Increasing Energetic Demands on Photoreceptors in Diabetes Corrects Retinal Lipid Dysmetabolism and Reduces Subsequent Microvascular Damage.

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but they likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice-pharmacologic visual cycle inhibition and prolonged dark adaptation-reduce photoreceptor anabolic lipid metabolism. Elevated retinal lipid biosynthetic signaling was observed in two mouse models of diabetes, with both models showing reduced retinal AMP-activated kinase (AMPK) signaling, elevated acetyl CoA carboxylase (ACC) signaling, and increased activity of fatty acid synthase, which promotes lipotoxicity in photoreceptors. Although retinal AMPK-ACC axis signaling was dependent on systemic glucose fluctuations in healthy animals, mice with diabetes lacked such regulation. Visual cycle inhibition and prolonged dark adaptation reversed abnormal retinal AMPK-ACC signaling in mice with diabetes. Although visual cycle inhibition reduced the severity of diabetic retinopathy in control mice, as assessed by retinal capillary atrophy, this intervention was ineffective in fatty acid synthase gain-of-function mice. These results suggest that early diabetic retinopathy is characterized by glucose-driven elevations in retinal lipid biosynthetic activity, and that two interventions known to increase photoreceptor glucose demands alleviate disease by reversing these signals.

ENDOGENOUS ENDOPHTHALMITIS CAUSED BY GROUP B STREPTOCOCCUS IN A HEALTHY, TERM NEONATE.

PURPOSE: The purpose of this study was to describe an unusual case of unilateral, endogenous endophthalmitis in an otherwise healthy, term neonate. METHODS: A 3-week-old otherwise healthy, term male infant was referred to St. Louis Children's Hospital for a second opinion of presumed panuveitis of the right eye. RESULTS: Diffusion-weighted magnetic resonance imaging demonstrating purulent intraocular contents facilitated the diagnosis of endophthalmitis. Examination of surgical vitreous samples by staining and cytology demonstrated gram-positive bacterial cocci in short chains, thereby confirming endophthalmitis. Polymerase chain reaction testing of vitreous fluid identified Streptococcus agalactiae , despite an unremarkable systemic workup and a negative prepartum maternal Group B streptococcal screen. CONCLUSION: Endogenous endophthalmitis is a rare but devastating cause of vision loss in otherwise healthy, term neonates. Prompt diagnosis may be facilitated by magnetic resonance imaging and diagnostic vitreous biopsy.

Silicone oil tamponade in managing recalcitrant endophthalmitis after cataract surgery secondary to Clostridium intestinale.

A woman presented two weeks after uncomplicated cataract surgery with decreased visual acuity from endophthalmitis. One week after initial management with intravitreal antibiotics, her visual acuity decreased further, undergoing pars plana vitrectomy with intravitreal and intravenous antimicrobial coverage with preliminary improvement. Three days after vitrectomy, her vision decreased with recurrent inflammation. Initial cultures grew Clostridium intestinale She underwent repeat vitrectomy with silicone oil tamponade with no subsequent recurrence. The silicone oil was removed after 4 months and her visual acuity returned to 20/20 after 1 month and through 1 year of follow-up. Postoperative endophthalmitis is rare, with cases due to Clostridium species particularly destructive. In this first reported case of C. intestinale endophthalmitis, conventional management did not achieve lasting quiescence until silicone oil tamponade was employed. Pars plana vitrectomy with silicone oil tamponade should be considered in the management of recurrent endophthalmitis or endophthalmitis secondary to a recalcitrant microbe.

Weight Reduction as an Adjunctive Management Strategy for Diabetic Retinopathy.

As rates of global obesity and diabetes increase, diabetic retinopathy continues to grow as a frequent cause of visual impairment. Despite tremendous recent strides in therapy, a significant fraction of patients remain poorly responsive to modern interventions. Adjunctive therapy in such settings could be widely beneficial. A growing body of evidence suggests that weight reduction strategies for obesity-related diabetes have the potential to serve as important supplements to modern ophthalmic care for preservation of vision.

Vitreous microparticles contain apoptotic signals suggesting a diabetic vitreopathy.

AIM: To evaluate differences in microparticle profiles in vitreous samples between diabetic and non-diabetic eyes undergoing vitrectomy. METHODS: Un-masked cross-sectional series of 34 eyes undergoing vitrectomy. Vitreous specimens were collected and processed to evaluate for membrane integrity (DAPI), apoptosis (Annexin-V), and endothelial-cell origin (V-Cadherin). A BD LSR II flow cytometer was used for analysis and standardized sub-micron-sized beads were used for size comparison. RESULTS: Thirty-four specimens underwent analysis. Greater levels of Annexin-V were found on microparticles from specimens in which blood had entered the vitreous (n=12) compared to those without blood (n=22; 52.3%±30.7% vs 19.6%±27.2%, P=0.002). Patients with diabetes having surgery with hemorrhage (n=7) had greater expression of Annexin-V than those without hemorrhage (n=8; 62.1%±31.7% vs 18.9%±20.9%, P=0.009). However, in patients with non-diabetic vitreous hemorrhage, the level of Annexin-V expression was not significantly different compared to other disease processes (38.6%±25.7%, n=5 vs 20.0%±30.9%, n=14, P=0.087). CONCLUSION: Increased expression of the apoptotic marker, Annexin-V is detected on vitreous microparticles in diabetes-related vitreous hemorrhage. When evaluating vitreous hemorrhage in patients without diabetes, the apoptotic signal is not significantly different. Vitrectomy in patients with diabetes, and improvement in visual outcomes, may be related to the removal of a serum-derived, pro-apoptotic vitreous. Further investigation is warranted in order to identify the molecular characteristics of microparticles that regulate disease.

Five-Year Cost-Effectiveness Modeling of Primary Care-Based, Nonmydriatic Automated Retinal Image Analysis Screening Among Low-Income Patients With Diabetes.

BACKGROUND: Artificial intelligence-based technology systems offer an alternative solution for diabetic retinopathy (DR) screening compared with standard, in-office dilated eye examinations. We performed a cost-effectiveness analysis of Automated Retinal Image Analysis System (ARIAS)-based DR screening in a primary care medicine clinic that serves a low-income patient population. METHODS: A model-based, cost-effectiveness analysis of two DR screening systems was created utilizing data from a recent study comparing adherence rates to follow-up eye care among adults ages 18 or older with a clinical diagnosis of diabetes. In the study, the patients were prescreened with an ARIAS-based, nonmydriatic (undilated), point-of-care tool in the primary care setting and were compared with patients with diabetes who were referred for dilated retinal screening without prescreening, as is the current standard of care. Using a Markov model with microsimulation resulting in a total of 600 000 simulated patient experiences, we calculated the incremental cost-utility ratio (ICUR) of the two screening approaches, with regard to five-year cost-effectiveness of DR screening and treatment of vision-threatening DR. RESULTS: At five years, ARIAS-based screening showed similar utility as the standard of care screening systems. However, ARIAS reduced costs by 23.3%, with an ICUR of $258 721.81 comparing the current practice to ARIAS. CONCLUSIONS: Primary care-based ARIAS DR screening is cost-effective when compared with standard of care screening methods.

Glucose-mediated de novo lipogenesis in photoreceptors drives early diabetic retinopathy.

Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis-either because of diabetes or because of FAS gain of function-was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear.

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration.

Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice.

Diabetic Retinopathy Screening with Automated Retinal Image Analysis in a Primary Care Setting Improves Adherence to Ophthalmic Care.

PURPOSE: Retinal screening examinations can prevent vision loss resulting from diabetes but are costly and highly underused. We hypothesized that artificial intelligence-assisted nonmydriatic point-of-care screening administered during primary care visits would increase the adherence to recommendations for follow-up eye care in patients with diabetes. DESIGN: Prospective cohort study. PARTICIPANTS: Adults 18 years of age or older with a clinical diagnosis of diabetes being cared for in a metropolitan primary care practice for low-income patients. METHODS: All participants underwent nonmydriatic fundus photography followed by automated retinal image analysis with human supervision. Patients with positive or inconclusive screening results were referred for comprehensive ophthalmic evaluation. Adherence to referral recommendations was recorded and compared with the historical adherence rate from the same clinic. MAIN OUTCOME MEASURE: Rate of adherence to eye screening recommendations. RESULTS: By automated screening, 8.3% of the 180 study participants had referable diabetic eye disease, 13.3% had vision-threatening disease, and 29.4% showed inconclusive results. The remaining 48.9% showed negative screening results, confirmed by human overread, and were not referred for follow-up ophthalmic evaluation. Overall, the automated platform showed a sensitivity of 100% (confidence interval, 92.3%-100%) in detecting an abnormal screening results, whereas its specificity was 65.7% (confidence interval, 57.0%-73.7%). Among patients referred for follow-up ophthalmic evaluation, the adherence rate was 55.4% at 1 year compared with the historical adherence rate of 18.7% (P < 0.0001, Fisher exact test). CONCLUSIONS: Implementation of an automated diabetic retinopathy screening system in a primary care clinic serving a low-income metropolitan patient population improved adherence to follow-up eye care recommendations while reducing referrals for patients with low-risk features.

Photoreceptor responses to light in the pathogenesis of diabetic retinopathy.

Vision loss, among the most feared complications of diabetes, is primarily caused by diabetic retinopathy, a disease that manifests in well-recognized, characteristic microvascular lesions. The reasons for retinal susceptibility to damage in diabetes are unclear, especially considering that microvascular networks are found in all tissues. However, the unique metabolic demands of retinal neurons could account for their vulnerability in diabetes. Photoreceptors are the first neurons in the visual circuit and are also the most energy-demanding cells of the retina. Here, we review experimental and clinical evidence linking photoreceptors to the development of diabetic retinopathy. We then describe the influence of retinal illumination on photoreceptor metabolism, effects of light modulation on the severity of diabetic retinopathy, and recent clinical trials testing the treatment of diabetic retinopathy with interventions that impact photoreceptor metabolism. Finally, we introduce several possible mechanisms that could link photoreceptor responses to light and the development of retinal vascular disease in diabetes. Collectively, these concepts form the basis for a growing body of investigative efforts aimed at developing novel pharmacologic and nonpharmacologic tools that target photoreceptor physiology to treat a very common cause of blindness across the world.

Factors Associated with Adherence to Screening Guidelines for Diabetic Retinopathy Among Low-Income Metropolitan Patients.

In this retrospective analysis of patients with diabetes in an academic primary care clinic in St. Louis, attendance at ophthalmic screening appointments was recorded over a two-year observation window. Factors associated with adherence were analyzed by multivariable regression. Among 974 total patients included, only 330 (33.9%) were adherent within a two-year period. Multivariate analyses identified older age, female gender, primary language other than English, and attendance at ancillary diabetes clinic visits as factors associated with improved diabetic retinopathy screening adherence. Factors not associated with adherence included race and insurance status.

Efficient Coding by Midget and Parasol Ganglion Cells in the Human Retina.

In humans, midget and parasol ganglion cells account for most of the input from the eyes to the brain. Yet, how they encode visual information is unknown. Here, we perform large-scale multi-electrode array recordings from retinas of treatment-naive patients who underwent enucleation surgery for choroidal malignant melanomas. We identify robust differences in the function of midget and parasol ganglion cells, consistent asymmetries between their ON and OFF types (that signal light increments and decrements, respectively) and divergence in the function of human versus non-human primate retinas. Our computational analyses reveal that the receptive fields of human midget and parasol ganglion cells divide naturalistic movies into adjacent spatiotemporal frequency domains with equal stimulus power, while the asymmetric response functions of their ON and OFF types simultaneously maximize stimulus coverage and information transmission and minimize metabolic cost. Thus, midget and parasol ganglion cells in the human retina efficiently encode our visual environment.

Impact of Intraoperative Ocular Lubricants on Corneal Debridement Rate During Vitreoretinal Surgery.

PURPOSE: To compare surgical parameters among patients receiving Viscoat (sodium chondroitin sulfate 4%-sodium hyaluronate 3%) or Goniosol (hydroxypropyl methylcellulose 2.5%) as topical lubricants for retinal surgery. METHODS: This was a retrospective analysis of patients undergoing retinal surgery between March 2013 and March 2018 using Goniosol or Viscoat as adjuvants. Primary outcome measures were rate of corneal debridement and operative time between groups, compared using χ 2 and t-tests, respectively. RESULTS: Compared to Viscoat (n=319), the Goniosol group (n=210) had more frequent intraoperative corneal debridement (21.4% vs 0, p<0.05) and longer surgical times (98 vs 78 minutes, p<0.05). Patients in the Viscoat group had higher rates of complex procedures (34.8% vs 26.7%, p<0.05), but were younger (50.7 vs 55.0 years, p<0.05) and more likely to be phakic (83.4% vs 70.5%, p<0.05). CONCLUSION: These findings suggest potential advantages of using Viscoat over Goniosol for corneal lubrication to aid visualization during vitreoretinal surgery.

Light deprivation reduces the severity of experimental diabetic retinopathy.

Illumination of the retina is a major determinant of energy expenditure by its neurons. However, it remains unclear whether light exposure significantly contributes to the pathophysiology of common retinal disease. Driven by the premise that light exposure reduces the metabolic demand of the retina, recent clinical trials failed to demonstrate a benefit for constant illumination in the treatment of diabetic retinopathy. Here, we instead ask whether light deprivation or blockade of visual transduction could modulate the severity of this common cause of blindness. We randomized adult mice with two different models of diabetic retinopathy to 1-3 months of complete dark housing. Unexpectedly, we find that diabetic mice exposed to short or prolonged light deprivation have reduced diabetes-induced retinal pathology, using measures of visual function, compared to control animals in standard lighting conditions. To corroborate these results, we performed assays of retinal vascular health in diabetic Gnat1-/- and Rpe65-/- mice, which lack phototransduction. Both mutants displayed less diabetes-associated retinal vascular disease compared to respective wild-type controls. Collectively, these results suggest that light-induced visual transduction promotes the development of diabetic retinopathy and implicate photoreceptors as an early source of visual pathology in diabetes.

Fenofibrate Reduces the Severity of Neuroretinopathy in a Type 2 Model of Diabetes without Inducing Peroxisome Proliferator-Activated Receptor Alpha-Dependent Retinal Gene Expression.

Fenofibrate slows the progression of clinical diabetic retinopathy (DR), but its mechanism of action in the retina remains unclear. Fenofibrate is a known agonist of peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor critical for regulating metabolism, inflammation and oxidative stress. Using a DR mouse model, db/db, we tested the hypothesis that fenofibrate slows early DR progression by activating PPARα in the retina. Relative to healthy littermates, six-month-old db/db mice exhibited elevated serum triglycerides and cholesterol, retinal gliosis, and electroretinography (ERG) changes including reduced b-wave amplitudes and delayed oscillatory potentials. These pathologic changes in the retina were improved by oral fenofibrate. However, fenofibrate did not induce PPARα target gene expression in whole retina or isolated Müller glia. The capacity of the retina to respond to PPARα was further tested by delivering the PPARα agonist GW590735 to the intraperitoneal or intravitreous space in mice carrying the peroxisome proliferator response element (PPRE)-luciferase reporter. We observed strong induction of the reporter in the liver, but no induction in the retina. In summary, fenofibrate treatment of db/db mice prevents the development of early DR but is not associated with induction of PPARα in the retina.

Association of Retinopathy and Insulin Resistance: NHANES 2005-2008.

Purpose: In animal models, insulin resistance without severe hyperglycemia is associated with retinopathy; however, corroborating data in humans are lacking. This study aims to investigate the prevalence of retinopathy in a population without diabetes and evaluate the association of insulin resistance and retinopathy within this group.Methods: The study population included 1914 adults age ≥40 without diabetes who were assigned to the morning, fasted group in the National Health and Nutrition Examination Survey 2005-2008, conducted by the Centers for Disease Control. Retinopathy was determined using fundus photos independently graded by a reading center and insulin resistance was determined using the homeostatic model of insulin resistance.Results: Prevalence of retinopathy in those without diabetes was survey design adjusted 9.4% (174/1914). In multivariable analyses, retinopathy was associated with insulin resistance (HOMA-IR OR: 1.09, 95% CI: 1.03, 1.16; p = .0030), male gender (OR: 1.39, 95% CI: 1.04, 1.85; p = .0267), and age (OR: 1.03, 95% CI: 1.01, 1.05; p = .0203).Conclusions: Insulin resistance in the absence of overt hyperglycemia could be an early driver of retinopathy.

Visual Field Loss in Patients With Diabetes in the Absence of Clinically-Detectable Vascular Retinopathy in a Nationally Representative Survey.

Purpose: Neuroretinopathy is increasingly being recognized as an independent cause of vision loss in diabetes. Visual field loss, as detected by frequency doubling technology (FDT)-based visual perimetry, is a sign of neuroretinopathy and occurs in early stages of diabetic retinopathy (DR). Here, we hypothesized that FDT visual field testing could identify patients with diabetic neuroretinopathy in the absence of clinically detectable microvascular DR. Methods: All National Health and Nutrition Examination Survey (NHANES) 2005-2008 participants receiving fundus photography and visual field screening by FDT were included in this study. Participants with self-reported glaucoma, use of glaucoma medications, or determination of glaucoma based on disk features were excluded. Visual fields were screened using FDT protocol in which participants underwent a 19-subfield suprathreshold test. Results: Patients with diabetes but no DR were more likely to have ≥1 subfield defects at 5%, 2%, and 1% probability levels than patients without diabetes (41.3% vs. 28.6%; 27.4% vs. 17.5%; 15.9% vs. 9.4%; all P < 0.0008). Multivariable regression showed that each additional glycated hemoglobin % (HbA1c) was associated with 19% greater odds of having ≥1 visual subfield defects in those with diabetes without DR (odds ratio: 1.19, 95% confidence interval: 1.07-1.33; P = 0.0020). Conclusions: Patients with diabetes have visual field defects in the absence of clinically detectable DR, suggesting neuroretinopathy precedes classical microvascular disease. These defects become more frequent with the onset of visible retinopathy and worsen as the retinopathy becomes more severe. Longitudinal studies are required to understand the pathogenesis of diabetic neuroretinopathy in relation to classic DR.

Complete Posterior Vitreous Detachment Reduces the Need for Treatment of Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: To evaluate the vitreomacular interface and its relation to treatment burden for diabetic macular edema (DME) in patients without overt vitreomacular traction (VMT). PATIENTS AND METHODS: A retrospective cohort study of 494 eyes from 274 patients who had macular spectral-domain optical coherence tomography (SD-OCT) and did not have proliferative diabetic retinopathy, DME, or VMT at the initial visit. Posterior vitreous detachment (PVD) was categorized at the initial visit into five stages (0-4) using SD-OCT parameters alone. RESULTS: Two of 34 eyes (6.9%) presenting with a complete PVD required DME treatment during follow-up, whereas 144 of 460 eyes (31.3%) without a complete PVD at baseline required treatment (P = .001, Chi-squared). After adjusting for age, ethnicity, gender, and HbA1c, complete PVD at baseline was associated with a significant reduction in risk of DME therapy (hazard ratio: 0.18; 95% confidence interval, 0.05-0.73; P = .02). CONCLUSION: Complete PVD is independently associated with a reduced need for DME treatment. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e266-e273.].

Emerging Insights and Interventions for Diabetic Retinopathy.

PURPOSE OF REVIEW: To introduce recent advances in the understanding of diabetic retinopathy and to summarize current and emerging strategies to treat this common and complex cause of vision loss. RECENT FINDINGS: Advances in retinal imaging and functional analysis indicate that retinal vascular and neural pathologies exist long before the development of clinically visible retinopathy. Such diagnostics could facilitate risk stratification and selective early intervention in high-risk patients. Antagonists of the vascular endothelial growth factor pathway effectively reduce vision loss in diabetes and promote regression of disease severity. Promising new strategies to treat diabetic retinopathy involve novel systemic diabetes therapy and ocular therapies that antagonize angiogenic growth factor signaling, improve blood-retina barrier function and neurovascular coupling, modulate neuroretinal metabolism, or provide neuroprotection. Long considered a pure microvasculopathy, diabetic retinopathy in fact affects the neural and vascular retina as well as neurovascular communication. Emerging therapies include those that target neuroretinal dysfunction in addition to those modulating vascular biology.

Successful treatment of an exudative choroidal hemangioma with oral propranolol in a 10-year-old boy.

A 10-year-old boy was referred for a circumscribed choroidal hemangioma with underlying exudative detachment of the left eye. To avoid general anesthetics required for laser-based therapy in a child, we began a trial of oral propranolol. The patient's exudative detachment resolved, with resulting improvement in visual acuity, and remained quiescent for 3 years.