A Recurrent Case of Full-Thickness Macular Hole After Successful Closure With Primary Vitrectomy and Epiretinal Proliferation Embedding.

Epiretinal proliferation (EP) is thought to be glial cell proliferation arising from the inner retina, seen in cases of lamellar or full-thickness macular holes (FTMH). Embedding EP within the macular hole is considered supportive for FTMH closure and functional recovery. We report a recurrent case of FTMH that was successfully closed after primary vitrectomy with the EP embedding technique. In the primary surgery, internal limiting membrane (ILM) peeling was avoided to reduce the potential risk of retinal nerve fiber layer damage associated with glaucoma. The FTMH was successfully closed, with complete recovery of macular layer structures. However, over one year later, the FTMH reopened, slightly dislocated from the position of the embedded EP scar. The reopened FTMH was closed again after the second surgery using the ILM inverted flap technique. This case indicates that macular hole closure with EP might not sufficiently support the tissue repair of FTMH as a new hole can form if tangential traction of the ILM remains.

Postoperative Proliferation Detection in Eyes Treated for Rhegmatogenous Retinal Detachment by WideField OCT Angiography.

Purpose: Proliferative retinal changes may occur postsurgery for rhegmatogenous retinal detachment (RRD), possibly preceding recurrent detachment. This study aims to establish the groundwork for an imaging system capable of discerning changes in retinal vessel tortuosity after RRD repair, analyzing widefield optical coherence tomography angiography (WF-OCTA) images. Methods: Eighty-eight eyes of 86 patients with RRD who underwent surgical procedures and had repeated imaging with clear widefield optical coherence tomography (WF-OCT) and WF-OCTA on different postoperative days were enrolled in this retrospective study. We compared WF-OCTA images over time to identify alterations in retinal vessel tortuosity and observed regional changes in retinal morphology. Results: After image processing, changes in retinal vessel tortuosity were detected in 66 quadrants. These changes, attributed to retinal traction from proliferative membranes, were observed in 56 quadrants, among which retinal thickness remained unchanged in seven sectors (12.5%) according to the WF-OCT map. In nine quadrants, changes in retinal vessel tortuosity were attributed to changes in subretinal fluid, aligning with observable variations in retinal thickness. Conclusions: Observation of vessel tortuosity changes using WF-OCTA can help detect early postoperative proliferative changes in eyes with RRD. Translational Relevance: Because WF-OCTA can detect minute vessel tortuosity changes, it can offer a noninvasive alternative for the detection of early postoperative proliferative changes.

Factors at the initial visit associated with poor visual outcomes in patients with acute retinal necrosis.

BACKGROUND/OBJECTIVE: Acute retinal necrosis (ARN) is a vision-threatening disease caused by herpesvirus infection. This study aimed to investigate the visual prognostic factors that could be determined at the initial visit. SUBJECTS AND METHODS: This retrospective study included 34 patients with ARN. Logistic regression analysis was employed to evaluate the associations between poor final visual outcomes and various factors, including poor initial visual acuity, presence of retinal detachment at the initial visit, posterior extension of necrotizing retinitis, and circumferential extension of necrotizing retinitis. Posterior extension was evaluated with three zonings, from the periphery (zone 3), mid-periphery (zone 2), and macula (zone 1). Circumferential extension was evaluated according to the degree of necrotizing retinitis lesions using ultra-wide fundus imaging. RESULTS: The mean logarithm of the minimum angle of resolution was 0.63 ± 0.68 at the initial visit and 0.83 ± 0.65 at 12 months after the initial visit. Seven patients had a retinal detachment. The distribution of posterior extension at the initial visit was 5 in zone 1, 20 in zone 2, and 9 in zone 3. The average of necrotizing retinitis lesion angle was 249 ± 115°. The logistic regression analysis revealed that participants with wide angles of necrotizing retinitis were associated with final poor vision, with an odds ratio of 1.28 per 30° increase (95%CI: 1.00-1.65, p = 0.03). CONCLUSIONS: Assessment of the widespread circumferential extension of white necrotizing retinal lesions at the initial visit is a crucial risk factor for the visual prognosis in ARN.

Three-month outcomes of treatment with faricimab or aflibercept for neovascular age-related macular degeneration: a propensity score matching study in a Japanese population.

PURPOSE: This study aimed to compare the treatment outcomes of patients with neovascular age-related macular degeneration (nAMD) who initially received faricimab or aflibercept treatment using propensity score matching (PSM) to align patient backgrounds. METHODS: Patients with treatment-naïve nAMD who received either faricimab or aflibercept for three consecutive monthly injections as the loading phase were enrolled in this study. In the 1:1 PSM, sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and AMD subtypes in the pre-treatment state were selected as covariates. We examined the BCVA, CMT, CCT, and remaining fluid at 1-, 2-, and 3-month after the first injection. RESULTS: After PSM, 43 eyes were included in the faricimab and aflibercept group each. Both groups showed significant improvements in BCVA, CMT, and CCT at 1-, 2-, and 3-month after the initial injection compared with baseline. Meanwhile, no significant differences were observed between the two groups at any time point regarding BCVA, CMT, and CCT. At 1-month, 18.6% of patients in the faricimab group and 41.9% in the aflibercept group demonstrated residual subretinal fluid or intraretinal fluid, with a significant difference between the groups (P = 0.03). CONCLUSION: The BCVA improved after three loading injections of both faricimab and aflibercept. Faricimab may provide a favorable early treatment response in reducing subretinal fluid in a Japanese cohort.

The factors associated with retinal pigment epithelium tear development in the early phase after treatment initiation for age-related macular degeneration.

PURPOSE: This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). METHODS: Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3 months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3 months of starting anti-VEGF therapy was examined. RESULTS: This study included 244 eyes (230 patients; mean age 75.0 years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3 months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100 µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07-2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22-7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12-850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). CONCLUSIONS: Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs.

Wide-Field Choroidal Thickness Analysis after Half-Fluence Photodynamic Therapy Combined with Intravitreal Aflibercept Injection in Pachychoroid Neovasculopathy.

Background: Pachychoroid neovasculopathy (PNV) is a pachychoroid-spectrum disease. As blood circulation throughout the choroid may be involved in PNV pathogenesis, analysis using ultra-wide-field (UWF) fundus imaging is crucial. We evaluated choroidal thickness after half-fluence photodynamic therapy (PDT) combined with intravitreal aflibercept injection for PNV using UWF swept-source optical coherence tomography. Methods: Seventeen eyes with PNV that underwent half-fluence PDT with an adjuvant single intravitreal aflibercept injection were analyzed. To compare choroidal thicknesses in the central and peripheral choroids, we set subfields <3, <9, and 9-18 mm from the fovea. The <9 and 9-18 mm subfields were divided into four quadrants. Results: Choroidal thickness in each subfield decreased significantly after half-fluence PDT (p < 0.001); this reduction was more pronounced in the central area. We also investigated the relationship between the dominant side of the deep choroidal veins that harbor choroidal vein efflux from the macula. When choroidal thickness in the supratemporal and infratemporal 9 mm subfields were evaluated, the ratio of choroidal thickness reduction was not significantly different between the dominant and non-dominant sides. The dominant side was not associated with the extent of choroidal thickness reduction in PNV. Conclusions: Half-fluence PDT caused thinning of the entire choroid, especially in the central area, in PNV.

Injectable in situ cross-linking hyaluronan hydrogel for easier removal of posterior vitreous cortex in vitrectomy.

PURPOSE: Removing transparent vitreous tissues, such as a residual vitreous cortex (VC) or proliferative membrane, without damaging the retina is often problematic in vitrectomy. We examined the feasibility of an injectable in situ cross-linking hyaluronan hydrogel (XL-HA) for vitrectomy. STUDY DESIGN: Experiments using ex vivo and in vivo animal models. METHODS: HA-dibenzocyclooctyne and HA-azidoethylamine solutions were mixed to form XL-HA, which then gradually formed a hydrogel. We tested the function of XL-HA in ex vivo porcine eyes. We then examined the performance of XL-HA in in vivo rabbit models of posterior vitreous detachment, posterior VC removal, and proliferative vitreoretinopathy. RESULTS: The ex vivo study showed that XL-HA rapidly embedded triamcinolone acetonide, mimicking VC attached to the retina, and became hard enough to be pinched with tweezers within 3 minutes, allowing us to remove only the triamcinolone acetonide without impairing the internal limiting membrane. In the in vivo rabbit models, XL-HA injection improved posterior vitreous detachment, and the thin and fragile posterior VC or fibrous proliferative membrane was readily peeled off without any damage to the underlying retina as compared with untreated controls. A short-term intraocular biocompatibility test demonstrated that the intraocular pressure remained normal with XL-HA injected into the eye. In addition, transmission electron microscopy showed no obvious abnormalities in the cornea or in the inner and outer retina. CONCLUSION: The results indicate that XL-HA is a potential adjunctive device to help make vitrectomy safe, effective, and successful.

Use of Ranibizumab for evaluating focal laser combination therapy for refractory diabetic macular edema patients: an exploratory study on the RELAND trials.

Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for diabetic macular edema (DME), but is less effective in some patients. We conducted a prospective study to determine whether laser combination therapy with anti-VEGF was more effective than Ranibizumab monotherapy in anti-VEGF-resistant DME patients. There was no significant difference in the improvement of the best-corrected visual acuity (BCVA) between the laser combination therapy and Ranibizumab monotherapy groups (3.2 letters and -7.5 letters, p = 0.165). BCVA did not significantly change between visits 1 and 7 (the laser combination group, 64.3 letters 70.3 letters, respectively, p = 0.537; the Ranibizumab monotherapy group, 72.3 letters and 64.8 letters, respectively, p = 0.554), with no significant improvements in central foveal retinal thickness (the laser combination therapy group, 9.3%: the Ranibizumab monotherapy groups, - 7.3%; p = 0.926). There was no significant difference in the number of Ranibizumab intravitreal therapy (IVT) sessions between the groups (laser combination therapy, 5.2; ranibizumab monotherapy, 6.0; p = 0.237). This study did not show that laser combination therapy was significantly more effective for anti-VEGF-resistant DME than anti-VEGF monotherapy alone. Therefore, for anti-VEGF-resistant DME, alternative therapeutic approaches beyond combined laser therapy may be considered.

Development of in situ crosslinked hyaluronan as an adjunct to vitrectomy surgery.

Ophthalmologists have used hyaluronan (HA) products as adjuncts to ocular surgery since the 1970s. However, HA products are not always functional in surgeries of the posterior eye segment due to their lack of biomechanical strength. In this study, we developed an in situ crosslinked HA (XL-HA) and evaluated its potential as an adjunct to vitrectomy surgery in an in vitro model with a triamcinolone acetonide (TA) layer used as a pseudo residual vitreous cortex (RVC). Within a few minutes at concentrations over 0.9%, XL-HA, generated by the click chemistry of HA-dibenzocyclooctyne and HA-azidoethylamine, formed a hydrogel with the appropriate hardness for tweezers peeling. XL-HA (concentration, 0.76-1.73%) without dispersion successfully entered the TA layer and removed more than 45% of the total TA. Dynamic viscoelasticity helps to explain the rheological behavior of hydrogels, and the assessment results for XL-HA indicated that suitable concentrations were between 0.97% and 1.30%. For example, 1.30% XL-HA hydrogel reached sufficient hardness at 3 min for tweezers peeling, and the TA removal ability exceeded 70%. These results demonstrated that XL-HA was a potential adjunct to successful vitrectomy.

Clinical Characteristics of Eyes with Neovascular Age-Related Macular Degeneration and Retinal Pigment Epithelium Tears.

BACKGROUND: Although anti-vascular endothelial growth factor (anti-VEGF) therapy is the first choice of treatment for eyes with neovascular age-related macular degeneration (AMD), it sometimes results in retinal pigment epithelium (RPE) tears. This study presents the detailed clinical characteristics of RPE tears to help predict their occurrence before anti-VEGF therapy initiation. METHODS: This study retrospectively analyzed neovascular age-related macular degeneration (nAMD) patients who visited the Kyushu University Hospital and started anti-VEGF therapy between April 2013 and June 2020. Using medical records, we collected the clinical data of patients with RPE tears, including age, sex, best-corrected visual acuity (BCVA), number of anti-VEGF drug injections and the type and size of pigment epithelial detachment (PED). RESULTS: RPE tears occurred in 16 (1.50%) eyes of 16 patients in all 1068 nAMD eyes of 987 patients. The mean age of these patients with RPE tear was 81.7 ± 8.7 years. Fifteen eyes had typical AMD and one eye had polypoidal choroidal vasculopathy. The mean number of anti-VEGF drug injections before RPE tears was 5.0 ± 5.1. All patients experienced PED before the RPE tear (hemorrhagic, 4 eyes; serous vascular, 2 eyes; fibrovascular, 10 eyes). The average PED height and area were 615.7 ± 175.3 µm and 21.0 ± 7.2 mm2, respectively. The sub-RPE cleft was observed in 10 eyes. The logMAR BCVA immediately after the RPE tear (0.73 ± 0.40) at 6 months (0.86 ± 0.51) and 12 months (0.84 ± 0.43) after the RPE tear were significantly worse than that before the RPE tear (0.58 ± 0.31; p < 0.05). The BCVA of patients with RPE tears that spread to the fovea was poorer than that of patients without RPE tears. CONCLUSIONS: In patients with nAMD, RPE tears tended to occur in typical AMD eyes with high or large PEDs, and sub-RPE clefts. The visual prognosis depended on whether the RPE tear included the fovea.

Differences in Central and Peripheral Choroidal Thickness among the Subtypes of Age-Related Macular Degeneration in an Asian Population.

Age-related macular degeneration (AMD) causes visual impairment in individuals who are >50 years of age. However, no study has investigated AMD when using ultra-wide-field swept-source optical coherence tomography (UWF SS-OCT). We aimed to evaluate central and peripheral choroidal thicknesses using UWF SS-OCT, and to compare these across the AMD subtypes. We included 75 eyes of patients with typical AMD (tAMD), 56 with polypoidal choroidal vasculopathy (PCV), 29 with pachychoroid neovasculopathy (PNV), and 12 with retinal angiomatous proliferation (RAP). To compare choroidal thicknesses in the central and peripheral choroids, we established subfields of <3 mm, <9 mm, and 9-18 mm from the fovea. PNV patients were significantly younger than those with tAMD (p = 0.01). The choroidal thicknesses of PNV were significantly greater than that of tAMD in all subfields (p < 0.01), and choroidal thickness significantly correlated with age and axial length in all subfields (p < 0.05). Even after adjusting for age and axial length, the choroidal thickness in PNV was significantly greater than that in tAMD (p < 0.05). In addition, the ratio of the posterior <9 mm to a peripheral 9-18 mm choroidal thickness in PNV was significantly greater than that in tAMD (p < 0.01). A thickened choroid in PNV was more pronounced in the posterior choroid than in the periphery.

Characterization and contribution of RPE senescence to Age-related macular degeneration in Tnfrsf10 knock out mice.

Background: Retinal pigment epithelial cells (RPE) play vital role in the pathogenesis of age-related macular degeneration (AMD). Our laboratory has shown that RPE cellular senescence contributed to the pathophysiology of experimental AMD, and SASP members are involved in this process. Recently, we presented confirmatory evidence to earlier GWAS studies that dysregulation of tumor necrosis factor receptor superfamily 10A (TNFRSF10A) dysregulation leads to AMD development and is linked to RPE dysfunction. This study aims to investigate the contribution of RPE senescence to AMD pathophysiology using TNFRSF10A silenced human RPE (hRPE) cells and Tnfrsf10 KO mice. Methods: Sub-confluent primary hRPE cells and TNFRSF10A silenced hRPE were exposed to stress-induced premature senescence with H2O2 (500 µM, 48h), and senescence-associated markers (ßgal, p16, and p21) were analyzed by RT-PCR and WB analysis. The effect of H2O2-induced senescence in non-silenced and silenced hRPE on OXPHOS and glycolysis was determined using Seahorse XF96 analyzer. Male C57BL/6J Tnfrsf10 KO ( Tnfrsf10 -/- ) mice were used to study the regulation of senescence by TNFRSF10A in vivo . Expression of p16 and p21 in control and KO mice of varying ages were determined by RT-PCR, WB, and immunostaining analysis. Results: The senescence-associated p16 and p21 showed a significant ( p < 0.01) upregulation with H2O2 induction at the gene (1.8- and 3-fold) and protein (3.2- and 4-fold) levels in hRPE cells. The protein expression of p16 and p21 was further significantly increased by co-treatment with siRNA ( p < 0.05 vs. H2O2). Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) (pmol/min/total DNA) increased with senescence induction by H2O2 for 48h in control RPE, and knockdown of TNFRSF10A caused a further increase in OCR and ECAR. In addition, co-treatment with PKC activator significantly improved all parameters. Similarly, in vivo studies showed upregulation of p16 and p21 by RT-PCR, WB, and immunostaining analysis in RPE/choroid of Tnfrsf10 KO mice. When subjected to examination across distinct age groups, namely young (1-3 months), middle (6-9 months), and old (12-15 months) mice, a discernible age-related elevation in the expression of p16 and p21 was observed. Conclusions: Our findings suggest that TNRSF10A is a regulator of regulates in RPE senescence. Further work on elucidating pathways of senescence will facilitate the development of new therapeutic targets for AMD.

Animal model of subretinal fibrosis without active choroidal neovascularization.

Subretinal fibrosis can occur during neovascular age-related macular degeneration (nAMD) and consequently provokes progressing deterioration of AMD patient's vision. Intravitreal anti-vascular endothelial growth factor (VEGF) injections decrease choroidal neovascularization (CNV), however, subretinal fibrosis remains principally unaffected. So far, no successful treatment nor established animal model for subretinal fibrosis exists. In order to investigate the impact of anti-fibrotic compounds on solely fibrosis, we refined a time-dependent animal model of subretinal fibrosis without active choroidal neovascularization (CNV). To induce CNV-related fibrosis, wild-type (WT) mice underwent laser photocoagulation of the retina with rupture of Bruch's membrane. The lesions volume was assessed with optical coherence tomography (OCT). CNV (Isolectin B4) and fibrosis (type 1 collagen) were separately quantified with confocal microscopy of choroidal whole-mounts at every time point post laser induction (day 7-49). In addition, OCT, autofluorescence and fluorescence angiography were carried out at designated timepoints (day 7, 14, 21, 28, 35, 42, 49) to monitor CNV and fibrosis transformation over time. From 21 to 49 days post laser lesion leakage in the fluorescence angiography decreased. Correspondingly, Isolectin B4 decreased in lesions of choroidal flat mounts and type 1 collagen increased. Fibrosis markers, namely vimentin, fibronectin, alpha-smooth muscle actin (α-SMA) and type 1 collagen were detected at different timepoints of tissue repair in choroids and retinas post laser. These results prove that the late phase of the CNV-related fibrosis model enables screening of anti-fibrotic compounds to accelerate the therapeutic advancement for the prevention, reduction, or inhibition of subretinal fibrosis.

Reduced Size of Telangiectatic Capillaries After Intravitreal Injection of Anti-Vascular Endothelial Growth Factor Agents in Diabetic Macular Edema.

Purpose: Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents reduces microaneurysms in patients with diabetic macular edema (DME). However, residual anti-VEGF-resistant telangiectatic capillaries (TelCaps) have been reported. In this study, we investigated changes in the size of TelCaps after intravitreal injection of anti-VEGF agents in DME. Patients and Methods: Indocyanine green angiography (IA) and optical coherence tomography were performed before and 3 months after the intravitreal injection of anti-VEGF agents (pro re nata regimen after three monthly loading doses) in 12 eyes of 12 patients (7 males and 5 females, mean age 65.2 ± 8.8 years) with DME. The number and size of TelCaps within a 6-mm diameter macular region of the edema were measured using optical coherence tomography B-scan images overlaid on IA images. Results: There were significant reductions in the number and size of TelCaps between the baseline and 3 months after anti-VEGF agent administration (P < 0.05 and P < 0.0001, respectively). The maximum corrected visual acuity (logMAR visual acuity) and the central macular thickness after anti-VEGF therapy were significantly improved (P < 0.01 and P < 0.02, respectively). The TelCaps remaining after loading three consecutive anti-VEGF agents had a significantly larger mean size at baseline than the TelCaps that resolved after the treatment (P < 0.03). Conclusion: Our study demonstrated that intravitreal injection of anti-VEGF agents could reduce TelCap size in patients with DME. We propose that larger-sized TelCaps detected by IA might be useful predictors of refractory DME, which could thus be principal targets of laser photocoagulation.

VOLUMETRIC THREE-DIMENSIONAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF RETINAL NEOVASCULARIZATION IN PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To evaluate structural and angiographic neovascularization in patients with proliferative diabetic retinopathy using volumetric three-dimensional optical coherence tomography angiography (OCTA). METHODS: This prospective, observational cross-sectional study included 29 eyes of 27 patients with proliferative diabetic retinopathy. The angiogenic structure, feeding vessel (epicenter), flow volume, and flow volume density of the neovasculatures were evaluated using three-dimensional OCTA imaging. The flow area and the flow area density were also measured using en face OCTA imaging. RESULTS: Sites of neovascularization were imaged successfully in 17 of the 29 eyes (58.6%). Three proposed types of neovascularization were identified on the basis of structural features seen on the three-dimensional OCTA images. Neovascularization of the adhesion type (9 of 17, 52.9%) adhered to the retinal vasculature. Those of the traction type (5 of 17, 29.4%) were partially separated from the retinal vascular plexus. Those of the mushroom type (3 of 17, 17.6%) were connected to the retinal vasculature by several epicenters. There was a significant difference between highly leaky (active) and faintly leaky (inactive) neovascularization for flow volume density, but not for flow area, flow volume, or flow area density ( P = 0.01, 0.9, 0.6, and 0.1, respectively). CONCLUSION: Volumetric three-dimensional OCTA revealed three types of neovascularization in proliferative diabetic retinopathy and may be useful for assessing neovascular activity and planning vitrectomies.

Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-Induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages.

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P < 0.01), which was reversed by anti-vascular endothelial growth factor (VEGF) therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P < 0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P < 0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67+ and CD11b+ cells were observed in preretinal tissues of DR patients, while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P < 0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.

Hyperreflective Membrane at the Vitreoretinal Interface in Diabetic Macular Edema: A Finding in Ultra-High-Resolution Optical Coherence Tomography.

Purpose: Detecting subtle vitreoretinal interface (VRI) findings, such as a posterior hyaloid membrane, is difficult with conventional retinal imaging. We compared ultra-high-resolution spectral domain optical coherence tomography (UHR-SD-OCT) with standard-resolution OCT (SD-OCT) for the imaging of VRI abnormalities in diabetic retinopathy (DR). Methods: This prospective cross-sectional study included 113 consecutive patients (91 patients with diabetes and 22 healthy controls). The VRI was evaluated, and the results were compared between the conventional SD-OCT and UHR-SD-OCT images. VRI findings were also investigated before and after internal limiting membrane peeling during vitrectomy for proliferative DR. Results: A total of 159 eyes (87.4%) of 91 patients with diabetes were analyzed. UHR-SD-OCT could detect a hyperreflective layer at the VRI, in which en face OCT showed a membrane-like structure, termed the hyperreflective membrane (HRMe). The preoperative HRMe could not be detected in all patients with proliferative DR who underwent internal limiting membrane peeling during vitrectomy. Although the HRMe did not correlate with the DR stage, eyes with diabetic macular edema (DME) (64.5%) showed a significant HRMe with UHR-SD-OCT more frequently than those without DME (35.8%) (P = 0.005). Conclusions: UHR-SD-OCT can detect the HRMe at the VRI in DR eyes, particularly in eyes with DME. The HRMe may present a thickened posterior hyaloid membrane that contributes to DME development. Translational Relevance: UHR-SD-OCT detects slight changes in the VRI in DR eyes. In the future, it may help to elucidate the mechanism of DME formation.

Characteristics of retinal pigment epithelium elevations preceding exudative age-related macular degeneration in Japanese.

INTRODUCTION: Drusen and pigmentary abnormality are found as the hallmark to predict progression of age-related macular degeneration (AMD). In Asian populations, exudative AMD often appears in the absence of drusen but are rather accompanied by pigmentary abnormality. Recently, shallow irregular retinal-pigment-epithelium (RPE) elevations (SIRE) has been shown as a sign of subclinical non-exudative macular neovascularization. In this study, we aimed to investigate the characteristics of optical coherence tomography (OCT) findings including SIRE before the appearance of exudative AMD. METHODS: We retrospective reviewed 32 cases of exudative AMD that occurred in the fellow eye within the 5-years-observation period. Color fundus photography, OCT, and fluorescein/indocyanine green angiography at the beginning of observation and at the time when exudative AMD appeared were examined to diagnose SIRE and the subtype of exudative AMD. RESULTS: Exudative AMD were found in 19 eyes with large drusen and 13 eyes without large drusen. Mean sub-foveal choroidal thickness without large drusen were significantly thicker than those with large drusen (336 ± 109 and 220 ± 96 µm, respectively; mean± SD). Six eyes with pachychoroid neovasculopathy, 4 eyes with Type 1 macular neovascularization, and 3 eyes with PCV had occurred in the fellow eye without large drusen. Among those, 6 eyes had been accompanied by SIRE with a greatest transverse linear dimension of 1 mm or more at the beginning of observation-period. Besides, small RPE elevations with a longest diameter of less than 1 mm had been observed in other 5 eyes. Three cases of polypoidal choroidal vasculopathy had originated from small RPE elevations. Moreover, pachyvessels, choriocapillaris thinning, or choroidal hyperpermeability were observed with SIRE or small RPE elevation. CONCLUSIONS: There is a non-drusen type of exudative AMD that originates from small RPE elevations as well as SIRE.

A Case of Bullous Central Serous Chorioretinopathy Treated with Surgical Removal of Submacular Fibrin and Subsequent Photodynamic Therapy under Silicone Oil.

Bullous retinal detachment is a rare complication in the chronic phase of central serous chorioretinopathy (CSC). Only a small subset of eyes with chronic CSC develops into the bullous variant of CSC (bCSC). In patients with bCSC, the elevated concentration of fibrin in the subretinal space leads to persistent retinal detachment and eventually, severe vision loss. We experienced a case of unilateral bCSC with a massive accumulation of subretinal fibrin. Multiple leakage points and dilated choroidal veins were also observed. The patient underwent surgical removal of subretinal fibrin and silicone oil injection followed by photodynamic therapy (PDT). After this treatment, the retina was successfully reattached, and the affected eye was free from recurrent exudative changes for more than 18 months. Massive subretinal fibrin could be surgically removed to prevent the formation of subretinal fibrosis and retinal fold, and PDT under silicone oil can control the underlying exudative changes in bCSC.

Postoperative follow-up of submacular hemorrhage displacement treated with vitrectomy and subretinal injection of tissue plasminogen activator: ultrawide-field fundus autofluorescence imaging in gas-filled eyes.

PURPOSE: To investigate the utility of Optos ultrawide-field fundus autofluorescence (UWF-FAF) imaging for postoperative follow-up of gas-filled eyes after vitrectomy with subretinal tissue-plasminogen activator (t-PA) injection for subretinal hemorrhage (SRH) displacement. STUDY DESIGN: Retrospective consecutive case series. METHODS: This study included 24 eyes with SRH. Vitrectomy with subretinal t-PA injection was performed, followed by postoperative prone positioning. FAF images acquired using Optos California were examined and the SRH occupancy in the macula was calculated. The main outcome measures were displacement rate and direction of SRH for 3 days postoperatively, and postoperative best-corrected visual acuity (BCVA). RESULTS: The postoperative BCVA ranged from improvement (23 eyes; 95.8%) to no change (one eye; 4.2%). Analysis was done using postoperative Optos FAF images for 20 eyes (83.3%). Postoperative SRH occupancy was significantly reduced, by 27.4%, compared with the preoperative occupancy (P = 0.03). A statistically significant reduction was found between the preoperative and postoperative day (POD)1 (P = 0.04), but not between POD1 and POD2 (P = 0.7), or between POD2 and POD3 (P = 1.0). CONCLUSION: UWF-FAF imaging is useful for postoperative follow-up of gas-filled eyes after vitrectomy with subretinal t-PA injection for SRH displacement.