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Purpose: To assess the cone photoreceptors' morphology and associated retinal sensitivity in laser-induced retinopathy (LIR) using adaptive optics scanning laser ophthalmoscopy (AO-SLO) and microperimetry (MP)., Design: Cohort study., Methods: This study included 13 patients (15 eyes) with LIR and 38 age-matched healthy volunteers (38 eyes). Participants underwent comprehensive evaluations including AO-SLO, MP, and spectral-domain OCT. Lesion morphology, cone density, dispersion, and regularity in AO-SLO were assessed and correlated with visual function., Results: In AO-SLO images, LIR lesions were predominantly characterized by hyporeflective regions, suggesting potential cone loss at the fovea, accompanied by the presence of sizable clumps of hyperreflective material within these lesions. The average size of lesions in affected eyes was 97,128±107,478 µm², ranging from 6705 to 673,348 µm². Compared with the healthy contralateral eye and control group, LIR demonstrated significantly reduced cone density, increased cone dispersion, and notably decreased cone regularity in all 4 quadrants at 3° eccentricity (all P values < .05). Lesion morphology in AO-SLO correlated with ellipsoid zone defects observed in OCT, showing a positive correlation in size (r = 0.84, P < .001) but not with retinal sensitivities (P = .09). Similarly, cone density at 3° eccentricity did not correlate with retinal sensitivities (P = .13)., Conclusions and Relevance: The study provides crucial insights into the morphologic and functional impacts of LIR on cone photoreceptors, revealing significant morphologic changes in cones that do not consistently align with functional outcomes. This research highlights the need for continued exploration into the relationship between retinal structure and function in LIR, and the importance of heightened public awareness and preventive strategies to mitigate the risk of LIR., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although there have been numerous innovations in the management of retinal detachment (RD) over the past decades, there is still limited understanding of the pathophysiological processes that take place before and after repair. Summarizing key concepts using animal studies may allow for a better assessment of common pre- and postoperative microstructural abnormalities in RD. We performed a systematic literature review on Ovid MEDLINE, EMBASE, and Cochrane Controlled Register of Trials from January 1968 to January 2022, searching animal or human studies reporting retinal histologic changes following primary or induced RD. Thirty-two studies were included. Main cellular events were summarized: photoceptor apoptosis occurs as early as 12 hours after RD and, although most cells survive, there is extensive remodeling. Outer segments progressively degenerate, while inner segments are reorganized. Rod and cone opsins are redistributed, and rod axons retract while cones undergo changes in shape. Second- and third-order neurons rearrange their dendritic processes, and Müller cells become hypertrophic, growing into the subretinal space. Finally, retinal pigment epithelium cells undergo a change in their morphology. Acknowledging critical morphologic changes following RD is crucial in understanding why anatomical and functional outcomes can vary. Insights from histological studies, together with high-resolution imaging, may be key in identifying novel biomarkers in RD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To evaluate cone photoreceptor density in clinically unremarkable retinal regions in patients with age-related macular degeneration (AMD) using adaptive optics scanning laser ophthalmoscopy (AOSLO)., Design: Prospective case series with normal comparison group., Methods: Ten eyes of 7 patients with intermediate AMD were studied, including 4 with predominantly subretinal drusenoid deposits (SDD) and 3 without SDD. Macular regions with a clinical absence of AMD-associated lesions were identified by cone packing structure on AOSLO and optical coherence tomography. Cone density was measured in 1174 clinically unremarkable regions within the central subfield (CSF), the inner (IR), and outer rings (OR) of the Early Treatment Diabetic Retinopathy Study grid over 39.6 ± 3.3 months and compared with age-matched normal values obtained in 17 participants., Results: Cone density decreased at 98.3% of the examined locations over time in the eyes with AMD. In the CSF, IR, and OR, cones declined by -255 ± 135, -133 ± 45, and -59 ± 24 cones/degree 2 /year, respectively, in eyes with SDD, and by -212 ± 89, -83 ± 37, and -27 ± 18 cones/degree 2 /year, respectively, in eyes without SDD. The percentage of retinal loci with cone density lower than normal (Z score < -2) increased over the follow-up: from 42% at the baseline to 80% at the last visit in eyes with SDD and from 31% to 70% in eyes without SDD., Conclusions: AOSLO revealed cone photoreceptor loss in regions that appear otherwise unremarkable clinically. These findings may help explain the loss of mesopic sensitivity reported in these areas in eyes with intermediate AMD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: We examined the incidence and natural history of macular retinochoroidal neovascularization (RCN) in enhanced S-cone syndrome (ESCS)., Design: Retrospective case series., Methods: This single-center study included 14 of 93 patients with ESCS who had signs of active or inactive RCN in ≥1 eye. We conducted multimodal retinal imaging, full-field electroretinography, and molecular genetic analysis of NR2E3 gene. Our main outcome measures included the cumulative incidence of RCN in ESCS, type of RCN, and mode of evolution of RCN., Results: Fourteen (15.1%) of 93 patients with ESCS had RCN in ≥1 eye at 2 to 27 years of age. All 22 RCNs (21 eyes of 14 patients) were macular. Twelve of the RCNs were active with exudates/hemorrhages. Of these, 5 appeared de novo in a subretinal location, with photographic evidence of no pre-existing lesions. The latter were compatible with type 3 neovascularization or retinal angiomatous proliferation and subsequently evolved into unifocal fibrotic nodules. The remaining active lesions all had some degree of pre-existing fibrosis and remained stable. Ten inactive fibrotic nodules, identical to end-stage de novo lesions, were found and were presumed to represent healed RCNs., Conclusions: RCN, a treatable condition, may occur as early as 2 years of age and may be much more common in patients with ESCS than previously estimated. It may be the primary cause of the unifocal submacular fibrosis that is commonly observed in this condition. Additional research is needed to establish the pathogenesis of RCN in patients with ESCS and its optimal management., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Retinitis pigmentosa 1-like 1 (RP1L1) is a component of the photoreceptor cilium. Pathogenic variants in RP1L1 lead to photoreceptor disease, suggesting an important role for RP1L1 in photoreceptor biology, though its exact function is unknown. To date, RP1L1 variants have been associated with occult macular dystrophy (a cone degeneration) and retinitis pigmentosa (a rod disease). Here, we summarize reported RP1L1-associated photoreceptor conditions and disease-causing RP1L1 variants. We also discuss novel associations between RP1L1 and additional photoreceptor conditions-besides occult macular dystrophy and retinitis pigmentosa-and fit RP1L1 into the broader scope of photoreceptor disease. RP1L1 appears to have a complex relationship with other photoreceptor proteins and may modify disease phenotype. Ultimately, further exploration of the relationship between RP1L1, other cilium components, and their impact on photoreceptor health is needed., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To describe the characteristics of MAK-related retinal degeneration using optical coherence tomography angiography (OCTA) and adaptive optics scanning laser ophthalmoscopy (AOSLO)., Design: Cross-sectional study., Methods: Six patients with rod-cone degeneration and disease-causing mutations in MAK were evaluated with visual acuity, spectral-domain OCT, confocal AOSLO, and OCTA. Foveal avascular zone (FAZ) area, vessel densities, and perfusion densities of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in the central macula in all 6 patients were compared with 5 normal subjects. Cone spacing was measured in 4 patients from AOSLO images and compared with 37 normal subjects., Results: Patients ranged from 25 to 81 years of age (mean, 52 years). Visual acuity varied from 20/13 to 20/40 +2 , except in 1 patient with cystoid macular edema whose vision was 20/60 - and 20/70 +1 . The SCP (P = .012) and DCP (P = .013) vessel density and perfusion density (P =.015 and .013, respectively) were significantly lower in patients compared to normal subjects in the parafoveal region 1.0-3.0 mm from the fovea, but were similar to normal subjects within 1.0 mm of the fovea. The FAZ area was not significantly different from normal (all P ≥ .24). Cone spacing was normal at almost all locations in 2 patients with early disease and increased in 2 patients with advanced disease., Conclusions: Although retinal vascular densities are reduced and cone spacing is increased in advanced disease, central foveal structure is maintained until late stages of disease, which may contribute to preservation of foveal vision in eyes with MAK-related retinal degeneration., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The endocannabinoid system is involved in some neurodegenerative diseases such as Alzheimer's disease. An endogenous constellation of proteins related to cannabinoid 1 receptor signaling, including free fatty acids, diacylglycerol lipase, and N-acylethanolamine-hydrolyzing acid amidase, are localized in the murine retina. Moreover, the expression levels of endogenous agonists of cannabinoid receptors are changed in the vitreous fluid. However, the role of the endocannabinoid system in the retina, particularly in the light-induced photoreceptor degeneration, remains unknown. Therefore, we investigated involvement of the cannabinoid 1 receptor in light-induced retinal degeneration using in vitro and in vivo models. To evaluate the effect of cannabinoid 1 receptors in light irradiation-induced cell death, the mouse retinal cone-cell line (661W) was treated with a cannabinoid 1 receptor antagonist, rimonabant. Time-dependent changes of expression and localization of retinal cannabinoid 1 receptors were measured using Western blot and immunostaining. Retinal damage was induced in mice by exposure to light, followed by intravitreal injection of rimonabant. Electroretinograms and histologic analyses were performed. Rimonabant suppressed light-induced photoreceptor cell death. Cannabinoid 1 receptor expression was upregulated by light exposure. Treatment with rimonabant improved both a- and b-wave amplitudes and the thickness of the outer nuclear layer. These results suggest that the cannabinoid 1 receptor is involved in light-induced retinal degeneration and it may represent a therapeutic target in the light-induced photoreceptor degeneration related diseases., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To investigate photoreceptor changes in eyes with glaucoma., Design: Cross-sectional study., Methods: The study included 35 eyes of 35 patients with primary open-angle glaucoma who had suffered parafoveal visual field loss at least 3 years previously, as well as 21 eyes of 21 normal subjects. Eyes with an axial length ≥26.0 mm were excluded. All subjects underwent a full ophthalmologic examination, including spectral-domain optical coherence tomography (SDOCT) and prototype adaptive-optics scanning laser ophthalmoscopy (AO-SLO) imaging., Results: As determined using AO-SLO, eyes with glaucoma did not differ significantly from normal eyes in terms of either cone density (26 468 ± 3392 cones/m 2 vs 26 147 ± 2700 cones/m 2 , respectively; P = .77; measured 0.5 mm from the foveal center) or cone spatial organization (ratio of hexagonal Voronoi domain: 43.7% ± 4.4% vs 44.3% ± 4.9%; P = .76; measured 0.5 mm from the foveal center). Furthermore, SDOCT showed that the 2 groups did not differ significantly in terms of the photoreceptor-related layer thickness, and that the photoreceptor ellipsoid zone band was continuous in all normal and glaucoma eyes. In glaucoma eyes with vertically asymmetric severity, the more affected side did not significantly differ from the less affected side in terms of cone density, cone spatial organization, or photoreceptor-related layer thickness. In 8 eyes (22.9%) with glaucoma, dark, partition-like areas surrounded the cones on the AO-SLO., Conclusions: Both AO-SLO and SDOCT showed cone integrity in eyes with glaucoma, even in areas with visual field and nerve fiber loss. In AO-SLO, microcystic lesions in the inner nuclear layer may influence images of the cone mosaic., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To characterize photoreceptor structure and mosaic integrity in subjects with ​RGS9- and R9AP-associated retinal dysfunction (bradyopsia) and compare to previous observations in other cone dysfunction disorders such as oligocone trichromacy., Design: Observational case series., Methods: setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA)., Study Population: Six eyes of 3 subjects with disease-causing variants in ​RGS9 or R9AP., Main Outcome Measures: Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy., Results: Cone density at 100 μm from foveal center ranged from 123 132 cones/mm(2) to 140 013 cones/mm(2). Cone density ranged from 30 573 to 34 876 cones/mm(2) by 600 μm from center and from 15 987 to 16,253 cones/mm(2) by 1400 μm from center, in keeping with data from normal subjects. Adaptive-optics imaging identified a small, focal hyporeflective lesion at the foveal center in both eyes of the subject with RGS9-associated disease, corresponding to a discrete outer retinal defect also observed on spectral-domain optical coherence tomography; however, the photoreceptor mosaic remained intact at all other observed eccentricities., Conclusions: Bradyopsia and oligocone trichromacy share common clinical symptoms and cannot be discerned on standard clinical findings alone. Adaptive-optics imaging previously demonstrated a sparse mosaic of normal wave-guiding cones remaining at the fovea, with no visible structure outside the central fovea in oligocone trichromacy. In contrast, the subjects presented in this study with molecularly confirmed bradyopsia had a relatively intact and structurally normal photoreceptor mosaic, allowing the distinction between these disorders based on the cellular phenotype and suggesting different pathomechanisms., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the relationship between outer retinal reflectivity on spectral-domain optical coherence tomography and cone density in the corresponding area., Design: Prospective cross-sectional observational study., Methods: In this institutional-based study, 20 eyes of 10 patients presenting maculopathies with various degrees of impairment of the photoreceptor layer (central serous chorioretinopathy, chronic central serous chorioretinopathy, maculopathy associated with hydroxychloroquine, and healthy eyes) were studied. Selection criteria were intended to ensure good image quality. Inner segment ellipsoid band reflectivity, global retinal reflectivity, and relative inner segment ellipsoid reflectivity (defined as the ratio of inner segment ellipsoid band reflectivity on overall retinal reflectivity) were measured on a longitudinal reflectance profile extracted from the spectral-domain optical coherence tomography B-scan. The cone metrics were measured in the same region of interest, located in the perifoveal area, using an adaptive optics retinal camera., Results: Inner segment ellipsoid and relative ellipsoid reflectivity were closely correlated with cone density (Pearson r: 0.72 and 0.70, respectively, P < .01)., Conclusion: Outer retinal reflectivity on the transversal optical coherence tomography scan can be correlated to adaptive optics in terms of photoreceptor density. This quantitative approach using optical coherence tomography images could have important implications in the management of maculopathies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To examine a female subject, her father, and a brother harboring a missense mutation of the retinitis pigmentosa 1-like 1 (RP1L1) gene, over 2 years of follow-up., Design: Observational case series., Methods: setting: Fondazione G.B. Bietti IRCCS, Rome, Italy., Study Population: RP1L1 family members and controls., Main Outcome Measures: Images of the cone mosaic acquired with an adaptive optics retinal camera, spectral-domain optical coherence tomography (SD OCT), and full-field and multifocal electroretinography (mfERG)., Results: In the proband, best-corrected visual acuity (≤0.7 logMAR) was stable in both eyes during follow-up, though analysis of adaptive optics images showed decreased cone density in the central 9 degrees from the fovea with respect to controls (P < .05) and cone density loss in the parafoveal area (2 degrees; <12%-16%) during follow-up. Texture analysis of SD OCT images identified abnormalities of the ellipsoid zone in the central 7 degrees, while mfERG response amplitudes were reduced only in the central 5 degrees relative to controls. In the proband's father, who had 0.0 logMAR visual acuity, significant cone loss was found in the central 7 degrees from the fovea (P < .05); abnormal SD OCT and mfERG values with respect to controls were found in corresponding retinal areas. No defects in the cone structure and function were found in the proband's brother, who had 0.0 logMAR visual acuity., Conclusions: Occult macular dystrophy was diagnosed based on genetic and multimodal ophthalmic findings. The quantitative assessment of photoreceptor survival or loss, based on analysis of adaptive optics retinal images, was valuable to monitor disease progression at a cellular level., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rod-derived cone viability factor (RdCVF) is a trophic factor of the thioredoxins family that promotes the survival of cone photoreceptors. It is encoded by the nucleoredoxin-like gene 1 Nxnl1 which also encodes by alternative splicing a long form of RdCVF (RdCVFL), a thioredoxin enzyme that interacts with TAU. The known role of thioredoxins in the defense mechanism against oxidative damage led us to examine the retinal phenotype of the Nxnl1(-/-) mice exposed to photooxidative stress. Here we found that, in contrast to wild-type mice, the rod photoreceptors of Nxnl1(-/-) mice are more sensitive to light after exposure to 1700 or 2500 lx. The delivery of RdCVF by AAV to mice deficient of Nxnl1(-/-) protects rod photoreceptors from light damage. Interestingly, the RdCVF2L protein, encoded by the paralog gene Nxnl2, is able to reduce TAU phosphorylation, as does RdCVFL, but does not protect the rod from light damage. Our result shows that the Nxnl1 gene, through the thioredoxin RdCVFL, is part of an endogenous defense mechanism against photooxidative stress that is likely of great importance for human vision., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To explore the anatomic correlation of the retinal cone mosaic on adaptive optics images., Design: Retrospective nonconsecutive observational case series., Methods: A retrospective review of the multimodal imaging charts of 6 patients with focal alteration of the cone mosaic on adaptive optics was performed. Retinal diseases included acute posterior multifocal placoid pigment epitheliopathy (n = 1), hydroxychloroquine retinopathy (n = 1), and macular telangiectasia type 2 (n = 4). High-resolution retinal images were obtained using a flood-illumination adaptive optics camera. Images were recorded using standard imaging modalities: color and red-free fundus camera photography; infrared reflectance scanning laser ophthalmoscopy, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography (OCT) images., Results: On OCT, in the marginal zone of the lesions, a disappearance of the interdigitation zone was observed, while the ellipsoid zone was preserved. Image recording demonstrated that such attenuation of the interdigitation zone co-localized with the disappearance of the cone mosaic on adaptive optics images. In 1 case, the restoration of the interdigitation zone paralleled that of the cone mosaic after a 2-month follow-up., Conclusion: Our results suggest that the interdigitation zone could contribute substantially to the reflectance of the cone photoreceptor mosaic. The absence of cones on adaptive optics images does not necessarily mean photoreceptor cell death., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To assess macular photoreceptor abnormalities in eyes with resolved branch retinal vein occlusion (BRVO) using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective observational cross-sectional case series., Methods: After complete resolution of macular edema and retinal hemorrhage, 21 eyes (21 patients) with BRVO underwent full ophthalmologic examination and imaging with optical coherence tomography (OCT) and a prototype AO-SLO system. Cone density and spatial mosaic organization were assessed using AO-SLO images., Results: Regular parafoveal cone mosaic patterns were clearly visualized with the prototype AO-SLO imaging system in the BRVO-unaffected side. However, in the side of the retina previously affected by the BRVO, cone mosaic patterns were disorganized and dark regions missing wave-guiding cones were apparent. Additionally, retinal capillaries were dilated, no longer had a uniform caliber, and had less direct paths through the retina. In the affected side, parafoveal cone density was significantly decreased, compared with the corresponding retinal area on the unaffected side (P < .001). Furthermore, the hexagonal Voronoi domain ratio and the nearest-neighbor distances were significantly lower than in the unaffected side (P < .05). These parameters were also correlated with photoreceptor layer integrity in the parafovea., Conclusions: After BRVO-associated retinal hemorrhage and macular edema resolved, affected parafoveal cone density decreases and the cone mosaic spatial arrangement is disrupted, becoming more irregular. These cone microstructural abnormalities may extend to parafovea in the BRVO-unaffected side., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To assess macular photoreceptor abnormalities in eyes with fundus albipunctatus with RDH5 mutation by using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective cross-sectional study., Methods: Ten eyes with fundus albipunctatus and 11 normal eyes underwent a full ophthalmologic examination, microperimetry, spectral-domain optical coherence tomography (SD OCT), and imaging with a prototype AO-SLO system. Cone density and spatial organization of the cone mosaic were assessed using AO-SLO images. Statistical analysis was done using data from right eyes of all patients., Results: Four patients had the same mutation in RDH5 (c.928delC/insGAAG), and 1 patient had a novel mutation in RDH5 (c.718delG). AO-SLO revealed the presence of small patchy dark areas representing cone loss in the macula of all eyes with fundus albipunctatus, including eyes for which fundus photographs showed no macular abnormalities and SD OCT did not reveal any visible defects in the photoreceptor layer. Compared to normal eyes, eyes with fundus albipunctatus demonstrated significantly lower cone density in areas at 0.5 mm from the center of the fovea (P = .020). At 0.5 mm and 1.0 mm from the center of the fovea, eyes with fundus albipunctatus showed fewer cones with 6 neighbors (P = .041 and P = .006). AO-SLO revealed hyperreflective mosaics surrounded by hyporeflective rings in areas corresponding to the retinal flecks., Conclusions: Macular cone density is lower and the regularity of the macular cone mosaic spatial arrangement is disrupted in eyes with fundus albipunctatus. AO-SLO imaging is a sensitive quantitative tool for detecting photoreceptor abnormalities in eyes with fundus albipunctatus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To compare pathologic changes in the photoreceptors of eyes with idiopathic macular telangiectasia types 1 and 2 using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective cross-sectional study., Methods: Eleven eyes with idiopathic macular telangiectasia type 1, 14 eyes with type 2, and 10 normal eyes underwent a full ophthalmologic examination, spectral-domain optical coherence tomography (SD-OCT), and imaging with an original prototype AO-SLO system. All eyes with idiopathic macular telangiectasia were examined with fluorescein angiography (FA), confocal blue reflectance, and microperimetry., Results: Compared with normal eyes (29 017 ± 5507 cones/mm(2)), those with idiopathic macular telangiectasia type 1 had significantly lower cone density on the temporal side (18 427 ± 4908 cones/mm(2), P = .010). The FA leakage area (5.90 ± 3.23 mm(2)) was larger than the dark regions (2.45 ± 2.40 mm(2)) on AO-SLO (P = .003)-which were observed only in the FA leakage area. Compared with normal eyes, those with idiopathic macular telangiectasia type 2 had significantly lower cone density in all areas (P < .05 for all). Patchy dark regions were also seen in areas without FA abnormalities in 12 eyes. Higher mean retinal sensitivity correlated with greater mean cone density 0.5 mm from the center of the fovea (type 1: P = .010; type 2: P < .001)., Conclusions: Idiopathic macular telangiectasia type-specific differences in the distribution of photoreceptor abnormalities were shown in the AO-SLO images. For both idiopathic macular telangiectasia types 1 and 2, visual impairment was associated with cone damage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We previously reported that nanoceria can slow retinal degeneration in the tubby mouse for two weeks by multiple systemic injections. However, the long-term protection of retinal structure and function by directly deliver of nanoceria to the eye had not been explored. In this study, 172 ng of nanoceria in 1 μl saline (1 mm) were intravitreally injected into tubby P7 pups and assays were performed at P28, P49, P80 and P120. The expression of antioxidant associated genes and photoreceptor-specific genes was significantly up regulated, the mislocalization of rod and cone opsins was decreased, and retinal structure and function were protected. These findings demonstrate that nanoceria can function as catalytic antioxidants in vivo and may be broad spectrum therapeutic agents for multiple types of ocular diseases., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the relationship between the integrity of the photoreceptor microstructures and retinal sensitivity after half-dose photodynamic therapy (PDT) in eyes with chronic central serous chorioretinopathy (CSC)., Design: Prospective, noncomparative, interventional case series., Methods: Thirteen eyes of 13 patients with chronic CSC who had received half-dose verteporfin PDT were studied. The best-corrected visual acuity (BCVA), macular retinal sensitivity in the central 12 degrees, and optical coherence tomographic (OCT) findings were evaluated at baseline and at 1, 3, 6, and 12 months after the half-dose PDT. The integrities of the external limiting membrane (ELM), the inner segment/outer segment junction (IS/OS) line, and the cone outer segment tips (COST) line were determined. The retinal sensitivity was determined by MP-1 microperimetry., Results: The serous retinal detachment (SRD) was completely resolved in 11 eyes at 1 month and in 1 eye at 3 months. The remaining eye had a persistent SRD throughout the follow-up period. The mean retinal sensitivity was significantly better at 1, 3, 6, and 12 months after the half-dose PDT than at baseline. Before the PDT, 12 eyes had a continuous ELM and 1 eye had a fragmented ELM. The number of eyes with an intact IS/OS line and COST line increased with increasing post-PDT time. At 12 months after PDT, the IS/OS line was detected in 11 eyes and the COST line in 6 eyes. At 6 and 12 months, the retinal sensitivity was significantly higher in eyes with an intact COST line and IS/OS lines than in eyes with an intact IS/OS line only. However, no difference was found in the visual acuity of these 2 groups. The 1 eye with a persistent SRD and another eye with fragmented ELM and absent IS/OS and COST lines through the follow-up periods were associated with poor retinal sensitivity of 8.5 dB and 10.9 dB respectively., Conclusions: Our findings show that there is a significant improvement in the macular sensitivity after half-dose PDT in eyes with chronic CSC. The improvement was correlated with the recovery of the IS/OS and COST lines at 6 and 12 months., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To correlate visual function with high-resolution images of retinal structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 4 patients with acute zonal occult outer retinopathy (AZOOR)., Design: Observational case series., Methods: Four women, aged 18 to 51, with acute focal loss of visual field or visual acuity, photopsia, and minimal funduscopic changes were studied with best-corrected visual acuity (BCVA), Goldmann kinetic and automated perimetry and fundus-guided microperimetry, full-field and multifocal electroretinography (ffERG and mfERG), spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Cone spacing was measured in 4 eyes and compared with 27 age-similar normal eyes. Additional functional testing in 1 patient suggested that cones were absent but rods remained. Serum from all patients was analyzed for anti-retinal antibody activity., Results: In all patients vision loss was initially progressive, then stable. Symptoms were unilateral in 2 and bilateral but asymmetric in 2 patients. In each patient, loss of retinal function correlated with structural changes in the outer retina. AOSLO showed focal cone loss in most patients, although in 1 patient with central vision loss such change was absent. In another patient, structural and functional analyses suggested that cones had degenerated but rods remained. Anti-retinal antibody activity against a ∼45 kd antigen was detected in 1 of the patients; the other 3 patients showed no evidence of abnormal anti-retinal antibodies., Conclusions: Focal abnormalities of retinal structure correlated with vision loss in patients with AZOOR. High-resolution imaging can localize and demonstrate the extent of outer retinal abnormality in AZOOR patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the prognostic value of the cone outer segment tips (COST) and other features using spectral-domain optical coherence tomography (SD-OCT) in patients undergoing epiretinal membrane (ERM) surgery., Design: Retrospective observational case series., Methods: Fifty eyes of 49 patients that underwent vitrectomy for idiopathic ERM were studied. Best-corrected visual acuity (BCVA) and SD-OCT images were examined preoperatively and at 1 and 6 months postoperatively. The SD-OCT features evaluated included central foveal thickness (CFT) and the status and defect diameter of the external limiting membrane (ELM), the photoreceptor inner/outer segment (IS/OS) junction, and the COST line. The associations between SD-OCT parameters and BCVA were analyzed., Results: There was no ELM disruption found, and thus the eyes were categorized into 3 groups: Group A, with a continuous IS/OS and COST line; Group B, with a continuous IS/OS but disrupted COST line; and Group C, with a disrupted IS/OS and COST line. At 6 months, Group A showed a significantly better BCVA than Group B (P<.005), and poorer BCVA was noted in Group C (P=.034). Defect diameters of IS/OS and COST line were also significantly correlated with BCVA postoperatively. The BCVA at 6 months was better in order of Group A, B, and C as assigned at baseline (P<.05) or 1 month (P<.001). There was no significant correlation between CFT and BCVA., Conclusions: The status of the COST line, in conjunction with the IS/OS junction, is a useful prognostic factor after ERM surgery., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine whether a recovery of the microstructures of the foveal photoreceptors after macular hole closure is correlated with best-corrected visual acuity (BCVA)., Design: Retrospective, consecutive, observational case series., Setting: Single-center academic practice., Study Population: Forty-one eyes of 41 patients with surgically closed macular holes. OBSERVATIONAL PROCEDURES: The presence and intactness of the cone outer segment tips (COST) line were determined by spectral-domain optical coherence tomography and compared with the presence of the inner segment/outer segment (IS/OS) junction and the external limiting membrane (ELM) at 1, 3, 6, 9, and 12 months after the macular hole surgery., Main Outcome Measure: The correlation between the integrity of the foveal photoreceptor microstructures and the BCVA., Results: A distinct COST line was first seen at 6 months after the surgery. A distinct or irregular COST line was observed only in eyes with an intact IS/OS junction and ELM. Eyes with a distinct or irregular COST line had significantly better BCVA than those with a disrupted COST line in eyes with an intact IS/OS junction and ELM at 12 months (P = .030). The BCVA was ≥20/25 at 12 months in 91% of the eyes with a distinct or irregular COST line but in only 44% of the eyes without a COST line (P = .015)., Conclusions: The significant correlation between the BCVA and a distinct or irregular COST line after successful macular hole surgery indicates that the recovery of foveal cone microstructure is associated with good postoperative BCVA., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Cone photoreceptor breakdown underlies functional vision loss in many blinding diseases. Cone loss is often secondary to that of rods, but little experimental data are available on the relationship between the two populations. Because of its high cone numbers, we used the diurnal rodent Arvicanthis ansorgei to explore changes in rod and cone survival and function during chemically-induced retinal degeneration. Adult animals received intraperitoneal injections of N-methyl-N-nitrosourea (MNU), and changes in retinal fundus appearance, histology, phenotype, apoptosis (TUNEL staining) and functionality (scotopic and photopic electroretinography) were monitored as a function of post-treatment time and retinal topography. Relative to control animals injected with vehicle only, MNU-injected animals showed time-, region- and population-specific changes as measured by morphological and immunochemical criteria. Histological (gradual thinning of photoreceptor layer) and phenotypical (reduced immunostaining of rhodopsin and rod transducin, and mid wavelength cone opsin and cone arrestin) modifications were first observed in superior central retina at 11 days post-injection. These degenerative changes spread into the superior peripheral and inferior hemisphere during the following 10 days. Rod loss preceded that of cones as visualized by differential immunolabelling and presence of apoptotic cells in rod but not cone cells. By 3 months post-injection, degeneration of the photoreceptor layer was complete in the superior hemisphere, but only partial in the inferior hemisphere. Despite the persistence of cone photoreceptors, scotopic and photopic electroretinography performed at 90 days post-treatment showed that both rod and cone function were severely compromised. In conclusion, MNU-induced retinal degeneration in Arvicanthis follows a predictable spatial and temporal pattern allowing clear separation of rod- and cone-specific pathogenic mechanisms. Compared to other rodents in which MNU has been used, Arvicanthis ansorgei demonstrates pronounced resistance to photoreceptor cell loss., ((c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Age-related macular degeneration (AMD) is a complex disease that has potential involvement of inflammatory and oxidative stress-related pathways in its pathogenesis. In search of effective therapeutic agents, we tested curcumin, a naturally occurring compound with known anti-inflammatory and antioxidative properties, in a rat model of light-induced retinal degeneration (LIRD) and in retina-derived cell lines. We hypothesized that any compound effective against LIRD, which involves significant oxidative stress and inflammation, would be a candidate for further characterization for its potential application in AMD. We observed significant retinal neuroprotection in rats fed diets supplemented with curcumin (0.2% in diet) for 2 weeks. The mechanism of retinal protection from LIRD by curcumin involves inhibition of NF-kappaB activation and down-regulation of cellular inflammatory genes. When tested on retina-derived cell lines (661W and ARPE-19), pretreatment of curcumin protected these cells from H(2)O(2)-induced cell death by up-regulating cellular protective enzymes, such as HO-1, thioredoxin. Since, curcumin with its pleiotropic activities can modulate the expression and activation of many cellular regulatory proteins such as NF-kappaB, AKT, NRF2, and growth factors, which in turn inhibit cellular inflammatory responses and protect cells; we speculate that curcumin would be an effective nutraceutical compound for preventive and augmentative therapy of AMD.

Retinitis pigmentosa (RP) is a group of diseases in which many different mutations cause rod photoreceptor cells to die and then gradually cone photoreceptors die due to progressive oxidative damage. In this study, we have shown that peroxynitrite-induced nitrosative damage also occurs. In the rd1 mouse model of RP, there was increased staining for S-nitrosocysteine and nitrotyrosine protein adducts that are generated by peroxynitrite. Peroxynitrite is generated from nitric oxide (NO) and superoxide radicals. After degeneration of rods, injection of hydroethidine resulted in strong fluorescence in the retina of rd1 mice, indicating high levels of superoxide radicals, and this was reduced, as was nitrotyrosine staining, by apocynin, suggesting that overaction of NADP(H) oxidase is at least partially responsible. Treatment of rd1 mice with a mixture of nitric oxide synthase (NOS) inhibitors markedly reduced S-nitrosocysteine and nitrotyrosine staining and significantly increased cone survival, indicating that NO-derived peroxynitrite contributes to cone cell death. Treatment with 7-nitroindazole, a relatively specific inhibitor of neuronal NOS, also significantly reduced cone cell death, but aminoguanidine, a relatively specific inhibitor of inducible NOS, did not. These data suggest that NO generated by neuronal NOS exacerbates oxidative damage to cones in RP and that combined therapy to reduce NO and oxidative stress should be considered.

Mouse models of retinal degeneration are useful tools to study therapeutic approaches for patients affected by hereditary retinal dystrophies. We have studied degeneration in the rd10 mice both by immunocytochemistry and TUNEL-labeling of retinal cells, and through electrophysiological recordings. The cell degeneration in the retina of rd10 mice produced appreciable morphological changes in rod and cone cells by P20. Retinal cell death is clearly observed in the central retina and it peaked at P25 when there were 800 TUNEL-positive cells per mm(2). In the central retina, only one row of photoreceptors remained in the outer nuclear layer by P40 and there was a remarkable deterioration of bipolar cell dendrites postsynaptic to photoreceptors. The axon terminals of bipolar cells also underwent atrophy and the inner retina was subject to further changes, including a reduction and disorganization of AII amacrine cell population. Glutamate sensitivity was tested in rod bipolar cells with the single cell patch-clamp technique in slice preparations, although at P60 no significant differences were observed with age-matched controls. Thus, we conclude that rod and cone degeneration in the rd10 mouse model is followed by deterioration of their postsynaptic cells and the cells in the inner retina. However, the functional preservation of receptors for photoreceptor transmission in bipolar cells may open new therapeutic possibilities.

During normal ageing, photoreceptors of the human retina undergo various structural changes. We examined retinas from 33 donors (56 eyes; age span 13-94 years) by electron microscopy to see morphological changes in the cones with ageing. We show mitochondrial alterations and occurrence of electron-dense globules in the cone inner segments from the fifth decade of life. The globules are more prevalent in the macular cones than those in the mid-peripheral or nasal retinas (p<0.05) and absent in peripheral retinal cones and rods. They peak in the sixth decade and then decline in the seventh decade (p<0.05), from seventh to ninth decade, however, there was no significant change in their occurrence in the cones. We also show a type of inclusion, made up of bundled microtubules, which occur exclusively in the macular cones at the eighth decade of life. Evidence suggests that altered cone mitochondria with cristae remnants and dense matrix participate in globule formation in the ageing retina. Such mitochondrial changes may cause energy depletion, and bundling of microtubules (to form filamentous inclusions) could result in decreasing intracellular transport, in which case cones may die in the long run. These factors may be responsible for reported cone loss in the human retina with ageing.

The cone and cone-rod dystrophies form part of a heterogeneous group of retinal disorders that are an important cause of visual impairment in children and adults. There have been considerable advances made in recent years in our understanding of the pathogenesis of these retinal dystrophies, with many of the chromosomal loci and causative genes having now been identified. Mutations in 12 genes, including GUCA1A, peripherin/RDS, ABCA4 and RPGR, have been described to date; and in many cases detailed functional assessment of the effects of the encoded mutant proteins has been undertaken. This improved knowledge of disease mechanisms has raised the possibility of future treatments for these disorders, for which there are no specific therapies available at the present time.

Purpose: To describe the use of red contact lenses to alleviate photophobia in patients with cone disorders., Design: Retrospective interventional case series., Methods: Twenty-three patients with achromatopsia or an acquired cone disorder with complaints of severe photophobia were fit with absorptive red soft contact lenses to alleviate photophobia and improve their ability to use their remaining vision more effectively, Results: The contact lenses immediately resolved the aversion to light, with dramatic improvement in visual function in all patients (determined by observation of the patient and by patient report). It allowed eight patients to become eligible to drive., Conclusions: Red contact lenses successfully alleviate photophobia in patients with cone disorders.

We have used the P23H line 1 homozygous albino rat to study how progressive photoreceptor degeneration affects rod and cone relay pathways. We examined P23H retinas at different stages of degeneration by confocal microscopy of immunostained sections and electroretinogram (ERG) recordings. By 21 days of age in the P23H rat retina, there is already substantial loss of rods and reduction in rod bipolar dendrites along with reduction of metabotropic glutamate receptor 6 (mGluR6) and rod-associated bassoon staining. The cone pathway is relatively unaffected. By 150 days, when rods are absent from much of the retina, some rod bipolars remain and dendrites of rod and cone bipolar cells form synaptic complexes associated with cones and horizontal cell processes. These complexes include foci of mGluR6 and bassoon staining; they develop further by 270 days of age. Over the course of degeneration, beginning at 21 days, bipolar axon terminals atrophy and the inner retina undergoes further changes including a reduced and disorganized AII amacrine cell population and thinning of the inner plexiform layer. Electroretinogram (ERG) results at 23 days show reductions in a-wave amplitude, in rod and cone-associated b-waves (using a double flash paradigm) and in the amplitude of oscillatory potentials (OPs). By 38 days, rod scotopic a-wave responses and OPs are lost. B-wave amplitudes decline until 150 days, at which point they are purely cone-driven and remain stable up to 250 days. The results show that during the course of photoreceptor loss in the P23H rat, there are progressive degenerative changes, particularly in the rod relay pathway, and these are reflected in the changing ERG response patterns. Later reactive changes involving condensation of cone terminals and neurotransmitter receptors associated with rod and cone bipolar dendrites and with horizontal cell processes suggest that at this stage, there are likely to be complex changes in the relay of sensory information through the retina.

Purpose: To report a case of enhanced S-cone syndrome associated with subfoveal neovascularization., Design: Observational case report., Methods: A 23-year-old man, who was first examined at age 9 years, was found to have enhanced S-cone syndrome by clinical, electrophysiological, and molecular genetic examinations., Results: At 9 years of age, a subfoveal neovascularization was present in his right eye and corrected visual acuity was RE: 0.15 and LE: 1.0. After he was 20 years old, cystoid changes in the macula of the left eye appeared and visual acuity, in the left eye, decreased from 1.0 to 0.02., Conclusion: The clinical course of enhanced S-cone syndrome is progressive, and we suggest that the subretinal neovascularization is a phenotypic variation of enhanced S-cone syndrome.

Purpose: To report the cotransmission of retinitis punctata albescens (RPA) and congenital sensorineural deafness., Methods: Case reports of two siblings with nyctalopia and profound bilateral sensorineural deafness., Results: The affected siblings, an 11-year-old female and a 7-year-old male, presented with decreased visual acuity and night blindness. In both eyes of both siblings, ophthalmoscopic evaluation disclosed numerous white spots at the level of the retinal pigment epithelium with macular sparing. The rod threshold dark adaptation and electroretinogram tracings were consistent with advanced rod-cone degeneration., Conclusion: Two affected members of a family were found to exhibit RPA and congenital sensorineural deafness. This pedigree supports the genetic cotransmission of the traits.

Purpose: To report the histopathologic and immunohistochemical findings in autosomal dominant cone degeneration., Methods: The autopsy eyes of a 75-year-old man with autosomal dominant cone degeneration were studied with both light and electron microscopy. In addition, immunofluorescent studies using antibodies to cone opsins and cone alpha transducin were performed., Results: Histopathologic examination of the fovea disclosed loss of photoreceptors and attenuated retinal pigment epithelium. Reduced numbers of cones could be seen in the parafovea, and only occasional cones were visible in the periphery; rods were preserved in the periphery., Conclusion: The histopathologic and immunohistochemical findings in this case of dominantly inherited cone degeneration correlate well with the loss of cone function and preservation of normal or nearly normal rod function upon clinical examination. This condition affects red, green, and blue cones.

Purpose: Autosomal dominant cone degeneration is an uncommon disorder characterized by progressive photophobia, hemeralopia, decreased central vision, and dyschromatopsia. To better understand the variable expressivity of autosomal dominant cone degeneration, we studied a single, large family., Methods: We performed comprehensive ophthalmic examinations, full-field electroretinography, foveal electroretinography, and color vision studies on 73 family members., Results: Of the 73 family members, 34 were affected. Symptoms generally began in the first decade of life and slowly progressed into midlife. Ophthalmoscopic findings consisted primarily of macular granularity or central macular atrophy. The photopic full-field electroretinogram was important in establishing the diagnosis, although the results of the electroretinographic measurements varied across individuals. Either the foveal electroretinogram amplitudes were abnormally low or the foveal/parafoveal ratio was abnormal in all affected subjects., Conclusions: No single test or finding was completely sensitive or specific for accurate diagnosis of autosomal dominant cone degeneration. Especially in the more mildly affected subjects, a constellation of symptoms, findings, and test results were used to diagnose autosomal dominant cone degeneration accurately.

Purpose: We studied a single, large family with autosomal dominant cone degeneration in order to map the disease-causing gene., Methods: Seventy-three individuals in this family were examined, and 34 were found to be affected. Blood samples from 34 affected and unaffected family members were obtained for DNA analysis and linkage mapping. Fifty-three genetic markers were analyzed in this family by using short tandem repeat markers. These markers were primarily in candidate genomic regions., Results: Marker D17S796 generated a significantly positive LOD score of 4.21 (theta = .04; 10,000:1 odds in favor of linkage). Marker D17S513 gave a significant LOD score of 3.1 (theta = .096; 1,000:1 odds in favor of linkage). Other markers in the region generated suggestive findings, such as D17S786, with a LOD score of 2.7, and D17S945, with a LOD score of 2.41., Conclusions: Our results indicate that a genetic defect that causes autosomal dominant cone degeneration is located on chromosome 17p in the region of recoverin. Recoverin, a retinal expressed gene, is an appealing candidate for this disease.

Purpose: To compare the loss of ganglion cells to cone loss in the macular area of monkey eyes with experimental glaucoma., Methods: Experimental glaucoma was induced in eyes of three cynomolgus monkeys by argon laser applications to the trabecular meshwork. The average duration +/- S.D. of glaucoma in the experimental animals was 3.8 +/- 0.5 months. Glaucomatous damage was estimated, before the animals were killed, by evaluating stereoscopic photographs of the optic disk and red-free photographs of the nerve fiber layer. Ganglion cell nucleoli and cone pedicles were counted by using light microscopy from slides containing strips of retinal tissue. Cell density was then calculated by using the modified Abercrombie formula. Percent loss of ganglion cells and cones was determined from three eyes of three monkeys in 300-micron segments that were 900 to 1,200 microns superior and inferior to the foveal center., Results: Cone loss was not found at 4.5 to 6 degrees eccentricity above and below the fovea, whether damage was mild or severe. The average loss +/- S.D. of ganglion cells was 81.1% +/- 10.7%, whereas the average cone loss was only 3.5% +/- 6.4%., Conclusions: Marked parafoveal cone loss was not found in experimental glaucoma in which extensive damage to ganglion cells occurred.