Ophthalmological involvement in wild-type transthyretin amyloidosis: A multimodal imaging study.

BACKGROUND AND AIMS: Ophthalmological abnormalities have been reported in hereditary transthyretin-related amyloidosis (ATTRv, v for variant) but not in wild-type transthyretin-related amyloidosis (ATTRwt). METHODS: Patients with ATTRwt, ATTRv, and light chain amyloidosis (AL) and healthy subjects (controls) underwent complete eye examination, including optical coherence tomography (OCT), OCT angiography (OCTA), and in vivo corneal confocal microscopy (CCM). RESULTS: Seventeen ATTRwt, nine ATTRv, two ATTRv carriers, and seven AL patients were enrolled. Compared with other groups, ATTRwt patients had 10 letters lower visual acuity and a higher prevalence of glaucoma, cataract, and retinal pigment epithelium alterations. In the whole group of patients, especially in ATTRwt, we observed (1) a reduced corneal nerve fiber length and more tortuous stromal nerves at CCM, (2) a reduced macular volume and peripapillary nerve fiber layer thickness at OCT, and (3) impairment of peripapillary and macular vascularization at OCTA. INTERPRETATION: Ophthalmological abnormalities are common in ATTRwt, significantly impairing visual acuity. Noninvasive imaging modalities allow for the identification of small nerve fibers and small vessel damage, which may represent further warning signs for early diagnosis of ATTRwt.

Additional measures of macular function beyond visual acuity.

PURPOSE: Visual function is a complex process in which external visual stimuli are interpreted. Patients with retinal diseases and prolonged follow-up times may experience changes in their visual function that are not detected by the standard visual acuity measure, as they are a result of other alterations in visual function. With the advancement of different methods to evaluate visual function, additional measurements have become available, and further standardization suggests that some methods may be promising for use in clinical trials or routine clinical practice. The objectives of this article are to review these additional measurements and to provide guidance on their application. METHODS: The Vision Academy's membership of international retinal disease experts reviewed the literature and developed consensus recommendations for the application of additional measures of visual function in routine clinical practice or clinical trials. RESULTS: Measures such as low-luminance visual acuity, contrast sensitivity, retinal fixation and microperimetry, and reading performance are measures which can complement visual acuity measurements to provide an assessment of overall visual function, including impact on patients' quality of life. Measures such as dark adaptation, color vision testing, binocular vision testing, visual recognition testing, and shape discrimination require further optimization and validation before they can be implemented in everyday clinical practice. CONCLUSION: Additional measurements of visual function may help identify patients who could benefit from earlier diagnosis, detection of disease progression, and therapeutic intervention. New and additional functional clinical trial endpoints are required to fully understand the early stages of macular disease, its progression, and the response to treatment.

The Disorganization of Retinal Inner Layers Is Correlated to Müller Cells Impairment in Diabetic Macular Edema: An Imaging and Omics Study.

The disorganization of retinal inner layers (DRIL) is an optical coherence tomography (OCT) biomarker strictly associated with visual outcomes in patients with diabetic macular edema (DME) whose pathophysiology is still unclear. The aim of this study was to characterize in vivo, using retinal imaging and liquid biopsy, DRIL in eyes with DME. This was an observational cross-sectional study. Patients affected by center-involved DME were enrolled. All patients underwent spectral domain optical coherence tomography (SD-OCT) and proteomic analysis of aqueous humor (AH). The presence of DRIL at OCT was analyzed by two masked retinal experts. Fifty-seven biochemical biomarkers were analyzed from AH samples. Nineteen eyes of nineteen DME patients were enrolled. DRIL was present in 10 patients (52.63%). No statistically significant difference was found between DME eyes with and without DRIL, considering the AH concentration of all the analyzed biomarkers except for glial fibrillary acidic protein (GFAP), a biomarker of Müller cells dysfunction (p = 0.02). In conclusion, DRIL, in DME eyes, seems to strictly depend on a major dysfunction of Müller cells, explaining its role not only as imaging biomarker, but also as visual function Müller cells-related parameter.

RADIATION MACULOPATHY IS ANTICIPATED BY OCT HYPERREFLECTIVE RETINAL FOCI: A Large, Prospective, Confirmation Study.

PURPOSE: To investigate, by means of spectral domain optical coherence tomography, retinal reflectivity changes as an early biomarker anticipating radiation-induced macular edema (ME) in patients treated by iodine-125 (I-125) brachytherapy. METHODS: Thirty patients planned for I-125 brachytherapy because of uveal melanoma were prospectively included and followed every 4 months for five years. Reflectivity alterations, namely hyperreflective retinal foci, were characterized and counted by two independent masked examiners by means of spectral domain optical coherence tomography imaging. Hyperreflective retinal foci were defined as discrete intraretinal reflectivity changes ≤30 µm, with reflectivity similar to nerve fiber layer and without back shadowing. RESULTS: Macular edema occurred in 17 patients (24.2 ±15.1 months) (group 1) after irradiation. Thirteen patients showed no signs of ME at the 5-year follow-up (group 2). The number of hyperreflective retinal foci was statistically higher in sequential visits until the evidence of ME in group 1 vs group 2 (P < 0.0001). In group 1, hyperreflective retinal foci at the follow-up before the evidence of ME were significantly related to the OCT central subfield thickness at ME appearance (P = 0.0002, r2=0.6129). The intergrader agreement was almost perfect (intraclass correlation coefficient = 0.80). CONCLUSION: Hyperreflective retinal foci may be considered as an early in vivo imaging biomarker of retinal inflammatory response to ocular irradiation, anticipating the development of radiation maculopathy.

Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy.

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.

RETINAL VASCULAR ABNORMALITIES RELATED TO NEUROFIBROMATOSIS TYPE 1: Natural History and Classification by Optical Coherence Tomography Angiography in 473 Patients.

PURPOSE: To analyze and classify neurofibromatosis Type 1 (NF1)-related retinal vascular abnormalities (RVAs), their natural history and correlation with disease severity, in a large cohort of patients. METHODS: This was an observational longitudinal study with prospective enrollment. Four hundred and seventy-three patients affected by NF1 and 150 age-matched healthy subjects were consecutively enrolled. Retinal vascular abnormalities were detected by means of near-infrared reflectance and studied by optical coherence tomography angiography. The superficial vascular plexus and the deep vascular complex (DVC) were quantitatively and qualitatively analyzed. RESULTS: We identified RVAs in 82 of 473 (17%) NF1 patients, but in none of the 150 healthy subjects. A comparison revealed that NF1 patients with RVAs showed a higher number of NF1 diagnostic criteria (4.3 ± 1.5 vs. 3.9 ±1.5, respectively; P = 0.02) than patients without RVAs. Three different RVA types were identified on optical coherence tomography angiography: macrovascular angiomatosis of the sole superficial vascular plexus; macrovascular angiomatosis of the superficial vascular plexus combined with microvascular angiomatosis of the deep vascular complex; and combined macrovascular angiomatosis of both superficial vascular plexus and deep vascular complex. The prospective analysis of optical coherence tomography angiography images showed no significant longitudinal evolution of RVAs (mean follow-up: 3.7 ± 2.8 years). A single patient developed a de novo single RVA, and two RVAs showed detectable changes during follow-up. CONCLUSION: In NF1 patients, RVAs are a characteristic sign that correlates with a more severe systemic disease expression, usually remaining stable during time. Optical coherence tomography angiography allows for the identification of different RVAs subtypes.

EFFICACY AND SAFETY OF INTRAVITREAL AFLIBERCEPT USING A TREAT-AND-EXTEND REGIMEN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: The ARIES Study: A Randomized Clinical Trial.

BACKGROUND/PURPOSE: Treating neovascular age-related macular degeneration with intravitreal aflibercept treat-and-extend (T&E) can reduce treatment burden. ARIES assessed whether intravitreal aflibercept early-start T&E was noninferior to late-start T&E. METHODS: A randomized, open-label, Phase 3b/4 study that included treatment-naïve patients aged ≥50 years with the best-corrected visual acuity 73-25 Early Treatment Diabetic Retinopathy Study letters and active choroidal neovascularization secondary to AMD. Patients received 2 mg intravitreal aflibercept at Week (W) 0, W4, W8, and W16. At W16, patients were randomized 1:1 to early-start (2W interval adjustments) or late-start T&E (8W intervals until W48 then 2W interval adjustments). Primary endpoint: the best-corrected visual acuity change from randomization to W104. RESULTS: Two-hundred seventy-one patients were randomized. The mean (SD) best-corrected visual acuity at baseline was 60.2 (12.1; early-T&E) and 61.3 (10.8; late-T&E) letters. The mean (SD) best-corrected visual acuity change (W16-104) was -2.1 (11.4) versus -0.4 (8.4) letters (early-T&E vs. late-T&E; least-squares mean difference: -2.0; 95% confidence interval: -4.75 to 0.71; P = 0.0162 for noninferior); +4.3 (13.4) versus +7.9 (11.9) letters (W0-104). The mean (SD) number of injections was 12.0 (2.3) versus 13.0 (1.8). From baseline to W104, 93.4% and 96.2% maintained best-corrected visual acuity; the mean (SD) central retinal thickness change was -161.6 (135.6) µm and -158.6 (125.1) µm. The last injection interval (W104) was ≥12W for 47.2% and 51.9% of patients. CONCLUSION: Outcomes were similar between patients with neovascular age-related macular degeneration treated with an intravitreal aflibercept early-T&E or late-T&E regimen after initial dosing, with one injection difference over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02581891 https://clinicaltrials.gov/ct2/show/NCT02581891. Supplemental Digital Contents (files 1 http://links.lww.com/IAE/B419).

Standardization of Optical Coherence Tomography Angiography Imaging Biomarkers in Diabetic Retinal Disease.

Optical coherence tomography Angiography (OCT-A) represents a revolution in the noninvasive evaluation of retinal and choroidal circulation especially in detecting early clinical signs of diabetic retinal disease (DRD). With appropriate use, OCT-A characteristics and measurements have the potential to become new imaging biomarkers in managing and treating DRD. Major challenges include (a) provision of standardized outputs from different OCT-A instruments providing standardized terminology to correctly interpret data; (b) the presence of artifacts; (c) the absence of standardized grading or interpretation method in the evaluation of DRD, similar to that already established in fundus photography; and (d) establishing how OCT-A might be able to provide surrogate markers to demonstrate blood retinal barrier breakdown and vascular leakage, commonly associated with DRD. In fact, OCT-A guidelines for DRD are still evolving. The outputs of quantitative OCT-A data offer a unique opportunity to develop tools based on artificial intelligence to assist the clinicians in diagnosing, monitoring, and managing patients with diabetes. In addition, OCT-A has the potential to become a useful tool for the evaluation of cardiovascular diseases and different neurological diseases including cognitive impairment. This article written by the members of Diabetic Retinopathy expert committee of the European Vision Clinical Research network will review the available evidence on the use of OCT-A as an imaging biomarker in DRD and discuss the limits and the current application as well as future developments for its use in both clinical practice and research trials of DRD.

A possible strategic role of air during pars plana vitrectomy for macula-involving rhegmatogenous retinal detachment.

AIM: To evaluate the advantages and safety of vitrectomy under air for treating macula-involving rhegmatogenous retinal detachment (RRD). METHODS: Consecutive patients with macula-involving RRD who underwent vitrectomy under air were recruited. Demographic and clinical data were: age, gender, eye, lens status, best corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR), axial length, intraocular pressure (IOP). RRD parameters were: RRD extent, retinal breaks number. Surgical data were: cataract surgery, tamponade used. Postoperative parameters were: BCVA, IOP at first, third, sixth month, recurrent RD, incidence of retinal folds, subretinal fluid (SRF) persistence, macular displacement. RESULTS: Seventy-one eyes (71 patients) were recruited. Cataract surgery was performed in 32 of 45 phakic patients. The tamponade used was: sulfur hexafluoride 18% (41), silicon oil (SO) (26), high-density SO (4). BCVA improved significantly from baseline (1.2 ± 0.4 logMAR) to the last control (0.8 ± 0.7 logMAR) (P = 0.03285). Recurrent RD incidence was 14.1%. Postoperative complications were: retinal folds (2), SRF persistence (3), macular displacement (2). CONCLUSION: Vitrectomy under air is a safe alternative technique for treating macula-involving RRD. Vitrectomy under air allows surgeon to remove accurately the vitreous from the peripheral retina and facilitates the removal of SRF reducing the complications related to its postoperative persistence.

MORPHOFUNCTIONAL EVALUATION OF MACULAR-FOVEAL CAPILLARIES: A Comparative Optical Coherence Tomography Angiography and Microperimetry Study.

PURPOSE: To analyze the macular function of eyes with macular-foveal capillaries (MFC), a condition characterized by the absence of the foveal avascular zone (FAZ), identified by optical coherence tomography angiography. METHODS: Eight eyes with MFC at optical coherence tomography angiography and normal visual acuity were consecutively recruited. Eight eyes of healthy subjects were enrolled as healthy controls. All eyes underwent optical coherence tomography, optical coherence tomography angiography, best-correct visual acuity, low-luminance visual acuity, contrast sensitivity measurement, colour vision tests, and both mesopic and scotopic microperimetry. RESULTS: Best-corrected visual acuity, low-luminance visual acuity, contrast sensitivity, and colour vision tests did not differ between the two groups. At mesopic microperimetry, both foveal retinal sensitivity and mean mesopic retinal sensitivity of the central 1° were statistically inferior in MFC versus control eyes (P < 0.0001 and P < 0.0001, respectively). At scotopic microperimetry, a dense foveal scotoma, normally present in control eyes, was completely lacking in MFC eyes. Scotopic foveal retinal sensitivity was statistically superior in MFC versus control eyes (P = 0.009). CONCLUSION: The absence of the foveal dense scotoma in scotopic conditions underlines that the foveal rod-free zone is not present when capillaries are present in this area. An anomalous foveal distribution of photoreceptors, with both rods and cones present in this area, may be postulated in MFC eyes.

CHANGES OF AQUEOUS HUMOR MÜLLER CELLS' BIOMARKERS IN HUMAN PATIENTS AFFECTED BY DIABETIC MACULAR EDEMA AFTER SUBTHRESHOLD MICROPULSE LASER TREATMENT.

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.

IDENTIFICATION AND CLASSIFICATION OF MACULAR MORPHOLOGIC BIOMARKERS RELATED TO VISUAL ACUITY IN RADIATION MACULOPATHY: A Multimodal Imaging Study.

PURPOSE: To identify and classify, by a multimodal imaging approach, the most relevant macular morphologic biomarkers related to visual acuity in patients affected by radiation maculopathy secondary to brachytherapy. METHODS: Fifty-one consecutive patients previously treated with Iodine-125 brachytherapy because of uveal melanoma were enrolled. Each patient underwent full ophthalmologic examination including best-corrected visual acuity and multimodal macular imaging analysis. Macular morphological parameters were processed by a stepwise selection analysis. RESULTS: Three macular parameters were identified as the most relevant macular morphologic biomarkers of poor visual acuity: the vertical thickness of the thickest macular cyst (P = 0.0001), the presence of foveal inner segment/outer segment (IS/OS) layer disruption (P = 0.0054), and the presence of foveal retinal pigment epithelium atrophy (0.0884). The intergrader agreement for these morphologic biomarkers was 0.98, 0.92, and 0.92, respectively (interclass correlation coefficient). CONCLUSION: The vertical thickness of the thickest macular cyst, the presence of foveal retinal pigment epithelium atrophy, and IS/OS layer disruption can be used to clinically characterize radiation maculopathy. These parameters allow for separation of the edematous component of radiation maculopathy, which is potentially treatable in early disease stages, from late onset atrophic components, which are theoretically irreversible.

Müller cells and choriocapillaris in the pathogenesis of geographic atrophy secondary to age-related macular degeneration.

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.

Lamellar Macular Hole: State of the Art.

Lamellar macular hole (LMH) is a vitreoretinal disorder characterized by an irregular foveal contour, a break in the inner fovea, dehiscence of the inner foveal retina from the outer retina, and the absence of a full-thickness foveal defect with intact foveal photoreceptors. The pathogenesis is only partially known. The advent of high-resolution optical coherence tomography has allowed distinguishing between two types of epiretinal membrane (ERM) associated with LMH: a conventional ERM (commonly found in macular pucker) and an atypical ERM (known by varied names: dense, epiretinal proliferation, or degenerative). These two types of ERM not only influence LMH morphology but also differ in cell and collagen composition. It remains unclear if these two types are indeed two distinct clinical entities or rather two stages of the same macular disorder. Studies of the natural evolution of LMH have not fully resolved this issue and also offered variable results. Surgical treatment leads to excellent anatomical and functional outcomes, but not without risks. This review provides a critical summary of the available data on LMH including some new insights.

A Double Inverted Flap Surgical Technique for the Treatment of Idiopathic Lamellar Macular Hole Associated with Atypical Epiretinal Membrane.

OBJECTIVES: To propose a new technique of a double inverted epiretinal membrane (ERM) and internal limiting membrane (ILM) flap (double flap group) for the treatment of idiopathic lamellar macular hole (LMH) with atypical ERM (AERM) and to compare surgical outcomes to those of the standard technique of ERM and ILM peeling of the fovea including LMH (control group). METHODS: AERM was tomographically defined as a medium reflective thickened membrane above the retinal fiber layers without retinal traction signs. A series of patients affected by LMH with AERM were recruited. Preoperative parameters were: intraretinal cysts (IRC), intraretinal splitting diameter, residual foveal thickness, and ellipsoid zone integrity. Postoperative findings were: full-thickness macular hole (FTMH) development, and persistence or new appearance of IRC. Best-corrected visual acuity (BCVA) at baseline, first, third, and sixth postoperative month was evaluated. RESULTS: A total of 48 eyes of 48 patients were included in this study. In the double flap group (30 eyes), a clear improvement of BCVA was noted (p = 0.004), and there were no complications. In the control group (18 eyes), BCVA did not improve and 3 patients developed postoperative FTMH. CONCLUSIONS: The double inverted flap technique is associated with better functional recovery compared to the standard technique and reduces the risk of postoperative FTMH development.

Surgically Induced Macular Detachment for Treatment of Refractory Full-Thickness Macular Hole: Anatomical and Functional Results.

PURPOSE: The purpose of this study was to investigate the efficacy and safety of surgically induced macular detachment (MD) for the treatment of refractory full-thickness macular hole (FTMH). MATERIALS AND METHODS: Clinical data were age, gender, lens status, and best corrected visual acuity (BCVA). Preoperative tomographic parameters were: FTMH morphology (intraretinal cyst and elevated or flat edges) and FTMH diameter. Postoperative FTMH closure and outer retinal layer (ORL) restoration were evaluated. Fundus autofluorescence (FAF), optical coherence tomography (OCT) findings, and BCVA were analyzed at the 1st, 3rd, and 6th postoperative month. The interval between the first surgery for idiopathic FTMH and the surgically induced MD for refractory FTMH was collected (intersurgical interval, days). RESULTS: Ten eyes of 10 patients were included. The mean age was 68.8 ± 6.8 years. FTMH closure was obtained in 9 patients; in 8 patients, ORL restoration was detected. BCVA improved from 1.06 ± 0.1 (baseline) to 0.56 ± 0.2 (final) logMAR (p = 0.0001). A negative correlation between the intersurgical interval and postoperative visual gain was demonstrated (r = -0.3618). FAF and OCT showed a permanent retinal pigment epithelium (RPE) damage corresponding to the retinotomy points. CONCLUSION: This study demonstrates the efficacy of this technique and highlights the risk of RPE damage, suggesting the need to perform the retinotomy points outside the macula.

Guidelines for the Management of Retinal Vein Occlusion by the European Society of Retina Specialists (EURETINA).

The high prevalence of cardiovascular disease particularly in the elderly population is associated with retinal vascular disease. Retinal vein occlusions represent severe disturbances of the hypoxia-sensitive neurosensory retina. Acute and excessive leakage leads to the diagnostic hallmarks of retinal hemorrhage and edema with substantial retinal thickening. Advanced diagnostic tools such as OCT angiography allow to evaluate retinal ischemia and identify the risk for late complications and will soon reach clinical routine besides fluorescein angiography. Accordingly, the duration of non-perfusion is a crucial prognostic factor requiring timely therapeutic intervention. With immediate inhibition of vascular leakage, anti-VEGF substances excel as treatment of choice. Multiple clinical trials with optimal potential for functional benefit or a lesser regenerative spectrum have evaluated aflibercept, ranibizumab, and bevacizumab. As retinal vein occlusion is a chronic disease, long-term monitoring should be individualized to combine maintenance with practicability. While steroids may be considered in patients with systemic cardiovascular risk, surgery remains advisable only for very few patients. Destructive laser treatment is an option if reliable monitoring is not feasible. Ophthalmologists are also advised to perform a basic systemic workup to recognize systemic concomitants. The current edition of the EURETINA guidelines highlights the state-of-the-art recommendations based on the literature and expert opinions in retinal vein occlusion.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

MORPHOFUNCTIONAL EVALUATION IN DOME-SHAPED MACULA: A MICROPERIMETRY AND OPTICAL COHERENCE TOMOGRAPHY STUDY.

PURPOSE: To investigate retinal sensitivity (Se) in dome-shaped macula (DSM) using microperimetry and to correlate functional findings to specific spectral domain optical coherence tomography features. METHODS: Patients affected by DSM in at least 1 eye were consecutively enrolled in a prospective, cross-sectional study. All studied eyes performed best-corrected visual acuity measurement, microperimetry to assess Se and optical coherence tomography to investigate DSM pattern and to measure bulge height and retinal and choroidal thicknesses. RESULTS: Fifty-three eyes of 29 patients were studied. Dome-shaped macula was vertically oriented (V-DSM) in 23 (43.4%), symmetric (S-DSM) in 17 (32.1%), and horizontally oriented (H-DSM) in 13 eyes (24.5%). Foveal subretinal fluid was present in 29/53 (54.7%) cases; it correlated to the bulge height (P < 0.0001) and determined a reduction of Se (P < 0.0001) not of best-corrected visual acuity (P = 0.7105). Mean Se was 13.9 ± 3.2 dB. Microperimetry parameters did not differ among the different DSM patterns. However, Se was significantly impaired if foveal subretinal fluid was present in V-DSM and in S-DSM, but not in H-DSM (V-DSM: P < 0.0001; S-DSM: P = 0.0252; H-DSM: P = 0.5723). In H-DSM, inferior choroidal thickness was thicker in cases with foveal subretinal fluid compared with those without it (P = 0.0363). CONCLUSION: In DSM, Se evaluation better reflects the central functional impairment than best-corrected visual acuity, particularly when some optical coherence tomography features, such as foveal subretinal fluid and higher bulge height, are present.

RETINAL VASCULAR ABNORMALITIES IN A LARGE COHORT OF PATIENTS AFFECTED BY NEUROFIBROMATOSIS TYPE 1: A Study Using Optical Coherence Tomography Angiography.

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.