specialist.

Swept-Source OCT for Evaluating the Lamina Cribrosa: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the published literature on the use of swept-source (SS) OCT for evaluating the lamina cribrosa in glaucoma. METHODS: A PubMed and Cochrane Library literature search initially conducted on March 3, 2017, and updated on June 26, 2018, yielded a total of 64 articles. Articles that were reviews or that were not published in English were excluded, and 29 were found to fit the inclusion criteria. The panel methodologist then assigned a level of evidence rating to each study. Fifteen studies were rated level III, 14 studies were rated level II, and no studies were rated level I. RESULTS: Different aspects of the lamina cribrosa were studied using SS-OCT, including the anterior lamina cribrosa curvature, anterior lamina cribrosa depth, anterior lamina cribrosa insertions, laminar thickness, focal lamina cribrosa defects (FLCDs), and lamina cribrosa microarchitecture. In general, imaging of the anterior lamina can be achieved reliably, although shadowing from blood vessels at the neuroretinal rim remains an issue. Imaging of the posterior lamina can be achieved with varying levels of success. In glaucoma, there is posterior migration of the anterior lamina cribrosa insertions as well as increased thinning and posterior curvature of the lamina cribrosa. Focal lamina cribrosa defects appear more commonly in glaucoma, and this may hint at the pathogenesis of axonal damage. In addition, there may be remodeling of the microarchitecture of the lamina, resulting in more variable laminar pores. There are limited studies comparing SS-OCT with spectral-domain (SD) OCT with regard to imaging of the lamina, but the difference in image quality between enhanced depth imaging (EDI) with SD-OCT and SS-OCT seems minimal. CONCLUSIONS: Imaging of the lamina cribrosa using SS-OCT has demonstrated that the lamina cribrosa is likely biomechanically active and that significant changes occur in glaucoma. The diagnostic utility of SS-OCT for lamina cribrosa imaging is promising, but standardized nomenclature, automated measurements, and longitudinal studies with larger and more diverse sample sizes are needed.

From Machine to Machine: An OCT-Trained Deep Learning Algorithm for Objective Quantification of Glaucomatous Damage in Fundus Photographs.

PURPOSE: Previous approaches using deep learning (DL) algorithms to classify glaucomatous damage on fundus photographs have been limited by the requirement for human labeling of a reference training set. We propose a new approach using quantitative spectral-domain (SD) OCT data to train a DL algorithm to quantify glaucomatous structural damage on optic disc photographs. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 32 820 pairs of optic disc photographs and SD OCT retinal nerve fiber layer (RNFL) scans from 2312 eyes of 1198 participants. METHODS: The sample was divided randomly into validation plus training (80%) and test (20%) sets, with randomization performed at the patient level. A DL convolutional neural network was trained to assess optic disc photographs and predict SD OCT average RNFL thickness. MAIN OUTCOME MEASURES: The DL algorithm performance was evaluated in the test sample by evaluating correlation and agreement between the predictions and actual SD OCT measurements. We also assessed the ability to discriminate eyes with glaucomatous visual field loss from healthy eyes with area under the receiver operating characteristic (ROC) curves. RESULTS: The mean prediction of average RNFL thickness from all 6292 optic disc photographs in the test set was 83.3±14.5 µm, whereas the mean average RNFL thickness from all corresponding SD OCT scans was 82.5±16.8 µm (P = 0.164). There was a very strong correlation between predicted and observed RNFL thickness values (Pearson r = 0.832; R2 = 69.3%; P < 0.001), with mean absolute error of the predictions of 7.39 µm. The area under the ROC curves for discriminating glaucomatous from healthy eyes with the DL predictions and actual SD OCT average RNFL thickness measurements were 0.944 (95% confidence interval [CI], 0.912-0.966) and 0.940 (95% CI, 0.902-0.966), respectively (P = 0.724). CONCLUSIONS: We introduced a novel DL approach to assess fundus photographs and provide quantitative information about the amount of neural damage that can be used to diagnose and stage glaucoma. In addition, training neural networks to predict SD OCT data objectively represents a new approach that overcomes limitations of human labeling and could be useful in other areas of ophthalmology.