Search

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. [ABSTRACT FROM AUTHOR]

We agree that also the analysis of the proteomic and metabolomic profiles of aqueous (AH) and vitreous humor (VH) in different stages and types of diabetes and their changes in response to different levels of metabolic control and treatments may be of great interest in the pathophysiology of diabetic eye damage, both from an ophthalmologic and systemic points of view. Dear Editor, We are grateful for the possibility to reply to the comment about our paper "Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy" proposed by Dmuchowska DA et al,. and we thank these authors for their interest in our work (1). Response to comment on "Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy.". [Extracted from the article]

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are multifactorial disorders that affect the macula and cause significant vision loss. Although inflammation and neoangiogenesis are hallmarks of DME and nAMD, respectively, they share some biochemical mediators. While inflammation is a trigger for the processes that lead to the development of DME, in nAMD inflammation seems to be the consequence of retinal pigment epithelium and Bruch membrane alterations. These pathophysiologic differences may be the key issue that justifies the difference in treatment strategies. Vascular endothelial growth factor inhibitors have changed the treatment of both diseases, however, many patients with DME fail to achieve the established therapeutic goals. From a clinical perspective, targeting inflammatory pathways with intravitreal corticosteroids has been proven to be effective in patients with DME. On the contrary, the clinical relevance of addressing inflammation in patients with nAMD has not been proven yet. We explore the role and implication of inflammation in the development of nAMD and DME and its therapeutical relevance., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. Vujosevic is a consultant for Abbvie, Boehringer and Ingelheim, Bayer, Novartis, Roche, Zeiss. C. Astarita and V. Gallinari are AbbVie employee and may own AbbVie stocks/options., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Achromatopsia (ACHM) is a rare autosomal, recessively inherited disease that is characterized by cone dysfunction, for which several gene therapies are currently on trial. The aim of this study was to find correlations between the morphological macular changes identified using optical coherence tomography (OCT) and some visual functional parameters. Visual acuity (VA), contrast sensitivity (CS), and macular sensitivity obtained by means of microperimetry were assessed. Methods: Adolescents with ACHM underwent macular microperimetry (S-MAIA device) in mesopic condition, macular OCT, best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), near vision acuity (NVA), and CS measurement. Results: Eight patients (15 eyes) with ACHM were analyzed. The mean age was 17 ± 2.7 years, and genetic variants involved the CNGA3 gene (37.5%) and CNGB3 gene (62.5%). OCT staging significantly correlated with microperimetry sensitivity parameters, namely the sensitivity of the central foveal point ( p = 0.0286) and of the first and second perifoveal rings ( p = 0.0008 and p = 0.0014, respectively). No correlations were found between OCT staging and VA measurements, nor with CS value. Conclusions: Among the extensive evaluated visual function tests, only microperimetry sensitivity showed a correlation with morphological macular changes identified at OCT. Microperimetry sensitivity may thus represent a useful visual function tool in natural ACHM history studies considering the upcoming research on gene therapies for the treatment of ACHM.

Histopathologic studies of diabetic choroid suggest that diabetic choroidopathy is a key aspect secondary to diabetes. Recently, hyperreflective choroidal foci (HCF) have been introduced as novel optical coherence tomography (OCT) parameter. The aim of this study was to identify and quantify HCF in diabetic subjects with retinopathy, with or without diabetic macular edema (DME). Eighty-five diabetic subjects with different degrees of DR were enrolled: 37 without DME and 48 with DME. All subjects underwent full ophthalmologic examination including spectral domain optical coherence tomography (OCT). OCT images were analyzed to quantify and localize HCF. Each image was analyzed by two independent, masked examiners. OCT images showed that all subjects (100%) had HCF in the different layers of the choroid. The number of HCF was significantly higher in diabetics with DME versus those without DME (p < 0.0001). HCF showed variable size, shape and location inside the choroid. They were mainly located in choriocapillaris and Sattler's layer, on the edges of blood vessels. The intraobserver and interobserver agreement was almost perfect (ICC >0.9). This study suggests that hyperreflective foci in the choroid of subjects with DR may be accurately identified with structural OCT. Their number significantly increases with the progression of DME. These HCF may represent, as in the retina, a sign of infiltration of inflammatory cells (mainly migrating microglia) into the choroid, according to the hypothesis raised by Jerry Lutty. HCF may confirm in vivo the histopathologic findings suggesting that diabetic choroidopathy may be primarily a neuroinflammatory disorder., Competing Interests: Declaration of competing interest The authors declare no relevant conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Geographic atrophy (GA), the atrophic late stage of age-related macular degeneration (AMD), is one of the leading causes of vision loss in developed countries. Based on genetic, histological and preclinical studies, the role of the innate immune system in the development and progression of GA is well established. Microglia, the principal resident immune cells, are recognized as key players in innate immunity and contributors to AMD development. Optical coherence tomography (OCT) allows to identify small hyperreflective retinal foci (HRF) with specific features known as aggregates of activated microglial cells as possible in vivo imaging feature of local neuroretinal inflammation. The purpose of this study was to evaluate the presence and amount of small HRF in the eyes of patients with different macular atrophic phenotypes. Patients with GA in both eyes (bilateral GA: B-GA group), patients with GA in one eye and macular new vessels (MNV) in the fellow-eye (unilateral GA: U-GA group) and patients with extensive macular atrophy with pseudodrusen (EMAP), a rare and aggressive variant of atrophic AMD, were retrospectively analyzed. HRF, defined as isolated punctiform elements of small dimensions (≤30 μm) with intermediate reflectivity (similar to that of the nerve fiber layer) and without a shadow cone, were manually identified and quantified. The amount of HRF was correlated to best corrected visual acuity (BCVA), GA lesion size, measured both at near infrared reflectance (NIR), and blue wavelength fundus autofluorescence (FAF) images, to some GA features (multifocal versus unifocal GA; presence versus absence of foveal sparing) and to central retinal thickness (CRT). Forty-six patients (26 in the B-GA group, 16 in the U-GA group and 4 in the EMAP group) were studied. Patients with EMAP were younger compared to patients with B-GA and to patients with U-GA (63.5 ± 6.8 years vs 80.4 ± 8.4 years B-GA, and vs 83.3 ± 6.1 years U-GA; p = 0.0004 and p= <0.0001, respectively). Mean BCVA, mean GA area at NIR and at FAF images, foveal sparing and multifocal versus unifocal GA distribution and mean CRT were not significantly different among groups. GA area was wider on NIR versus FAF in all groups, significantly in B-GA and U-GA groups (11.7 ± 7.6 mm 2 vs 10.6 ± 7.1 mm 2 , p = 0.0087 in B-GA; 7.8 ± 9.2 mm 2 vs 7.7 ± 9.4 mm 2 , p = 0.004 in U-GA). The number of HRF was significantly higher in U-GA compared to B-GA and to EMAP (47.4 ± 7.1 vs 31.6 ± 7.3 B-GA and 28.0 ± 4.9 EMAP, p < 0.0001 for both), while mean HRF number did not significantly differ between B-GA and EMAP (p = 0.1960). HRF count correlated only to CRT, positively in B-GA and negatively in U-GA group. The increase of small HRF, which mirrors retinal microglial activation, characterizes eyes with unilateral GA (and MNV in the fellow eye) but not eyes with bilateral GA or EMAP. The role of activated microglia in the retina of GA eyes needs to be better investigated, mainly considering the actual and new therapeutic strategies with which to reduce either the development or progression of the atrophic macular changes., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug's mechanism of intrathecal action., Objective: To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS., Materials and Methods: The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months., Results: HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12., Conclusion: In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology., Competing Interests: MPu, report travel grants, consultancy, and board membership from Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, Bristol Myers Squibb, Janssen, and Alexion. EB, MPo, AM, EP, and FB have nothing to disclose. VM reports travel grants from Sanofi Genzyme, Biogen, and Viatris. PP reports grants from Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, Roche, Alexion, Janssen, Brystol Mayer Squibb; consultancy for Novartis, Biogen Italy, Sanofi Genzyme, Roche, Janssen, Brystol Mayer Squibb. FR report grants from Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, consultancy for Novartis, Biogen Italy, Sanofi Genzyme. PG reports grant, consultancy, and board membership for Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, Roche, Bristol Myers Squibb, Janssen, and Alexion., (Copyright © 2024 Puthenparampil, Basili, Ponzano, Mauceri, Miscioscia, Pilotto, Perini, Rinaldi, Bovis and Gallo.)

This study aimed to assess outer retinal layer (ORL), retinal pigment epithelium (RPE), choroid (Ch) and choriocapillaris (CC) modifications in adolescents with long-lasting (>10 years) type 1 diabetes (T1D) without (noDR) or with diabetic retinopathy (DR). ORL and RPE thickness were measured at optical coherence tomography (OCT) macular scans. Vascular parameters of Ch and CC were quantified after elaboration of macular OCT-angiography (OCTA) images. Insulin dose and auxological and metabolic parameters were correlated with OCT and OCTA findings in patients. ORL thickness was higher in DR eyes than in noDR and healthy controls (HC), and RPE thickness was higher in noDR and DR eyes than in HC, with statistical significance for some sectors in noDR versus HC. No OCTA parameters of CC and Ch differed among groups, and no significant correlation was observed with auxological and metabolic parameters. In conclusion, ORL and RPE were both increased in adolescents with long-lasting T1D. Such changes were not associated with insulin dose and glycemia control, nor to any choroid or choriocapillaris flow change clinically detectable at OCTA, and they could be potential imaging biomarkers of disease progression.

Purpose: To report and investigate proptosis in a young girl with Noonan syndrome., Methods: Observational case report., Results: A 16-year-old girl affected by Noonan syndrome underwent a complete ophthalmological examination showing bilateral proptosis with hypofunction of lateral rectus and superior oblique muscles. Visual acuity, color discrimination and fundus examination were unremarkable. The orbital MRI showed bilateral proptosis and symmetrical enlargement of extraocular muscles, with bellies thickening and tendon sparing. The young patient also complained restrictive hypertrophic cardiomyopathy., Conclusions: Proptosis is an uncommon ocular manifestation of Noonan syndrome and its pathophysiology has never been clarified. The MRI evidence of extraocular muscles enlargement associated with hypertrophic cardiomyopathy, led us to hypothesize a common altered pathway beneath these features, more specifically the MAP kinase pathway, since extraocular and cardiac muscles share a mesenchymal embryological origin.

Purpose: von Hippel-Lindau (VHL) disease is caused by a mutation of the VHL gene and characterized by the development of retinal hemangioblastomas (RH). Current pathophysiologic mechanisms of RH development and progression are still insufficient to predict RH behavior. VHL gene is involved in the cellular response to hypoxia and in many intracellular signaling pathways expressed both in angiogenesis and inflammation. Optical coherence tomography (OCT) allows to identify hyper-reflective retinal foci (HRF) known as aggregates of activated microglial cells as possible in vivo biomarker of local inflammation. The aim of the present study was to investigate the presence of HRF in patients with genetically confirmed VHL disease., Methods: In this cross-sectional study, patients with VHL underwent complete ophthalmological examination and OCT with HRA + OCT Spectralis. HRF were manually identified and calculated in inner (IR), outer (OR) and full retina. Age-matched healthy subjects were enrolled as controls., Results: 113 eyes of 63 VHL patients and 56 eyes of 28 healthy subjects were evaluated. HRF number was significantly higher in VHL than in controls in IR (28.06 ± 7.50 vs 25.25 ± 6.64, p = 0.042). No difference was observed in OR and in full retina (OR: 7.73 ± 2.59 vs 7.95 ± 2.51, p = 0.599; full retina: 35.79 ± 8.77 vs 33.20 ± 7.47, p = 0.093)., Conclusion: The increase of HRF, which mirror retinal microglial activation, characterizes VHL eyes. The role of activated microglia in the retina of VHL eyes needs to be better investigated, mainly considering local VHL disease manifestations., Competing Interests: The authors have declared that no competing interests exist.

The study retraces the healthcare pathway of patients affected by diabetic macular edema (DME) through the direct voice of patients and caregivers by using a "patient journey" and narrative method approach. The mapping of the patient's journey was developed by a multidisciplinary board of health professionals and involved four Italian retina centers. DME patients on intravitreal injection therapy and caregivers were interviewed according to the narrative medicine approach. Narratives were analyzed through a quali-quantitative tool, as set by the narrative medicine method. The study involved four specialized retina centers in Italy and collected a total of 106 narratives, 82 from DME patients and 24 from caregivers. The narratives reported their difficulty in identifying the correct pathway of care because of a limited awareness of diabetes and its complications. Patients experienced reduced autonomy due to ocular complications. In the treatment of diabetes and its complications, a multidisciplinary approach currently appears to be missing. DME reduces the quality of life of affected patients. The narrative medicine approach offers qualitative and emotional patient-guided information. The patient journey provides all of those involved in the management of DME with flowcharts to refer to, identifying the critical points in the healthcare journey of DME patients to improve the management of the disease.

The purpose of this study was to evaluate retinal changes in adolescents with childhood-onset, long-lasting type 1 diabetes mellitus (T1D). Patients and healthy controls (HC) underwent optical coherence tomography (OCT) and OCT-angiography (OCTA). Individual macular layers, peripapillary retinal nerve fiber layer (pRNFL), and vascular parameters (vessel area density (VAD), vessel length fraction (VLF) and vessel diameter index (VDI)) of macular superficial vascular (SVP), intermediate (ICP), deep (DCP) and radial peripapillary capillary plexuses (RPCP) were quantified. Thirty-nine patients (5 with (DR group) and 34 without (noDR group) diabetic retinopathy) and 20 HC were enrolled. The pRNFL and ganglion cell layer (GCL) were thicker in noDR compared to HC and DR, reaching statistically significant values versus HC for some sectors. At the macular level, VAD and VLF were reduced in DR versus HC in all plexuses, and versus noDR in SVP (p < 0.005 for all). At the RPCP level, VAD and VDI were increased in noDR versus HC, significantly for VDI (p = 0.0067). Glycemic indices correlated to retinal parameters. In conclusion, in T1D adolescents, retinal capillary and neuronal changes are present after long-lasting disease, even in the absence of clinical DR. These changes modify when clinical retinopathy develops. The precocious identification of specific OCT and OCTA changes may be a hallmark of subsequent overt retinopathy.

Background and Objectives: Microglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS)., Methods: At baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study., Results: Compared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count ( p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA ( p = 0.017) and rNEDA ( p = 0.002)., Discussion: We found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation., Classification of Evidence: This study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Increasing evidence suggests that retinal hyper-reflecting foci (HRF) might be clusters of activated and proliferating microglia. Since microglia are widespread activated in multiple sclerosis (MS) brain, its evaluation in retina may help to understand and monitor MS-related pathology., Aim: This study aims at investigating the association of HRF with cerebrospinal fluid (CSF) cytokines and MRI parameters in relapsing-remitting MS (RRMS)., Methods: Nineteen RRMS at clinical onset and 15 non-inflammatory neurological disorders (NIND) underwent brain 3T MRI and CSF examination. Optical coherence tomography (OCT) analysis, including HRF count, was performed on RRMS patients. Sixty-nine cytokines/chemokines were analyzed in the CSF by multiplex technology., Results: In RRMS, HRF count in the ganglion cell layer (GCL) was associated with IL-1Ra, IL-9, IL-15, IFN-γ, and G-CSF. Moreover, in RRMS patients CSF concentrations of IL-1Ra and G-CSF associated with global cortical thickness. The HRF count in the inner nuclear layer (INL) correlated with IL-22, IL-34, IL-35, CXCL-2, CXCL-10, and CXCL-13, and multivariate analysis confirmed a strong association (r 2 : 0.47) with both CXCL-2 (β: -0.965, p = 0.0052) and CXCL-13 (β: 0.241, p = 0.018). This latter cytokine increased in RRMS with high HRF count compared with NIND and RRMS with low HRF count. Finally, the CXCL-13/CXCL-2 ratio strongly associated with HRF count (r: 0.8, p < 0.005) and cortical lesion volume (r: 0.5, p < 0.05)., Conclusions: The association of HRF with intrathecally produced monocyte/microglia-derived cytokines confirms their microglial origin and indicates they are worth further evaluating as markers of activated microglia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Puthenparampil, Torresin, Franciotta, Marin, De Napoli, Mauceri, Miante, Pilotto, Midena and Gallo.)

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.)

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.)