The role of graft cross-linking during keratoplasty in patients with corneal melting.

The purpose of this study was to investigate the role of corneal crosslinking (CXL) of grafts during keratoplasty (KP) in patients with refractory corneal melting (CM). This is a retrospective case series reporting the clinical outcomes of patients who received a crosslinked corneal graft during penetrating or deep anterior lamellar KP for refractory infectious or sterile CMs. Outcome measures were the recurrence of CM, the time required for epithelial healing following KP, incidence of complications, and necessity for re-transplantation. Twenty eyes of 18 patients with a follow-up of 29.2 ± 15.8 months were included in this study. All but two eyes had undergone previous KPs during the course of their disease (mean 1.9 ± 1.6). After CXL-enhanced KP, three eyes (15%) experienced recurrence of CM, three eyes developed an infectious keratitis and six eyes (30%) required a re-transplantation (three of them within 12 months). The mean time to epithelium closure after CXL-enhanced KP was 63 ± 90 days. The number of postoperative re-transplantations was significantly lower than the number of KPs performed before the CXL-enhanced transplantation (before CXL 1.9 ± 1.6 vs after CXL: 0.3 ± 0.57, p = 0.002). To conclude, CXL of the graft at the time of keratoplasty decreased the need for re-transplantations. However, further studies are needed in order to establish its role in the management of severe CM necessitating therapeutic corneal transplantation.

Predictive factors for re-bubbling after DMEK: focus on the posterior corneal surface.

PURPOSE: To understand whether the preoperative morphology of the posterior corneal surface influences the rate of re-bubbling after Descemet membrane endothelial keratoplasty (DMEK). METHODS: After retrospectively analyzing the medical records of patients undergoing DMEK, in this multicentric cross-sectional study, we performed a binomial logistic regression analysis to assess significant predictors of re-bubbling and re-transplantation after surgery. Analyzed parameters included the preoperative diagnosis, anterior and posterior surface K1/K2, central corneal thickness, posterior Q value, and other posterior corneal surface parameters evaluated on the elevation maps produced by anterior segment optical coherence tomography. Results were stratified based on the surgeons' experience. RESULTS: We included 202 eyes of 202 patients with a mean age of 69.5 ± 12.4 years; 154 eyes were operated by a high-volume surgeon and 48 by one with less experience; 48 eyes (23.8%) underwent ≥ 1 re-bubbling and 14(6.9%) ≥ 1 re-transplantation. The presence of positive/less-negative posterior corneal irregularities and irregularities with greater absolute height had a significantly higher risk of re-bubbling in both the expert and less expert group (OR = 2.85 and 1.42, OR = 3.22 and 3.01, respectively, p < 0.05), whereas more negative posterior K1 and K2 were significant risk factors only in the former group (OR = 0.67 and 0.55, respectively, p < 0.05). Endothelial decompensation other than Fuchs and pseudophakic bullous keratopathy, more negative posterior Q values and smaller distances between center, and the highest/lowest posterior corneal surface irregularity correlated with an increased risk of graft failure (OR 1.23, 1.21, and 1.29, respectively, p < 0.05). CONCLUSION: Posterior corneal surface morphology significantly influences the risk of re-bubbling after DMEK.

Non-invasive quantification of corneal vascularization using anterior segment optical coherence tomography angiography.

The presence of corneal vascularization (CV) interferes with the angiogenic and immune privilege of the cornea, risking rejection in eyes following keratoplasty. Pre-operative (lymph)-angioregression is a promising therapeutic approach, but objective monitoring by non-invasive CV imaging is needed. The purpose of this study was to investigate anterior-segment optical coherence tomography angiography (AS-OCTA) for CV visualization and quantification, and to show its superiority over slit-lamp photography in high-risk eyes scheduled for keratoplasty. This institutional pilot study included 29 eyes of 26 patients (51 ± 16 years, 8 female) with significant CV scheduled for keratoplasty that were imaged by slit-lamp photography (Zeiss SL 800) and AS-OCTA (Zeiss Plex Elite 9000). After manual corneal layer segmentation correction, CV maximum/relative depth was measured with the inbuilt software. Slit-lamp photographs and AS-OCTA images were compared for visualization of vascular details. Angiotool software allowed a semi-automated determination of CV-related parameters in the vascular complex of AS-OCTA images. The predominant causes of CV were the herpes simplex virus keratitis (n = 7) and chemical burn (n = 4). Visualization of vascular morphology in AS-OCTA was superior to slit-lamp photography in all except one eye. Vascular metrics including total vessel length, number of junctions/endpoints, junction density, lacunarity, and vessel area/density were defined using Angiotool, with CV depth localization despite scarring and opacification. AS-OCTA proved effective for angioregressive treatment monitoring. AS-OCTA enables non-invasive and objective three-dimensional visualization of corneal vascularization superior to slit-lamp photography, and could be a precious tool for monitoring angioregressive preconditioning prior to keratoplasty.

Bilateral corneal perforation in Ipilimumab/Nivolumab - associated peripheral ulcerative keratitis.

Purpose: To present a case of immune checkpoint inhibitor-induced bilateral peripheral ulcerative keratitis that progressed to corneal perforation requiring keratoplasty in both eyes. Observations: We describe the course of a 60-year-old man treated with a combination of Ipilimumab and Nivolumab for metastatic melanoma who presented with foreign body sensation and epiphora in both eyes.Bilateral immune-related peripheral ulcerative keratitis was refractory to topical anti-inflammatory therapy, necessitating repetitive, but unsuccessful cyanoacrylate gluing procedure followed by bilateral lamellar mini-keratoplasty. Conclusions and importance: Combined immune checkpoint inhibition revokes the corneal immune privilege and can lead to auto-immune keratitis with recalcitrant progression to ulceration and perforation.

Identification of Treatment Protocols for Effective Cross-Linking of the Peripheral Cornea: An Experimental Study.

INTRODUCTION: This study aimed to test and evaluate modified corneal cross-linking (CXL) protocols regarding improved treatment effects on the peripheral cornea in terms of tissue stability and cellular response. METHODS: Peripheral CXL (pCXL) was performed within a ring of 9-11 mm of 36 human donor corneas with variations in applied energy (5.4, 7.2, and 10 J/cm2) at 9 mW/cm2 irradiance. Each energy level was additionally modulated regarding the oxygen level surrounding the cornea during treatment (21%; 100%). Stress-strain tests with endpoints at 12% strain and collagenase A-assisted digestions to complete digestion were performed to evaluate the rigidity and resistance of treated and control tissue. Further, corneas were processed histologically via TUNEL assay and H&E staining to demonstrate the effects on stromal cells during treatment under varying CXL conditions. RESULTS: Increases in energy dosage achieved significant increases in resistance to stress in all variations except when comparing protocols A and B under normoxic conditions. Supplemental oxygen significantly increased rigidity in protocols B (p < 0.01) and C (p = 0.018). Hyperoxic conditions significantly increased resistance to digestion in all protocols. The number of DNA strand breaks in TUNEL assay staining showed significant increases in all increases in energy as well as with oxygen supplementation. CONCLUSIONS: Increases in energy and supplemental oxygen improved the effect of CXL, though endothelial safety could not be verified with confidence in high-fluence CXL with supplemental oxygen. Results suggest that CXL protocols using 7.2 J/cm2 with 100% O2 or 10 J/cm2 without supplemental oxygen prove most effective without anticipated risk of endothelial damage.

Corneal Toxicity Associated With Belantamab Mafodotin Is Not Restricted to the Epithelium: Neuropathy Studied With Confocal Microscopy.

PURPOSE: The purpose of this study was to investigate epithelial and neuronal changes in patients with refractory/relapsed multiple myeloma (RRMM) before/during belantamab mafodotin (belamaf) treatment using confocal microscopy. DESIGN: Retrospective case series. METHODS: RRMM patients underwent best-corrected visual acuity (BCVA) testing and slitlamp examination/photography, followed by corneal confocal microscopy (CCM), to evaluate the epithelium and subbasal nerve plexus (SNP) to measure corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) before and during belamaf treatment. RESULTS: In 14 eyes of 7 patients (4 female, 68 ± 10 years of age) with complete follow-up (4 ± 2 months), the median BCVA dropped from 20/25 (20/25-20/20) to 20/40 (20/200-20/32) in the worse eye at the end of follow-up. Microcystic epithelial changes and ocular surface disease were demonstrated biomicroscopically. CCM showed "grape-like" hyperreflective spots in the central basal epithelium that changed to polymorphous-structured cysts in the superficial epithelium, with no pathology detected at the(peri-)limbal structures. The baseline, normal SNP morphology with a mean CNFD, CNBD, and CNFL of 20.25 ± 7.06/mm2, 19.49 ± 12.34/mm2, and 11.8 ± 3.74mm/mm2 respectively, showed severe fiber fragmentation during follow-up, and an observed complete loss of the SNP at the end of follow-up in all eyes. CONCLUSIONS: This study is the first to illustrate neurotoxic effects of belamaf on the human cornea.

Atezolizumab induced immune-related adverse event mimicking conjunctival metastatic disease.

Purpose: To describe a case of an immune-related adverse event associated with Atezolizumab therapy which was aggravated by ocular surgery. Observations: A 59-year-old man treated with Atezolizumab for metastatic non-small-cell lung cancer developed a conjunctival hypertrophic lesion mistaken for metastatic tissue. Biopsy surgery induced fulminant and multifocal granulomatous conjunctival tissue growth and sterile corneal ulceration. The immune-related adverse event was refractory to topical therapy, with curative success only after introduction of systemic prednisone. Conclusions: Atezolizumab use may be associated with severe and recalcitrant ocular surface inflammation with potential exacerbation after surgical interventions.

Comparison of SDOCT Scan Types for Grading Disorganization of Retinal Inner Layers and Other Morphologic Features of Diabetic Macular Edema.

Purpose: To assess grading reproducibility of disorganization of the retinal inner layers (DRIL) and other morphologic features of diabetic macular edema (DME) across spectral domain optical coherence tomography (SDOCT) instruments and scan types. Methods: A cross-sectional study enrolled participants with current or recent center-involved DME. In group A (27 eyes), we obtained two Cirrus scans (512 × 128 macular cube [Cube] and high-definition five-line raster [HD 5-Line]) and two Spectralis scans (high-resolution [HR] and high-speed [HS]). In group B, 26 eyes underwent HR scans and Optovue AngioVue (OP) 3 × 3-mm scans. All scans were graded for type and extent of DRIL, intraretinal cysts, cone outer segment tip visibility, and subretinal fluid (SRF). Results: In the total cohort, mean central subfield thickness was 342.9 ± 83.4 µm. Intraclass correlations were high for DRIL extent across the four different imaging settings (HR vs. HS, r = 0.93; HR vs. Cube, r = 0.84, HR vs. HD 5-Line, r = 0.76, HR vs. OP, r = 0.87) and ranged from good to excellent for intraretinal cyst and SRF area. There were significantly smaller mean normalized differences between HR/HS scans versus HR and all other scan modalities (HR/HS vs. HR/Cube, P = 0.02; HR/HD 5-Line, P = 0.0005; HR/OP, P < 0.0001). Conclusions: Our data suggest that the reproducibility for SDOCT parameters of DRIL and intraretinal cysts was high across all five SDOCT scan types; thus, evaluation of DRIL is feasible using multiple SDOCT models in eyes with DME. Translational Relevance: DME morphological changes can be evaluated on multiple SDOCT devices with good reproducibility, allowing clinicians and researchers flexibility in DME assessment for clinical care and research.

Endothelial Safety and Efficacy of Ex Vivo Collagen Cross-linking of Human Corneal Transplants.

PURPOSE: To assess endothelial safety and efficacy of ex vivo corneal collagen cross-linking (CXL) in human corneal transplants stored in 2 different culture media. DESIGN: Fellow-eye controlled laboratory study of ex vivo human donor corneas. METHODS: Three sets of paired human donor corneas, 5 pairs each, were stored in organ culture medium before deswelling either at 31 C or at room temperature. One eye of each pair was cross-linked by 0.1% riboflavin in hydroxylpropyl methylcellulose (HPMC) instillation for 10 minutes followed by 10 minutes of ultraviolet-A (9 mW/cm2) irradiation while contralateral eyes served as controls. In Set 1, endothelial cell densities were determined. In Set 2, paired samples were assigned to the 2 deswelling media and CXL efficacy was assessed comparing to untreated controls using collagenase-A-assisted enzymatic digestion. In Set 3, biomechanical testing was performed in the eye pairs (treated vs control) by stress/strain measurements. RESULTS: There was no difference in endothelial cell counts between CXL samples and controls (P = .21). No statistically significant difference in digestion dynamics was found between tissues stored in the 2 different culture media. Complete enzymatic digestion was slowed down by 3 hours in the cross-linked samples (P = .036). Stress needed for a 12% strain was increased by 34% in the treatment group compared to control (P = .04). CONCLUSIONS: Ex vivo CXL of human donor tissue is an effective and safe procedure with no difference regarding efficacy between 2 commercially available deswelling media. Biochemical and biomechanical resistance were significantly increased after CXL. Patients requiring keratoplasty owing to corneal melting might benefit from the strengthening effect of preoperative CXL of donor tissue.

Systematic ultrastructural comparison of swept-source and full-depth spectral domain optical coherence tomography imaging of diabetic macular oedema.

BACKGROUND/AIMS: Optical coherence tomography (OCT) is commonly used to diagnose and assess diabetic macular oedema (DME). Swept-source OCT (SS-OCT) promises improved imaging depth and more independence from media opacities. Heidelberg Spectralis full-depth imaging (FDI) combines details at different depths to one representation. The aim of this study was to determine the comparability of the imaging methods concerning DME ultrastructure. METHODS: Two graders assessed the presence of typical DME phenomena in eyes with centre-involving DME on Topcon Atlantis SS-OCT and Heidelberg Spectralis FDI spectral-domain OCT (SD-OCT) B-scans. Retinal layer segmentation was corrected and choroidal layers were manually segmented. Graders measured cyst and subretinal fluid (SRF) diameters and counted hyper-reflective foci (HRF). Findings were recorded and statistically analysed. RESULTS: Statistically significant systematic biases (Spectralis-Atlantis) were found for the HRF count (outside the central mm, -6.39, p=0.0338), chorioretinal thickness (central mm: -35.45 µm, p=0.00034), choroidal thickness (central mm: -60.97 µm, p=0.00004) and Sattler's layer thickness (-42.69 µm, p=0.0001). Intergrader agreement was excellent or very good for posterior vitreous detachment, vitreomacular attachment (central mm) and SRF presence in both devices. Manually delineated Sattler's layer thickness showed an intraclass correlation of 0.85 with FDI SD-OCT but 0.26 with SS-OCT (p=0.003). CONCLUSION: Prominent aspects such as cysts in the outer nuclear layer and SRF can be identified with comparable confidence, while a significant systematic bias underlies chorioretinal, choroidal and Sattler's layer thickness and HRF count. Specialists should use the same device at every examination during longitudinal clinical consideration or cross-sectional evaluation of these ultrastructural biomarkers.

Large Field of View Corneal Epithelium and Bowman's Layer Thickness Maps in Keratoconic and Healthy Eyes.

PURPOSE: To assess differences between epithelium thickness (ET) and Bowman's layer thickness (BLT) maps in keratoconic eyes and healthy eyes. DESIGN: Cross-sectional study. METHODS: Setting: institutional. STUDY POPULATION: 47 patients (1 eye) with keratoconus (KC) and 20 healthy subjects (1 eye). OBSERVATION PROCEDURE: epithelium and Bowman's layer measurements were performed by using custom-designed polarization-sensitive optical coherence tomography (PS-OCT) with a conical scanning optics design. En face corneal ET and BLT maps with a diameter of 11 mm were computed. Main outcome measurements were mean ET and BLT of 25 sectors; the thinnest (minET, minBLT) and thickest sectors (maxET, maxBLT) were assessed. Ratios between thinnest/thickest sectors (R1) and between mean ET and BLT of the inferior temporal quadrant/superior nasal quadrant (R2) were calculated (R1ET, R1BLT; R2ET, R2BLT). Receiver operator characteristic (ROC) curve analysis was used to assess the diagnostic power of statistically different parameters. RESULTS: In healthy eyes, smooth ET maps were observed. KC eyes showed a "doughnut pattern." The BLT maps of healthy eyes had a smooth appearance, but highly irregular "moth"-like damage pattern could be observed in keratoconic eyes. Highest area under the curve values were found for the thinnest sector of the BLT map, the R1ET, and the thinnest sector of the ET map. CONCLUSIONS: PS-OCT imaging enables the visualization of significant differences of the corneal epithelium and the Bowman's layer in en face maps covering almost the entire cornea. ET and BLT profiles could clearly show their diagnostic importance for the distinguishing of keratoconic eyes and healthy eyes.

Corneal crosslinking for pellucid marginal degeneration.

PURPOSE: To investigate the efficacy of corneal crosslinking (CXL) for pellucid marginal degeneration (PMD). SETTING: Medical University of Vienna. DESIGN: Retrospective study. METHODS: In eyes with a crab-claw pattern on corneal topography of a study cohort of 808 eyes, manual measurements of the cornea's thinnest point on the inferior vertical Scheimpflug image (mCTi) and on the superior vertical Scheimpflug image (mCTs) were conducted. Eyes with paralimbal thinning were supposed as having PMD and included. A ratio between mCTi and mCTs was calculated. CXL was performed by irradiation of the inferior periphery of the cornea. During the follow-up, the mCTi, the mean keratometry (K) values in a central zone of 5.0 mm and in a 2.5 mm zone of the inferior cornea and the topographical corneal astigmatism were measured. The corrected distance visual acuity (CDVA) was also evaluated. Patients were followed postoperatively for 12 months. RESULTS: Forty-eight eyes showed a crab-claw pattern in corneal topography. Twenty-two eyes matched the inclusion criteria for PMD and 16 eyes underwent CXL. The mCTi increased during the 12-month follow-up. The K value in the 2.5 mm zone of the inferior cornea decreased after 1 year, whereas the K value in the central zone of 5.0 mm remained stable. The corneal astigmatism continuously decreased, and the CDVA improved after 1 year. CONCLUSION: Manual pachymetric measurements in Scheimpflug images showed the potential for screening for PMD and the evaluation of the efficacy of CXL in eyes with PMD in the study cohort. A thickening of the mCTi and a flattening in the inferior part of the cornea was observed.

Mapping of Corneal Layer Thicknesses With Polarization-Sensitive Optical Coherence Tomography Using a Conical Scan Pattern.

Purpose: We demonstrate segmentation and mapping of corneal layers (epithelium, Bowman's layer, and stroma) across the entire cornea (limbus to limbus), using additional contrast provided by polarization-sensitive optical coherence tomography (PS-OCT) and analyze the reproducibility of the procedure. Methods: A custom built PS-OCT system operating at 1045 nm central wavelength with conical scanning was used for image acquisition. Conical scanning allows for almost perpendicular beam incidence on the corneal surface and provides good signal quality over the entire field of view. Epithelium, Bowman's layer, and stroma were segmented using the additional contrast provided by PS-OCT. Thickness maps were computed and analyzed in sectors. Both eyes of 20 healthy volunteers were imaged at least three times to test this method and to quantify reproducibility. Results: Thickness maps of the epithelium show significant (P < 0.001) superior thinning and an inferior thickening. Bowman's layer appears homogeneous within the central 7 to 8 mm diameter of the cornea and gets thinner toward the periphery until this layer disappears between 4 and 5.5 mm eccentricity from the center. Intersubject variations of the measured thicknesses of epithelium (coefficient of variation [CV] ∼8%), Bowman's layer (CV∼25%), and stroma (CV∼10%) were observed. Very good reproducibility of thickness measurements of epithelium (CV < 3%), Bowman's layer (CV < 5%), and stroma (CV < 2%) was found. Furthermore, a significant correlation (P < 0.001) between layer thicknesses of the right and left eyes of the same subject was found. Conclusions: PS-OCT with conical scanning is a feasible approach for determining thickness maps of corneal layers on a large field of view with high reproducibility.

Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes.

Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.

Characterization of In Vivo Retinal Lesions of Diabetic Retinopathy Using Adaptive Optics Scanning Laser Ophthalmoscopy.

PURPOSE: To characterize hallmark diabetic retinopathy (DR) lesions utilizing adaptive optics scanning laser ophthalmoscopy (AOSLO) and to compare AOSLO findings with those on standard imaging techniques. METHODS: Cross-sectional study including 35 eyes of 34 study participants. AOSLO confocal and multiply scattered light (MSL) imaging were performed in eyes with DR. Color fundus photographs (CF), infrared images of the macula (Spectralis, Heidelberg), and Spectralis spectral domain optical coherence tomography SDOCT B-scans of each lesion were obtained and registered to corresponding AOSLO images. MAIN OUTCOME MEASURES: Individual lesion characterization by AOSLO imaging. AOSLO appearance was compared with CF and SDOCT imaging. RESULTS: Characterized lesions encompassed 52 microaneurysms (MA), 20 intraretinal microvascular abnormalities (IRMA), 7 neovascularization (NV), 11 hard exudates (HE), 5 dot/blot hemorrhages (HEM), 4 cotton wool spots (CWS), and 14 intraretinal cysts. AOSLO allowed assessment of perfusion in vascular lesions and enabled the identification of vascular lesions that could not be visualized on CF or SDOCT. CONCLUSIONS: AOSLO imaging provides detailed, noninvasive in vivo visualization of DR lesions enhancing the assessment of morphological characteristics. These unique AOSLO attributes may enable new insights into the pathological changes of DR in response to disease onset, development, regression, and response to therapy.

Association of Changes in Macular Perfusion With Ranibizumab Treatment for Diabetic Macular Edema: A Subanalysis of the RESTORE (Extension) Study.

Importance: Anti-vascular endothelial growth factor treatment is the first-line therapy in the treatment of center-involving diabetic macular edema. Data on capillary perfusion changes under repeated treatment in a possibly compromised vascular network are limited. Objective: To evaluate the association of repeated ranibizumab injections on macular perfusion in patients with diabetic macular edema. Design, Setting, and Participants: This study analyzed prospectively collected data from the 12-month RESTORE core study and the 24-month open label RESTORE extension study, which assessed the efficacy and safety of ranibizumab in patients with visual impairment due to diabetic macular edema. Of 345 patients with center-involving diabetic macular edema who had enrolled in the 12-month RESTORE core study, 240 entered the 24-month RESTORE extension study. Of these, 83 (34.6%) received ranibizumab, 83 (34.6%) received ranibizumab and laser combination therapy, and 74 (30.8%) received laser monotherapy in the first year of the study; 208 completed the 24-month extension study. Fluorescence angiography images were taken from each participant twice each year graded by Vienna Reading Center on severity of capillary loss in the parafoveal area, regularity of the foveal avascular zone outline, and measurement of the size of the foveal avascular zone, following a standardized protocol. Data analysis took place from July 2014 through December 2017. Main Outcomes and Measures: Change in 3 fluorescence angiography perfusion parameters over the course of treatment. Results: Mean (SD) patient age was 62.6 (8.8) years; 124 of 208 (59.2%) were male and 197 of 208 (94.6%) were white. The number of patients with definite altered foveal avascular zone regularity at baseline was 103 of 240 patients (42.9%); another 118 patients (49.2%) had questionably altered regularity at baseline. Definitive capillary loss was found in 65 of 240 patients (27.1%) at baseline. Mean (SD) foveal avascular zone size at baseline was 0.261 (0.232) mm2 in ranibizumab monotherapy, 0.231 (0.219) mm2 in ranibizumab and macular laser combination therapy, and 0.201 (0.13) mm2 in laser monotherapy. No treatment arm experienced significant increase in foveal avascular zone size at any time in the study period. At month 36, ranibizumab monotherapy resulted in a mean increase of 0.073 mm2 (95% CI, 0.005-0.142 mm2) and combination therapy resulted in a mean increase of 0.117 mm2 (95% CI, 0.045-0.188 mm2), but no changes were statistically significant. No changes occurred in foveal avascular zone regularity in any treatment group, and no differences were found in capillary loss around the fovea in the 3 treatment groups; neither element could be correlated with visual acuity or central retinal thickness. Conclusions and Relevance: Repeated ranibizumab treatment was not associated with impaired macular perfusion in our study cohort. Because our data do not suggest a harmful effect of anti-vascular endothelial growth factor therapy on capillary integrity, patients with severe microangiopathy and advanced capillary dropout should not be denied these treatments.

Distinguishing Keratoconic Eyes and Healthy Eyes Using Ultrahigh-Resolution Optical Coherence Tomography-Based Corneal Epithelium Thickness Mapping.

PURPOSE: To find differences in epithelial thickness (ET) maps of eyes with keratoconus (KC) and healthy eyes. DESIGN: Institutional cross-sectional study. METHODS: In this study 40 keratoconic eyes and 76 healthy eyes were scanned using a custom-built ultrahigh-resolution optical coherence tomography system. Automated segmentation ET maps with 17 subsectors were calculated (central, temporal inferior, temporal superior, nasal inferior, and nasal superior area). The thinnest point of the epithelium (minET), the thickest point of the epithelium (maxET), and the thinnest point diagonally opposing the thickest point (ETmax/op) were additional parameters. Ratios were calculated as follows: minET/diagonally opposing point (R1), maxET/diagonally opposing point (R2), inferior temporal area/superior nasal area (RTI/NS), and inferior/superior hemisphere (RI/S). Furthermore, collected parameters were analyzed regarding their diagnostic accuracy (area under the curve; AUC). RESULTS: Statistically significant differences were as follows: central ET, 46.25 ± 2.56/50.91 ± 1.66; minET, 38.50 ± 2.10/46.79 ± 1.27; ETmax/op, 47.14 ± 2.45/49.60 ± 1.57; temporal inferior area: 43.93 ± 2.95/51.04 ± 1.51 (all mean ± standard deviation, µm); R1, 0.76 ± 0.09/0.93 ± 0.04; R2, 1.08 ± 0.04/1.21 ± 0.16; RTI/NS, 0.85 ± 0.08/1.02 ± 0.04; RI/S: 0.92 ± 0.07/0.99 ± 0.02. AUC values were R1: 0.979 (confidence interval [CI]: 0.957-1.000), RTI/NS: 0.977 (CI: 0.951-1.000), and minET: 0.928 (CI: 0.880-0.977). CONCLUSIONS: Epithelial thickness maps could clearly visualize different ET patterns. Parameters with the highest potential of diagnostic discrimination between eyes with KC and healthy eyes were, in descending order, R1, RTI/NS, and minET. Consequently, epithelial thickness irregularity and asymmetry seem to be the most promising diagnostic factor in terms of discriminating between keratoconic eyes and healthy eyes.

Correlation between central stromal demarcation line depth and changes in K values after corneal cross-linking (CXL).

PURPOSE: A stromal demarcation line (DL) after corneal cross-linking (CXL) has lately been suggested as a surrogate parameter for the success of CXL. The aim of this study was to investigate the correlation between depth of the central DL 1 month and the change in K values 12 months after CXL. METHODS: Treatment-naive subjects with keratoconus were treated using an accelerated CXL protocol [A-CXL(9*10)]. Depth of the DL/relative depth of the DL (DL%) was measured using Visante OCT imaging 1 month postoperatively (OP). Kmax/K2.5 (preOP) and change in Kmax/K2.5 (preOP - 12 months postOP) were assessed using corneal tomography (Pentacam HR, Oculus GmBH). RESULTS: Forty eyes were treated following the A-CXL(9*10). The mean DL depth was 200 ± 99 µm (range 71 to 479)/mean DL% = 42.70 ± 20.00% (range 17-90). There was no statistically significant correlation between stromal depth of the DL and change in Kmax or K2.5, respectively (Spearman rho DL/∆Kmax - 0.14 and DL/∆K2.5 - 0.14). Between DL% and the changes in maximum K values or K2.5, no statistically significant correlation was found as well (Spearman rho DL%/∆Kmax - 0.10 and DL%/∆K2.5 - 0.19). Mean change in Kmax after 12 months was - 0.68 ± 2.26 diopters (D) (median - 0.35 D) and - 0.82 ± 1.6 D (median - 0.65 D) for K2.5 (p = 0.07; p = 0.02). CONCLUSIONS: No statistically significant correlation was found between the stromal central depth of the DL and any outcome parameter for CXL after 12 months. Therefore, the interpretation of the DL as a predictive parameter for the effect of the procedure may not apply.

COMPARISON OF GANGLION CELL INNER PLEXIFORM LAYER THICKNESS BY CIRRUS AND SPECTRALIS OPTICAL COHERENCE TOMOGRAPHY IN DIABETIC MACULAR EDEMA.

PURPOSE: Reduced thickness of the ganglion cell inner plexiform layer indicates diabetic neurodegeneration and can be assessed by spectral domain optical coherence tomography. The authors investigated the comparability of ganglion cell inner plexiform layer measurements from two spectral domain optical coherence tomography devices in patients with diabetic macular edema (DME). METHODS: Analysis of optical coherence tomography data sets of eyes with and fellow eyes without DME. Macular cube scans of sufficient signal strength on Cirrus (Carl Zeiss Meditec) were compared with correlating scans on Spectralis (Heidelberg Engineering, Germany) being acquired within 1 hour. RESULTS: Eighty-one equivalent data sets for 20 eyes with DME (20 patients; 6 female) and 33 for 9 fellow eyes without DME (9 patients; 2 female) were included from each device. In DME eyes, mean ganglion cell inner plexiform layer thicknesses were 62.5 ± 20.4 µm on Cirrus and 91.2 ± 9.3 µm on Spectralis. Ganglion cell inner plexiform layer was significantly thicker on Spectralis analyzing eyes with and without signs of DME (P < 0.001). The ganglion cell inner plexiform layer variance (54.2%) related to device differences decreased to 34.8% in eyes without DME. CONCLUSION: Ganglion cell inner plexiform layer data from different devices vary considerably and cannot be used interchangeably. As spectral domain optical coherence tomography is indispensable for identifying ganglion cell loss associated with diabetic neurodegeneration, clinicians should be aware of the difference when monitoring patients.

Analysis of retinal layer thickness in diabetic macular oedema treated with ranibizumab or triamcinolone.

PURPOSE: To evaluate detailed changes in retinal layer thickness in spectral-domain optical coherence tomography (SD-OCT) images during a 1-year follow-up of patients treated for diabetic macula oedema (DME). METHODS: Post hoc analysis of retinal layer thickness changes applying the automated layer segmentation of SD-OCT images in eyes with DME that were randomly assigned to receive pro re nata (PRN) treatment with either 0.5 mg ranibizumab or 8 mg triamcinolone. In each patient, seven retinal layers were segmented in 49 scans covering a 20° × 20° area of the macula at baseline and after 1 year of treatment. Changes in individual layer thickness were correlated with visual acuity (VA) and compared between treatment arms. RESULTS: Twenty-five patients (seven female, 60.2 ± 15.1 years) were evaluated. Thickness decrease of retinal nerve fibre layer (RNFL) was associated with a gain in VA over 12 months (r > 0.54; p < 0.05). Decrease in ganglion cell layer (GCL) and GCL+IPL thickness pooled for nasal Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields correlated with VA as follows: ranibizumab r = 0.74 (GCL) and r = 0.63 (GCL+IPL); and triamcinolone r = 0.45 (GCL) and r = 0.46 (GCL+IPL). CONCLUSION: In DME therapy, reduction in RNFL thickness may have a considerable impact on retinal function, unrelated to the type of pharmacological treatment. Precise morphologic quantification of neurosensory layers by SD OCT offers new insight into disease pathology and therapeutic targets.