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Objectives: To investigate the real-life experience of patients affected by neovascular age-related macular degeneration (nAMD), in the healthcare pathway for the management of the disease, using a "patient journey" and narrative method approach., Methods: The patient journey of subjects affected by nAMD was designed using a process-mapping methodology involving a team from 11 Italian centres. Subsequently, narratives were collected from nAMD patients and family members. The interviews were analyzed using the narrative medicine methodology., Results: Eleven specialized retina centres across Italy were involved and 205 narratives collected. In 29% of cases, patients underestimated their symptoms or attributed them to non-pathological causes, thus delaying the specialist consultation. The delay in accessing to care was due to a lack of awareness of this disease (50% of the participants didn't know what nAMD is) and to critical issues faced at first visit (long waiting lists, failed diagnosis, underestimation of the problem). Despite anti-VEGF therapies were perceived as effective in improving or stabilizing vision in 91% of narratives collected, 77% of patients still reduced or ceased daily activities such as reading and driving. Within the pathway of care there was not a multidisciplinary approach, and the patients were treated just by the ophthalmologist., Conclusions: nAMD may significantly affect the quality of life of affected patients, both from a functional and psychological point of view. The narrative medicine approach highlights some critical points in the healthcare journey of nAMD patients and represents a useful background in implementing patient management algorithms and pathways of care., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Von Hippel-Lindau (VHL) disease is a neoplastic syndrome caused by a mutation of the VHL tumor suppressor gene. Retinal hemangioblastoma (RH) is a vascularized tumor and represents the most common ocular manifestation of this disease. At the retinal level, VHL protein is able to regulate tumor growth, angiogenic factors, and neuroinflammation, probably stimulating retinal glial cells. The aim of the present study was to analyze in vivo the optical coherence tomography (OCT) biomarkers of retinal macroglia and microglia in a cohort of VHL patients., Methods: The mean thicknesses of macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL), and peripapillary retinal nerve fiber layer (pRNFL) were measured with OCT as biomarkers of retinal macroglia. OCT images were also analyzed to detect and quantify hyperreflective retinal foci (HRF), a biomarker of retinal activated microglia., Results: 61 eyes of 61 VHL patients (22 eyes (36.07%) with peripheral RH and 39 eyes (63.93%) without RH) and 28 eyes of 28 controls were evaluated. pRNFL was thinner in VHL patients ( p < 0.05) and in VHL without RH ( p < 0.01) compared to controls, and thicker in VHL patients with RH than in those without RH ( p < 0.05). The thickness of mRNFL ( p < 0.0001) and GCL ( p < 0.05) was reduced in VHL patients and in VHL without RH compared to controls, whereas mRNFL ( p < 0.0001) and GCL ( p < 0.05) were increased in VHL patients with RH compared to those without RH. HRF were significantly higher in number in VHL patients and in VHL without RH, than in controls, and significantly lower ( p < 0.05) in the eyes of VHL patients with RH, than in those without RH., Conclusions: The OCT analysis, which detects and allows to quantify the biomarkers of retinal microglia (HRF) and macroglia (pRNFL, mRNFL and GCL), showed a different behavior of these two retinal glial cells populations in VHL patients, related to the presence or absence of peripheral RH. These data allow to hypothesize a novel pathophysiologic pathway of retinal hemangioblastoma in VHL disease.

Purpose: This article aims to review the impact of detecting and quantifying intraocular biomarkers (liquid biopsy) in both aqueous and vitreous humor in eyes of people affected by diabetes mellitus., Methods: This is a detailed review about aqueous and/or vitreous humor sampling in human diabetic eyes for proteomic and/or metabolomic analysis contributing to the understanding of the pathophysiology and treatment effects of diabetic retinopathy., Results: Aqueous and vitreous humor molecular biomarkers proved to be directly correlated to each other and valuable to study retinal conditions. Moreover, proteomic and metabolomic analysis showed that the biomarkers of neuroinflammation, neurodegeneration, and vasculopathy are detectable in intraocular fluids and that their concentration changes in different stages of disease, and in response to treatment of all diabetic retinopathy aspects, mainly diabetic macular edema and proliferative retinopathy., Conclusions: Liquid biopsy offers the possibility to improve our knowledge of intraocular eye disease induced by diabetes mellitus. The exact quantification of intraocular biomarkers contributes to the precision medicine approach even in the diabetic retinopathy scenario. The diffusion of this approach should be encouraged to have quantifiable information directly from the human model, which may be coupled with imaging data., (© 2021. The Author(s).)

Von Hippel-Lindau (VHL) disease is an autosomal dominant genetic disease caused by VHL gene mutation. Retinal hemangioblastomas (RH) are vascularized tumors and represent the main ocular manifestation of the disease. Histopathologically, RH are composed of capillary vessels and stromal cells, the neoplastic population of the lesion. The origin of these stromal cells remains controversial, even if they are hypothesized to be glial cells. The aim of the present study was to investigate neuronal and microvascular changes of the peripapillary retinal nerve fiber layer, in which glial cells, neurons and capillaries (the radial peripapillary capillary plexus) interact. VHL patients with or without peripheral RH were enrolled and compared to healthy controls. Mean peripapillary retinal nerve fiber layer (pRNFL) thickness was measured by means of optical coherence tomography (OCT). The following vascular parameters of the radial peripapillary capillary plexus were quantified using OCT angiography: Vessel Area Density,Vessel Length Fraction, Vessel Diameter Index and Fractal Dimension. One hundred and nine eyes of 61 patients, and 56 eyes of 28 controls were consecutively studied. Mean pRNFL was significantly thinner in VHL eyes without RH versus eyes with RH and controls. Mean pRNFL thickness did not differ between VHL eyes with RH and controls. All OCTA vascular parameters were reduced in VHL eyes with or without RH versus controls, with significative difference for Vessel Diameter Index. The same OCTA parameters did not significantly differ between VHL eyes with or without RH. In VHL eyes without RH, pRNFL thinning may be the consequence of impaired perfusion of the radial peripapillary capillary plexus, while the increase of pRNFL thickness in VHL eyes with RH may depend on possible activation and proliferation of the other RNFL resident cells, the glial cells.

Purpose: To evaluate the changes in activity of biomarkers of Mu[Combining Diaeresis]ller cells (MC) in aqueous humor of patients with diabetic macular edema after subthreshold micropulse laser, over 1 year., Methods: Patients with untreated diabetic macular edema and central retinal thickness ≤ 400 μm were enrolled. Best-corrected visual acuity, full ophthalmic examination, and optical coherence tomography were performed. Subthreshold micropulse laser was applied every 3 months. Glial fibrillary acidic protein and inwardly rectifying potassium channel (Kir 4.1), MC activity markers, and vascular endothelial growth factor were quantified in the aqueous humor collected at baseline and at 1, 3, and 12 months after laser. Changes in the macular thickness and inner nuclear layer thickness, where MC bodies are located, were measured., Results: Ten eyes of 10 patients were included. Best-corrected visual acuity improved at 3 months (P = 0.047) and remained stable. Inner nuclear layer thickness significantly reduced at 12 months (P = 0.012). Glial fibrillary acidic protein, Kir 4.1, and vascular endothelial growth factor decreased at 1 and/or 3 and/or 12 months compared with baseline (P < 0.05)., Conclusion: Subthreshold micropulse laser improves visual function in diabetic macular edema. Kir 4.1 and glial fibrillary acidic protein decrease and inner nuclear layer thickness reduction demonstrate that subthreshold micropulse laser may restore MC function. Subthreshold micropulse laser also reduces vascular endothelial growth factor concentration. The effect of subthreshold micropulse laser in diabetic macular edema may in part be due to changes of MC metabolic activity.

Purpose: To better understand the pathophysiology of geographic atrophy (GA), secondary to age-related macular degeneration, eyes affected by unilateral GA (and CNV in the fellow eye; U-GA group) or by bilateral GA (B-GA group) were evaluated using an integrated morpho-functional approach and quantifying biomarker of retinal macroglial activity., Methods: Patients with U-GA and B-GA and foveal-sparing were consecutively enrolled in a prospective study. All included eyes underwent fundus photography, fundus autofluorescence (FAF), foveal retinal and choroidal thicknesses (RT, CT), contrast sensitivity, best-corrected visual acuity (BCVA), low-luminance VA (LLVA) and low-luminance deficit (LLD), and mesopic and scotopic microperimetry and multifocal electroretinography (mfERG). Glial fibrillary acidic protein (GFAP), biomarker of Müller cell activation, was quantified in the aqueous humor (AH)., Results: Forty eyes of 40 patients (18 in the U-GA group and 22 in the B-GA group) were studied. RT, GA area, BCVA, contrast sensitivity, mfERG, and microperimetry (at both background luminances) were not different between groups. CT was significantly thinner in U-GA compared to B-GA group (p = 0.020). Both LLVA and LLD were significantly worse in the B-GA vs U-GA group (p = 0.033 and p = 0.048, respectively). GFAP intraocular concentration was significantly higher in the B-GA group (p = 0.01)., Conclusions: Different pathophysiologic mechanisms may be responsible for GA in unilateral (with CNV in the fellow eye) compared to bilateral GA cases. In unilateral cases, a thinner choroid seems to play a key role. Whereas, in bilateral cases, Müller cells and their supported photoreceptors may be primarily involved.

Purpose: To investigate the pathophysiologic interrelations between retinal neural and vascular changes, detected by spectral-domain OCT (SD-OCT) and OCT angiography (OCTA), resulting from optic nerve axonal degeneration., Design: Institutional, observational, case-control study with prospective enrollment., Participants: Twenty-six patients affected by optic nerve axonal degeneration secondary to posterior optic pathway glioma (OPG) involving the chiasma, the postchiasmatic visual pathway, or both (but not involving optic nerves) and 24 gender- and age-matched healthy participants were included consecutively., Methods: Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study score) was measured and SD-OCT (Heidelberg Engineering, Heidelberg, Germany) and OCTA (Nidek RS-3000 Advance device; Nidek, Gamagori, Japan) were performed., Main Outcome Measures: Peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (GCC), and inner nuclear layer (INL) were analyzed using SD-OCT. The radial peripapillary capillary plexus, full-thickness peripapillary retina vascularization, and the macular superficial plexus (SCP) and deep capillary plexus (DCP) were analyzed using OCTA., Results: Peripapillary retinal nerve fiber layer and GCC thickness were reduced in eyes affected by OPG (P < 0.0001). Radial peripapillary capillary plexus perfusion also was reduced, as well as full-thickness peripapillary retina vascularization (P < 0.01 and P < 0.05, respectively). Macular DCP perfusion was reduced in eyes affected by OPG, whereas macular SCP perfusion did not differ between the 2 groups (P < 0.05 and P > 0.05, respectively). Global pRNFL thickness reduction correlated with the reduction of peripapillary perfusion (P < 0.01). Macular GCC thickness reduction did not correlate with SCP reduction (P > 0.05). The reduction of macular DCP perfusion did not correlate with inner nuclear layer thickness (P > 0.05)., Conclusions: Retinal neural remodeling secondary to optic nerve axonal degeneration resulting from OPG located at or posterior to the chiasm is accompanied by a secondary retinal vascular remodeling involving not only the peripapillary area, but also the macular area (DCP)., (Copyright © 2017. Published by Elsevier Inc.)

Purpose: To evaluate the prevalence, the vascular features, and the clinical diagnostic implication of retinal vascular abnormalities (RVAs) associated with neurofibromatosis Type 1 (NF1) in a large cohort of patients., Methods: Two hundred and ninety-four patients affected by NF1 were consecutively enrolled. The presence of RVAs was detected by means of infrared confocal scanning laser ophthalmoscopy images. Three hundred age- and race-matched healthy subjects were enrolled as a healthy control group. Fluorescein angiography, indocyanine green angiography, and optical coherence tomography angiography were also performed in patients with RVAs., Results: Retinal vascular abnormalities were detected in 18 patients with NF1 (6.1%) and in none of the healthy subjects. Retinal vascular abnormalities appeared in all cases as well-defined, small, tortuous retinal vessels with a spiral aspect, originating from small tributaries of retinal veins. The presence of RVAs did not correlate with the presence of other specific ocular or systemic NF1 features (P > 0.05). On optical coherence tomography angiography, RVAs appeared as an isolated tortuous vessel of the superficial vascular plexus in all cases, associated with localized anomalous crowded and congested capillary network of the deep vascular plexus in 75% of cases., Conclusion: Retinal vascular abnormalities are present in a limited proportion of patients affected by NF1 and can be considered an additional distinctive sign of the disease.

Aims: To evaluate the efficacy and duration of activity of a single intravitreal dexamethasone implant in patients affected by radiation maculopathy., Methods: Thirteen consecutive eyes of 13 patients affected by radiation maculopathy secondary to eye irradiation for a primary uveal melanoma (Iodine-125 brachytherapy) and treated with a single intravitreal 0.7 mg dexamethasone implant were retrospectively evaluated. Each patient underwent full ophthalmological examination, including fluorescein angiography and spectral domain optical coherence tomography (SD-OCT), even in en-face modality. Follow-up was performed monthly over a 6-month period., Results: At preinjection visit, the median central subfield thickness (CST) by SD-OCT was 407 µm (IQR, 357-524 µm) and the median best-corrected visual acuity (BCVA) was 61 ETDRS score (IQR, 54-67). The median gain of ETDRS letter at 1 month was 6.5 (IQR, 4-15) (p<0.01). The median CST showed a reduction of 120 µm (IQR, 62-134) (p<0.01). Further CST reduction was reported at 2 months' follow-up, with CST stabilisation at 3 months and maintenance of BCVA. At 4, 5 and 6 months' follow-up, all patients presented progressive retinal thickening (p<0.01) and BCVA reduction (p<0.01). No side effects were documented., Conclusion: Intravitreal dexamethasone implant reduces macular oedema secondary to radiation maculopathy and also improved visual acuity in a consistent proportion of patients. Signs of macular oedema recurrence may be detected at a median of 4 months after injection., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Diabetic retinopathy (DR) is a frequent complication of diabetes mellitus (DM). Persistent hyperglycemia leads to the activation of multiple cellular pathways involved in the pathogenesis of DR, resulting in increased inflammation, oxidative stress, and vascular dysfunction. DR has been considered a "chronic, low-grade inflammatory disease of the retina". However, an increasing body of evidence suggests that inflammation and neurodegeneration both occur in human diabetes even before the development of clinical signs of DR. One of the first signs of inflammation in DM is the activation of retinal glia cells (RGC). RGC include microglia and macroglial cells (Müller cells and astrocytes). Activated RGC release cytotoxic substances responsible for the recruitment of leukocytes, blood-retinal barrier breakdown, direct glial dysfunction, and neuronal cell death. Recently, many inflammatory mediators, growth factors, and other molecules have been investigated in human vitreous and aqueous humor samples to better understand, in vivo, the multiple pathways and mechanisms leading to the pathogenesis of DR and its complications, such as diabetic macular edema, with potential for more tailored treatment. Moreover, non-invasive techniques, like optical coherence tomography, have allowed to detect new findings in the retinal layers, such as the hyperreflective intraretinal spots, which have been hypothesized to represent an in vivo marker of microglial activation, and early neural cell loss, confirming the hypothesis that neurodegeneration occurs early both in type 1 and 2 diabetes. These new emerging insights foster a better understanding of the pathogenesis of DR, which can no longer be considered as a pure retinal vascular complication of DM., (© 2017 S. Karger AG, Basel.)

Objective: To compare static (during a pure fixation task) versus dynamic (during microperimetry) quantification of fixation stability using microperimetry in normal and pathologic eyes, by means of 2 available (clinical and bivariate contour ellipse area [BCEA]) classification methods., Design: Prospective comparative observational study., Participants: One hundred and forty-nine eyes (110 patients) with different macular diseases and 171 normal eyes (109 subjects)., Methods: In all eyes studied, fixation stability was acquired during an isolated fixation task (static fixation) and during microperimetry (dynamic fixation). All fixation data were analyzed and compared by means of a clinical classification and by means of BCEA quantification., Results: Pathologic eyes were classified as follows: 41 eyes with diabetic macular edema (DME group), 13 eyes with vitreoretinal interface disease, 60 eyes with age-related macular degeneration (AMD group), and 35 eyes with primary open-angle glaucoma. Fixation stability was not uniform among groups according to clinical classification in both static and dynamic modalities (p < 0.0001). AMD group showed larger BCEA areas compared with all other groups (p < 0.0001). All pathologic groups showed more unstable fixation in dynamic fashion according to both clinical and BCEA methods (p < 0.0001). The variation of fixation stability of control group in dynamic task was highlighted only by BCEA analysis (p < 0.0001). A deterioration of retinal fixation according to clinical method matches a significant increase in BCEA areas (p < 0.0001)., Conclusions: The detection of clinical fixation stability changes improves when acquired in the dynamic modality. BCEA analysis provides more accurate evaluation of fixation stability and may detect minimal quantitative changes of the fixation area. However, a standard clinical classification can also detect changes in fixation stability in pathologic eyes. Both methods are useful tools in the evaluation of fixation stability., (© 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze correlation among microperimetry, inner and outer retinal layers, and fundus autofluorescence (FAF) changes in eyes with progressing geographic atrophy (GA) secondary to age-related macular degeneration., Methods: Microperimetry, spectral-domain optical coherence tomography (SD-OCT), standard short-wavelength FAF (SW-FAF), and near-infrared-wavelength FAF (NIR-FAF) were performed for all patients at both baseline and follow-up visits. FAF pattern, integrity of photoreceptor inner segment/outer segment (IS/OS) junction, total retinal thickness (RT), inner retinal layers (IRL), and outer retinal layers (ORL) thickness changes of every microperimetry extrafoveal tested point were analyzed., Results: A total of 366 microperimetry tested points were analyzed (6 patients, 7 eyes). Mean retinal sensitivity significantly decreased (p = 0.0149), and the percentage of dense scotomas significantly increased (p = 0.0125). Mean RT and mean ORL thickness significantly decreased (both p < 0.0001). Mean IRL thickness significantly increased (p = 0.0001). The decrease of ORL thickness was inversely correlated to the IRL thinning (rho = -0.710). FAF pattern at baseline was correlated to RT and ORL thickness (both p < 0.0001) and was significantly correlated to the risk to evolve to dense scotoma during follow-up (p = 0.0001 at SW-FAF, p < 0.0001 at NIR-FAF). Tested points showing at baseline the loss of photoreceptor IS/OS junction had a greater risk for evolving to dense scotoma compared with those with intact photoreceptor IS/OS junction (odds ratio 3.56, 95% CI 2.41-5.27)., Conclusions: Retinal sensitivity changes are correlated to IRL and ORL thickness changes, and to photoreceptor IS/OS junction integrity. FAF patterns remain a relevant factor in predicting GA evolution. Microperimetry, SW-FAF and NIR-FAF, and SD-OCT should be combined to obtain adequate morphologic and functional prospective information., (© 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy and safety of prompt intravitreal triamcinolone acetonide injection (4 mg/0.1 mL) vs intravitreal bevacizumab injection (1.25 mg/0.05 mL) compared with observation in the management of extensive exudative retinal detachment secondary to posterior uveal melanoma., Design: Retrospective, nonrandomized, interventional case series., Methods: setting: Institutional. patients: Ninety-six patients affected by posterior uveal melanoma with large exudative retinal detachment (>10 mm in largest basal diameter) were included. intervention: Patients received intravitreal triamcinolone acetonide (32 eyes) or intravitreal bevacizumab (32 eyes) at plaque removal. Thirty-two patients served as controls (observation group). All groups were matched for age, sex, initial tumor thickness and largest basal diameter, largest exudative retinal detachment basal diameter, tumor location, and Bruch membrane rupture. Patients underwent monthly follow-up examinations in the first 6 months and every 3 months thereafter. Follow-up was longer than 24 months. main outcome measure: Exudative retinal detachment resolution (B-scan ultrasonography), steroid-induced cataract, steroid-induced increased IOP., Results: Follow-up was 37 ± 7 months. Marked exudative retinal detachment regression was documented in 22 (69%) intravitreal triamcinolone acetonide-treated vs 11 (34%) intravitreal bevacizumab-treated and 9 (28%) untreated eyes (P = .0007 and P = .0001, respectively). No statistical significance was found between intravitreal bevacizumab group vs observation group (P = .45) Steroid-induced cataract was observed in 4 intravitreal triamcinolone acetonide-treated patients (12%). Neither steroid-induced increased IOP nor other short- or long-term side effects were documented., Conclusion: Intraoperative intravitreal triamcinolone acetonide injection induces earlier and marked exudative retinal detachment resolution after brachytherapy of posterior uveal melanoma. Risk and benefit should be balanced vs steroid-induced cataract., (Copyright © 2013 Elsevier Inc. All rights reserved.)