Dry eye and cataract surgery: Narrative review and recommendations for management.

Cataract surgery is the most frequently performed surgical procedure in the elderly in Western countries and patients' expectations for postoperative outcomes are very high.Dry eye disease (DED) is a common multifactorial symptomatic disease of the ocular surface with a complex etiopathogenesis and a prevalence significantly increasing with age.Cataract surgery and DED have a complex relationship, which needs to be acknowledged, understood, and properly managed, as suggested by daily clinical experience and growing scientific evidence. The surgical procedure can have a relevant impact on the tear film and the ocular surface, and it can, usually transiently, induce or exacerbate DED symptoms. Moreover, preoperative DED can affect surgical refractive outcomes, while postoperative DED symptoms can significantly worsen patients reported outcomes and satisfaction.At the end of this narrative review summarizing the evidence on this topic, the "Dry Eye and Cataract Surgery" subcommittee of the DROPS workshop formulated some recommendations for ocular surface and DED management pre-, intra-, and post-cataract surgery.

PREVALENCE AND RISK FACTORS OF ELLIPSOID ZONE DAMAGE AFTER PARS PLANA VITRECTOMY FOR IDIOPATHIC EPIRETINAL MEMBRANE.

PURPOSE: To assess factors associated with external limiting membrane (ELM)/ellipsoid zone (EZ) damage after pars plana vitrectomy (PPV) for epiretinal membrane and evaluate ELM/EZ damage impact on functional and anatomical outcomes. METHODS: Patients who underwent PPV with epiretinal membrane ± inner limiting membrane peeling were retrospectively analyzed. Best-corrected visual acuity and central macular thickness were longitudinally collected based on the available follow-up. Demographic data, clinical data, and surgical details were included in logistic regression models having ELM/EZ damage as a binary outcome. RESULTS: Overall, 179 eyes (171 patients) were included; 93 had a 12-month follow-up. Thirty-four eyes (19%) had ELM/EZ damage after surgery; in nine eyes (5%), ELM/EZ damage persisted at 12 months. Phacoemulsification during PPV (odds ratio = 6.97; P = 0.007) and ELM/EZ damage before PPV (odds ratio = 6.91; P = 0.007) were risk factors for postoperative ELM/EZ disruption. Thicker outer nuclear layer (P = 0.002), thicker ectopic inner foveal layer (P < 0.001), and higher endoillumination power (P = 0.03) were associated with slower visual recovery. Inner limiting membrane peeling (P = 0.04) was associated with slower anatomical recovery. CONCLUSION: Cataract extraction and outer retinal damage before PPV are associated with higher risk of photoreceptor damage postoperatively. The rate of visual improvement varies as a function of retinal layers' distortion before surgery; additional retinal manipulation slows restoration of the macular anatomy.

Intraocular perfluorodecalin and silicone oil tamponade (double filling) in the management of complicated retinal detachment: functional and anatomical outcomes using small-gauge surgery.

PURPOSE: To describe the functional and anatomical results of complicated retinal detachment (RD) treated with small-gauge pars plana vitrectomy (PPV) and combined perfluorodecalin and polydimethylsiloxane tamponade (double filling, DF). METHODS: Retrospective analysis of consecutive patients with complex RD (severe proliferative vitreoretinopathy, inferior/posterior/giant retinal tears, and traumatic detachments) treated with small-gauge PPV, membrane peeling, and DF at the Department of Ophthalmology at San Gerardo Hospital, Monza, Italy. Main outcome measures included best-corrected visual acuity (BCVA), rates of retinal reattachment, and complications. RESULTS: This study included 15 patients with a median follow-up (FU) of 6 months (range 1-22). Three patients with early retinal redetachment under tamponade and FU shorter than 3 months were excluded from the final functional analysis, but they were considered anatomical failure. At the last examination, BCVA improved in 50% of patients and remained stable in 25% of patients and anatomical success was achieved in 73% of eyes, 64% of them without any endotamponade. Three eyes had retinal redetachment after perfluorodecalin/silicone oil exchange because of diffuse proliferative vitreoretinopathy (PVR) and required reoperation to achieve retinal attachment. In eyes with anatomical success, macular pucker was the most frequent long-term complication (27%). CONCLUSION: In the management of complex RD, small-gauge pars plana vitrectomy, and double filling endotamponade using wide-angle viewing systems was a well-tolerated and effective technique to preserve visual acuity and achieve anatomical success.

The visual outcomes of idiopathic epiretinal membrane removal in eyes with ectopic inner foveal layers and preserved macular segmentation.

PURPOSE: To analyze the functional impact of ectopic inner foveal layers (EIFL), along with other clinical and optical coherence tomography biomarkers, on patients with epiretinal membrane (ERM) and preserved foveal layers' segmentation undergoing ERM removal. METHODS: Retrospective review of consecutive patients with ERM who underwent pars plana vitrectomy with ERM peeling from December 2018 to December 2019. Baseline factors including age, gender, lens status, phacoemulsification at the time of surgery, tamponade agent, dye used for ERM and internal limiting membrane (ILM) enhancement, ILM peeling, best-corrected visual acuity (BCVA) and central macular thickness (CMT), presence and thickness of EIFL, thickness of outer nuclear layer (ONL), presence of a cotton ball, subfoveal state of photoreceptors, and presence of cystoid macular edema were included in a multivariable model having the BCVA at 12 months as the main outcome. The changes in EIFL and ONL thickness over time were also analyzed. RESULTS: Fifty-one patients (58 eyes, 23 eyes in the no EIFL group, and 35 eyes in the EIFL group) were enrolled. The BCVA significantly improved over 12 months after surgery, regardless of the presence of EIFL (p < 0.001). Eyes with no EIFL had better BCVA at month 3 (p = 0.04), but this difference was no longer detectable at 6 and 12 months. The presence of EIFL was not associated with the final BCVA (p = 0.9), while the CMT at 12 months correlated with EIFL thickness (r = 0.8, p = 0.008). CONCLUSION: Patients with EIFL could reach optimal visual acuity in the absence of disorganization of the inner retinal layers but should be warned of potentially longer healing times. None of the morphologic signs included in this study precluded good visual recovery on long-term follow-up.

Bilateral Acute Macular Neuroretinopathy in a Young Patient: Imaging and Visual Field during Two-Year-Follow-Up.

Acute macular neuroretinopathy (AMN) is a rare disorder. We report a case of bilateral AMN in a young female patient, without any risk factors. She referred a positive scotoma in both eyes after flu-like symptoms. Fundus examination revealed parafoveal dark-reddish oval lesions in both eyes. Therefore, we performed visual field, optical coherence tomography (OCT), fluorescein angiography (FA) and indocyanine green angiography (ICG) at baseline and several times during the two years of follow-up. The infrared (IR) imaging showed one rounded hyporeflective lesion in the left eye and two similar lesions in the right eye. The OCT demonstrated the characteristic alterations in the outer retina. The visual field also demonstrated scotomas corresponding with these lesions. The OCT and IR features disappeared at the end of the follow-up except for the left eye, which continued to have hyperreflective spots in the outer plexiform layer. The patient complained about a residual scotoma only in the left eye after two years. Our case shows a difference in disease progression in the two eyes of the same patient, suggesting that several mechanisms can be implicated in the pathology of AMN.

Activated Retinal Pigment Epithelium, an Optical Coherence Tomography Biomarker for Progression in Age-Related Macular Degeneration.

Purpose: To summarize and contextualize recent histology and clinical imaging publications on retinal pigment epithelium (RPE) fate in advanced age-related macular degeneration (AMD); to support RPE activation and migration as important precursors to atrophy, manifest as intraretinal hyperreflective foci in spectral-domain optical coherence tomography (SDOCT). Methods: The Project MACULA online resource for AMD histopathology was surveyed systematically to form a catalog of 15 phenotypes of RPE and RPE-derived cells and layer thicknesses in advanced disease. Phenotypes were also sought in correlations with clinical longitudinal eye-tracked SDOCT and with ex vivo imaging-histopathology correlations in geographic atrophy (GA) and pigment epithelium detachments (PED). Results: The morphology catalog suggested two main pathways of RPE fate: basolateral shedding of intracellular organelles (apparent apoptosis in situ) and activation with anterior migration. Acquired vitelliform lesions may represent a third pathway. Migrated cells are packed with RPE organelles and confirmed as hyperreflective on SDOCT. RPE layer thickening due to cellular dysmorphia and thick basal laminar deposit is observed near the border of GA. Drusenoid PED show a life cycle of slow growth and rapid collapse preceded by RPE layer disruption and anterior migration. Conclusions: RPE activation and migration comprise an important precursor to atrophy that can be observed at the cellular level in vivo via validated SDOCT. Collapse of large drusen and drusenoid PED appears to occur when RPE death and migration prevent continued production of druse components. Data implicate excessive diffusion distance from choriocapillaris in RPE death as well as support a potential benefit in targeting drusen in GA.

VISUALIZING RETINAL PIGMENT EPITHELIUM PHENOTYPES IN THE TRANSITION TO GEOGRAPHIC ATROPHY IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence imaging in geographic atrophy (GA) of age-related macular degeneration by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy in donor eyes. METHODS: In RPE-Bruch membrane flat mounts of two GA eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at ±500 and ±100 µm from the descent of the external limiting membrane (ELM) toward Bruch membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE plus BLamD were measured. RESULTS: A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at -100 µm from the ELM descent than that at -500 µm (23.1 ± 10.7 µm vs. 19.3 ± 8.2 µm; P = 0.05). CONCLUSION: The distribution of RPE phenotypes at the GA transition supports the idea that these morphologies represent defined stages of a degeneration sequence. The idea that RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA is supported. The ELM descent and RPE plus BLamD thickness profile may have utility as spectral domain optical coherence tomography metrics in clinical trials.

VISUALIZING RETINAL PIGMENT EPITHELIUM PHENOTYPES IN THE TRANSITION TO ATROPHY IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To enable future studies of retinal pigment epithelium (RPE) fate in the macular atrophy occurring in eyes with neovascular age-related macular degeneration (nvAMD), the authors determined how RPE morphology changes across the transition from health to atrophy in donor eyes with nvAMD. METHOD: In RPE-Bruch membrane flat mounts of 5 nvAMD eyes, the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histologic sections of 27 nvAMD eyes, RPE phenotypes were assessed at ±500 µm and ±100 µm from the descent of the external limiting membrane (ELM) toward the Bruch membrane. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE + BLamD were determined. Shapes of the ELM descent were recorded. RESULTS: Approaching the ELM descent, the percentage of different RPE phenotypes and the thickness of RPE, BLamD, and RPE + BLamD each stayed roughly constant. Compared with a separately described cohort of eyes with geographic atrophy, eyes with nvAMD were more likely to have RPE dysmorphia that did not worsen toward the atrophy border, thinner BLamD overall (3.25 ± 3.46 µm vs. 7.99 ± 7.49 µm for geographic atrophy), and a higher proportion of oblique ELM descents (47.9 vs. 31.9%). CONCLUSION: The distribution of RPE phenotypes at the transition to macular atrophy in eyes with nvAMD differs from that in primary geographic atrophy, likely reflecting greater photoreceptor loss and the effects of exudation in nvAMD. This distribution, the shape of ELM descents, and thickness profiles may be useful metrics in clinical studies of macular atrophy using optical coherence tomography and fundus autofluorescence.

Re-accumulation of macular pigment after successful macular hole surgery.

AIMS: To investigate macular pigment optical density (MPOD) during follow-up of sealed macular holes and to study correlations of MPOD with progressive changes in spectral-domain optical coherence tomography (SD-OCT) and functional results. METHODS: Consecutive patients (n=18) who had undergone successful vitrectomies for idiopathic macular holes were evaluated postoperatively at 1, 3, 6 and 9 months. At each follow-up visit, MPOD was measured with a modified confocal scanning laser ophthalmoscope and the outer retina evaluated by SD-OCT. The changes of MPOD postoperatively and the relationship of MPOD and SD-OCT findings to best corrected visual acuity were examined. RESULTS: MPOD did not change significantly throughout follow-up, from 0.49±0.22 (mean±SD) at month 1 to 0.42±0.18 at month 9. There was a tendency towards a significant association between amount of MPOD and recovery of external limiting membrane during follow-up (p=0.068). Best corrected visual acuity increased significantly from 0.24±0.12 before surgery to 0.65±0.25 at month 9. Recovery of the ellipsoid zone determined most of visual acuity improvement (p=0.024). MPOD was not associated with visual acuity changes (p=0.394). CONCLUSIONS: Revisualisation of macular pigment after successful macular hole surgery is not associated with improved visual acuity and may merely be an accompanying sign of the reapposition of the edges of the hole.

The Onion Sign in Neovascular Age-Related Macular Degeneration Represents Cholesterol Crystals.

PURPOSE: To investigate the frequency, natural evolution, and histologic correlates of layered, hyperreflective, subretinal pigment epithelium (sub-RPE) lines, known as the onion sign, in neovascular age-related macular degeneration (AMD). DESIGN: Retrospective observational cohort study and experimental laboratory study. PARTICIPANTS: Two hundred thirty eyes of 150 consecutive patients with neovascular AMD and 40 human donor eyes with histopathologic diagnosis of neovascular AMD. METHODS: Spectral-domain optical coherence tomography (SD OCT), near-infrared reflectance (NIR), color fundus images, and medical charts were reviewed. Donor eyes underwent multimodal ex vivo imaging, including SD OCT, before processing for high-resolution histologic analysis. MAIN OUTCOME MEASURES: Presence of layered, hyperreflective sub-RPE lines, qualitative analysis of their change in appearance over time with SD OCT, histologic correlates of these lines, and associated findings within surrounding tissues. RESULTS: Sixteen of 230 eyes of patients (7.0%) and 2 of 40 donor eyes (5.0%) with neovascular AMD had layered, hyperreflective sub-RPE lines on SD OCT imaging. These appeared as refractile, yellow-gray exudates on color imaging and as hyperreflective lesions on NIR. In all 16 patient eyes, the onion sign persisted in follow-up for up to 5 years, with fluctuations in the abundance of lines and association with intraretinal hyperreflective foci. Patients with the onion sign disproportionately were taking cholesterol-lowering medications (P=0.025). Histologic analysis of 2 donor eyes revealed that the hyperreflective lines correlated with clefts created by extraction of cholesterol crystals during tissue processing. The fluid surrounding the crystals contained lipid, yet was distinct from oily drusen. Intraretinal hyperreflective foci correlated with intraretinal RPE and lipid-filled cells of probable monocytic origin. CONCLUSIONS: Persistent and dynamic, the onion sign represents sub-RPE cholesterol crystal precipitation in an aqueous environment. The frequency of the onion sign in neovascular AMD in a referral practice and a pathology archive is 5% to 7%. Associations include use of cholesterol-lowering medication and intraretinal hyperreflective foci attributable to RPE cells and lipid-filled cells of monocyte origin.

Subducted and melanotic cells in advanced age-related macular degeneration are derived from retinal pigment epithelium.

PURPOSE: To describe, illustrate, and account for two cell types plausibly derived from RPE in geographic atrophy (GA) and choroidal neovascularization (CNV) of AMD, using melanosomes, lipofuscin, and basal laminar deposit (BLamD) as anatomical markers. METHODS: Human donor eyes with GA (n = 13) or CNV (n = 39) were histologically processed, photodocumented, and analyzed for frequencies of occurrence. We defined RPE as cells containing spindle-shaped melanosomes and RPE lipofuscin, internal to basal lamina or BLamD, if present, or Bruch's membrane if not, and RPE-derived cells as those plausibly derived from RPE and not attached to basal lamina or BLamD. RESULTS: 'Subducted' cells contain RPE melanosomes and localize to the sub-RPE space, on Bruch's membrane. Credible transitional forms from RPE cells were seen. Grades of RPE overlying 'Subducted' cells were 'Atrophic with BLamD' (32.2% vs. 37.0% of 'Subducted,' for GA and CNV eyes, respectively), 'Dissociated' (22.0% vs. 21.7%), 'Nonuniform' (22.0% vs. 23.9%), and 'Sloughed' RPE (10.2% vs. 4.3%). Found exclusively in CNV scars, 'Melanotic' cells containing spherical melanosomes were adjacent to 'Entombed' RPE with spindle-shaped and spherical melanosomes. Of subretinal 'Melanotic' cells, 40.0% associated with 'Atrophy with BLamD,' 36.8% with 'Atrophy without BLamD,' and 20.6% with 'Entombed.' CONCLUSIONS: 'Dissociated' RPE within atrophic areas may be the source of 'Subducted' cells. 'Entombed' RPE within fibrovascular and fibrocellular scars may be the source of 'Melanotic' cells. An imaging correlate for 'Subducted' cells awaits discovery; 'Melanotic' cells appear gray-black in the CNV fundus. Results provide a basis for future molecular phenotyping studies.

The Project MACULA Retinal Pigment Epithelium Grading System for Histology and Optical Coherence Tomography in Age-Related Macular Degeneration.

PURPOSE: To seek pathways of retinal pigment epithelium (RPE) fate in age-related macular degeneration via a morphology grading system; provide nomenclature, visualization targets, and metrics for clinical imaging and model systems. METHODS: Donor eyes with geographic atrophy (GA) or choroidal neovascularization (CNV) and one GA eye with previous clinical spectral-domain optical coherence tomography (SDOCT) imaging were processed for histology, photodocumented, and annotated at predefined locations. Retinal pigment epithelial cells contained spindle-shaped melanosomes, apposed a basal lamina or basal laminar deposit (BLamD), and exhibited recognizable morphologies. Thicknesses and unbiased estimates of frequencies were obtained. RESULTS: In 13 GA eyes (449 locations), 'Shedding,' 'Sloughed,' and 'Dissociated' morphologies were abundant; 22.2% of atrophic locations had 'Dissociated' RPE. In 39 CNV eyes (1363 locations), 37.3% of locations with fibrovascular/fibrocellular scar had 'Entombed' RPE; 'Sloughed,' 'Dissociated,' and 'Bilaminar' morphologies were abundant. Of abnormal RPE, CNV and GA both had ~35% 'Sloughed'/'Intraretinal,' with more Intraretinal in CNV (9.5% vs. 1.8%). 'Shedding' cells associated with granule aggregations in BLamD. The RPE layer did not thin, and BLamD remained thick, with progression. Granule-containing material consistent with three morphologies correlated to SDOCT hyperreflective foci in the previously examined GA patient. CONCLUSIONS: Retinal pigment epithelium morphology indicates multiple pathways in GA and CNV. Atrophic/scarred areas have numerous cells capable of transcribing genes and generating imaging signals. Shed granule aggregates, possibly apoptotic, are visible in SDOCT, as are 'Dissociated' and 'Sloughed' cells. The significance of RPE phenotypes is addressable in longitudinal, high-resolution imaging in clinic populations. Data can motivate future molecular phenotyping studies.