Shotgun lipidomics of human subretinal fluids under rod-dominant retina reveals cone-dominated lipids.

Subretinal fluid (SRF) accumulates between photoreceptor outer segments and retinal pigment epithelium during rhegmatogenous retinal detachment. Biomolecular components such as lipids originate from cells surrounding the SRF. Knowledge of the composition of these molecules in SRF potentially provides mechanistic insight into the physiologic transfer of lipids between retinal tissue compartments. Using mass spectrometry and tandem mass spectrometry analysis on an electrospray ionization quadrupole-time-of-flight mass spectrometer, we identified a total of 115 lipid molecular species of 11 subclasses and 9 classes in two samples from two patients with rhegmatogenous retinal detachment. These included 47 glycerophosphocholines, 6 glycerophosphoethanolamines, 1 glycerophosphoinositol, 18 sphingomyelins, 9 cholesteryl esters, free cholesterol, 3 ceramides, 22 triacylglycerols and 8 free fatty acids. Glycerophosphocholines were of the highest intensity. By minimizing the formation of different adduct forms or clustering ions of different adducts, we determined the relative intensity of lipid molecular species within the same subclasses. The profiles were compared with those of retinal cells available in the published literature. The glycerophosphocholine profile of SRF was similar to that of cone outer segments, suggesting that outer segment degradation products are constitutively released into the interphotoreceptor matrix, appearing in SRF during detachment. This hypothesis was supported by the retinal distributions of corresponding lipid synthases' mRNA expression obtained from an online resource based on publicly available single-cell sequencing data. In contrast, based on lipid profiles and relevant gene expression in this study, the sources of free cholesterol and cholesteryl esters in SRF appeared more ambiguous, possibly reflecting that outer retina takes up plasma lipoproteins. Further studies to identify and quantify lipids in SRF will help better understand etiology of diseases relevant to outer retina.

Morphological and Functional Correlations in Acute Central Serous Chorioretinopathy.

PURPOSE: We evaluate morphological and functional correlations in patients with acute central serous chorioretinopathy (CSC). METHODS: A prospective study was conducted on 50 patients with an acute CSC episode lasting less than 3 months. At baseline, assessments included optical coherence tomography (OCT), best-corrected visual acuity (BCVA), contrast sensitivity (CS), microperimetry (MP), and multifocal electroretinography (mfERG). A correlation analysis between OCT morphological parameters (maximal subretinal fluid height (SRF), central retinal thickness (CRT), and macular volume (MV)) and functional parameters was conducted on the affected eye for each patient. RESULTS: Among the morphological parameters, SRF showed the strongest correlations with functional parameters (r absolute value range = 0.10-0.70). Weak correlations were observed between BCVA and morphological parameters (r absolute value range = 0.14-0.26). Average retinal sensitivity (MP-A) was the functional parameter displaying the most robust negative correlation with morphological parameters (r absolute value range = 0.61-0.70). In contrast, average contrast sensitivity (CS-A) and mfERG average amplitude density in the first (mfERG-A1) and second (mfERG-A2) ring showed weak to moderate (r absolute value range = 0.35-0.56) yet statistically significantly nonzero correlations. CONCLUSIONS: SRF and CRT could serve as the most representative morphological proxies for visual function deficit in acute CSC patients. Retinal sensitivity, as measured by MP, may be superior to BCVA in clinical research studies or when an in-depth visual function evaluation is needed.

Factors associated with the development of exudation in treatment-naive eyes with nonexudative macular neovascularization.

PURPOSE: To identify the predictive factors for development of exudation in patients with treatment-naïve nonexudative macular neovascularization (MNV). METHODS: We retrospectively analyzed 61 treatment-naïve patients with nonexudative MNV who had not received treatment for nonexudative MNV before the exudation developed. Baseline characteristics and changes in MNV were evaluated using multivariate modeling to determine the potential risk factors for exudative conversion. RESULTS: Exudation development was identified in 31.1% (19/61 eyes) of the study eyes during the 46.2 ± 8.2-month mean follow-up period. The mean period of development of exudation from the baseline was 21.5 ± 6.7 months. Multivariate Cox regression analysis identified that older age (hazard ratio [HR] of 1.380, 95% confidence interval [CI] 1.129-1.688, P = 0.008), larger MNV area at baseline (HR of 1.715, CI 1.288-2.308; P = 0.006), increase of MNV area by doubling (HR of 4.992, CI 1.932-9.246; P = 0.002), and retinal pigment epithelium (RPE) elevation more than 100 µm (HR of 1.017, CI 1.006-1.233; P = 0.015) were associated with increased risk of the development of exudation. CONCLUSION: Older age, larger MNV area, increasing MNV area, and higher RPE elevation were associated with an increased risk of exudative conversion in patients with treatment-naïve nonexudative MNV. Identifying these risk factors may be helpful in establishing treatment strategies and monitoring patients.

SURGICAL DRAINAGE METHODS DURING PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT: A Systematic Review and Meta-Analysis.

PURPOSE: To assess efficacy and safety outcomes of subretinal fluid drainage methods during pars plana vitrectomy for rhegmatogenous retinal detachment. METHODS: A systematic search strategy was conducted for studies published between January 2000 and October 2022. Included studies reported on either the safety or efficacy of two or more drainage methods during pars plana vitrectomy for patients with rhegmatogenous retinal detachment. RESULTS: Two randomized and five observational studies consisting of 1,524 eyes were included. Best-corrected visual acuity at the last study observation and primary reattachment rates were similar across groups. A significantly lower risk of epiretinal membrane formation was associated with draining subretinal fluid through preexisting retinal breaks (risk ratio = 0.70, 95% confidence interval = [0.60, 0.83], P = <0.01, I 2 = 0%) or with perfluorocarbon liquid (risk ratios = 0.70, 95% confidence interval = [0.59, 0.83], P = <0.01, I 2 = 0%) compared with posterior retinotomy. The risk of an abnormal foveal contour was significantly greater in perfluorocarbon liquid-treated eyes relative to posterior retinotomy (risk ratios = 1.56, 95% confidence interval = [1.13, 2.17], P = <0.01, I 2 = 0%). CONCLUSION: No significant differences were observed in the final best-corrected visual acuity at the last study observation and primary reattachment rates across different drainage methods. There remains limited information on the topic, so future research is warranted.

NONEXUDATIVE INTRARETINAL FLUID IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

BACKGROUND: To describe the occurrence of nonexudative intraretinal fluid (IRF) in intermediate age-related macular degeneration. METHODS: A retrospective study was designed to include consecutive cases with intermediate age-related macular degeneration associated with IRF. A multimodal imaging approach was used to confirm diagnosis of IRF in intermediate age-related macular degeneration. Multimodal imaging included color fundus photograph, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography. RESULTS: Ten eyes of 10 patients (2 male and 8 female patients, ages 68-80 years) showing IRF in intermediate age-related macular degeneration were included in the study. The mean best-corrected visual acuity was 20/40 Snellen equivalent. Multimodal imaging including fluorescein angiography/indocyanine green angiography and optical coherence tomography demonstrated the absence of macular neovascularization in all cases; optical coherence tomography-angiography did not detect any abnormal flow signal associated with IRF. Seven of 10 patients developed IRF in correspondence of pigment epithelium detachment. Three of 10 patients presented IRF in correspondence of an area of nascent geographic atrophy. CONCLUSION: Nonexudative intraretinal fluid in intermediate age-related macular degeneration is a novel, distinctive feature that is characterized by the presence of IRF with no evidence of macular neovascular lesions. The authors described different phenotypes of IRF in intermediate age-related macular degeneration. The definite diagnosis of this condition requires further studies with thorough application of multimodal imaging.

PERSISTENT SUBRETINAL FLUID AFTER VITRECTOMY FOR MACULAR HOLE-ASSOCIATED RETINAL DETACHMENT.

PURPOSE: To evaluate the incidence, associated factors, and outcome of persistent subretinal fluid (SRF) after vitrectomy for macular hole-associated retinal detachment (MHRD). METHODS: A total of 158 eyes from 156 patients with MHRD who achieved macular hole closure after primary vitrectomy were included in the analysis; persistent SRF was defined as the presence of SRF for more than 1 month after first surgery. Preoperative and postoperative parameters were analyzed for their relationship with SRF development. RESULTS: Persistent SRF was observed in 19 eyes (12.0% of 158) postoperatively. Seven eyes (36.8% of 19) with persistent SRF eventually displayed complete absorption during follow-up. Univariate analysis revealed that eyes with persistent SRF were statistically associated with internal limiting membrane inverted flap, duration of symptoms, tamponade (perfluoropropane/silicone oil: 14/5 vs. 35/104, P < 0.001), and MHRD subtype (Type 1/Type 2/Type 3: 15/4/0 vs. 60/40/39, P = 0.003). In multivariate analysis, only internal limiting membrane inverted flap (odds ratio, 15.778, 95% confidence interval, 3.170-78.523; P = 0.001) was positively associated with persistent SRF. There were no significant differences in best-corrected visual acuity improvement ( P = 0.425) between the SRF involved foveal and without involved foveal groups and no significant differences between the SRF complete absorption and incomplete absorption groups. CONCLUSION: Absorption of persistent SRF may be more difficult in MHRD eyes than in ordinary rhegmatogenous retinal detachment eyes. The internal limiting membrane inverted flap in MHRD was associated with a greater likelihood of persistent SRF. The location and incomplete absorption of persistent SRF did not seem to be associated with the final visual outcome.

Efficacy of Subthreshold Micropulse Laser for Central Serous Chorioretinopathy.

PURPOSE: To evaluate the efficacy of a subthreshold micropulse laser (SML) in patients with central serous chorioretinopathy (CSCR). METHODS: Retrospective clinical study conducted at the Departments of Ophthalmology at a university and a municipal hospital in Zurich, Switzerland. We enrolled acute and chronic CSCR patients with persistent subretinal fluid (SRF) treated with SML. Two treatment protocols (fluorescein/indocyanine green angiography or optical coherence tomography guided) were evaluated for efficacy after 3 and 6 months. The primary outcomes of the study were reduction and percentage of eyes with complete resolution of SRF 3 and 6 months after SML treatment. Secondary endpoints included changes in central subfield thickness (CST) and visual acuity (VA) after 3 and 6 months. RESULTS: The study involved 37 eyes (35 patients, 48.6% chronic). A statistically significant reduction in SRF height and CST could be shown, irrespective of SRF duration, type of CSCR, or chosen guidance after 3 and 6 months: SRF - 40 µm (p < 0.01), CST - 52 µm (p < 0.01). Percentage of eyes with complete resolution of fluid at 3 and 6 months after SML were 24.3 and 21.6%, respectively. No statistically significant functional improvement (VA) could be shown. Multivariable regression and linear mixed regression analyses did not identify statistically significant differences in SRF reduction, CMT change, or VA improvement with respect to the type of CSCR or the treatment plan used (p > 0.05). CONCLUSION: The effectiveness of SML in CSCR is under continuous debate. Our study findings demonstrate structural but only little functional changes with SML. In view of the shortage of verteporfin for photodynamic therapy, SML remains an important therapeutic option for CSCR patients.

Difference in characteristics and lesion reactivation between type 3 macular neovascularization with and without subretinal fluid at baseline.

PURPOSE: To compare the characteristics and incidence rates of lesion reactivation after anti-vascular endothelial growth factor (VEGF) treatment in type 3 macular neovascularization (MNV) with and without subretinal fluid (SRF) at baseline. METHODS: This retrospective study included 95 patients diagnosed with type 3 MNV. After the initial loading injections, re-treatment was performed when lesion reactivation occurred defined as the re-accumulation of subretinal or intraretinal fluid or the new development of a retinal/subretinal hemorrhage. The differences in the baseline characteristics and the incidence rates of lesion reactivation were compared between patients with SRF (SRF group, n = 42) and those without SRF (non-SRF group, n = 53). RESULTS: At diagnosis, the mean visual acuity was worse (0.68 ± 0.41 vs 0.50 ± 0.36; P = 0.032), mean central retinal thickness was greater (515.4 ± 145.9 µm vs 383.8 ± 105.5 µm; P < 0.001), and the incidence of focal retinal hemorrhages was higher (90.5% vs 66.0%; P = 0.005) in the SRF group than in the non-SRF group. In the SRF group, the first lesion reactivation was noted in 89.7% at a mean of 5.8 ± 4.4 months after the third injection. In the non-SRF group, the first lesion reactivation was noted in 70.6% at a mean of 6.1 ± 3.8 months. There was a significant difference in lesion reactivation between the two groups (P = 0.019). CONCLUSIONS: The difference in the baseline characteristics and incidence of lesion reactivation between type 3 MNV with and without SRF suggests that the presence of SRF may be indicative of more advanced disease with a high risk of visual deterioration. This result also suggests the need for more active treatment to preserve vision in patients with SRF.

PATTERNS OF SUBRETINAL AND/OR INTRARETINAL FLUID RECURRENCE IN PATIENTS WHO RECEIVED AS-NEEDED RANIBIZUMAB THERAPY IN THE HARBOR TRIAL.

PURPOSE: To evaluate subretinal fluid (SRF) and/or intraretinal fluid recurrence in patients with neovascular age-related macular degeneration who received as-needed (PRN) ranibizumab in a HARBOR (NCT00891735) post hoc analysis. METHODS: Analyses included patients with SRF and/or intraretinal fluid at baseline and fluid recurrence after a ≥3-month absence (N = 222). Baseline fluid location(s) were compared with location of recurrence after a ≥3-month absence. RESULTS: At baseline, fluid was equally distributed across all locations. On recurrence, the location was most frequently central (69%). Eyes with central fluid at baseline typically had recurrence in the same location (72% vs. 47%-53% with fluid in other locations). The type of recurrent fluid was typically the same as at baseline (SRF, 64%; intraretinal fluid, 75%). Overall, 37% (39/105) of eyes exhibited fluid recurrence in a new location, most frequently central (53%). There was a significant gain in best-corrected visual acuity (mean [95% confidence interval], +2.2 [0.4-4.0] letters) between the months of SRF resolution and recurrence. CONCLUSION: Although the location of SRF and/or intraretinal fluid was equally distributed at baseline, recurrent fluid was typically centrally located. The authors identified a subgroup of eyes exhibiting fluid recurrence in a different location than at baseline, potentially indicating new choroidal neovascularization.

QUANTITATIVE ASSESSMENT OF AUTOMATED OPTICAL COHERENCE TOMOGRAPHY IMAGE ANALYSIS USING A HOME-BASED DEVICE FOR SELF-MONITORING NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate a prototype home optical coherence tomography device and automated analysis software for detection and quantification of retinal fluid relative to manual human grading in a cohort of patients with neovascular age-related macular degeneration. METHODS: Patients undergoing anti-vascular endothelial growth factor therapy were enrolled in this prospective observational study. In 136 optical coherence tomography scans from 70 patients using the prototype home optical coherence tomography device, fluid segmentation was performed using automated analysis software and compared with manual gradings across all retinal fluid types using receiver-operating characteristic curves. The Dice similarity coefficient was used to assess the accuracy of segmentations, and correlation of fluid areas quantified end point agreement. RESULTS: Fluid detection per B-scan had area under the receiver-operating characteristic curves of 0.95, 0.97, and 0.98 for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid, respectively. On a per volume basis, the values for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid were 0.997, 0.998, and 0.998, respectively. The average Dice similarity coefficient values across all B-scans were 0.64, 0.73, and 0.74, and the coefficients of determination were 0.81, 0.93, and 0.97 for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid, respectively. CONCLUSION: Home optical coherence tomography device images assessed using the automated analysis software showed excellent agreement to manual human grading.

ADVANTAGES OF OPTICAL COHERENCE TOMOGRAPHY AS A HIGH DYNAMIC RANGE IMAGING MODALITY IN SUBRETINAL HYPERREFLECTIVE MATERIAL.

PURPOSE: To describe the utility of high dynamic range optical coherence tomography imaging to study subretinal hyperreflective material (SHRM) in patients with age-related macular degeneration. METHODS: Clinical information including visual acuity and optical coherence tomography images (Heidelberg Engineering GmbH, Heidelberg, Germany) of patients undergoing antiangiogenic treatment for neovascular age-related macular degeneration and showing SHRM at baseline were retrospectively reviewed. Contrast between strong signal structures (high dynamic range image) reclassifying SHRM as hyperreflective (HyperR), isoreflective, and hyporeflective was increased. The patients at baseline, 3, 6, and 12-months follow-up were evaluated. RESULTS: Forty-four eyes were classified as 15 HyperR (34.1%), 21 as isoreflective (47.7%), and eight as hyporeflective (18.2%). During follow-up, hyporeflective SHRM disappeared in all cases, isoreflective SHRM faded in 16 cases (76.2%); HyperR SHRM remained in all cases. Hyporreflective SHRM showed a greater visual acuity improvement than HyperR SHRM group ( P = 0.033). After 12-month follow-up, only the hyporeflective and isoreflective groups significantly reduced the presence of fluid in 37.5% ( P = 0.250) and 46.62% ( P = 0.006) of the patients, respectively; outer retinal layers were disrupted more frequently in the presence of HyperR SHRM (ellipsoid zone, P = 0.16; external limiting membrane, P = 0.007). CONCLUSION: Contrast-enhanced optical coherence tomography images enabled us to classify SHRM according to its reflectivity, showing groups with different disappearance rates, visual acuity improvement, and outer retinal layer disruption. This easy-to-access tool may be helpful as a prognostic factor in neovascular age-related macular degeneration cases.

PREDISPOSING CHARACTERISTICS OF OPTICAL COHERENCE TOMOGRAPHY FOR PATIENTS WITH PERSISTENT SUBRETINAL FLUID AFTER SUCCESSFUL REPAIR OF RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To investigate the predisposing clinical parameters and characteristics of fundus imaging of patients with persistent subretinal fluid (PSF) after successful repair of rhegmatogenous retinal detachment. METHODS: A retrospective study recruiting 57 patients was conducted. All patients underwent pars plana vitrectomy with silicone oil tamponade. Patients were divided into two groups: patients presenting PSF by the time of silicone oil removal as PSF group and patients presenting no PSF by the time of silicone oil removal as control group. All patients were followed up for 3 months or longer after primary surgery. Ophthalmic examinations, including fundus photography and optical coherence tomography, were performed. RESULTS: There were significant differences between the two groups in average age, durations of preoperative symptoms, and type of retinal breaks ( P < 0.05). These clinical parameters showed statistical correlations with PSF ( P < 0.05). The proportions of patients presenting distinctive boundaries of the detached retina on fundus photograph and patients showing a hyperreflective line underlying the detached retina on optical coherence tomography in the PSF group were both significantly higher than the control group ( P < 0.05). The macular detachment heights on optical coherence tomography in the PSF group were significantly lower than the control group ( P < 0.05). These imaging characteristics also showed strong correlations with PSF ( P < 0.05). CONCLUSION: This study suggests that patients with PSF have younger age, longer symptom duration, and higher incidence of retinal holes. The distinctive detachment boundary on fundus photograph, lower macular detachment height, and hyperreflective line underlying the detached retina on optical coherence tomography may be the predisposing characteristics of PSF.

SUBRETINAL FLUID ASSOCIATED WITH DRUSENOID PIGMENT EPITHELIAL DETACHMENT.

PURPOSE: To analyze the clinical characteristics of drusenoid pigment epithelial detachment (PED) with subretinal fluid (SRF) and to evaluate the impact of SRF on the long-term visual and anatomical outcomes. METHODS: Forty-seven eyes with drusenoid PED (47 patients) who completed >24 months of follow-up were retrospectively analyzed. Intergroup comparisons of the visual and anatomical outcomes with and without SRF were made. RESULTS: The mean duration of follow-up was 32.9 ± 18.7 months. The group with drusenoid PED with SRF (14 eyes) showed significantly higher PED height (468 ± 130 µ m vs. 313 ± 88 µ m, P < 0.001), larger PED diameter (2,328 ± 953 µ m vs. 1,227 ± 882 µ m, P < 0.001), and larger PED volume (1.88 ± 1.73 mm 3 vs. 1.12 ± 1.35 mm 3 , P = 0.021) than that in the group with drusenoid PED without SRF (33 eyes) at baseline. No significant intergroup difference was found regarding the best-corrected visual acuity at the final visit. In addition, the incidence of complete retinal pigment epithelial and outer retinal atrophy (cRORA; 21.4%) and the development of macular neovascularization (MNV; 7.1%) for the group with drusenoid PED with SRF showed no difference compared with those (39.4% for cRORA development and 9.1% for MNV development) with drusenoid PED without SRF. CONCLUSION: The size, height, and volume of drusenoid PED were associated with the development of SRF. The SRF in drusenoid PED did not affect the visual prognosis or the development of macular atrophy during long-term follow-up.

INCIDENCE AND TIMING OF PIGMENT EPITHELIAL DETACHMENT AND SUBRETINAL FLUID DEVELOPMENT IN TYPE 3 MACULAR NEOVASCULARIZATION ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the incidence and timing of pigment epithelial detachment (PED) and subretinal fluid (SRF) development in type 3 macular neovascularization. METHODS: This retrospective study included 84 patients who were diagnosed with treatment-naïve type 3 macular neovascularization who did not show SRF at diagnosis. All patients were initially treated with three loading injections of ranibizumab or aflibercept. After the initial loading injections, as-needed regimen was performed for retreatment. The development of either PED or SRF was identified. The incidence and timing of PED development in patients without PED at diagnosis and that of SRF development in patients with PED at diagnosis were evaluated. RESULTS: The mean follow-up period was 41.3 ± 20.7 months after diagnosis. Among the 32 patients without serous PED at diagnosis, PED developed in 20 (62.5%) at a mean of 10.9 ± 5.1 months after diagnosis. PED development was noted within 12 months in 15 patients (46.8%; 75.0% among the PED development cases). In 52 patients with serous PED and without SRF at diagnosis, 15 developed SRF (28.8%) at a mean of 11.2 ± 6.4 months after diagnosis. SRF development was noted within 12 months in nine patients (17.3%; 66.6% among the SRF development cases). CONCLUSION: PED and SRF developed in a substantial proportion of patients with type 3 macular neovascularization. The average period of development of these pathologic findings was within 12 months of diagnosis, suggesting the need for active treatment during the early treatment period to improve treatment outcomes.

Preliminary analysis of predicting the first recurrence in patients with neovascular age-related macular degeneration using deep learning.

BACKGROUND: To predict, using deep learning, the first recurrence in patients with neovascular age-related macular degeneration (nAMD) after three monthly loading injections of intravitreal anti-vascular endothelial growth factor (anti-VEGF). METHODS: Optical coherence tomography (OCT) images were obtained at baseline and after the loading phase. The first recurrence was defined as the initial appearance of a new retinal hemorrhage or intra/subretinal fluid accumulation after the initial resolution of exudative changes after three loading injections. Standard U-Net architecture was used to identify the three retinal fluid compartments, which include pigment epithelial detachment, subretinal fluid, and intraretinal fluid. To predict the first recurrence of nAMD, classification learning was conducted to determine whether the first recurrence occurred within three months after the loading phase. The recurrence classification architecture was built using ResNet50. The model with retinal regions of interest of the entire region and fluid region on OCT at baseline and after the loading phase is presented. RESULTS: A total of 1,444 eyes of 1,302 patients were included. The mean duration until the first recurrence after the loading phase was 8.20 ± 15.56 months. The recurrence classification system revealed that the model with the fluid region of OCT after the loading phase provided the highest classification performance, with an area under the receiver operating characteristic curve (AUC) of 0.725 ± 0.012. Heatmap analysis revealed that three pathological fluids, subsided choroidal neovascularization lesions, and hyperreflective foci were important areas for the first recurrence. CONCLUSIONS: The deep learning algorithm allowed for the prediction of the first recurrence for three months after the loading phase with adequate feasibility. An automated prediction system may assist in establishing patient-specific treatment plans and the provision of individualized medical care for patients with nAMD.

MicroRNA Expression in Subretinal Fluid in Eyes Affected by Rhegmatogenous Retinal Detachment.

Proliferative vitreoretinopathy (PVR) is an abnormal intraocular scarring process that can complicate cases of rhegmatogenous retinal detachment (RRD). Although previous studies have examined the relevance of microRNAs (miRNAs) in ophthalmic diseases, only a few studies have evaluated the expression profiles of microRNAs in subretinal fluid. We hypothesized that the expression profiles of specific miRNAs may change in response to RRD, in the subretinal fluid that is directly in contact with photoreceptors and the retinal pigment epithelium (RPE). We looked for a potential correlation between the expression of specific miRNAs in eyes with RRD and known clinical risk factors of PVR. A total of 24 patients (59 ± 11 years) who underwent scleral buckling procedure were enrolled in this prospective study. Twenty-four undiluted subretinal fluid samples were collected, RNA was isolated and qRT-PCR was performed to analyze the expression of 12 miRNAs. We found the existence of a positive association between the expression of miR-21 (p = 0.017, r = 0.515) and miR-34 (p = 0.030, r = 0.624) and the duration of symptoms related to retinal detachment. Moreover, the expression of miR-146a tended to decrease in patients who developed PVR. Subretinal fluid constitutes an intriguing biological matrix to evaluate the role of miRNAs leading to the development of PVR.

Transthyretin proteoforms of intraocular origin in human subretinal fluid.

Understanding the molecular composition of ocular tissues and fluids could inform new approaches to prevalent causes of blindness. Subretinal fluid accumulating between the photoreceptor outer segments and retinal pigment epithelium (RPE) is potentially a rich source of proteins and lipids normally cycling among outer retinal cells and choroid. Herein, intact post-translationally modified proteins (proteoforms) were extracted from subretinal fluids of five patients with rhegmatogenous retinal detachment (RRD), analyzed by tandem mass spectrometry, and compared to published data on these same proteins as synthesized by other organs. Single-nuclei transcriptomic data from non-diseased human retina/RPE were used to identify whether proteins in subretinal fluid were of potential ocular origin. Two human donor eyes with normal maculas were immunoprobed for transthyretin (TTR) with appropriate controls. The three most abundant proteins detected in subretinal fluid were albumin, TTR, and apolipoprotein A-I. Remarkably, TTR relative to the other proteins was more abundant than its serum counterpart, suggestive of TTR being synthesized predominantly locally. Six proteoforms of TTR were detected, with the relative amount of glutathionylated TTR being much higher in the subretinal fluid (12-43%) than values reported for serum (<5%) and cerebrospinal fluid (0.4-13%). Moreover, a putative glycosylated TTR dimer of 32,428 Da was detected as the fourth most abundant protein. The high abundance of TTR and putative TTR dimer in subretinal fluid was supported by analysis of available single-nuclei transcriptomic data, which showed strong and specific signal for TTR in RPE. Immunohistochemistry further showed strong diffuse TTR immunoreactivity in choroidal stroma that contrasted with vertically aligned signal in the outer segment zone of the subretinal space and negligible signal in RPE cell bodies. These results suggest that TTR in the retina is synthesized intraocularly, and glutathionylation is crucial for its normal function. Further studies on the composition, function, and quantities of TTR and other proteoforms in subretinal fluid could inform mechanisms, diagnostic methods, and treatment strategies for age-related macular degeneration, familial amyloidosis, and other retinal diseases involving dysregulation of physiologic lipid transfer and oxidative stress.

Relationship between retinal fluid characteristics and vision in neovascular age-related macular degeneration: HARBOR post hoc analysis.

PURPOSE: To evaluate the relationship between retinal fluid location, amount/severity, and vision with ranibizumab-treated neovascular age-related macular degeneration (nAMD). METHODS: In the phase 3 HARBOR trial (NCT00891735), treatment-naive patients with nAMD received ranibizumab 0.5 or 2.0 mg through month 24. This post hoc analysis included eyes with subretinal fluid (SRF) and/or intraretinal fluid (IRF) at screening, baseline, or week 1, and optical coherence tomography data at months 12 and 24 (n = 917). Outcomes were best-corrected visual acuity (BCVA) change from baseline and proportion of eyes with 20/40 or better vision at months 12 and 24. Eyes were stratified by the location, amount, and/or severity of fluid. RESULTS: At baseline, 86% and 63% of eyes had SRF and IRF, respectively. Among eyes with residual SRF, mean BCVA gains at each time point were greater in eyes with central versus noncentral SRF; location did not affect the odds of having 20/40 or better vision over 24 months. Eyes with 20/40 or better BCVA at month 12 had significantly lower SRF thickness versus eyes with worse vision; however, no difference was apparent at month 24. Vision was comparatively worse in eyes with residual IRF at months 12 and 24; location and severity did not appear to affect this outcome. CONCLUSION: Residual IRF was associated with worse vision outcomes, regardless of location/severity, whereas, despite continued treatment, residual SRF was not associated with worse vision outcome at 24 months, regardless of location/thickness. These data suggest complex relationships between residual fluid, severity, and vision.

Risk factors of persistent subretinal fluid after half-dose photodynamic therapy for treatment-naïve central serous chorioretinopathy.

PURPOSE: To investigate the prognostic factors on spectral domain optical coherence tomography (SD-OCT) associated with incomplete subretinal fluid (SRF) absorption in treated-naïve eyes with central serous chorioretinopathy (CSC) after the half-dose verteporfin photodynamic therapy (vPDT). METHODS: Patients with CSC who underwent half-dose vPDT with a follow-up period of more than 3 months were included in this retrospective study. Logistic regression was performed to determine the risk factors associated with the SRF persistence at 3 months after the treatment. RESULTS: A total of 143 patients with 150 eyes were enrolled in this study (102 male and 41 female patients). The rate of complete SRF resolution was 82.7% at 3 months for all cases. The duration of symptoms > 6 months (odds ratio [OR] = 3.135, 95% confidence interval [95% CI] (1.147-8.573), p = 0.026), larger SRF area with base diameter > 3 mm (odds ratio (OR) = 4.051, 95% CI: 1.336-12.284, p = 0.013), and larger flat irregular pigment epithelium detachment (FI-PED) area with base diameter > 1 mm (OR = 3.311, 95% CI: 1.249-8.780, p = 0.016) on OCT B-scans were risk factors for incomplete SRF absorption after half-dose vPDT, while outer nuclear layer (ONL) thickness was not significantly associated with the anatomical outcome (OR = 1.015, 95% CI: 0.995-1.036, p = 0.145). CONCLUSION: The duration of symptoms, baseline SRF, and FI-PED base diameter on SD-OCT were important predictors for the anatomical outcome at 3 months after half-dose vPDT. Further studies are needed to establish a better therapeutic strategy for patients with poor response to half-dose vPDT.

IMPACT OF FLUID COMPARTMENTS ON FUNCTIONAL OUTCOMES FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Systematic Literature Review.

PURPOSE: Understanding the impact of fluid in different retinal compartments is critical to developing treatment paradigms that optimize visual acuity and reduce treatment burden in neovascular age-related macular degeneration. This systematic review aimed to determine the impact of persistent/new subretinal fluid, intraretinal fluid, and subretinal pigment epithelial fluid on visual acuity over 1 year of treatment. METHODS: Publication eligibility and data extraction were conducted according to Cochrane methods: 27 of the 1,797 screened records were eligible. RESULTS: Intraretinal fluid negatively affected visual acuity at baseline and throughout treatment, with foveal intraretinal fluid associated with lower visual acuity than extrafoveal intraretinal fluid. Some studies found that subretinal fluid (particularly subfoveal) was associated with higher visual acuity at Year 1 and longer term, and others suggested subretinal fluid did not affect visual acuity at Years 1 and 2. Data on the effects of subretinal pigment epithelial fluid were scarce, and consensus was not reached. Few studies reported numbers of injections associated with fluid status. CONCLUSION: To optimally manage neovascular age-related macular degeneration, clinicians should understand the impact of fluid compartments on visual acuity. After initial treatment, antivascular endothelial growth factor regimens that tolerate stable subretinal fluid (if visual acuity is stable/improved) but not intraretinal fluid may enable patients to achieve their best possible visual acuity. Confirmatory studies are required to validate these findings.