Retinal Pigment Epithelium Atrophy Research Articles

Differentiating drusen and drusenoid deposits subtypes on multimodal imaging and risk of advanced age-related macular degeneration

Drusen are extracellular material considered a precursor lesion to advanced age-related macular degeneration (AMD), located either on the retinal pigment epithelium (RPE) or the sub-RPE; they contain various proteins associated with inflammation and lipids. Previous studies suggest that the lifecycle of drusen varies depending on drusen type and size. In general, conventional drusen grow and aggregate/coalesce in the first stage, and in the second stage, they regress with or without showing RPE atrophy. The risk of advanced AMD also varies depending on the drusen and drusenoid deposit types' along with their size and RPE abnormalities. In eyes with macular neovascularization (MNV), specific drusen/drusenoid deposits are closely associated with the MNV subtype. Recently, pachychoroid-associated drusen (pachydrusen) were proposed and clinical findings regarding this entity have been accumulating, as more attention is focused on drusen as well as pachychoroid diseases. With the advance in imaging modalities, various modalities can show specific characteristics depending on drusen types. To assess the risk of advanced AMD, it is essential for physicians to have accurate clinical knowledge about each druse/drusenoid lesion and correctly evaluate its imaging characteristics using multimodal imaging. This review summarizes the latest clinical knowledge about each druse/drusenoid lesions and documents their imaging characteristics on multimodal imaging, allowing clinicians to better manage patients and stratify the risk of developing advanced AMD. The most representative cases are illustrated, which can be helpful in the differential diagnosis of drusen and drusenoid deposits.

Experience of use of the extended complex of ophthalmononeurostimulation in patients with non-exudative atrophic (geographic) form of age-of-aged macular degeneration

BACKGROUND: Non-exudative atrophic (geographic) macular degeneration of the retina is one of the causes of irreversible loss of central vision in the elderly. Its frequency of occurrence increases with age.
 AIM: to evaluate the effectiveness of the extended complex of ophthalmoneurostimulation in patients with non-exudative atrophic (geographical) form of age-related macular degeneration.
 MATERIAL AND METHODS: The study included 49 people (98 eyes) with geographic retinal atrophy, whose average age was 741.7 years, who were divided into 2 groups: group 1 ― 24 patients (48 eyes) aged 71.01.8 years, who underwent an extended complex of ophthalmoneurostimulation, including a course of endonasal electrophoresis of vitamin B12 (for a course of 10 daily procedures), transocular infrared stimulation (for a course of 10 daily procedures), oxygen therapy with Heliox-21 breathing mixture (for a course of 10 daily procedures), and acupuncture (for a course of 10 daily procedures), and group 2 ― 25 patients (50 eyes) aged 751.1 years, who underwent a course of conservative treatment with vitamins according to existing ophthalmological standards, which served as a background in group 1. Visual acuity was assessed (visual acuity), indicators of optical coherence tomography and optical coherence tomography with angiography function of the retina, local photosensitivity, autofluorescence of the retina and bioelectric potential in pattern-electroretinography. Studies were performed before therapy, after 2 weeks, 3 months, 6 months, and 12 months, after a course of treatment.
 RESULTS: Visual acuity and anatomical parameters of the retina in high resolution (thickness of the central zone and the thickness of the choroid) did not change during the entire observation period. Analysis of light sensitivity showed a significant normalization of the average threshold of retinal photosensitivity when prescribing an extended complex of ophthalmoneurostimulation.
 CONCLUSION: Conducted extended course of physiotherapy significantly reduced the functional depression of the central visual field, coordinating with foci of retinal pigment epithelium atrophy. Most likely, this positive effect was achieved due to the activation of the level of the ganglionic and bipolar layers of the retina.

Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.

Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient-specific RPE cells with the Complement Factor H Y402H high-risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi-omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury-induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.

Geographic atrophy in AMD ‐ prognostic factors based on long‐term follow‐up

AbstractPurpose: So far, the natural course of geographic atrophy (GA) progression in age‐related macular degeneration (AMD) has primarily been investigated by colour fundus photography (CF) and fundus autofluorescence (FAF) imaging. The aim of this long‐term retrospective, observational clinical study was to show the enlargement rate (ER) of GA, defined as complete retinal pigment epithelium and outer retinal atrophy (cRORA) and to find predictors of progression.Methods: All patients available in the database of Vista Augenklinik Binningen, Switzerland, with follow‐up of at least 24 months and existing GA in at least one eye, regardless of neovascular AMD (nAMD) being present initially or in the course of disease, were included. SD‐OCT and FAF evaluations were performed according to a standardized protocol. The cRORA area ER (mm2/year), the cRORA square root area ER (mm/yr), the FAF GA area and the condition of the outer retina (inner−/outer segment (IS/OS) and external limiting membrane (ELM) disruption scores) were determined.Results: 204 eyes of 129 patients (64% females) were included. Mean follow‐up time was 4.2 ± 2.2 (range 2–10) years. 109 of 204 (53.4%) eyes were classified as wet AMD (neovascular aspect being present initially or in the course of disease), 95 of 204 (46.6%) eyes were classified as exclusively dry AMD. The primary lesion was unifocal in 146 (72%) eyes and multifocal in 58 (28%) eyes. A strong correlation was observed between the area of cRORA (SD‐OCT) and the FAF GA area (r = 0.924; p < 0.001). Mean ER was 1.44 ± 1.2 mm2/year and mean square root ER 0.29 ± 0.19 mm/year. There was no significant difference in mean ER between eyes without (dry AMD) and with intravitreal anti‐VEGF injections (nAMD) (0.30 ± 0.19 mm/year vs. 0.28 ± 0.20 mm/year; p = 0.466). Eyes with a multifocal atrophy pattern at baseline (n = 58) had a significantly higher mean ER compared to eyes with a unifocal pattern (0.34 ± 0.19 mm/year vs. 0.27 ± 1.19 mm/year; p = 0.008). There were moderate significant correlations between ELM and IS/OS disruption scores and visual acuity at baseline, 5 and 7 years (all r values ca. −0.5; p < 0.001).Conclusions: SD‐OCT evaluated cRORA area might serve as a GA parameter comparable to traditional FAF measurement. The dispersion pattern might be a predictor of ER, whereas anti‐VEGF treatment seems not to be associated with ER.

Optical coherence tomography angiography in Bietti crystalline dystrophy.

Bietti crystalline dystrophy (BCD) is a rare autosomal recessive retinal dystrophy caused by pathogenic variants of CYP4V2 gene and characterized by shiny yellow deposits in the retina and progressive atrophy of the retinal pigment epithelium (RPE) and choriocapillaris. The main aim of the present study is to describe the optical coherence tomography angiography (OCTA) characteristics of a patient affected by BCD. A 59-years-old female with genetically confirmed BCD underwent an ophthalmological examination complete of OCTA performed in the atrophic retina, the junctional zone and the apparently normal retina. The area of choriocapillaris (CC) atrophy was compared to the area of RPE atrophy on fundus autofluorescence (FAF) imaging. A severe vessel density (VD) deficit at the level of superficial and deep capillary plexa as well as CC was registered in atrophic areas, which resulted deeper with respect to the junctional area, whereas the apparently preserved retina revealed VD values similar to that of control eyes. The area of RPE atrophy on FAF was larger (55.90 mm2 in right eye and 48.76 mm2 in left eye) than the area of CC atrophy on OCTA imaging (51.86 mm2 and 42.44 mm2 respectively in right and left eye). Our findings suggest that VD impairment of retinal plexa and CC follows the degeneration of RPE as demonstrated by the greater size of the area of RPE atrophy compared to CC atrophy. Further investigations based on OCTA imaging are necessary to enhance our knowledge of this rare disease.

The possible pathogenesis of macular caldera in patients with North Carolina macular dystrophy

BackgroundThis study provides a detailed description of a Chinese family with North Carolina macular dystrophy (NCMD) and explores its possible pathogenesis.MethodsFive individuals from a three-generation family underwent general ophthalmic examination, multi-imaging examinations and visual electrophysiology examinations when possible. Genetic characterization was carried out by target region sequencing and high-throughput sequencing in affected patients.ResultsDespite severe fundus changes, patients had relatively good visual acuity. Genetic analysis showed that affected patients had PRDM13 gene duplication and heterozygous mutations of the ABCA4 gene. Optical coherence tomography (OCT) showed an abnormal retinal pigment epithelium (RPE) layer in patients with grade 2 lesions, while the neurosensory retina was relatively normal. In grade 3 patients, RPE and choroid atrophy were greater than that of the neurosensory retina, showing concentric atrophy.ConclusionsRPE and choroidal atrophy were found to play an important role in the development of macular caldera.

Impact of intravitreal ranibizumab, aflibercept and bevacizumab on retinal ganglion cell and nerve fibre layer thickness in Neovascular age-related macular degeneration.

To compare the effects of monotherapy with intravitreal ranibizumab, aflibercept and bevacizumab on retinal ganglion cell layer (RGCL) and retinal nerve fibre layer (RNFL) in patients with naïve neovascular age-related macular degeneration (nAMD). This is a retrospective cohort study with three-groups comparison. 83 patients and 97 eyes on continuous monotherapy with an intravitreal anti-vascular endothelial growth factor (anti-VEGF) were followed for 24 months and divided into three groups according to anti-VEGF (aflibercept: 25 eyes, ranibizumab: 34 eyes, bevacizumab: 38 eyes). Main outcome measures included: RGCL and RNFL thickness, best corrected visual acuity (BCVA), central macular thickness (CMT), macular volume (MV) and the presence of intraretinal fluids (IRF), subretinal fluids (SRF) and retinal pigment epithelial atrophy (RPE-atrophy). All outcome measures were recorded at the time of the first injection, 1 and 2 years after treatment and compared longitudinally and between groups. The mean age was 79 ± 7 years. The RGCL thickness, MV, CMT and the presence of IRF and SRF decreased significantly within all three medication groups (p < 0.05 for all) with no significant difference between groups over the 2-year follow-up period (p > 0.10 for all). The decrease in RNFL thickness was not significant within or between the groups after a 2-year follow-up (p > 0.055 for all). RPE-atrophy increased significantly after 2 years in all three groups (p < 0.028 for all) with no significant difference between groups at all three time points (p > 0.307 for all). BCVA was comparable between the three groups over the 2-year follow-up period (p > 0.22 for all). Monotherapy with intravitreal aflibercept, bevacizumab and ranibizumab was associated with comparable significant decreases in RGCL thickness, CMT, MV, IRF and SRF in naïve nAMD patients during the first 2 years of treatment. Furthermore, no significant differences either in BCVA or RNFL thickness were observed between the three intravitreal anti-VEFGs during the first 2 years of treatment.

Presumed Bietti crystalline dystrophy with optic nerve head drusen: a case report

BackgroundBietti crystalline dystrophy is primarily a retinal dystrophy caused by a CYP4V2 mutation and typically presents with crystalline retinal deposits in the posterior fundus.Case presentationWe present the case of an otherwise healthy 39-year-old Iranian woman with no family history of ocular disease who suffered with progressive vision loss that had started 2 years prior to presentation. Ocular examination revealed blurry optic nerve head margin and diffuse retinal crystalline deposit in both eyes. Spectral domain optical coherence tomography images showed retinal crystals, located mostly in outer retinal layers, with some areas of outer retinal tubulation and attenuation of outer retinal layers. Crystalline deposits were better visualized on near-infrared images as hyperreflective spots. Fundus autofluorescence images showed hyperautofluorescence areas on optic nerve head consistent with optic nerve head drusen and large hypoautofluorescence areas in posterior retina consistent with retinal pigment epithelium atrophy. Cystinosis was ruled out by blood testing.ConclusionBietti crystalline dystrophy may be associated with optic nerve head drusen.

Cell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells.

Stargardt retinopathy is an inherited form of macular degeneration caused by mutations in gene ABCA4 and characterized by the accumulation of lipid-rich deposits in the retinal pigment epithelium (RPE), RPE atrophy, and photoreceptor cell death. Inadequate mechanistic insights into pathophysiological changes occurring in Stargardt RPE have hindered disease treatments. Here, we show that ABCA4 knockout and induced pluripotent stem cell-derived RPE (STGD1-iRPE) from patients with Stargardt differentiate normally but display intracellular lipid and ceramide deposits reminiscent of the disease phenotype. STGD1-iRPE also shows defective photoreceptor outer segment (POS) processing and reduced cathepsin B activity-indicating higher lysosomal pH. Lipid deposits in STGD1-iRPE are lowered by increasing the activity of ABCA1, a lipid transporter, and ABCA4 ortholog. Our work suggests that ABCA4 is involved in POS and lipid handling in RPE cells and provides guidance for ongoing gene therapy approaches to target both RPE and photoreceptor cells for an effective treatment.

Scanning Laser Ophthalmoscopy Retromode Imaging Compared to Fundus Autofluorescence in Detecting Outer Retinal Features in Central Serous Chorioretinopathy.

Central serous chorioretinopathy (CSCR) is a retinal disease characterized by a heterogeneous clinical phenotype, depending on the influence of different factors in its pathogenesis, including the presence of subretinal fluid (SRF), trophism of the retinal pigmented epithelium (RPE) and choroidal hyper-permeability. Our study has the purpose of assessing the ability of scanning laser ophthalmoscopy (SLO) retromode imaging, compared to fundus autofluorescence (FAF), to identify outer retinal features in a cohort of patients with a diagnosis of CSCR. A total of 27 eyes of 21 patients were enrolled in our study. All patients underwent full ophthalmological examination, including fundus retinography, fundus fluorescein angiography, optical coherence tomography (OCT), FAF and SLO retromode imaging. For each patient, the following features were evaluated: SRF, the presence of pigmented epithelium detachment (PED), RPE dystrophy, and RPE atrophy. RPE dystrophy was further characterized according to the appearance in FAF of iso-, hyper- and hypo-autofluorescent dystrophy. The ability to identify each feature was evaluated for FAF and SLO retromode alone, compared to a multimodal imaging approach. FAF identified SRF in 11/14 eyes (78%), PED in 14/19 (74%), RPE dystrophy with iso-autofluorescence in 0/13 (0%), hyper-autofluorescence in 18/19 (95%), hypo-autofluorescence in 20/20 (100%), and RPE atrophy in 7/7 (100%). SLO retromode imaging identified SRF in 13/14 eyes (93%), PED in 15/19 (79%), RPE dystrophy with iso-autofluorescence in 13/13 (100%), hyper-autofluorescence in 13/19 (68%), hypo-autofluorescent in 18/20 (90%), and RPE atrophy in 4/7 (57%). SLO retromode imaging is able to detect retinal and RPE changes in CSCR patients with a higher sensitivity than FAF, while it is not able to identify the depth of lesions or supply qualitative information about RPE cells' health status, meaning that it is less specific. SLO retromode imaging may have a promising role in the assessment of patients with CSCR, but always combined with other imaging modalities such as OCT and FAF.

A Bietti Crystalline Dystrophy Mouse Model Shows Increased Sensitivity to Light-Induced Injury.

Bietti crystalline corneo-retinal dystrophy (BCD) is an autosomal recessive inherited retinal dystrophy characterized by multiple shimmering yellow-white deposits in the posterior pole of the retina in association with atrophy of the retinal pigment epithelium (RPE), pigment clumps, and choroidal atrophy and sclerosis. Blindness and severe visual damage are common in late-stage BCD patients. We generated a Cyp4v3 knockout mouse model to investigate the pathogenesis of BCD. This model exhibits decreased RPE numbers and signs of inflammation response in the retina. Rod photoreceptors were vulnerable to light-induced injury, showing increased deposits through fundoscopy, a decrease in thickness and a loss of cells in the ONL, and the degeneration of rod photoreceptors. These results suggest that an inflammatory response might be an integral part of the pathophysiology of BCD, suggesting that it might be reasonable for BCD patients to avoid strong light, and the results provide a useful model for evaluating the effects of therapeutic approaches.

Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332). Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12. Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] + 0.29 z-score units [0.16, 0.42], P < 0.001). The same was evident for eyes treated with pegcetacoplan every other month (+ 0.26 z-score units [0.13, 0.4], P < 0.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12. These findings suggest that pegcetacoplan could slow GA progression and lead to reduced thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration.

Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study

PurposeTo report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland.Study...

Long-Term Outcomes of Nonadherence to Anti-VEGF Therapy in Advanced Neovascular Age-Related Macular Degeneration

Purpose: To study long-term outcomes in neovascular age-related macular degeneration (nAMD) patients with low visual acuity and nonadherence to a treatment regimen of anti-vascular endothelial growth factor (VEGF) therapy.Patients and methods. In this study we included nAMD patients with best corrected visual acuity lower than 0.1 decimal equivalent, nonadherent to anti-VEGF therapy (13 eyes, group I), treatment-naïve (15 eyes, group II) or nonadherence to anti-VEGF therapy followed by termination of anti-VEGF treatment (18 eyes, group III). All participants received comprehensive ophthalmic examination and optical coherence tomography baseline and at the end of the follow-up period.Results: In group I, 7.6 ± 4.3 intravitreal anti-VEGF injections were performed over a mean period of 38.9 ± 27.5 months. In group II, a mean follow-up was 31.7 ± 28.6 months. In group III 4.8 ± 2.2 intravitreal anti-VEGF injections were performed over a mean period of 26.9 ± 26.4 months followed by treatment discontinuation for a mean period of 24.6 ± 18.6 months. None of study groups showed statistically significant changes in BCVA or an increase of central retinal thickness (p &gt; 0.05). At baseline all study eyes frequently demonstrated severe morphological changes in the macula including atrophy of retinal pigment epithelium (RPE), subretinal fibrosis, RPE tear, or giant intraretinal cysts.Conclusion: In nAMD patients with low BCVA and severe anatomical changes in the macula nonadherence to a treatment regimen of anti-VEGF therapy results in non-superior long-term outcomes compared to natural course of the disease.

OCT Risk Factors for Development of Atrophy in Eyes with Intermediate Age-Related Macular Degeneration

To determine the frequency of multiple OCT biomarkers of intermediate age-related macular degeneration (iAMD) and their relationship with the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) after 2 years. Retrospective cohort study. This retrospective analysis included 330 eyes of 330 consecutive patients with iAMD in ≥ 1 eye who had 24 months of follow-up data. Spectralis OCT volume scans (49 B-scans over 6× 6 mm, automatic real time = 6, fovea-centered) at baseline were evaluated for the previously described iAMD biomarkers, including a high-central drusen volume (DV; ≥ 0.03 mm3), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits (SDDs), hypo-reflective drusen cores (hDCs), and a thin or thick (multilayered) double-layer sign (DLS). The age-related macular degeneration (AMD) status in the fellow eye was also assessed and classified as normal or early AMD, iAMD, exudative macular neovascularization, or cRORA. Incidence of cRORA, odds ratio for demographics, and OCT features. At month 24, 16.36% (54/330) of the iAMD eyes developed cRORA. Several baseline features, including high-central DV, IHRF, SDD, hDC, thin DLS, and cRORA in the fellow eye, were associated with a significantly greater risk for development of cRORA at 2 years. The odds ratio, 95% confidence interval, P value, and baseline frequencies of these biomarkers were DV (6.510, 2.467-17.176, P < 0.001, 49.1%), IHRF (12.763, 4.763-34.202, P < 0.001, 38.8%), SDD (2.307, 1.003-5.304, P= 0.049, 34.2%), hDC (3.012, 1.152-7.873, P= 0.024, 13.0%), thin DLS (4.517, 1.555-13.126, P= 0.006, 11.8%), and cRORA in the fellow eye (7.184, 1.938-26.623, P= 0.003, 8.2%). In addition to the 4 previously reported factors that are present in a significant proportion of iAMD (DV, IHRF, hDC, and SDD), a thin DLS and cRORA in the fellow eye were associated with an increased risk of progression to cRORA over 2 years. These biomarkers may aid in prognostication, risk stratification, and selection of patients for clinical trials.

Long-term observations of macular thickness after subretinal implantation of a photovoltaic prosthesis in patients with atrophic age-related macular degeneration

Objective. Subretinal prostheses electrically stimulate the residual inner retinal neurons to partially restore vision. We investigated the changes in neurosensory macular structures and it is thickness associated with subretinal implantation in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Approach. Using optical coherence tomography, changes in distance between electrodes and retinal inner nuclear layer (INL) as well as alterations in thickness of retinal layers were measured over time above and near the subretinal chip implanted within the atrophic area. Retinal thickness (RT) was quantified across the implant surface and edges as well as outside the implant zone to compare with the natural macular changes following subretinal surgery, and the natural course of dry AMD. Main results. GA was defined based on complete retinal pigment epithelium and outer retinal atrophy (cRORA). Based on the analysis of three patients with subretinal implantation, we found that the distance between the implant and the target cells was stable over the long-term follow-up. Total RT above the implant decreased on average, by 39 ± 12 µm during 3 months post-implantation, but no significant changes were observed after that, up to 36 months of the follow-up. RT also changed near the temporal entry point areas outside the implantation zone following the surgical trauma of retinal detachment. There was no change in the macula cRORA nasal to the implanted zone, where there was no surgical trauma or manipulation. Significance. The surgical delivery of the photovoltaic subretinal implant causes minor RT changes that settle after 3 months, and then remain stable over long-term with no adverse structural or functional effects. Distance between the implant and the INL remains stable up to 36 months of the follow-up.

Changes of alpha-2-macroglobulin activity in tear fluid in experimental retinal pigment epithelium atrophy of rabbits

Purpose. To assess the validity of alpha-2-macroglobulin ( 2-MG) activity and endothelin-1 (ET-1) concentration for the characterization of local metabolic disorders in experimental retinal pigment epithelium atrophy (RPE).Material and methods. To reproduce RPE atrophy, 22 New Zealand Albino rabbits were given a subretinal injection of bevacizumab or saline. Tear fluid was collected before the injection and 3 months after it. In the second series of the experiment, tear fluid was also collected on the 3rd, 7th, 14th, 21st and 28th days after bevacizumab injection. Tear fluid was analyzed for the activity of 2-MG using the fermentation method and for ET-1 concentration by the immunoenzymatic method.Results. 3 months after bevacizumab injection, 2-MG activity in the tear remained normal, while after saline injection it was, on average, twice as high as the initial one. ET-1 concentration showed a significant increase of over 1.5 times on the 3rd day after bevacizumab injection both in the tear of the operated and the contralateral eyes.Conclusion. Subretinal bevacizumab injection had no significant lasting damaging effect on the retina, as opposed to saline injection that led to an increase of 2-MG activity in the tear. A transitory increase of ET-1 concentration in the tears after bevacizumab injection may indicate vascular tone elevation in the eye during this period. The study of 2-MG activity and ET-1 concentration in the tear may be used to monitor local metabolic shifts in experimental RPE atrophy development, as well as to assess the post-transplantation process and therapy adequacy.

Pigmentary Maculopathy in Interstitial Cystitis/Bladder Pain Syndrome Treated with Oral Pentosan Polysulfate: A Review

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a rare and chronic bladder condition. Pentosan polysulfate sodium (PPS) is the only oral medication approved specifically for the management of IC/BPS. In 2018, Pearce et al. reported for the first time a unique pattern of ocular pigmentary maculopathy exclusively in IC/BPS patients following PPS exposure. This publication triggered several published studies, case reports, case series, and media reports claiming a link between PPS and pigmentary maculopathy; however, a clear interpretation of these data is still awaited and there are currently no prospective, well researched, confirmatory data available. The clinical presentation of pigmentary maculopathy is characterised by moderate visual impairments and macular hyperpigmented spots, yellow-orange deposits, and/or patchy retinal pigment epithelium (RPE) atrophy. Most patients experiencing this ocular effect used high doses of PPS over an extended period, with risk of pigmentary maculopathy associated with PPS increasing with exposure. Studies that rule out prevalent retinal abnormalities are lacking. The cause of this particular maculopathy remains unclear and further research is required. The current data suggest that a median duration of 15 years of PPS exposure must elapse before pigmentary maculopathy is detected. Furthermore, no increased incidence of any type of maculopathy is found up to a median duration of 5 years of PPS use. Thus, in line with the current European Medicines Agency (EMA) recommendation, if patients respond to therapy and a decision is made to continue PPS for longer than 6 months, a fundoscopy with optical coherence tomography (OCT) and fundus autofluorescence should be performed. In cases of no findings, the next eye examination should be after a further 5 years of PPS use; in cases of findings, continuation of the treatment should be re-evaluated by the urologist and monitored by yearly ocular fundus examinations. This review provides a framework for evidence-based treatment with PPS in patients with IC/BPS using appropriate monitoring and gives an overview of the current understanding and evidence of the association of PPS and a specific pigmentary maculopathy.

Non-neovascular fluid in age-related macular degeneration: observe-and-extend regimen in a case-series study

ObjectifDécrire l’évolution du liquide non néovasculaire dans la dégénérescence maculaire liée à l’âge (DMLA) après l'administration d'anti-VEGF (facteur de croissance endothélial vasculaire) ou après une période d'observation sans injection. NatureÉtude rétrospective portant sur une série de cas. MéthodesOnt été inclus des yeux qui présentaient une DMLA s'accompagnant de drusens maculaires et/ou d'un décollement drusénoïde de l’épithélium pigmentaire associée à l'apparition d'un liquide non néovasculaire. On a réalisé une angiographie-tomographie par cohérence optique (OCTA) dans tous les yeux afin d'exclure la présence d'une néovascularisation maculaire. Le liquide sous-rétinien (LSR) a été mesuré afin de déterminer la réponse à la suite de l'administration d'anti-VEGF et après une période d'observation sans injection. RésultatsAinsi, 10 yeux de 9 patients qui présentaient une DMLA intermédiaire s'accompagnant de LSR ont été étudiés pendant une médiane de 59,5 mois (fourchette : 7–128 mois). De ce nombre, 6 patients (6 yeux) avaient déjà reçu un anti-VEGF. La durée médiane du suivi sans injection était de 13,5 mois (fourchette : 4–44 mois). L’épaisseur du LSR est demeurée stable et n'a pas changé pendant le suivi sans injection dans tous les yeux (n = 6) qui avaient reçu des injections et dans tous les yeux (n = 4) qui n'avaient jamais reçu d'injection. Par ailleurs, on a observé une atrophie complète de l’épithélium pigmentaire rétinien (EPR) et des couches externes de la rétine dans 6 yeux, tandis qu'on a noté une atrophie incomplète de l'EPR et des couches externes de la rétine dans 1 seul œil. Tous les yeux présentaient au moins 2 biomarqueurs visibles à l'OCT et associés à un risque élevé de progression vers l'atrophie. ConclusionNotre étude fournit des données préliminaires sur la progression du liquide non néovasculaire dans la DMLA, avec ou sans injection d'anti-VEGF. L'apparition de liquide pourrait tenir à une dysfonction de la pompe de l'EPR. Il est essentiel de faire la distinction entre le liquide néovasculaire et le liquide non néovasculaire par l'intermédiaire de techniques d'imagerie multimodale, notamment l'OCTA, pour éviter d'administrer inutilement un anti-VEGF. On peut envisager un regime « d'observation-et-extension » (observe-and-extend) en présence de DMLA qui s'accompagne d'un liquide non néovasculaire.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy: Longitudinal Evaluation in Age-Related Macular Degeneration

To examine the association between incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) on OCT imaging and the subsequent risk of developing geographic atrophy (GA) defined on conventional color fundus photography (CFP) and to compare this with the specific features that define nascent GA (nGA). Retrospective analysis of data from a longitudinal study. A total of 280 eyes from 140 participants with bilateral large drusen without specific nGA-defining features or late age-related macular degeneration (AMD) at baseline. OCT imaging and CFP were performed at baseline and then at 6-month intervals for up to 36 months. Eyes that developed neovascular AMD were censored on the day it was detected. OCT volume scans were graded for the presence of iRORA and nGA separately, and CFP images were graded for the presence of GA. Association with and variance explained in time to GA development. A total of 58 eyes (21%) from 46 participants (33%) had iRORA at baseline, and a further 87 eyes (31%) developed iRORA over the follow-up period. Time-to-event analyses demonstrated that prevalent orincident iRORA was associated with an increased rate of GA development (adjusted hazard ratio [HR], 12.1; P= 0.021), as was incident nGA (adjusted HR, 78.6; P < 0.001). However, only the specific nGA features (adjusted P < 0.001), and not iRORA (adjusted P= 0.520), were associated with an increased rate of GA development when both features were included in the same multivariable model. The proportion of variance explained in the time to GA development by iRORA itself (R2= 43%) was significantly lower than explained by nGA alone (R2= 91%; P= 0.010). In this cohort, iRORA is a significant risk factor for GA development, but its association with GA development appears to be accounted for by the development of the specific features that define nGA. Although requiring replication, these findings provide useful guidance on the relative utility of nGA and iRORA as risk factors for GA and as potential surrogate end points for future interventional studies in the early stages of AMD.