Selective retina therapy with real-time feedback-controlled technology in central serous chorioretinopathy: a 24-month follow-up real-world prospective study.

OBJECTIVE: Although central serous chorioretinopathy (CSC) treatment using selective retinal therapy (SRT) has presented favourable outcomes, no long-term studies with a real-world clinical practice regimen have been conducted. METHODS AND ANALYSIS: We performed a long-term assessment of CSC treatment using SRT with real-time feedback (RTF) technology. 50 patients (53 eyes) with CSC and more than a 1-month symptom duration were recruited and treated with SRT using a 1.7 µs pulse width, 527 nm neodymium-doped yttrium lithium fluoride (Nd:YLF) laser equipped with an RTF system. RESULTS: After 6 months of treatment, complete subretinal fluid resolution was achieved in 62% of the eyes. The mean best-corrected visual acuity (BCVA; logarithm of the minimum angle of resolution, mean±SD) improved slightly from 0.15±0.18 at baseline to 0.12±0.21 at 6 months (p=0.062). The central retinal thickness (CRT; mean±SD) was reduced significantly from 350.6±100.1 µm at baseline to 268.2±70.6 µm at 6 months (p<0.001). Long-term follow-up revealed significant improvements in BCVA, from 9 months until 24 months, and in CRT, from 1 month until 24 months. No treatment-related adverse events were observed during the 24-month follow-up period. CONCLUSION: Our results suggest that SRT with RTF technology is a long-term safe treatment with anatomical improvement for patients with CSC.

Volumetric fluid analysis of fixed monthly anti-VEGF treatment in patients with neovascular age-related macular degeneration.

AIM: To evaluate visual outcomes and changes in fluid after administering monthly anti-vascular endothelial growth factor (VEGF) injections to treat neovascular age-related macular degeneration (nAMD) with subretinal fluid (SRF) and pigment epithelial detachment (PED). METHODS: This prospective study included eyes with nAMD previously treated with as-needed anti-VEGF injections. The patients were treated with six monthly intravitreal injections of ranibizumab. Quantitative volumetric segmentation analyses of the SRF and PED were performed. The main outcome measures included best-corrected visual acuity (BCVA), and SRF and PED volumes. RESULTS: Twenty eyes of 20 patients were included in this study. At the 6-month follow-up, BCVA and PED volume did not change significantly (P=0.110 and 0.999, respectively) but the mean SRF volume decreased from 0.53±0.82 mm3 at baseline to 0.08±0.23 mm3 (P=0.002). The absorption rate of the SRF volume was negatively correlated with the duration of previous anti-VEGF treatment (P=0.029). Seven of the 20 eyes (35%) showed a fluid-free macula and significant improvement in BCVA (P=0.036) by month 6. CONCLUSION: Quantifying the SRF can precisely determine the patient's responsiveness to anti-VEGF treatment of nAMD.

A deep learning-based framework for retinal fundus image enhancement.

PROBLEM: Low-quality fundus images with complex degredation can cause costly re-examinations of patients or inaccurate clinical diagnosis. AIM: This study aims to create an automatic fundus macular image enhancement framework to improve low-quality fundus images and remove complex image degradation. METHOD: We propose a new deep learning-based model that automatically enhances low-quality retinal fundus images that suffer from complex degradation. We collected a dataset, comprising 1068 pairs of high-quality (HQ) and low-quality (LQ) fundus images from the Kangbuk Samsung Hospital's health screening program and ophthalmology department from 2017 to 2019. Then, we used these dataset to develop data augmentation methods to simulate major aspects of retinal image degradation and to propose a customized convolutional neural network (CNN) architecture to enhance LQ images, depending on the nature of the degradation. Peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM), r-value (linear index of fuzziness), and proportion of ungradable fundus photographs before and after the enhancement process are calculated to assess the performance of proposed model. A comparative evaluation is conducted on an external database and four different open-source databases. RESULTS: The results of the evaluation on the external test dataset showed an significant increase in PSNR and SSIM compared with the original LQ images. Moreover, PSNR and SSIM increased by over 4 dB and 0.04, respectively compared with the previous state-of-the-art methods (P < 0.05). The proportion of ungradable fundus photographs decreased from 42.6% to 26.4% (P = 0.012). CONCLUSION: Our enhancement process improves LQ fundus images that suffer from complex degradation significantly. Moreover our customized CNN achieved improved performance over the existing state-of-the-art methods. Overall, our framework can have a clinical impact on reducing re-examinations and improving the accuracy of diagnosis.

Vitreous Fatty Amides and Acyl Carnitines Are Altered in Intermediate Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) is the leading cause of visual impairment worldwide. In this study, we aimed to investigate the vitreous humor metabolite profiles of patients with intermediate AMD using untargeted metabolomics. Methods: We performed metabolomics using high-resolution liquid chromatography mass spectrometry on the vitreous humor of 31 patients with intermediate AMD and 30 controls who underwent vitrectomy for epiretinal membrane with or without cataract surgery. Univariate analyses after false discovery rate correction were performed to discriminate the metabolites and identify the significant metabolites of intermediate AMD. For biologic interpretation, enrichment and pathway analysis were conducted using MetaboAnalyst 5.0. Results: Of the 858 metabolites analyzed in the vitreous humor, 258 metabolites that distinguished patients with AMD from controls were identified (P values < 0.05). Ascorbic acid and uric acid levels increased in the AMD group (all P values < 0.05). The acyl carnitines, such as acetyl L-carnitine (1.37-fold), and fatty amides, such as anandamide (0.9-fold) and docosanamide (0.67-fold), were higher in patients with intermediate AMD. In contrast, nicotinamide (-0.55-fold), and succinic acid (-1.69-fold) were lower in patients with intermediate AMD. The metabolic pathway related oxidation of branched chain fatty acids and carnitine synthesis showed enrichment. Conclusions: Multiple metabolites related to fatty amides and acyl carnitine were found to be increased in the vitreous humor of patients with intermediate AMD, whereas succinic acid and nicotinamide were reduced, suggesting that altered metabolites related to fatty amides and acyl carnitines and energy metabolism may be implicated in the etiology of AMD.

Retinal vessel geometry in patients with idiopathic epiretinal membrane.

We investigated the associations between retinal vascular geometric measurements and idiopathic epiretinal membrane (ERM). Whether changes in retinal vascular geometry are independent of systemic cardiovascular risk factors was also evaluated. This retrospective, cross sectional study included 98 patients with idiopathic ERM, and 99 healthy age-matched controls. Quantitative retinal vascular parameters were measured from digital retinal fundus photographs using a semi-automated computer-assisted program. Multivariate logistic regression analyses were performed to evaluate associations between retinal vascular geometric parameters and the presence of idiopathic ERM after adjusting for systemic cardiovascular risk factors. There was no significant difference in the baseline characteristics of the two groups, except that the ERM group had a higher proportion of females than the control group. In multivariate regression analyses, female sex (odds ratio [OR] 0.402; 95% CI 0.196-0.802; P = 0.011), wider retinal venular caliber (OR 16.852; 95% CI 5.384-58.997; P < 0.001) and decreased total fractal dimension (OR 0.156; 95% CI 0.052-0.440; P = 0.001) were associated with idiopathic ERM. Idiopathic ERM was associated with alterations in global retinal microvascular geometric parameters, wider retinal venules, and less complex vascular branching patterns, independent of cardiovascular risk factors.

Neurologic Dysfunction Assessment in Parkinson Disease Based on Fundus Photographs Using Deep Learning.

Importance: Until now, other than complex neurologic tests, there have been no readily accessible and reliable indicators of neurologic dysfunction among patients with Parkinson disease (PD). This study was conducted to determine the role of fundus photography as a noninvasive and readily available tool for assessing neurologic dysfunction among patients with PD using deep learning methods. Objective: To develop an algorithm that can predict Hoehn and Yahr (H-Y) scale and Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score using fundus photography among patients with PD. Design, Settings, and Participants: This was a prospective decision analytical model conducted at a single tertiary-care hospital. The fundus photographs of participants with PD and participants with non-PD atypical motor abnormalities who visited the neurology department of Kangbuk Samsung Hospital from October 7, 2020, to April 30, 2021, were analyzed in this study. A convolutional neural network was developed to predict both the H-Y scale and UPDRS-III score based on fundus photography findings and participants' demographic characteristics. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) was calculated for sensitivity and specificity analyses for both the internal and external validation data sets. Results: A total of 615 participants were included in the study: 266 had PD (43.3%; mean [SD] age, 70.8 [8.3] years; 134 male individuals [50.4%]), and 349 had non-PD atypical motor abnormalities (56.7%; mean [SD] age, 70.7 [7.9] years; 236 female individuals [67.6%]). For the internal validation data set, the sensitivity was 83.23% (95% CI, 82.07%-84.38%) and 82.61% (95% CI, 81.38%-83.83%) for the H-Y scale and UPDRS-III score, respectively. The specificity was 66.81% (95% CI, 64.97%-68.65%) and 65.75% (95% CI, 62.56%-68.94%) for the H-Y scale and UPDRS-III score, respectively. For the external validation data set, the sensitivity and specificity were 70.73% (95% CI, 66.30%-75.16%) and 66.66% (95% CI, 50.76%-82.25%), respectively. Lastly, the calculated AUROC and accuracy were 0.67 (95% CI, 0.55-0.79) and 70.45% (95% CI, 66.85%-74.04%), respectively. Conclusions and Relevance: This decision analytical model reveals amalgamative insights into the neurologic dysfunction among PD patients by providing information on how to apply a deep learning method to evaluate the association between the retina and brain. Study data may help clarify recent research findings regarding dopamine pathologic cascades between the retina and brain among patients with PD; however, further research is needed to expand the clinical implication of this algorithm.

Deep Learning-based Prediction of Axial Length Using Ultra-widefield Fundus Photography.

PURPOSE: To develop a deep learning model that can predict the axial lengths of eyes using ultra-widefield (UWF) fundus photography. METHODS: We retrospectively enrolled patients who visited the ophthalmology clinic at the Seoul National University Hospital between September 2018 and December 2021. Patients with axial length measurements and UWF images taken within 3 months of axial length measurement were included in the study. The dataset was divided into a development set and a test set at an 8:2 ratio while maintaining an equal distribution of axial lengths (stratified splitting with binning). We used transfer learning-based on EfficientNet B3 to develop the model. We evaluated the model's performance using mean absolute error (MAE), R-squared (R2), and 95% confidence intervals (CIs). We used vanilla gradient saliency maps to illustrate the regions predominantly used by convolutional neural network. RESULTS: In total, 8,657 UWF retinal fundus images from 3,829 patients (mean age, 63.98 ±15.25 years) were included in the study. The deep learning model predicted the axial lengths of the test dataset with MAE and R2 values of 0.744 mm (95% CI, 0.709-0.779 mm) and 0.815 (95% CI, 0.785-0.840), respectively. The model's accuracy was 73.7%, 95.9%, and 99.2% in prediction, with error margins of ±1.0, ±2.0, and ±3.0 mm, respectively. CONCLUSIONS: We developed a deep learning-based model for predicting the axial length from UWF images with good performance.

Efficacy and safety of a new ranibizumab biosimilar CKD-701 using a pro re nata treatment regimen in neovascular age-related macular degeneration: A phase 3 randomized clinical trial.

PURPOSE: This study aimed to establish the efficacy, safety, and immunogenicity equivalence of the proposed biosimilar CKD-701 with the reference ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: A total of 312 participants with active subfoveal choroidal neovascularization were randomly assigned to either the CKD-701 (n = 156) or reference ranibizumab (n = 156) arms. The initial 3-month loading intraocular injections were followed by pro re nata (PRN) dosing for 9 months. The primary outcome was the proportion of patients with less than 15-letters of corrected visual acuity (BCVA) loss at 3 months visit (one month after last loading injection) compared to the baseline time point. The presence of retinal fluid, and changes in BCVA and central retinal thickness (CRT) were assessed as secondary efficacy outcomes. Immunogenicity and safety were evaluated in both treatment arms. RESULTS: In the CKD-701 arm, 143 (97.95%) patients lost <15 letters in the BCVA at 3 months compared to 143 (98.62%) in the reference arm (P = 0.67). The BCVA improved with a mean improvement of +7.0 (CKD-701) and +6.2 (ranibizumab) letters at 3 months (P = 0.43). The least-squares mean (SE) changes in CRT at 3 months from the baseline were -119.3 (12.0) µm and -124.5 (11.9) µm in the CKD-701 and ranibizumab groups, respectively (P = 0.74). The proportion of participants with subretinal or intraretinal fluid at 3, 6, and 12 months was similar between the study arms. The number (SE) of injections were 8.36 (3.13) in the CKD-701 and 8.26 (2.92) in ranibizumab (P = 0.62). The occurrence of adverse events and antidrug antibody in the study arms were also not statistically different. CONCLUSION: CKD-701 is a biosimilar to the reference ranibizumab in terms of efficacy, safety, and immunogenicity for the treatment of patients with nAMD. Moreover, improvement and maintenance of visual outcome were achieved through PRN regimen.

DETECTION AND LOCALIZATION OF RETINAL BREAKS IN ULTRAWIDEFIELD FUNDUS PHOTOGRAPHY USING a YOLO v3 ARCHITECTURE-BASED DEEP LEARNING MODEL.

PURPOSE: We aimed to develop a deep learning model for detecting and localizing retinal breaks in ultrawidefield fundus (UWF) images. METHODS: We retrospectively enrolled treatment-naive patients diagnosed with retinal break or rhegmatogenous retinal detachment and who had UWF images. The YOLO v3 architecture backbone was used to develop the model, using transfer learning. The performance of the model was evaluated using per-image classification and per-object detection. RESULTS: Overall, 4,505 UWF images from 940 patients were used in the current study. Among them, 306 UWF images from 84 patients were included in the test set. In per-object detection, the average precision for the object detection model considering every retinal break was 0.840. With the best threshold, the overall precision, recall, and F1 score were 0.6800, 0.9189, and 0.7816, respectively. In the per-image classification, the model showed an area under the receiver operating characteristic curve of 0.957 within the test set. The overall accuracy, sensitivity, and specificity in the test data set were 0.9085, 0.8966, and 0.9158, respectively. CONCLUSION: The UWF image-based deep learning model evaluated in the current study performed well in diagnosing and locating retinal breaks.

Longitudinal Microstructure Changes of the Retina and Choroid in Retinitis Pigmentosa.

PURPOSE: To investigate longitudinal changes in the retinal and choroidal microstructure of the macula in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, observational cohort study. METHODS: A total of 69 patients with RP and 69 age- and sex-matched controls who underwent optical coherence tomography (OCT) over a 4-year follow-up period were included. The severity of RP was classified into 3 stages according to the integrity of the inner segment ellipsoid zone. The retinal and choroidal layers were segmented manually from OCT images. The areas of retinal pigment epithelium (RPE) atrophy and choroidal vascular index (CVI) were also analyzed. Longitudinal changes in the OCT parameters were compared among the groups. RESULTS: Significant decreases (median [interquartile range]) in the thickness of the ganglion cell inner plexiform layer (GCIPL; -1.04 [-2.41 to -0.17]), outer nuclear layer (ONL; -1.44 [-1.86 to -0.28]), and inner segment ellipsoid (ISE; -0.74 [-1.33 to -0.49]) at the moderate stage and retinal nerve fiber layer (RNFL; -1.49 [-2.08 to -0.66]) and GCIPL (0.58 [-1.79 to 0.06]) at the advanced stage were observed. Choroidal thickness decreased significantly from -7.62 to -9.40 µm per year at all stages. RPE atrophy and CVI reduction were observed at the advanced stage. There was no change in the control group. CONCLUSIONS: ONL and GCIPL thicknesses decreased at the moderate and advanced stages of RP; RNFL thickness decreased only at the advanced stage; and choroidal thickness decreased continuously. In addition, RPE atrophy and CVI reduction were prominent at the advanced stage. These results indicate that there is a temporal variation in the damage of each retinal layer and the choroid in RP patients.

VISUAL PROGNOSTIC VALUE OF NEUTROPHIL-TO-LYMPHOCYTE RATIO AND PLATELET-TO-LYMPHOCYTE RATIO IN BEHÇET UVEITIS.

PURPOSE: To investigate the significance of systemic indicators, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as long-term visual prognostic factors in patients with Behçet uveitis. METHODS: This study comprised 114 eyes from 114 patients diagnosed with Behçet uveitis. Ophthalmologic evaluations and biochemical measurements including NLR and PLR values were consecutively obtained at each visit. Patients were divided into good and poor visual outcome groups, based on the visual acuity of 0.5 logarithm of the minimum angle of resolution in the worse-seeing eyes at the last visit. Factors associated with poor visual outcomes were analyzed, and optimal cutoff values of NLR and PLR were also evaluated. RESULTS: Sixty-six eyes (57.9%) were included in the good visual outcome group. Multivariate regression analysis showed that younger age of onset (odds ratio = 0.939; P = 0.010), longer disease duration (odds ratio = 1.164; P < 0.001), higher maximum NLR (odds ratio = 1.215; P = 0.033), and higher initial PLR (odds ratio = 1.014; P = 0.039) were significantly associated with poor visual outcomes. The optimal cutoff value for patients with poor visual outcome was 5.608 for NLR and 128.078 for PLR. CONCLUSION: A higher maximum NLR and higher initial PLR, as well as a younger age of onset and longer disease duration, were significantly associated with poor visual outcomes. Systemic inflammatory factors might be important indicators of visual prognosis in Behçet uveitis.

Ultra-Widefield Fluorescein Angiography to Monitor Therapeutic Response to Adalimumab in Behcet's Uveitis.

PURPOSE: To investigate the role of ultra-widefield fluorescein angiography (UWFA) for monitoring therapeutic response to adalimumab in patients with Behcet's uveitis. METHODS: Patients with Behcet's uveitis treated with adalimumab for ≥30 weeks were included. Intraocular inflammation, best-corrected visual acuity, systemic medications, and UWFA scores were evaluated. RESULTS: Thirty-eight eyes of 20 patients were included. Significant decreases in grading of anterior chamber cells and vitreous haze were observed at 6, 14, and 30 weeks after adalimumab administration (p < .001 for all). UWFA scores on vascular and capillary leakage were decreased at week 6 and further improved at weeks 14 and 30. Moreover, UWFA score further decreased at 14 and 30 weeks, even after manifest inflammation became quiescent at 6 weeks. (p = .004 and 0.001, respectively). CONCLUSION: UWFA scores significantly improved in Behcet's uveitis patients treated with adalimumab, and further improvement of UWFA scores was found in patients with a clinically quiescent inflammatory state.

Role of Ultra-widefield Imaging in the evaluation of Long-term change of highly myopic fundus.

PURPOSE: To evaluate the impact of posterior staphyloma identified using ultra-widefield fundus imaging on the long-term progression of myopic maculopathy in highly myopic patients. METHODS: In this observational cohort study, highly myopic patients who were followed up for at least 5 years using ultra-widefield fundus imaging were analysed for fundus abnormalities and the progression of myopic maculopathy based on the International Meta-analysis of Pathologic Myopia classification. RESULTS: This study included 390 eyes (210 patients) with the mean follow-up period of 69.2 ± 7.5 months (range, 60-88). Posterior staphyloma was identified in 198 eyes (50.8%) in the baseline ultra-widefield fundus images. The border of staphyloma was not identified within 50° view circle corresponding to conventional fundus photography in 42 eyes (21.2%) with staphyloma, most of that were wide macular type. Progression of myopic maculopathy during follow-up was observed in 202 eyes (51.8%), and eyes with staphyloma were more likely to show progression compared to those without (142/198 [71.7%] versus 60/192 [31.3%]; p < 0.001). In multivariable regression analysis, the presence of posterior staphyloma was an independent risk factor for the progression of myopic maculopathy (p = 0.005). One or more peripheral retinal lesions were observed in 302 eyes (77.4%) and 321 eyes (82.3%) in the baseline and final ultra-widefield fundus images, respectively. CONCLUSION: Posterior staphyloma was associated with the long-term progression of myopic maculopathy. With a wider field of view, ultra-widefield fundus imaging is useful for identifying the posterior staphyloma and monitoring the progression of myopic maculopathy in highly myopic patients.

RETINITIS PIGMENTOSA SINE PIGMENTO: Clinical Spectrum and Pigment Development.

PURPOSE: To investigate the clinical findings, natural course, and pigment development of patients with retinitis pigmentosa (RP) sine pigmento using multimodal imaging. METHODS: We reviewed the medical records of 810 consecutive patients with RP and assessed serial ultra-widefield fundus photography, fundus autofluorescence, and optical coherence tomography images. Electrophysiological and visual field analysis findings were also reviewed. RESULTS: Of the 774 patients with RP who met the inclusion criteria, 88 were diagnosed with RP sine pigmento, with a prevalence of 11.4%. The mean age of the patients was 35.57 years compared with 49.83 years for patients with typical RP. Fifty-nine patients (67%) demonstrated minimal color change, whereas 29 (33%) presented with grayish flecks in the retinal pigment epithelium on fundus photography. All patients with RP sine pigmento had abnormalities on fundus autofluorescence, and the commonest fundus autofluorescence findings were punctate or reticular hypoautofluorescence. Of the 62 patients without pigmentation at the first visit and at the follow-up visits, 14 (22.6%) had developed pigmentation at their follow-up visit, with an average time of 3.92 years. Most patients retained a visual acuity of ≥20/50 within the age of 50 years. CONCLUSION: Diagnosing RP sine pigmento based solely on ophthalmoscopic findings is more difficult than in more typical cases. Multimodal imaging can provide insights into the clinical characteristics to facilitate the diagnosis, classification, and follow-up of patients.

Unilateral Cilioretinal Artery and Advanced Age-Related Macular Degeneration: A Retrospective Cross-Sectional Study.

PURPOSE: To investigate the association between the presence of a cilioretinal artery (CRA) and advanced age-related macular degeneration (AMD), including the prevalence of choroidal neovascularization (CNV) and geographic atrophy (GA). DESIGN: Retrospective cross-sectional study. METHODS: This was a single-center study. A total of 738 patients with AMD who underwent optical coherence tomography angiography (OCTA) were included in the study. Fundus photographs were reviewed to determine the presence of the CRA. In patients with a unilateral CRA, paired tests were performed between eyes with and without the CRA to compare AMD severity and prevalence of CNV and GA. The main outcomes of interest were AMD stage and prevalence of CNV and GA. Macular vasculature, including vessel density, perfusion density, and foveal avascular zone, were examined using OCTA. RESULTS: A total of 174 eyes from 87 patients with a unilateral CRA were examined. A total of 27.8% and 8.1% of patients had a CRA in 1 eye and both eyes, respectively. Eyes with a CRA showed lower AMD stage (4-step AREDS category; P = .037) and a lower prevalence of CNV (23.0% vs 41.4%; P = .024) than those without a CRA. The prevalence of GA and macular vessel density, perfusion density, and foveal avascular zone measured by OCTA were similar in both groups. CONCLUSIONS: In the eyes with a CRA, AMD stage and prevalence of CNV were lower than those in the eyes without a CRA. However, the effect of the CRA on the macular vascular system remains unclear.

Subretinal versus intravitreal administration of human CD34+ bone marrow-derived stem cells in a rat model of inherited retinal degeneration.

BACKGROUND: To evaluate whether subretinal or intravitreal injection of human CD34+ bone marrow-derived stem cells (BMSC) can have protective effects on retinal degeneration that may be enhanced by coadministration of exosomes harvested from human bone marrow mesenchymal stem cells (MSCs). METHODS: Human CD34+ cells were harvested from the mononuclear cell fraction of bone marrow using magnetic beads and labeled with EGFP. Exosomes were harvested from cultured human MSCs under hypoxic conditions. Royal College of Surgeons (RCS) 3-weeks-old rats, immunosuppressed with cyclosporine A, received subretinal or intravitreal injection of CD34+ cells (50,000 cells), CD34+ cells with exosomes (50,000 cells+10 µg), exosomes alone (10 µg), or PBS. Retinal function was examined using electroretinography (ERG), and the eyes were harvested for histologic and immunohistochemical analysis. RESULTS: The b-wave amplitude of ERG at 2 weeks after injection was significantly higher in eyes with subretinal or intravitreal CD34+ BMSC alone or in combination with exosomes when compared to PBS injected eyes or untreated contralateral eyes. At 4 weeks after injection, the ERG signal decreased in all groups but eyes with subretinal CD34+ BMSCs alone or combined with exosomes showed partially preserved ERG signal and preservation of the outer nuclear layer of the retina near the injection site on histology when compared to eyes with PBS injection. Immunohistochemical analysis identified the human cells in the outer retina. Subretinal or intravitreal exosome injection had no effect on retinal degeneration when administered alone or in combination with CD34+ cells. CONCLUSIONS: Both subretinal and intravitreal injection of human CD34+ BMSCs can provide functional rescue of degenerating retina, although the effects were attenuated over time in this rat model. Regional preservation of the outer retina can occur near the subretinal injection site of CD34+ cells. These results suggest that CD34+ cells may have therapeutic potential in retinal degeneration.

Impact of kidney transplantation on the risk of retinal vein occlusion in end-stage renal disease.

It has been known that retinal vein occlusion (RVO) is associated with chronic kidney disease, especially end-stage renal disease (ESRD). However, little is known about the effect of kidney transplantation (KT) on RVO incidence in ESRD patients. This study aimed to compare the incidence of RVO in KT recipients (n = 10,498), matched ESRD patients (n = 10,498), and healthy controls (HCs, n = 10,498), using a long-term population-based cohort. The incidence of RVO was 2.74, 5.68, and 1.02 per 1000 patient-years, for the KT group, the ESRD group, and the HCs group, respectively. Adjusted hazard ratios for RVO development compared to the HCs group, were 1.53 and 3.21, in the KT group and the ESRD group, respectively. In the KT group, multivariable regression analysis indicated that an age over 50, a Charlson Comorbidity Index score over 4, and a history of desensitization therapy were associated with an increased risk of RVO. In summary, KT recipients have a lower risk for development of RVO than ESRD patients treated with dialysis. However, the risk is still higher compared to healthy people who have normal kidney functions.

Embryonic stem cell-derived photoreceptor precursor cells differentiated by coculture with RPE cells.

Purpose: To describe the derivation of photoreceptor precursor cells from human embryonic stem cells by coculture with RPE cells. Methods: Human embryonic stem cells were induced to differentiate into neural precursor cells and then cocultured with RPE cells to obtain cells showing retinal photoreceptor features. Immunofluorescent staining, reverse transcription-PCR (RT-PCR), and microarray analysis were performed to identify photoreceptor markers, and a cGMP assay was used for in vitro functional analysis. After subretinal injection in rat animal models, retinal function was determined with electroretinography and optokinetic response detection, and immunofluorescent staining was performed to assess the survival of the injected cells. Results: Cocultured cells were positive for rhodopsin, red and blue opsin, recoverin, and phosphodiesterase 6 beta on immunofluorescent staining and RT-PCR. Serial detection of stem cell-, neural precursor-, and photoreceptor-specific markers was noted in each stage of differentiation with microarray analysis. Increased cGMP hydrolysis in light-exposed conditions compared to that in dark conditions was observed. After the subretinal injection in the rats, preservation of optokinetic responses was noted up to 20 weeks, while electroretinographic response decreased. Survival of the injected cells was confirmed with positive immunofluorescence staining of human markers at 8 weeks. Conclusions: Cells showed photoreceptor-specific features when stem cell-derived neurogenic precursors were cocultured with RPE cells.

Association of Retinal Changes With Alzheimer Disease Neuroimaging Biomarkers in Cognitively Normal Individuals.

IMPORTANCE: Retinal biomarkers reflecting in vivo brain Alzheimer disease (AD) pathologic abnormalities could be a useful tool for screening cognitively normal (CN) individuals at the preclinical stage of AD. OBJECTIVES: To investigate the association of both functional and structural alterations of the retina with in vivo AD pathologic abnormalities in CN older adults and model a screening tool for detection of preclinical AD. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included a total of 49 CN individuals, and all assessment was done at the Seoul National University Hospital, Seoul, South Korea. All participants underwent complete ophthalmic examination, including swept-source optical coherence tomography (SS-OCT) and multifocal electroretinogram as well as amyloid-ß (Aß) positron emission tomography and magnetic resonance imaging. Data were collected from January 1, 2016, through October 31, 2017, and analyzed from February 1, 2018, through June 30, 2020. MAIN OUTCOMES AND MEASURES: For structural parameters of the retina, the thickness of the macula and layer-specific thicknesses, including peripapillary retinal nerve fiber layer and ganglion cell-inner plexiform layer measured by SS-OCT, were used for analysis. For functional parameters of the retina, implicit time and amplitude of rings 1 to 6 measured by multifocal electroretinogram were used. RESULTS: Of the 49 participants, 25 were women (51.0%); mean (SD) age was 70.6 (9.4) years. Compared with 33 CN individuals without Aß deposition (Aß-CN), the 16 participants with Aß (Aß+CN) showed reduced inner nasal macular thickness (mean [SD], 308.9 [18.4] vs 286.1 [22.5] µm; P = .007) and retinal nerve fiber layer thickness, particularly in the inferior quadrant (133.8 [17.9] vs 103.8 [43.5] µm; P = .003). In addition, the Aß+CN group showed prolonged implicit time compared with the Aß-CN group, particularly in ring 5 (41.3 [4.0] vs 38.2 [1.3] milliseconds; P = .002). AD-related neurodegeneration was correlated with the thickness of the ganglion cell-inner plexiform layer only (r = 0.41, P = .005). The model to differentiate the Aß+CN vs Aß-CN groups derived from the results showed 90% accuracy. CONCLUSIONS AND RELEVANCE: The findings of this study showing both functional as well as structural changes of retina measured by multifocal electroretinogram and SS-OCT in preclinical AD suggest the potential use of retinal biomarkers as a tool for early detection of in vivo AD pathologic abnormalities in CN older adults.

Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration.

BACKGROUND: To date, no genetic analysis of inherited retinal disease (IRD) using whole-exome sequencing (WES) has been conducted in a large-scale Korean cohort. The aim of this study was to characterise the genetic profile of IRD patients in Korea using WES. METHODS: We performed comprehensive molecular testing in 168 unrelated Korean IRD patients using WES. The potential pathogenicity of candidate variants was assessed using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant interpretation guidelines, in silico prediction tools, published literature, and compatibility with known phenotypes or inheritance patterns. RESULTS: Causative variants were detected in 86/168 (51.2%) IRD patients, including 58/107 (54.2%) with retinitis pigmentosa, 7/15 (46.7%) with cone and cone-rod dystrophy, 2/3 (66.6%) with Usher syndrome, 1/2 (50.0%) with congenital stationary night blindness, 2/2 (100.0%) with Leber congenital amaurosis, 1/1 (100.0%) with Bietti crystalline dystrophy, 1/1 (100.0%) with Joubert syndrome, 9/10 (90.0%) with Stargardt macular dystrophy, 1/10 (10.0%) with vitelliform macular dystrophy, 1/11 (9.1%) with other forms of macular dystrophy, and 3/4 (75.0%) with choroideraemia. USH2A, ABCA4, and EYS were the most common causative genes associated with IRD. For retinitis pigmentosa, variants of USH2A and EYS were the most common causative gene mutations. CONCLUSIONS: This study demonstrated the distribution of causative genetic mutations in Korean IRD patients. The data will serve as a reference for future genetic screening and development of treatment modalities for Korean IRD patients.