A Remote Consult Retinal Artery Occlusion Diagnostic Protocol.

PURPOSE: To report a novel protocol for diagnosis of retinal artery occlusions at the point of care using OCT and a remote consult model. DESIGN: Retrospective case series and evaluation of a diagnostic test or technology. PARTICIPANTS: Adult patients who presented with painless monocular vision loss and were diagnosed with a nonarteritic retinal artery occlusion. METHODS: OCT machines were placed in the stroke center or emergency department at 3 hospitals within our health system. Patients who presented with painless monocular vision loss were evaluated by the stroke neurology service and an OCT was acquired. The images were interpreted remotely by the retina service. An in-house ophthalmology consult was not required to make the final treatment decision. Eligible patients were treated with intra-arterial tissue plasminogen activator (IA-tPA). Patients were followed by ophthalmology during their admission when an in-house consultation service was available or otherwise evaluated immediately after discharge. MAIN OUTCOME MEASURES: Visual acuity (VA) before and after treatment with IA-tPA; time from last known well (LKW) to treatment; and time from presentation to treatment. RESULTS: In the first 18 months since the protocol went live, 59 patients were evaluated. Twenty-five patients (42%) had a confirmed retinal artery occlusion based on OCT and follow-up examination. Ten patients were eligible for treatment, and 9 patients received treatment with IA-tPA. There was a statistically significant improvement in mean VA from logarithm of the minimum angle of resolution (logMAR) 2.14 to logMAR 0.7 within 24 hours after treatment (P = 0.0001) and logMAR 1.04 after 4 weeks (P = 0.01). Clinically significant improvement was noted in 66% of patients within 24 hours and maintained through 1 month in 56% of all treated patients. The mean time to treatment from LKW was 543 minutes and from presentation at the stroke center was 146 minutes. CONCLUSIONS: We report the successful implementation of a remote consult protocol using point-of-care automated OCT. This novel paradigm demonstrates the potential utility of remote consult services for the diagnosis of time-sensitive ophthalmic emergencies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effects of Toll-like receptor 1 and 2 agonist Pam3CSK4 on uveal melanocytes and relevant experimental mouse model.

Pam3CSK4 activates Toll-like receptors 2 and 1 (TLR1/2), which recognize mainly molecules from gram-positive pathogens. The effect of Pam3CSK4 on various cytokine and chemokine expression in cultured human uveal melanocytes (UM) has not been studied systematically. The purpose of this study was to investigate the mechanistic expressions of seven cytokines and chemokines of interleukin- (IL-) 6, IL-10, MCP-1 (CCL-2), CXCL-1 (GRO-α), CXCL-8 (IL-8), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) in UM. These cytokines are reported to be increased in intraocular fluids or tissues of the patients with endophthalmitis and non-infectious uveitis, as well as in various experimental animal uveitic models in the literature. Flow cytometry was used to measure the effects of Pam3CSK4 on the expression of TLR1/2 in UM. ELISA and Real-time PCR analysis were used to estimate the ability of Pam3CSK4 to elevate these cytokines and chemokines levels in conditioned media and cell lysates of UM, respectively. Flow cytometry measured and compared the phosphorylated MAPK pathway and activated NF-κB signals pathway in UM, treated with and without Pam3CSK4. ELISA analysis tested the effect of various signal inhibitors (ERK1/2, JNK1/2, p38 and NF-κB) on Pam3CSK4-induced IL-6 levels in cultured UM. The role of TLR2 in Pam3CSK4-induced acute anterior uveitis in experimental mouse model was tested in TLR2 knockout (TLR2 KO) mice and their wild-type C57Bl/6 controls. Pam3CSK4 increased the expression of TLR1/2 proteins in cultured UM. Pam3CSK4 significantly elevated the IL-6, MCP-1, CXCL-1, CXCL-8 protein, and mRNA levels in cultured UM, but not IL-10, TNF-α, or IFN-γ. Pam3CSK4 activated NF-κB, ERK, JNK, and p38 expression. Pam3CSK4-induced expression of IL-6 was decreased by NF-κB, ERK, INK, and p38 inhibitors; especially the NF-κB inhibitor, which can completely block the IL-6 stimulation. Intravitreal injection of Pam3CSK4 induced acute anterior uveitis in C57Bl/6 mice, this effect was significantly reduced in TLR2 KO mice. TLR1/2 plays an important role against invading pathogens, especially gram-positive bacteria; but an excessive reaction to molecules from gram-positive bacteria may promote non-infectious uveitis. UM can produce IL-6, MCP-1, CXCL-1, and CXCL-8, and are one of the target cells of TNF-α and IFN-γ. TLR-2 inhibitors might have a beneficial effect in the treatment of certain types of uveitis and other ocular inflammatory-related diseases and warrant further investigation.

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the Lumithera Valeda Light Delivery System.

PURPOSE: The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) age-related macular degeneration (AMD) using the LumiThera Valeda Light Delivery System. METHODS: LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were given multiwavelength PBM (590, 660, and 850 nm) or Sham treatment delivered in a series of nine sessions over 3 to 5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS: A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy best-corrected visual acuity endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 to -0.1, P = 0.02) (PBM alone: 5.4 letters (SE 0.96), CI: 3.5 to 7.3, P < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7-5.2, P < 0.0001). The PBM group showed a significant decrease in new onset geographic atrophy ( P = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSION: LIGHTSITE III provides a prospective, randomized, controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM therapy.

Cytokines in PD-1 immune checkpoint inhibitor adverse events and implications for the treatment of uveitis.

Immune checkpoint inhibitors (ICI) such as Programmed cell Death 1 (PD-1) inhibitors have improved cancer treatment by enhancing the immune system's ability to target malignant cells. Their use is associated with immune-related adverse events (irAEs), including uveitis. The profile of pro-inflammatory cytokines underlying Anti-PD-1-induced uveitis shares significant overlap with that of non-infectious uveitis. Current corticosteroid treatments for uveitis while effective are fraught with vision threatening side effects. The cytokine profile in ICI-related uveitis has a large overlap with that of noninfectious uveitis, this overlap strongly supports the potential for therapy that activates the PD-1 axis in the eye to treat uveitis. Indeed, ICI related uveitis often resolves with cessation of the ICI, restoring the endogenous PD-1 axis. The potential benefit of targeting many pro-inflammatory cytokines via local PD-1 axis activation is mitigating ocular inflammation while minimizing adverse effects.

Evaluating dermatology education in Australia: Medical students' and junior doctors' perceptions.

BACKGROUND: Despite a high frequency of dermatological general practice and emergency department presentations, including serious and potentially fatal skin conditions, evidence suggests that undergraduate dermatological education remains sparse. Given this, there exists a need to gauge dermatology-relevant knowledge and skill in our new doctors. METHODS: An online survey was completed by final-phase medical students and junior doctors from Australian medical schools. The survey appraised self-perceived confidence of dermatology knowledge and skills, in addition to 5 knowledge-based multiple-choice questions. RESULTS: Nine hundred and forty-two eligible responses were completed. Respondents reported low confidence in identifying dermatological conditions in people with skin of colour (µ = 1.69), handing over to dermatology colleagues (µ = 2.00) and in diagnosing and managing acute/emergency dermatology conditions (µ = 1.84). In contrast, participants felt most confident in counselling sun-protective behaviours (µ = 3.95) and suturing small wounds (µ = 3.43). 76.4% of respondents had not undertaken any dermatology placement, and 70.9% had never been formally assessed in dermatology. Those who received dermatology placement had a significantly higher aggregated self-reported confidence (p < 0.0001) and answered significantly more MCQs correctly (p = 0.0419). Those who had been formally assessed had a significantly higher self-reported confidence (p < 0.001) and answered significantly more MCQs correctly (p = 0.007). CONCLUSION: Final-phase medical students and junior doctors exhibit low confidence across many dermatology competencies. Participants believed they need more dermatology education, and seldom feel prepared when exposed to dermatologic pathologies. Introduction of a standardised curriculum, formal assessments and increased clinical exposure are possible solutions.

Toll-like receptor 2 and 6 agonist fibroblast-stimulating lipopeptide increases expression and secretion of CXCL1 and CXCL2 by uveal melanocytes.

Fibroblast-stimulating lipopeptide (FSL-1) can activate Toll-like receptor 2 and 6 (TLR2/6), which recognize relevant molecules from gram-positive pathogens, fungus, and mycoplasma, and elevates the expression of CXCL1 and CXCL2, neutrophil chemoattractants, in certain types of cells. This effect has not previously been reported in the uveal melanocytes (UM). This study was designed to test the hypothesis that FSL-1 can induce the expression and secretion of CXCL1 and CXCL2 via activation of TLR2/6 in cultured human UM and producing an acute non-infectious uveitis reaction in the mouse. Flow cytometry and fluorescent immunostaining were used to measure the effect of FSL-1 on the expression of TLR2/6 in UM. Real time PCR and ELISA analysis were used to assess the ability of FSL-1 to elevate CXCL1/CXCL2 levels in cell lysates and conditioned media of UM, respectively. Flow cytometry measured phosphorylated MAPK and activated NF-κB signals in UM, with and without FSL-1 treatment. ELISA analysis tested the impact of various signal inhibitors (NF-κB, p38 MAPK, JNK1/2 and ERK1/2) and TLR2/6 antagonists on FSL-1-induced CXCL1/CXCL2 levels in cultured UM. The effects of neutralizing antibodies to TLR2 on FSL-1-induced mouse uveitis were tested in an experimental animal model. FSL-1 induced the expression of TLR2/6 proteins in cultured UM. FSL-1 significantly elevated the CXCL1 and CXCL2 proteins and mRNA levels in cultured UM time- and dose-dependently. FSL-1 mainly activated NF-κB, JNK, and expression of TLR2. FSL-1-induced expression of CXCL1 and CXCL2 was blocked by NF-κB, JNK, ERK inhibitors and TLR2 antagonists. Intravitreal injection of FSL-1 induced acute non-infectious mouse uveitis, which was significantly reduced in severity by a TLR2 antagonist. These results suggest that UM may play a role in the immune reaction, which targets invading pathogens, especially gram-positive bacteria. On the other hand, an excessive reaction to molecules from gram-positive bacteria may promote an inflammatory state of non-infectious uveitis.

SUBRETINAL DRUSENOID DEPOSITS AND SOFT DRUSEN: Are They Markers for Distinct Retinal Diseases?

PURPOSE: Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks, and associated systemic diseases. METHODS: One hundred and twenty-six subjects with AMD were classified as SDD (with or without soft drusen) or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. RESULTS: There were 62 subjects with SDD and 64 non-SDD subjects, of whom 51 had CVD or stroke. SDD correlated significantly with lower mean serum high-density lipoprotein (61 ± 18 vs. 69 ± 22 mg/dL, P = 0.038, t-test), CVD and stroke (34 of 51 SDD, P = 0.001, chi square), ARMS2 risk allele (P = 0.019, chi square), but not with CFH risk allele (P = 0.66). Non-SDD (drusen only) correlated/trended with APOE2 (P = 0.032) and CETP (P = 0.072) risk alleles (chi square). Multivariate independent risks for SDD were CVD and stroke (P = 0.008) and ARMS2 homozygous risk (P = 0.038). CONCLUSION: Subjects with subretinal drusenoid deposits and non-SDD subjects have distinct systemic associations and serum and genetic risks. Subretinal drusenoid deposits are associated with CVD and stroke, ARMS2 risk, and lower high-density lipoprotein; non-SDDs are associated with higher high-density lipoprotein, CFH risk, and two lipid risk genes. These and other distinct associations suggest that these lesions are markers for distinct diseases.

Vascular Patterning as Integrative Readout of Complex Molecular and Physiological Signaling by VESsel GENeration Analysis.

The molecular signaling cascades that regulate angiogenesis and microvascular remodeling are fundamental to normal development, healthy physiology, and pathologies such as inflammation and cancer. Yet quantifying such complex, fractally branching vascular patterns remains difficult. We review application of NASA's globally available, freely downloadable VESsel GENeration (VESGEN) Analysis software to numerous examples of 2D vascular trees, networks, and tree-network composites. Upon input of a binary vascular image, automated output includes informative vascular maps and quantification of parameters such as tortuosity, fractal dimension, vessel diameter, area, length, number, and branch point. Previous research has demonstrated that cytokines and therapeutics such as vascular endothelial growth factor, basic fibroblast growth factor (fibroblast growth factor-2), transforming growth factor-beta-1, and steroid triamcinolone acetonide specify unique "fingerprint" or "biomarker" vascular patterns that integrate dominant signaling with physiological response. In vivo experimental examples described here include vascular response to keratinocyte growth factor, a novel vessel tortuosity factor; angiogenic inhibition in humanized tumor xenografts by the anti-angiogenesis drug leronlimab; intestinal vascular inflammation with probiotic protection by Saccharomyces boulardii, and a workflow programming of vascular architecture for 3D bioprinting of regenerative tissues from 2D images. Microvascular remodeling in the human retina is described for astronaut risks in microgravity, vessel tortuosity in diabetic retinopathy, and venous occlusive disease.

ACUTE MACULAR AND PERIPAPILLARY ANGIOGRAPHIC CHANGES WITH INTRAVITREAL INJECTIONS.

PURPOSE: Intravitreal injections acutely and temporarily increase intraocular pressure (IOP), and this may have cumulative long-term effects including an increased risk for glaucoma surgery. This study was designed to measure retinal perfusion density changes on optical coherence tomography (OCT) angiography and OCT thickness alterations associated with acutely increased IOP after intravitreal injections. METHODS: Retrospective observational clinical study of 40 eyes (39 patients) with various retinopathies from October 2016 to June 2017 at a tertiary care retina clinic in NYC. Patients were older than 18 years, with vision >20/100, able to fixate and without media opacities precluding OCT angiography, receiving intravitreal bevacizumab or aflibercept for diabetic retinopathy, retinal vein occlusion, macular degeneration, retinal neovascularization, or radiation retinopathy. The 3-mm × 3-mm macular and 4.5-mm × 4.5-mm peripapillary OCT angiography perfusion density, macular OCT thickness, and IOP were measured before and immediately after intravitreal injections. Paired t-test was used to compare preinjection and postinjection values for perfusion density and OCT thickness. Regression analysis was performed for potential effects of baseline IOP, IOP change, and age. RESULTS: Statistically significant decreases in angiographic perfusion density (P < 0.05) were found in most areas of the superficial and deep layer macular OCT angiography, and the overall optic nerve head and the radial peripapillary capillary layer, preferentially temporal. Macular OCT thickness was significantly decreased in the temporal region and increased in the nasal region. Regression analysis showed relationships between age and decreased superficial macular perfusion. Preinjection IOP was only related to OCT thickness in the fovea. Intraocular pressure change was related only to decreased superficial macular perfusion density. CONCLUSION: Intravitreal injections produce acute IOP changes that are associated with reduced macular and peripapillary perfusion density. Therefore, it is possible that patients receiving regular intravitreal injections may be sustaining perfusion-related injury to ocular structures that may produce glaucomatous damage to the macula and optic nerve.

ASSOCIATION OF RETINAL VEIN OCCLUSION WITH CARDIOVASCULAR EVENTS AND MORTALITY: A Systematic Review and Meta-analysis.

PURPOSE: Previous studies examining the association of retinal vein occlusion (RVO) and cardiovascular events have been inconsistent and have mostly focused on stroke and myocardial infarction. The goal of this study is to use meta-analysis to examine the available evidence examining the association of RVO with incident cardiovascular events and mortality. METHODS: Systematic review and meta-analysis of all longitudinal cohort studies published in PubMed, Embase, and the Cochrane Library from inception to April 7, 2018, that evaluated the association of baseline RVO and incident cardiovascular events and/or mortality, that provided multivariate-adjusted risk estimates with 95% confidence intervals (95% CIs), and that had average follow-up ≥1 year. The Newcastle-Ottawa scale was used to assess study quality. Multivariate-adjusted risk estimates with 95% CI along with study characteristics were extracted from each study, and pooled risk ratios (RRs) with 95% CI were generated using a random-effects model with inverse-variance weighting to account for heterogeneity. Main outcomes were incident stroke (fatal or nonfatal), myocardial infarction, heart failure, peripheral arterial disease, all-cause mortality, and cardiovascular mortality. RESULTS: Fifteen cohort studies with a total of 474,466 patients (60,069 with RVO and 414,397 without RVO) were included. Each study had Newcastle-Ottawa scale score ≥6, indicating moderate-to-high quality. Retinal vein occlusion was associated with increased risk of stroke (RR = 1.45; 95% CI, 1.31-1.60), myocardial infarction (RR = 1.26; 95% CI, 1.17-1.37), heart failure (RR = 1.53; 95% CI, 1.22-1.92), peripheral arterial disease (RR = 1.26; 95% CI, 1.09-1.46), and all-cause mortality (RR = 1.36; 95% CI, 1.02-1.81), but was not associated with increased risk of cardiovascular mortality (RR = 1.78; 95% CI, 0.70-4.48). CONCLUSION: This review suggests patients with RVO have an increased risk of cardiovascular events and all-cause mortality. More studies are needed to determine the highest risk periods for cardiovascular events and mortality after RVO and whether immediate cardiovascular evaluation and intervention will improve outcomes.

Uveal melanocytes express high constitutive levels of MMP-8 which can be upregulated by TNF-α via the MAPK pathway.

Matrix metalloproteinase (MMP)-8 is the most potent MMP for degrading collagen type-1 and plays an important role in inflammatory reactions and tissue remolding processes. MMP-8 is expressed mainly by polymorphonuclear leukocytes and is not expressed constitutively by most non-leukocytes. We studied the constitutive and TNF-α-induced expression of MMP-8 in cultured human uveal melanocytes (UM) and the relevant signal pathways involved. Conditioned media and cells were collected from UM and other cell types. MMP-8 proteins and mRNA were measured using ELISA kit, western blot and real time RT-PCR, respectively. Phosphorylated p38 MAPK, ERK1/2, and JNK1/2 were measured by ELISA kit and western blot. Very high levels of MMP-8 proteins and mRNA were detected in the conditioned media and cell lysates in 11 UM cell lines and three uveal melanoma cell lines cultured without serum, but not in media and cell lysates from other ocular resident cells or 12 malignant cell lines from other tissues, with exception of cutaneous melanoma cells. TNF-α moderately increased MMP-8 mRNA and protein levels in a dose- and time-dependent manner, accompanied by a significant increase of phosphorylated JNK1/2 and ERK1/2 in cell lysates. ERK1/2 (U0126) and JNK1/2 (SP600125) inhibitors significantly blocked TNF-α-induced and constitutive expression of MMP-8 in UM. This is the first report on the expression and secretion of MMP-8 by UM and uveal melanoma cells. The data suggest that UM may play a role in the remolding process and pathogenesis of inflammatory-related diseases in the eye via secretion of MMP-8.

VALUE OF FRACTAL ANALYSIS OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN VARIOUS STAGES OF DIABETIC RETINOPATHY.

PURPOSE: To use fractal dimensional analysis to investigate retinal vascular disease patterns in patients with diabetic retinopathy using spectral domain optical coherence tomography angiography. METHODS: A retrospective study was conducted which included 49 eyes from 26 control subjects and 58 eyes from 35 patients known to have diabetic retinopathy. Of the 58 eyes with known retinopathy, 31 were categorized as nonproliferative diabetic retinopathy (13 mild, 9 moderate, and 9 severe) and 27 were categorized as proliferative diabetic retinopathy. Optical coherence tomography angiography images were acquired using the RTVue XR Avanti (Optovue, Inc). Automated segmentation was obtained through both the superficial and deep capillary plexuses for each eye. Grayscale optical coherence tomography angiography images were standardized and binarized using ImageJ (National Institutes of Health). Fractal box-counting analyses were conducted using Fractalyse (ThéMA). Fractal dimensions (FDs) and correlation coefficient of the superficial and deep capillary plexuses were compared between control eyes and those in various stages of diabetic retinopathy. RESULTS: The superficial and deep capillary plexuses from diabetic and control eyes were analyzed. The average FD for diabetic eyes was significantly lower than in control eyes in the superficial plexus (P = 2.4 × 10) and in the deep capillary plexus (P = 1.87 × 10 ) with a more statistically significant difference noted in the deep capillary plexus. When analyzing diabetic patients without edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 0.001) and deep (P = 1.49 × 10) plexuses. When analyzing diabetic patients with edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 2.0 × 10) and deep (P = 1.85 × 10) plexuses. CONCLUSION: The optical coherence tomography angiography FD is significantly lower in both superficial and deep capillary plexuses in eyes with all stages studied of diabetic retinopathy. The results were more often significant for the deep capillary plexus. The use of fractal analysis provides an objective criterion to assess microvascular disease burden in diabetic retinopathy.

Sutureless Belt Loops versus Sutured Buckle Technique in Combination with Vitrectomy for Retinal Detachment Repair: A Comparative Analysis.

OBJECTIVE: To compare the anatomic and visual outcomes in primary rhegmatogenous retinal detachment repair involving combined pars plana vitrectomy (PPV)/scleral buckle (SB) using a sutureless belt loops technique versus a conventional sutured buckle technique. METHODS: This is a retrospective, consecutive, interventional, comparative case series study using patients treated for primary retinal detachment who underwent the SB procedure in combination with PPV. Details regarding anatomic and visual outcome were analyzed. RESULTS: Thirty-five eyes were included in this study: 18 eyes (18 patients) treated with combined PPV and SB performed using a sutureless belt loops technique (group A) and 17 eyes (17 patients) treated with combined PPV and SB sutured to the sclera (group B). Successful anatomic attachment and appropriate buckle height were achieved in all 35 cases. There was 1 case of redetachment in each group during the follow-up: 1/17 (5.9%) in group A and 1/18 (5.6%) in group B (p = 0.97). No cases of buckle infection, extrusion, or intrusion were noted during the follow-up period. CONCLUSION: SBs installed using a belt loops sutureless technique appear to be as safe and effective as those applied using conventional suturing for repair of retinal detachment, with similar anatomic and functional outcomes.

Hypoxia-induced vascular endothelial growth factor secretion by retinal pigment epithelial cells is inhibited by melatonin via decreased accumulation of hypoxia-inducible factors-1α protein.

BACKGROUND: Hypoxia is the most important stimulus leading to up-regulation of vascular endothelial growth factor (VEGF) in the retina via elevation of hypoxia-inducible factors-1α (HIF-1α) protein. The purpose of this study was to test the effects of melatonin on the expression of VEGF and HIF-1α in the cultured human retinal pigment epithelial (RPE) cells under normoxia and hypoxia. METHOD: An in vitro RPE cell hypoxia model was established by placing cells under 1% oxygen pressure or by adding cobalt chloride (CoCl2 ) to the culture medium. RPE cells and conditioned media were collected from cultures treated with and without melatonin under normoxia and hypoxia. The protein and RNA levels of VEGF and HIF-1α were measured by ELISA kits and RT-PCR, respectively. RESULT: Hypoxia induced a significant increase of expression and secretion of VEGF and accumulation of HIF-1α protein in RPE cells (P < 0.05). Melatonin at 10-5 to 10-8 M significantly inhibited hypoxia-induced expression, the secretion of VEGF and the accumulation of HIF-1α protein (P < 0.05), but not affected expression of VEGF and HIF-1α under normoxia (P > 0.05). CONCLUSION: This study suggests that melatonin may have potential value in the prevention and treatment of various retinal diseases associated with increase of VEGF, vascular leakage and angiogenesis.

Optical Coherence Tomography Angiography in Diabetes.

Diabetic retinopathy is a progressive microvascular disease that leads to increased vessel permeability, retinal ischemia, and retinal neovascularization. Optical coherence tomography angiography (OCTA) is a novel angiography technique that has the capability to advance our understanding of diabetic eye disease by providing high-resolution images of retinal and choroidal microvasculature blood flow and structure. Using OCTA, the vascular changes of diabetic retinopathy including microaneurysms, retinal non-perfusion, intraretinal microvascular abnormalities, and neovascularization can be clearly visualized. OCTA offers several advantages over fluorescein angiography (FA) in that it is faster, safer, and non-invasive, allows better visualization of retinal vessels in both the superficial and deep capillary layers, and can provide quantitative measurements of areas of non-perfusion of the macula and nerve. OCTA capillary perfusion density maps and average perfusion density values provide an easy way to grade progressive vascular change. Despite these advantages, imaging with OCTA can only provide a limited view of the peripheral retina and is unable to demonstrate leakage, staining, or pooling. OCTA requires patients to maintain good fixation to obtain high-resolution images which can be a challenge for those with severe macular disease. In patients who cannot safely undergo FA, OCTA may serve as an alternative form of angiography that can be safely and more frequently performed for the management of diabetic retinopathy.

EXPANDED CLINICAL SPECTRUM OF MULTIPLE EVANESCENT WHITE DOT SYNDROME WITH MULTIMODAL IMAGING.

PURPOSE: To evaluate and characterize multiple evanescent white dot syndrome abnormalities with modern multimodal imaging modalities. METHODS: This retrospective cohort study evaluated fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, enhanced depth imaging optical coherence tomography, short-wavelength autofluorescence, and near-infrared autofluorescence. RESULTS: Thirty-four multiple evanescent white dot syndrome patients with mean age of 28.7 years were studied (range, 14-49 years). Twenty-six patients were women, and eight were men. Initial mean visual acuity was 0.41 logMAR. Final mean visual acuity was 0.03 logMAR. Fluorescein angiography shows a variable number of mid retinal early fluorescent dots distributed in a wreathlike pattern, which correlate to fundus photography, fundus autofluorescence, and indocyanine green angiography. Indocyanine green angiography imaging shows the dots and also hypofluorescent, deeper, and larger spots, which are occasionally confluent, demonstrating a large plaque of deep retinal hypofluorescence. Optical coherence tomography imaging shows multifocal debris centered at and around the ellipsoid layer, corresponding to the location of spots seen with photography, indocyanine green angiography, and fluorescein angiography. Protrusions of the hyperreflectant material from the ellipsoid layer toward the outer nuclear layer correspond to the location of dots seen with photography, indocyanine green angiography, and fluorescein angiography. CONCLUSION: Multimodal imaging analysis of the retina in patients with multiple evanescent white dot syndrome shows additional features that may help in the diagnosis of the disease and in further understanding its etiology. Multiple evanescent white dot syndrome is predominantly a disease of the outer retina, centered at the ellipsoid zone, but also involving the interdigitation zone and the outer nuclear layer.

Longitudinal imaging of microvascular remodelling in proliferative diabetic retinopathy using adaptive optics scanning light ophthalmoscopy.

PURPOSE: To characterise longitudinal changes in the retinal microvasculature of type 2 diabetes mellitus (T2DM) as exemplified in a patient with proliferative diabetic retinopathy (PDR) using an adaptive optics scanning light ophthalmoscope (AOSLO). METHODS: A 35-year-old T2DM patient with PDR treated with scatter pan-retinal photocoagulation at the inferior retina 1 day prior to initial AOSLO imaging along with a 24-year-old healthy control were imaged in this study. AOSLO vascular structural and perfusion maps were acquired at four visits over a 20-week period. Capillary diameter and microaneurysm area changes were measured on the AOSLO structural maps. Imaging repeatability was established using longitudinal imaging of microvasculature in the healthy control. RESULTS: Capillary occlusion and recanalisation, capillary dilatation, resolution of local retinal haemorrhage, capillary hairpin formation, capillary bend formation, microaneurysm formation, progression and regression were documented over time in a region 2° superior to the fovea in the PDR patient. An identical microvascular network with same capillary diameter was observed in the control subject over time. CONCLUSIONS: High-resolution serial AOSLO imaging enables in vivo observation of vasculopathic changes seen in diabetes mellitus. The implications of this methodology are significant, providing the opportunity for studying the dynamics of the pathological process, as well as the possibility of identifying highly sensitive and non-invasive biomarkers of end organ damage and response to treatment.

RETINAL VASCULAR PERFUSION DENSITY MAPPING USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN NORMALS AND DIABETIC RETINOPATHY PATIENTS.

PURPOSE: To describe a new method of retinal vascular perfusion density mapping using optical coherence tomography angiography and to compare current staging of diabetic retinopathy based on clinical features with a new grading scale based on perifoveal perfusion densities. METHODS: A retrospective review was performed on subjects with diabetic retinopathy and age-matched controls imaged with a spectral domain optical coherence tomography system (Optovue XR Avanti, Fremont, CA). Split-spectrum amplitude-decorrelation angiography (SSADA) generated optical coherence tomography angiograms of the superficial retinal capillaries, deep retinal capillaries, and choriocapillaris. Skeletonized optical coherence tomography angiograms were used to create color-coded perfusion maps and capillary perfusion density values for each image. Capillary perfusion density values were compared with clinical staging, and groups were compared using analysis of variance and Kruskal-Wallis analyses. RESULTS: Twenty-one control and 56 diabetic retinopathy eyes were imaged. Diabetic eyes were grouped according to clinical stage. Capillary perfusion density values from each microvascular layer were compared across all groups. Capillary perfusion density values were significantly lower in nearly all layers of all study groups compared with controls. Trend analysis showed a significant decrease in capillary perfusion density values as retinopathy progresses for most layers. CONCLUSION: Quantitative retinal vascular perfusion density mapping agreed closely with grading based on clinical features and may offer an objective method for monitoring disease progression in diabetic retinopathy.