Characterization and validation of a chronic retinal neovascularization rabbit model by evaluating the efficacy of anti-angiogenic and anti-inflammatory drugs

AIM: To establish a rabbit model with chronic condition of retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA), a retinal glial (Müller) cell toxin, extensive characterization of DL-AAA induced angiographic features and the suitability of the model to evaluate anti-angiogenic and anti-inflammatory therapies for ocular vascular diseases. METHODS: DL-AAA (80 mmol/L) was administered IVT into both eyes of Dutch Belted rabbit. Post DL-AAA delivery, clinical ophthalmic examinations were performed weekly following modified McDonald-Shadduck Scoring System. Color fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT) procedures were performed every 2 or 4wk until stable retinal vascular leakage was observed. Once stable retinal leakage (12wk post DL-AAA administration) was established, anti-vascular endothelial growth factor (VEGF) (bevacizumab, ranibizumab and aflibercept) and anti-inflammatory (triamcinolone, TAA) drugs were tested for their efficacy after IVT administration. Fluorescein angiograms were scored before and after treatment following a novel grading system, developed for the DL-AAA rabbit model. RESULTS: Post DL-AAA administration, eyes were presented with moderate to severe retinal/choroidal inflammation which was accompanied by intense vitreous flare and presence of inflammatory cells in the vitreous humor. Retinal hemorrhage was restricted to the tips of neo-retinal vessels. FA revealed maximum retinal vascular leakage at 2wk after DL-AAA injection and then persisted as evidenced by stable mean FA scores in weeks 8 and 12. Retinal vascular angiographic and tomographic features were stable and consistent up to 36mo among two different staggers induced for RNV at two different occasions. Day 7, mean FA scores showed that 1 µg/eye of bevacizumab, ranibizumab, aflibercept and 2 µg/eye of TAA suppress 65%, 90%, 100% and 50% retinal vascular leakage, respectively. Day 30, bevacizumab and TAA continued to show 66% and 44% suppression while ranibizumab effect was becoming less effective (68%). In contrast, aflibercept was still able to fully (100%) suppress vascular leakage on day 30. On day 60, bevacizumab, ranibizumab and TAA showed suppression of 7%, 12%, and 9% retinal vascular leakage, respectively, however, aflibercept continued to be more effective showing 50% suppression of vascular leakage. CONCLUSION: The DL-AAA rabbit model mimics RNV angiographic features like RNV and chronic retinal leakage. Based on these features the DL-AAA rabbit model provides an invaluable tool that could be used to test the therapeutic efficacy and duration of action of novel anti-angiogenic formulations, alone or in combination with anti-inflammatory compounds.

Pigmentary abnormality without significant drusen as a risk factor for late age-related macular degeneration

We investigated the incidence and risk factors of late age-related macular degeneration (AMD) in the fellow eye (FE) without significant drusen of patients with unilateral exudative macular neovascularization (MNV). In this retrospective study, 241 eligible patients who were followed-up for more than 3 years were enrolled. We analyzed the incidence and hazard ratios (HRs) of late AMD in the FE according to demographic and ophthalmologic variables. Hypopigmentation on color fundus photography (CFP) corresponds to shallow irregular RPE elevation (SIRE), so-called “double-layer sign” and/or “attenuation or disruption of RPE and/or ellipsoid zone” on OCT. The 5-year incidence of FE exudative MNV conversion was 8.6%. The 5-year incidence of FE exudative MNV of large hypopigmentation (≥ 0.5 disc area; DA) and small hypopigmentation (< 0.5 DA) on CFP, and SIRE (≥ 1000 µm) and small RPE elevation (< 1000 µm) on OCT were 36.2%, 14.2%, 55.0%, and 15.6%, respectively. The multivariate Cox proportional hazard model revealed that large hypopigmentation, small hypopigmentation, SIRE, and small RPE elevation showed HRs of 23.230, 8.037, 132.589, and 41.823 for FE exudative MNV occurrence, respectively. Hypopigmentation on CFP and SIRE on OCT could represent the same lesion. Even small hypopigmentation and small RPE elevation were significant risk factors for progression to exudative MNV.

Feasibility and clinical utility of handheld fundus cameras for retinal imaging

Background/objectives Handheld fundus cameras are portable and cheaper alternatives to table-top counterparts. To date there have been no studies comparing feasibility and clinical utility of handheld fundus cameras to table-top devices. We compare the feasibility and clinical utility of four handheld fundus cameras (Remidio NMFOP, Volk Pictor Plus, Volk iNview, oDocs visoScope) to a table-top camera (Zeiss VisucamNM/FA). Subjects/methods Healthy participants (n = 10, mean age ± SD = 21.0 ± 0.9 years) underwent fundus photography with five fundus cameras to assess success/failure rates of image acquisition. Participants with optic disc abnormalities (n = 8, mean age ± SD = 26.8 ± 15.9) and macular abnormalities (n = 10, mean age ± SD = 71.6 ± 15.4) underwent imaging with the top three scoring fundus cameras. Images were randomised and subsequently validated by ophthalmologists masked to the diagnoses and devices used. Results Image acquisition success rates (100%) were achieved in non-mydriatic and mydriatic settings for Zeiss, Remidio and Pictor, compared with lower success rates for iNview and oDocs. Image quality and gradeability were significantly higher for Zeiss, Remidio and Pictor (p < 0.0001) compared to iNview and oDocs. For cup:disc ratio estimates, similar levels of bias were seen for Zeiss (−0.09 ± SD:0.15), Remidio (−0.07 ± SD:0.14) and Pictor (−0.05 ± SD:0.16). Diagnostic sensitivities were highest for Zeiss (84.9%; 95% CI, 78.2–91.5%) followed by Pictor (78.1%; 95% CI, 66.6–89.5%) and Remidio (77.5%; 95% CI, 65.9–89.0%). Conclusions Remidio and Pictor achieve comparable results to the Zeiss table-top camera. Both devices achieved similar scores in feasibility, image quality, image gradeability and diagnostic sensitivity. This suggests that these devices potentially offer a more cost-effective alternative in certain clinical scenarios.

Three-dimensional locations of ruptured retinal arterial macroaneurysms and their associations with the visual prognosis

The aim of this retrospective, observational study was to examine the intraretinal locations of ruptured retinal arterial macroaneurysms (RMAs) and investigate the associations with the visual prognosis. Fifty patients (50 eyes) with untreated RMA rupture who visited the Department of Ophthalmology at Kyoto University Hospital (April 2014–July 2019) were included. The intraretinal position of the ruptured RMAs relative to the affected retinal artery was examined using optical coherence tomography (OCT) and color fundus photography (CFP). The relative RMA positions were anterior to (anterior type, 44%), at the same level as (lateral type, 20%), or posterior to (posterior type, 34%) the affected artery. At the initial visit, the posterior type showed greater subretinal hemorrhage thickness than did the lateral and anterior types (P = 0.016 and 0.006, respectively), and poorer visual acuity (VA) than did the anterior type (P = 0.005). At the final visit, the length of the foveal ellipsoid zone band defect was longer (P = 0.005) and VA was poorer (P < 0.001) for the posterior type than for the anterior type. The intraretinal positions of ruptured RMAs vary, affect the thickness of foveal subretinal hemorrhage and predict future damage to the foveal photoreceptors. The visual prognosis may be poor for posteriorly ruptured RMAs.

Baseline predictors for subretinal fibrosis in neovascular age-related macular degeneration

To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk.

An integrated analysis of clinical and morphometric indications of atrophic forms of age-related macular degeneration

The atrophic form of late age-related macular degeneration (AMD) is a common cause of severe vision loss. Recently, a new classification system has been proposed, which identifies two types of atrophy in the late stage of AMD that require a more detailed study: (1) drusenassociated geographic atrophy (GA), which is the final stage of progression of dry AMD, and (2) macular atrophy (MA), which occurs in wet AMD, including the period of AMD treatment with angiogenesis inhibitors. Purpose: an integrated analysis of clinical and morphometric signs of atrophic AMD forms. Material and methods. 48 people (61eyes) aged 48–84 with GA (group 1) and MA (group 2) and a control group, recruited from age-matching 25 healthy volunteers (35 eyes), underwent standard ophthalmological examinations, fundus autofluorescence (FAF) with lesion area measurement, fundus photography, optical coherence tomography (OCT) in the standard mode and Enhanced Depth Imagine Mode, Multicolor, and OCT angiography. Results. The comparative analysis of two atrophic AMD forms showed that in GA eyes, foci of atrophy capturing the fovea were significantly more common, while, contrariwise in MA eyes atrophic foci not capturing the fovea were more frequent (p < 0.05). Photoreceptor tubulation was diagnosed mainly in eyes with GA (p < 0.05). The morphometric analysis showed a significant decrease in the subfoveal thickness of the choroid in the groups with GA and MA as compared to the control (p < 0.05), whilst no significant differences between two groups were noted. The assessment of the frequency of occurrence of types of fundus AF patterns in groups 1 and 2 followed by a comparative analysis, showed the presence of all types of patterns in GA patients, including the heterogeneous and the bordering pattern (p < 0.05). In the MA group, diffuse and focal types of patterns were revealed, while the frequency of the diffuse pattern turned out to be significantly more frequent (p < 0.05). Conclusion. The integrated analysis revealed the main semiological signs and morphometric parameters, their features and prevalence in GA and MA, which may have diagnostic and prognostic importance for the management and treatment of patients with AMD.

Time-related OCT-A changes in preclinical retinopathy and their association with systemic factors

Background. Optical coherence tomography angiography (OCT-A) is a promising tool for the detection of microvascular impairment at the preclinical stage of diabetic retinopathy (DR). Evaluation of dynamic OCT-A changes and their association with systemic factors can help to reveal early biomarkers of DR progression.Aim: to evaluate time-related OCT-A changes and their association with systemic factors in type 1 diabetes mellitus (DM1) patients with no apparent DRMaterials and methods. 38 DM1 patients with no apparent DR and 39 healthy volunteers were included in the study. All participants underwent 7-fi eld fundus photography, OCT and OCT-A. We analyzed OCT-A parameters (foveal avascular zone (FAZ) area (mm2), acircularity index (AI), vessel density (VD), skeletonized density (SD)) as well as the results of blood and urea tests.Results. After one year of observation, AI was significantly higher (р = 0.005) and VD0–300 was signifi cantly lower in superfi cial vascular plexus (SVP, p < 0.0001) and deep capillary plexus (DCP, р = 0.032) in DM1 patients. We have also registered a positive correlation between AI and triglycerides (TG) level (r = 0.627, p = 0.007) as well as a negative correlation between ketones and VD (SVP VD0–300: r = –0.695, p = 0.030; intermediate capillary plexus (ICP, VD0–300: r = –0.551, p = 0.041; DCP, VD0–300: r = –0.704, p = 0.003; SVP, VD300–600: r = –0.853, p = 0.001).Conclusions. After one year of observation, we have registered an increase in AI level and a decline in VD in SVP and DCP which can be the earliest signs of DR progression. A signifi cant correlation between these parameters and systemic factors indicates their role as potential DR biomarkers.

Subthreshold Laser Treatment for Serous Retinal Detachment Associated with Tilted Disc Syndrome

Persistent serous retinal detachment (SRD) is a common complication of tilted disc syndrome (TDS). The purpose of this study is to evaluate the efficacy of subthreshold laser photocoagulation for SRD associated with TDS. This retrospective, single-center study included 5 eyes of 5 patients with TDS-associated SRD treated by subthreshold laser treatment. SRD was completely absorbed in 4 eyes within 4 months after initial treatment. However, it recurred in 2 eyes; one required additional laser treatment and one showed spontaneous resolution. Eventually, all 4 eyes showed complete SRD resorption. The mean visual acuities at enrollment and 1 and 3 months showed no significant differences. The mean central macular thickness showed a significant decrease at 3 months. Two eyes showed changes in fundus autofluorescence findings at the laser ablation site. However, there were no instances of laser scotoma and no laser-induced retinal scarring on color fundus photography performed at the end of treatment. In conclusion, subthreshold laser photocoagulation is an effective treatment for SRD associated with TDS. Thus, the clinical indications of subthreshold laser photocoagulation may be extended to SRD in patients with TDS.

Retinal Progression Biomarkers of Early and Intermediate Age-Related Macular Degeneration

Early and intermediate AMD patients represent a heterogeneous population with an important but variable risk of progression to more advanced stages of the disease. The five-year progression from early and intermediate AMD to late disease is known to range from 0.4% to 53%. This wide variation explains the particular interest in searching predictive AMD biomarkers. Clinical parameters such as drusen size, presence of pigmentary abnormalities, and fellow eye status were, traditionally, the more important predictive elements. Multimodal retinal assessment (Color Fundus Photography, Optical Coherence Tomography, Optical Coherence Angiography and Fundus Autofluorescence) is providing new and accurate image biomarkers, useful in research and in daily practice. If individual progression risk could be anticipated, then management plans should be adapted accordingly, considering follow-up intervals and therapeutic interventions. Here, we reviewed the most important image progression biomarkers of early and intermediate AMD with relevant interest in clinical practice.

Outcomes of a Foldable Capsular Vitreous Body Implantation: A Retrospective Study

Background. The vitreous body is an important part of the ocular body fluid. A foldable capsular vitreous body (FCVB) is designed to treat chronic adverse complications in severe ocular trauma and silicone oil-dependent eyes. This study is aimed at investigating a method for implanting an FCVB, its postoperative efficacy, and clinical value. Methods. A retrospective analysis was performed on data from 18 patients who underwent vitrectomy and FCVB implantation for severe ocular trauma and silicone oil-dependent eyes between March 2019 and May 2020. All treated eyes underwent clinical examinations involving the best-corrected visual acuity, intraocular pressure, FCVB position, anterior segment photography, and wide-angle fundus photography regularly after surgery. Results. Eighteen eyes from 18 patients were enrolled in this study. A total of 2.00–4.20 ( 3.46 ± 0.78 ) ml of silicone oil were injected into the FCVB during surgery. The patients were followed up at 1, 2, and 4 weeks and 3, 6, and 12 months after surgery. Twelve months after surgery, visual acuity improved in 7 (38.89%) eyes. In contrast, 10 (55.56%) eyes showed no obvious improvement, and 1 (5.56%) eye had decreased vision. Intraocular pressure at 12 months was 10.13 ± 3.52 mmHg, which was comparable to that before the surgery ( t = 0.38 , P = 0.71 ). The anterior chamber depth examined by slit lamp was 2.00–3.00 cornea thickness (CT) in 7 eyes, 1.00–2.00 CT in 2 eyes, and <1.00 CT in one eye. The anterior chamber disappeared in eight eyes. There were eight eyes with clear cornea, four eyes with localized opacity, and two eyes with obvious gray-white opacity. There was no case of severe FCVB deflection, rupture, or exposure during the observation period. Conclusion. FCVB implantation is an effective and safe treatment for eyes with severe ocular trauma and silicone oil-dependent eyes. It may support retinal reattachment, slow down eyeball atrophy, reduce the risk of chronic adverse complications such as corneal endothelial decompensation, and maintain intraocular pressure and preoperative visual function.