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.

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.

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.

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.

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.

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.

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.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy Complicated by Fatal Cerebral Vasculitis.

A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite high-dose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes.

Visual Outcomes after Vitrectomy for Terson Syndrome Secondary to Traumatic Brain Injury.

PURPOSE: To evaluate visual outcomes after vitrectomy for intraocular hemorrhages secondary to traumatic brain injury. DESIGN: Retrospective, observational case series. PARTICIPANTS: A total of 28 eyes in 20 patients undergoing vitrectomy for Terson syndrome secondary to traumatic brain injury between 1997 and 2015. METHODS: We reviewed the records of patients undergoing a standard 20-gauge or 23-gauge pars plana vitrectomy for intraocular hemorrhages secondary to traumatic brain injury, and the timing of vitrectomy in relation to the inciting intracranial event was recorded. MAIN OUTCOME MEASURES: The primary outcome measure was the change in the preoperative visual acuity score at postoperative month 1 and at the last noted clinic appointment. RESULTS: A total of 28 eyes in 20 patients (all male) underwent pars plana vitrectomy for intraocular hemorrhages secondary to traumatic brain injury. The mean preoperative baseline logarithm of the minimum angle of resolution (logMAR) (Snellen) best-corrected visual acuity (BCVA) was 1.81±0.56 (20/1290). At 1-month postoperative follow-up, the mean BCVA was 0.30±0.33 (20/40). At the date of the last follow-up, the mean BCVA was 0.15±0.24 (20/30) and the median BCVA was 0.00 (20/20). Although the difference between preoperative and postoperative BVCA was significantly different at 1 month and the final postoperative clinic visits (P < 0.001), there was not a correlation between preoperative visual acuity as a predictor of final postoperative visual acuity outcome (r=-0.32; P = 0.09; 95% confidence interval [CI] -0.62 - 0.06). At the date of the last follow-up, the differences in visual outcomes between the individuals undergoing vitrectomy within 3 months of the inciting event, 0.08±0.15 (20/25), were not significantly different than those undergoing surgical intervention after 3 months, 0.18±0.27 (20/30) (P = 0.28). Three cases among those undergoing vitrectomy after 3 months were complicated by retinal detachment, none of which resulted in a BCVA worse than when the patient originally presented preoperatively. CONCLUSIONS: In this retrospective series of patients without other ocular pathology, surgical intervention effectively provided rapid visual recovery in the majority of individuals with intraocular hemorrhages secondary to traumatic brain injury, irrespective of the timing of vitrectomy or of preoperative visual acuity.

Modern Strategies to Save Sight in Diabetes.

Owing to the global epidemic of obesity, the incidence of diabetes and its complications are rapidly increasing around the world. Yet, visual impairment caused by diabetic retinopathy is paradoxically on the decline. This improvement is due to better understanding of etiologic mechanisms, increased screening, and advent of newer therapies. Here, we discuss salient developments in the comprehension of the root causes of diabetic retinopathy and the molecular mechanisms underlying current treatment approaches.

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.

Visual involvement in corticobasal syndrome.

Corticobasal syndrome (CBS) is the clinical presentation of corticobasal degeneration (CBD), a rare neurodegenerative disorder, with features of both cerebral and basal ganglia involvement. Visual disturbance is uncommonly a predominant symptom but when present can be markedly debilitating. Visual findings primarily manifest as oculomotor apraxia, but significant cognitive impairment may result in the inability to process visuospatial information and can result in simultagnosia and visuomotor ataxia. A 60-year-old woman with a history of CBS presented with progressive visual impairment. Her symptoms were primarily due to severe oculomotor apraxia, optic ataxia, and pronounced simultagnosia. We present the case and review the literature regarding visual dysfunction in CBS.

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.

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.

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.

Diagnostic testing and treatment choices in primary vitreoretinal lymphoma.

BACKGROUND: Primary vitreoretinal lymphoma is a rare intraocular malignancy often seen in the context of central nervous system lymphoma. This review updates the current approaches to the management of primary vitreoretinal lymphoma. METHODS: A review of current literature on the management of primary vitreoretinal lymphoma with an emphasis on contemporary diagnostic and treatment methods. RESULTS: Techniques for diagnosing primary vitreoretinal lymphoma from ocular biopsy specimens include cytologic analysis, immunocytochemistry, flow cytometry, polymerase chain reaction to detect V-J immunoglobulin gene rearrangements, and analysis of IL-6 and IL-10 in aqueous or vitreous fluid. Treatment options include external beam radiotherapy, systemic chemotherapy, and intravitreal chemotherapy. CONCLUSION: Cytologic examination of intraocular biopsy specimens remains the gold standard for the diagnosis of PVRL, but ancillary tests can be very helpful in selected patients. Successful primary treatment of the eyes can be accomplished with external beam radiotherapy or intravitreal chemotherapy. Management decisions should be individualized on patient factors, local expertise, and patient preferences. Improvements in molecular diagnostics and local drug delivery are needed to improve the management of PVRL.

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.