Effectiveness of Nonmydriatic Ultra-Widefield Retinal Imaging to Screen for Diabetic Eye Disease: A Randomized Controlled Trial (Clearsight).

OBJECTIVE: Suboptimal diabetic eye disease screening is a major cause of preventable vision loss. Screening barriers include mydriasis and the need for dedicated screening appointments. The Clearsight trial assessed whether nonmydriatic ultra-widefield (NM UWF) screening on the day of a diabetes clinic visit improved detection of clinically important eye disease versus usual screening. RESEARCH DESIGN AND METHODS: This single-center, randomized, parallel-group controlled trial was conducted at St. Joseph's Health Care, London, Ontario, Canada. Adults with diabetes due for screening were randomized to same-day, on-site screening (NM UWF imaging) on the day of a scheduled diabetes clinic visit or usual screening (encouraged to arrange optometrist screening). The primary outcome was detection of actionable eye disease (AED), defined as the need for an ophthalmology referral or increased ocular surveillance. The primary analysis (modified intention-to-screen) compared the proportions of AED between groups within 1 year of enrollment. RESULTS: Of 740 participants randomized between 7 March 2016 and 17 April 2019, 335 on-site screening and 323 usual screening participants met criteria for the primary analysis. More AED was detected in the on-site screening group than in the usual screening group (50 of 335 [14.9%] vs. 22 of 323 [6.8%]; adjusted odds ratio 2.51; 95% CI 1.49-4.36). The number needed to screen by on-site screening in order to detect 1 additional patient with AED was 13 (95% CI 8-29). CONCLUSIONS: Same-day, on-site screening by NM UWF imaging increased the detection of clinically important diabetic eye disease versus usual screening. Integration of NM UWF imaging into routine diabetes clinic visits improved screening adherence and has the potential to prevent vision loss.

Prospective evaluation of aflibercept in pigment epithelial detachments secondary to neovascular age related macular degeneration.

OBJECTIVE: To assess the efficacy of intravitreal aflibercept in treating visual loss and structural changes in patients with pigment epithelial detachments (PED) secondary to neovascular age-related macular degeneration (nAMD). METHODS: Prospective, exploratory, open-label study (ClinicalTrials.gov Identifier: NCT02142296). Participants with PED secondary to nAMD were enrolled and received intravitreal aflibercept injection on a monthly basis for 3 months, followed by injections on a bimonthly basis for another 9 months. Best-corrected visual acuity (BCVA), ophthalmic examinations, optical coherence tomography (OCT) imaging, and fluorescein angiography were performed based on a predetermined schedule. RESULTS: Thirty-six participants (37 eyes) were enrolled. At the end of study, 74.3% eyes demonstrated PED height reduction of 25% or more and 34.3% demonstrated complete resolution. The average reduction in retinal thickness was 128.4 µm. Participant eyes who had at least a 25% reduction in PED height at month 4 were labelled as "responders" (73.0%, n = 27), and those who had less than 25% reduction in PED height were labelled as "partial-responders" (27.0%, n = 10). Responders demonstrated more significant reduction in PED height than partial-responders (p <0.0001). The average gain in BCVA was 10.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Responders demonstrated more gain in BCVA than partial-responders (p = 0.0018). Among the responders, 57.7% demonstrated disease recurrences with increase in PED height during bimonthly dosing. CONCLUSIONS: Intravitreal aflibercept injection for patients with PEDs secondary to nAMD has high response rate with few adverse events. Responders demonstrated BCVA gains, as well as structural improvements. However, high recurrence rate was found on bimonthly maintenance dosing.

Comparison of in vitro toxicity of single vs double exposures of indocyanine green in human retinal pigment epithelial cell cultures.

PURPOSE: To compare the in vitro effect of a single brief indocyanine green (ICG) exposure with a double exposure on retinal pigment epithelial (RPE) cells. DESIGN: In vitro laboratory experimental study. METHODS: Human ARPE-19 cells were exposed to a single dilute ICG exposure (0.5 mg/ml) or to two sequential exposures of identical volume and concentration. Viability was measured with a mitochondrial dehydrogenase assay and compared with nonexposed control cells. RESULTS: Cell viability was not statistically different between the single-exposed, double-exposed, or control cell populations. CONCLUSIONS: When used intraoperatively to stain the internal limiting membrane, dilute ICG dye sometimes does not adequately enhance visualization of the internal limiting membrane. Occasionally, it is necessary to repeat the dye exposure to achieve the desired visibility. In this study, RPE cells subjected to two consecutive short exposures of ICG showed no marked difference in cell survival when compared with cells exposed to a single application of ICG and to control cells.

A randomised trial of non-mydriatic ultra-wide field retinal imaging versus usual care to screen for diabetic eye disease: rationale and protocol for the Clearsight trial.

INTRODUCTION: Suboptimal screening for diabetic eye disease is a major cause of preventable vision loss. Screening barriers include mydriasis and the extra time patients need to attend dedicated eye screening appointments. In the Clearsight trial, we are testing whether screening by non-mydriatic ultra-wide field (NM UWF) imaging on the day patients attend their diabetes outpatient clinic visit improves detection of clinically important eye disease compared with usual screening. METHODS AND ANALYSIS: Patients with diabetes due for a screening eye exam by the 2013 Canadian Diabetes Association (CDA) practice guidelines are being randomised to on-site screening by NM UWF imaging on the day of their clinic visit or to usual screening where, per CDA guidelines, they are encouraged to arrange an exam by an optometrist. The primary outcome is actionable eye disease (AED) based on a need for referral to ophthalmology and/or increased ocular surveillance. The primary analysis will use an intention-to-screen approach that compares the proportions of detected AED between on-site and usual screening groups under a superiority hypothesis in favour of on-site screening. With 740 randomised participants, the study will have 80% power to detect ≥5% absolute increase in the AED rate among on-site screening versus usual screening participants. This difference translates into a number-needed-to-screen by on-site screening of 20 to detect 1 additional person with AED. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board of Western University. The findings of the trial will be disseminated directly to participants and through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov NCT02579837 (registered 16 October 2015). PROTOCOL ISSUE DATE: 18 November 2015.

Endothelins: regulators of extracellular matrix protein production in diabetes.

Fibronectin (FN), a key extracellular matrix protein, is upregulated in target organs of diabetic angiopathy and in cultured cells exposed to high levels of glucose. FN has also been reported to undergo alternative splicing to produce the extra domain-B (ED-B) containing isoform, which is exclusively expressed during embryogenesis, tissue repair, and tumoral angiogenesis. The present study was aimed at elucidating the role and mechanism of endothelins (ETs) in FN and ED-B FN expression in diabetes. We investigated vitreous samples for ED-B FN expression from patients undergoing vitrectomy for proliferative diabetic retinopathy. Our results show increased FN and ED-B FN expression in the vitreous of diabetic patients in association with augmented ET-1. Using an antibody specific to the ED-B segment of FN, we show an increase in serum ED-B FN levels in patients with diabetic retinopathy and nephropathy. We further examined retinal tissues, as well as renal and cardiac tissues, from streptozotocin-induced diabetic rats. Diabetes increased FN and ED-B FN in all three organs, which was prevented by ET antagonist bosentan. To provide insight into the mechanism of glucose-induced and ET-mediated ED-B FN upregulation, we assayed endothelial cells (ECs). Inhibition of mitogen-activated protein kinase with pharmacological inhibitors and protein kinase B with dominant negative transfections prevented glucose- and ET-1-mediated FN and ED-B FN expression. Furthermore, treatment of cells exposed to high levels of glucose with ET antagonist prevented the activation of all signaling pathways studied and normalized glucose-induced ED-B FN expression. We then determined the functional significance of ED-B in ECs and show that ED-B FN is involved in vascular endothelial growth factor expression and cellular proliferation. These studies show that glucose-induced and ET-mediated FN and ED-B FN expressions involve complex interplays between signaling pathways and that ET may represent an ideal target for therapy in chronic diabetic complications.

A case of unilateral and spontaneously resolving posterior uveitis with overlapping features of Vogt-Koyanagi-Harada disease and Acute Posterior Multifocal Placoid Pigment Epitheliopathy.

INTRODUCTION: VKH disease is a chronic, bilateral, granulomatous panuveitis with potential involvement of neurological, auditory and integumentary systems. On the other hand, APMPPE is believed to be an immune-driven chorioretinal vascular disease characterized by multifocal, flat, grey-white placoid lesions at the level of the RPE. We describe a case with overlapping figures of both conditions. CASE DESCRIPTION: A 19-year-old female presented with unilateral blurry vision and was found to have clinical and IVFA findings consistent with APMPPE. Her OCT study demonstrated typical VKH findings with large areas of serous neurosensory retinal detachment and intra-retinal cystoid spaces with enclosed membranous structures. She was closely followed but was not treated with high dose corticosteroid. Spontaneous and complete resolution of her symptoms and clinical, IVFA and OCT findings were achieved by day 25. DISCUSSION: This is the first reported case of spontaneously resolving, unilateral VKH disease in the absence of high dose corticosteroid treatment with overlapping features of APMPPE. CONCLUSIONS: The imaging and clinical findings of both VKH disease and APMPPE raise the notion that VKH disease and APMPPE could be an overlapping spectrum of inflammatory processes, rather than distinct disease entities.

Oncofetal fibronectin in diabetic retinopathy.

PURPOSE: Imbalance between extracellular matrix protein synthesis and degradation is a key feature of diabetic retinopathy. Fibronectin, a predominant constituent of the extracellular matrix, has been shown to undergo alternative splicing to produce embryonic isoforms in various pathologic conditions, such as fibrotic diseases and tumorigenesis. Two such isoforms, oncofetal fibronectin variants that are characterized by the inclusion of the oncofetal domains A and B, were the focus of the present study. METHODS: The expression of oncofetal fibronectin variants was determined in human vitreous samples obtained from patients undergoing vitrectomy for proliferative diabetic retinopathy and nondiabetes-associated ocular conditions such as macular hole. In addition, an animal model of chronic diabetes and cultured endothelial cells was used to elucidate the mechanistic basis for this aberrant expression of oncofetal fibronectin. RESULTS: Expression of fibronectin containing the oncofetal domain B was upregulated in the vitreous of patients with diabetic retinopathy. CONCLUSIONS: Use of a well-established animal model of chronic diabetic complications and cultured endothelial cells showed that diabetes-induced upregulation of oncofetal fibronectin is, in part, dependent on hyperglycemia-induced transforming growth factor-beta1 and endothelin-1. Furthermore, the data suggest that oncofetal fibronectin is involved in endothelial cell proliferation.

Comparison of the in vitro toxicity of indocyanine green to that of trypan blue in human retinal pigment epithelium cell cultures.

PURPOSE: To compare the in vitro toxicity of indocyanine green (ICG) to that of trypan blue (TB) in human retinal pigment epithelium cell cultures. The use of ICG and TB in macular hole surgery is discussed. DESIGN: In vitro cell biology experimental study. METHODS: The ICG dye and TB were applied to ARPE-19, a commercially available human retinal pigment epithelium cell line. Cultures were established and maintained according to supplier protocols. The ICG dye, TB or Hank's balanced salt solution (controls) were then applied to the cells at varying concentrations and over various exposure periods. Fiberoptic light was also applied to cells to assess for the possibility of a potentiating phototoxic effect. Cell viability fractions were determined using a well-studied mitochondrial dehydrogenase assay. RESULTS: The TB was not toxic to the retinal pigment epithelium cell cultures at any concentration or over any period of exposure, whereas ICG dye demonstrated dose-dependent and exposure-dependent toxicity. The ICG dye was found to be toxic to the cells at all tested concentrations between 5.0 mg/ml (stock concentration, 26.1% cell survival) and 0.5 mg/ml (92.8% cell survival) over a 3-minute exposure. No toxicity to TB was seen at the stock concentration of 1.5 mg/mL. Addition of light to the cultures did not significantly alter cell viability with either dye. Long periods of exposure, 2 hours, 24 hours, and 72 hours, to minute concentrations of either dye did not produce significant cell death. CONCLUSIONS: Indocyanine green demonstrates more toxicity than TB to human retinal pigment epithelium cell cultures. This is independent of any phototoxic potentiating effect of fiberoptic light or solvent toxicity. A clinically useful concentration of 0.5-mg/ml ICG causes low cytotoxicity at 3 minutes' exposure (cell survival 92.8%) and shows no detectable toxicity at 1-minute exposure (cell survival 102%).

Costs and Quality of Life in Diabetic Macular Edema: Canadian Burden of Diabetic Macular Edema Observational Study (C-REALITY).

Purpose. To characterize the economic and quality of life burden of diabetic macular edema (DME) in Canadian patients. Patients and Methods. 145 patients with DME were followed for 6 months with monthly telephone interviews and medical chart reviews at months 0, 3, and 6. Visual acuity in the worst-seeing eye was assessed at months 0 and 6. DME-related healthcare costs were determined over 6 months, and vision-related (National Eye Institute Visual Functioning Questionnaire) and generic (EQ-5D) quality of life was assessed at months 0, 3, and 6. Results. Mean age of patients was 63.7 years: 52% were male and 72% had bilateral DME. At baseline, visual acuity was categorized as normal/mild loss for 63.4% of patients, moderate loss for 10.4%, and severe loss/nearly blind for 26.2%. Mean 6-month DME-related costs/patient were as follows: all patients (n = 135), $2,092; normal/mild loss (n = 88), $1,776; moderate loss (n = 13), $1,845; and severe loss/nearly blind (n = 34), $3,007. Composite scores for vision-related quality of life declined with increasing visual acuity loss; generic quality of life scores were highest for moderate loss and lowest for severe loss/nearly blind. Conclusions. DME-related costs in the Canadian healthcare system are substantial. Costs increased and vision-related quality of life declined with increasing visual acuity severity.

Dynamic atypical optic nerve coloboma associated with transient macular detachment.

PURPOSE: Macular schisis or detachment is frequently observed in eyes with optic pits or colobomas. Although spontaneous resolution of the maculopathy has been reported, concurrent changes in the optic nerve coloboma have not. We report three cases of atypical optic nerve colobomas in which dynamic optic nerve changes coincide with the development and subsequent resolution of the associated maculopathy. METHODS: We reviewed the records of three patients with dynamic optic nerve changes associated with maculopathy. All patients were observed for at least 6 months. Fundus photography and fluorescein angiography were used to document the optic nerve and macular changes. RESULTS: Three patients were noted to have macular detachments without apparent optic nerve excavation. With observation, the maculopathy spontaneously resolved in each case. We documented concurrent optic nerve changes whereby atypical optic nerve colobomas became apparent over several months in all cases. In one case, we noted the simultaneous development of maculopathy in association with obscuration of a prior disc anomaly. None of the eyes had a posterior vitreous detachment. We could not identify any associated systemic conditions or reproduce the findings with external stimulation. Initial Snellen acuity ranged from 20/60 to 20/200. Final Snellen acuity ranged from 20/20 to 20/40. CONCLUSIONS: Fluctuating optic nerve changes may occur in the setting of atypical optic nerve coloboma and associated maculopathy. In cases of macular schisis or detachment where an optic nerve coloboma is not readily apparent, and no other causes are identified, consideration of a period of observation prior to therapeutic intervention seems appropriate.