Efficacy of Brolucizumab in Polyp Regression of Treatment-Naïve Polypoidal Choroidal Vasculopathy and Its Effect on One-Year Treatment Outcome.

Purpose: To evaluate the efficacy of intravitreal brolucizumab in polyp regression of treatment-naïve polypoidal choroidal vasculopathy (PCV) patients and its effect on one-year treatment outcome. Methods: Medical records of 31 treatment-naïve PCV patients, who received three monthly intravitreal brolucizumab injections followed by as-needed injections for at least a year, were retrospectively reviewed. Visual and anatomical outcomes were evaluated at 3-month, 6-month, and 12-month. Complete polyp regression rate and percentage change of vascular lesion and polyp area were evaluated after three monthly injections of brolucizumab. The effect of complete polyp regression and the impact of vascular lesion and polyp reduction rate on one-year treatment outcome were also evaluated. Additionally, the incidence of brolucizumab-related intraocular inflammation (IOI) and its clinical course were examined. Results: In terms of visual outcome, best-corrected visual acuity(BCVA) significantly improved after 12 month follow-up (p<0.001). In terms of anatomical outcome, central macular thickness(CMT) and central choroidal thickness(CCT) significantly decreased after 12 month follow-up (p<0.001). Complete polyp regression was observed in 74.2% (23/31) after three monthly injections. Group with complete polyp regression had a higher rate of achieving dry macula at 3-month(p=0.026) and fewer number of injections(p<0.001) compared to the group without complete polyp regression. Higher polyp reduction rate was significantly associated with higher CMT change from baseline at 3-month (p=0.048) while higher vascular lesion reduction rate was significantly associated with higher CMT change from baseline at 12-month(p=0.031) and fewer number of injections(p=0.012). Brolucizumab related IOI occurred in one eye (1/31, 3.2%). Conclusion: Intravitreal brolucizumab injection effectively improved visual and anatomical outcomes and achieved significant polyp regression in treatment-naïve PCV patients. Complete polyp regression and the reduction rate of vascular lesion size and polyp size after loading injection significantly influence the treatment outcome of PCV patients. However, careful monitoring and preoperative warning is warranted due to occurrence of brolucizumab-related IOI.

Retinal Artery and Vein Occlusion Risks after Coronavirus Disease 2019 or Coronavirus Disease 2019 Vaccination.

PURPOSE: To evaluate the incidence of new retinal artery occlusion (RAO) and retinal vein occlusion (RVO) after the diagnosis of coronavirus disease 2019 (COVID-19) or vaccination against COVID-19 and compare the incidences with the population with neither. DESIGN: Nationwide population-based cohort study. PARTICIPANTS: From a nationwide population-based cohort, 8 418 590 patients were categorized into control (group 1), COVID-19 infection (group 2), and COVID-19 vaccination (group 3) groups. METHODS: The cumulative incidence of RAO and RVO was calculated in groups 1, 2, and 3 using the Kaplan-Meier method. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) based on the Poisson distribution for RAO and RVO according to each group and subgroup using Cox proportional hazards models, with group 1 as the reference. We conducted univariable and multivariable analyses for the risk factors of RAO and RVO according to each subgroup. MAIN OUTCOME MEASURES: Cumulative incidence and risks of incidence of RAO and RVO from the index date to day 60. RESULTS: In multivariable analysis, no significant increase in RAO and RVO risks after COVID-19 or COVID-19 vaccination were observed in either men or women. These results were observed consistently across various conditions in sensitivity analyses. In subgroup analysis, individuals who were vaccinated before infection showed no significant increase in RAO or RVO risks in both sexes compared with the control group. In the subgroup analysis of vaccinated patients, the HRs of RAO and RVO for different vaccine types did not show an increase compared with the control group; however, an exception was observed in women who received mRNA-1273 vaccines, who showed a higher RAO HR (4.65; 95% CI, 1.27-17.03; P = 0.021). CONCLUSIONS: Within 60 days of COVID-19 diagnosis or vaccination, RAO and RVO occurred rarely. We observed no increase in the HR of RVO and RAO relative to COVID-19 or COVID-19 vaccination except for a possible increase in the RAO HR in women who received mRNA-1273, for which the raw incidence was extremely low. Further investigation is required to validate this result. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Retinal vascular occlusion risks during the COVID-19 pandemic and after SARS-CoV-2 infection.

The coronavirus disease 2019 (COVID-19) has been reported to affect vascular networks including the eye. However, evidence on the causal relationship between COVID-19 infection and retinal vascular occlusions remains limited. This study aimed to determine the change in retinal vascular occlusion incidence during COVID-19 era and whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces retinal vascular occlusion. Retinal vein occlusion (RVO) and retinal artery occlusion (RAO) incidences during 2018-2019 and 2020-July 2021 were compared, those in confirmed and suspected COVID-19 patients diagnosed from 2020 to January 2021 were calculated, and those in COVID-19 patients during 180 days prior and 180 days after diagnosis were assessed. Additionally, the standardized incidence ratio of RVOs in COVID-19 patients was analyzed. Incidence rates per 100,000 people/year of RVO during 2018-2019 and 2020-2021 was 102.0 and 98.8, respectively. RAO incidence rates during 2018-2019 and 2020-2021 were 11.7 and 12.0, respectively. In both confirmed and suspected COVID-19 patients, the incidence of RVO and RAO did not change significantly from 180 days before to after diagnosis in the adjusted model. RVO incidence slightly decreased while RAO incidence increased during the COVID-19 pandemic. SARS-CoV-2 infection did not significantly increase RVO or RAO incidence.

Subset of retinoblastoma tumours is associated with BRCA1/2 mutations.

BACKGROUND: We investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity. METHODS: In this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma diagnosed between March 2017 and October 2021. Bioinformatics prediction tools were then used to conduct in silico pathogenicity assessments for patients with BRCA1/2 family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germline BRCA1 variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis for RB1 and BRCA using the patient's tumour and blood samples. RESULTS: Of 30 retinoblastoma patients who underwent panel sequencing, six (20%) were found to carry germline variants in the BRCA1/2 or BRIP1 genes. Among these six patients, two had pathogenic or likely pathogenic variants as per the ACMG variant classification. Additionally, three patients showed potential pathogenic BRCA1/2 family variants through further analysis with alternative bioinformatics prediction tools. In the WGS analysis of a tumour from a patient with a germline likely pathogenic BRCA1 variant in one allele, we observed the loss of one RB1 allele due to a large deletion. No somatic non-synonymous mutations or frameshift indels were detected in the RB1 locus of the remaining allele. This sample also showed BRCA1 gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing. CONCLUSION: This study demonstrated that some retinoblastoma patients harboured germline BRCA1/2 family variants, which may be associated with the development of retinoblastoma along with RB1 mutations.

Intravitreal Administration of Retinal Organoids-Derived Exosomes Alleviates Photoreceptor Degeneration in Royal College of Surgeons Rats by Targeting the Mitogen-Activated Protein Kinase Pathway.

Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.

PROGRESSION OF MYOPIC MACULOPATHY IN PATIENTS WITH MYOPIC TRACTION MACULOPATHY AFTER VITRECTOMY.

PURPOSE: To compare the progression of myopic maculopathy with or without vitrectomy in patients with myopic traction maculopathy (MTM). METHODS: Seventy-seven eyes with MTM were classified into either the observation group (n = 38) or the vitrectomy group (n = 39). Progression of myopic maculopathy was assessed with fundus photography using infrared images. Progression within stage was evaluated as an increase in the area of atrophic lesions on infrared images using ImageJ software. The rate of progression was compared using the paired t -test. RESULTS: The mean follow-up period was 60.0 ± 47.5 months. The initial mean stage of myopic maculopathy for the observation group was 1.86 ± 0.86, and it progressed to 2.00 ± 0.83 ( P = 0.023) at the last visit. For the vitrectomy group, the stage progressed from 1.82 ± 0.96 to 2.05 ± 1.09 ( P = 0.011). Four eyes (10.5%) in the observation group showed progression at 87.3 months, and seven eyes (17.9%) in the vitrectomy group showed progression at 31.3 months. CONCLUSION: Surgery in patients with MTM may accelerate the progression of myopic maculopathy. Therefore, care should be taken when considering surgery for patients with MTM.

Expanded spectrum of focal scleral nodule: focal scleral nodules can be bifocal.

BACKGROUND: To assess multimodal imaging findings of focal scleral nodule (FSN) to evaluate its origin and natural course. METHODS: This was a retrospective observational case series and included 14 patients with FSN who underwent multimodal imaging. Clinical information was gathered from patients' medical records. Primary outcome measures were standardized grading of imaging features. RESULTS: The mean follow-up duration was 68.8 ± 43.6 months (range, 6-139 months). Most lesions were solitary (92.6%), but one patient had two adjacent lesions (7.1%). Optical coherence tomography revealed that all lesions were confined to the sclera. Lesions showed mostly outer retinal abnormality, with external limiting membrane thinning or absence in 41.6% of lesions and ellipsoid layer absence in 84.6% of lesions. Most lesions showed an absence (69.2%) or thinning (23.1%) of the choroid above the lesion, and the mean choroidal thickness above the lesion for choroids with measurable thickness was 36 ± 75 µm (median, 0; range, 0-265 µm). Of 13 lesions with available follow-up data, only three lesions showed minimal growth over time. CONCLUSIONS: This study demonstrates for the first time that bifocal lesions of FSN in the same eye are possible and reaffirms the relative stability of this entity.

EFFICACY OF COMBINED SYSTEMIC CORTICOSTEROID AND EARLY IMMUNOMODULATORY THERAPY WITHIN THREE MONTHS OF ONSET IN VOGT-KOYANAGI-HARADA DISEASE.

PURPOSE: To evaluate the clinical outcomes of combined systemic corticosteroid and early immunomodulatory therapy (IMT) within 3 months of onset in Vogt-Koyanagi-Harada (VKH) disease compared with conventional therapy. METHODS: This retrospective observational case series included 73 eyes of 38 patients with VKH, categorized into the conventional (n = 41) and the early IMT (n = 32) groups. Clinical information was gathered from patients' medical records. Primary outcome measures were visual acuity, subfoveal choroidal thickness, and uveitis outcome including occurrence of sunset glow fundus. RESULTS: The logarithm of minimal angle of resolution visual acuity of both groups improved, with statistically significant difference at the last follow-up (P < 0.01, Mann-Whitney U test). Their mean subfoveal choroidal thickness decreased, with no statistically significant difference at the last follow-up (P = 0.21, T-test). In the conventional and early IMT groups, 27 (65.9%) and 15 (46.9%) eyes, respectively, had chronic or chronic recurrent VKH and sunset glow fundus was observed in 33 (80.5%) and 16 (50.0%) eyes, respectively. CONCLUSION: Combined systemic corticosteroid and early IMT within 3 months of onset was superior to conventional therapy in the final visual and uveitis outcome of patients with VKH disease. Therefore, IMT may be added early in cases of VKH disease, even when under control with high-dose corticosteroid.

Incidence and risk factors of progressive nasal inner nuclear layer thickening after surgical peeling of epiretinal membrane.

To assess incidence and risk factors of postoperative progressive nasal inner nuclear layer (INL) thickening after epiretinal membrane (ERM) surgery. Progressive nasal INL thickening was defined as 1.5-fold increase in thickness of nasal INL after ERM surgery compared to preoperative examination. Kaplan-Meier survival analysis was done to compare the cumulative risk ratio between groups stratified by presence of progressive nasal INL thickening. Logistic regression was performed to identify possible risk factors. Progressive nasal INL thickening occurred in 13.0% of ERM removal patients. Patients without progressive nasal INL thickening showed better visual acuity recovery compared to patients with nasal INL thickening (p = 0.029). Presence of cystoid space in inner retinal layer before surgery (odds ratio [OR] = 0.143, 95% confidence interval [CI] 0.028-0.736; p = 0.020), older age (OR = 0.896, 95% CI 0.817-0.982, p = 0.020), and thicker preoperative central macular thickness (OR = 0.994, 95% CI 0.988-1.000, p = 0.039) were correlated inversely with thickening of nasal INL. Correlation between nasal INL thickness and postoperative visual outcome was significant. Absence of cystoid space before ERM surgery, younger age, and thinner central macular thickness were risk factors for progressive postoperative nasal INL thickening. Progressive nasal INL thickening may serve as a new biomarker for worsened visual symptom after ERM surgery.

Pathogenic Risk Factors and Associated Outcomes in the Bullous Variant of Central Serous Chorioretinopathy.

PURPOSE: To compare the clinical features, treatments, and outcomes between bullous and chronic variants of central serous chorioretinopathy (CSC). DESIGN: Retrospective, observational case series. PARTICIPANTS: Sixty-two eyes of 44 patients with bullous-variant CSC (bvCSC) and 97 eyes of 85 patients with nonbullous CSC. METHODS: We conducted a national survey between September 1, 2020, and March 31, 2021, of members of the Korean Retina Society and obtained data of patients with bvCSC from 11 retinal centers. A comparator group comprised consecutive chronic CSC patients without bullous detachment. MAIN OUTCOME MEASURES: Baseline demographics and patient characteristics were compared between groups. Secondary outcomes included factors associated with visual prognosis within the bvCSC group. RESULTS: Compared with the nonbullous CSC group, the bvCSC group presented at a younger age (49 vs. 52 years; P = 0.047) and with more bilateral involvement (41% vs. 14%; P < 0.001). Systemic corticosteroid use was more prevalent in the bvCSC group, both in terms of any exposure (50% vs. 20%; P = 0.001) and long-term exposure (36% vs. 9%; P < 0.001). The bvCSC group had distinct imaging features (all P < 0.05): retinal folding (64% vs. 1%), subretinal fibrin (75% vs. 13%), multiple retinal pigment epithelium tears (24% vs. 2%), and multifocal fluorescein leakages with terminal telangiectasia (36% vs. 1%). Although bvCSC patients had worse vision at diagnosis (20/80 vs. 20/44; P = 0.003), treatment response was more robust (fluid resolution by final follow-up, 84% vs. 68%; P = 0.034) even with conservative management, resulting in similar final vision (20/52 vs. 20/45; P = 0.52). History of kidney-related (odds ratio [OR] 5.4; 95% confidence interval [CI] 1.3-18.5; P = 0.045) and autoimmune/rheumatoid diseases (OR 25.4, 95% CI 2.8-195.0; P = 0.004) showed associations with the bvCSC group. Apart from vision at diagnosis (OR 0.1, 95% CI 0.05-0.36; P < 0.001), a history of renal transplantation was most predictive of visual prognoses for bvCSC eyes (OR 0.2, 95% CI 0.04-0.75; P = 0.020). CONCLUSIONS: Bullous-variant CSC may be associated with pathogenic risk factors based on underlying medical conditions and systemic corticosteroid use. Poor vision at diagnosis and history of renal transplantation were associated with poor visual outcome.

Retinal Hemorrhage after SARS-CoV-2 Vaccination.

To report retinal vein occlusion (RVO) and age-related macular degeneration (AMD)-related submacular hemorrhage developing after administration of SARS-CoV-2 vaccines, a single-center, retrospective observational case series was conducted. Clinical data including fundus photographs and optical coherence tomography (OCT) scans were reviewed. Twenty-three eyes of 21 patients were included with the median age at symptom presentation being 77 years (range: 51-85 years). Twelve eyes (52.2%) had submacular hemorrhage and 11 (47.8%) had RVO. Twelve patients (60.9%) had been vaccinated with the Pfizer vaccine (BNT162b2) and 8 with the AstraZeneca (ChAdOx1) vaccine. Sixteen patients (76.2%) experienced ocular disease exacerbation after the first vaccination and 4 (19.0%) after the second vaccination. The median visual acuity (logarithm of the minimal angle of resolution; logMAR) before symptom development was 0.76 (interquartile range: 0.27-1.23); the median logMAR at symptom presentation was 1.40 (interquartile range 0.52-1.70). The median time between vaccination and symptom exacerbation was 2.0 days (interquartile range: 1.0-3.0 days). Five patients (23.8%) underwent tests for hematological abnormalities, including the presence of anti-PF4 antibodies; all were negative. Further studies with larger patient group for evaluation of effect of SARS-CoV-2 vaccination on retinal hemorrhage are necessary.

Progression patterns of normal-tension glaucoma groups classified by hierarchical cluster analysis.

OBJECTIVES: To investigate differences in progression patterns of normal-tension glaucoma (NTG) patients in three clusters classified by hierarchical cluster analysis (HCA). MATERIALS AND METHODS: In a retrospective study, 200 eyes of NTG patients classified by HCA in 2015 who were followed up to the current date were evaluated. Peripapillary retinal nerve fibre layer (RNFL) thicknesses were measured by Cirrus HD-OCT and progression rate was calculated by trend analysis (Guided Progression Analysis [GPA]). VF progression rate was evaluated by linear regression analysis of mean deviation (MD). Progression patterns of three clusters were compared by histograms. RESULTS: In total, 153 eyes of 153 patients were followed up. Mean observation period was 5 years. RNFL reduction rate was -0.83 µm/year in cluster 1, which showed early glaucomatous damage in previous reports; -0.45 µm/year in cluster 2, which showed moderate glaucomatous damage; and -0.36 µm/year in cluster 3, which showed young and myopic glaucomatous damage. The progression pattern of cluster 3 showed a double-peak distribution; RNFL reduction rate was 0.11 µm/year in the non-progressive group and -1.07 µm/year in the progressive group. CONCLUSION: The progression patterns were different among three NTG groups that were divided by HCA. In particular, the group of young and myopic eyes showed a mixture of two different patterns.