Diabetic retinopathy: New concepts of screening, monitoring, and interventions.

The science of diabetes care has progressed to provide a better understanding of the oxidative and inflammatory lesions and pathophysiology of the neurovascular unit within the retina (and brain) that occur early in diabetes, even prediabetes. Screening for retinal structural abnormalities, has traditionally been performed by fundus examination or color fundus photography; however, these imaging techniques detect the disease only when there are sufficient lesions, predominantly hemorrhagic, that are recognized to occur late in the disease process after significant neuronal apoptosis and atrophy, as well as microvascular occlusion with alterations in vision. Thus, interventions have been primarily oriented toward the later-detected stages, and clinical trials, while demonstrating a slowing of the disease progression, demonstrate minimal visual improvement and modest reduction in the continued loss over prolonged periods. Similarly, vision measurement utilizing charts detects only problems of visual function late, as the process begins most often parafoveally with increasing number and progressive expansion, including into the fovea. While visual acuity has long been used to define endpoints of visual function for such trials, current methods reviewed herein are found to be imprecise. We review improved methods of testing visual function and newer imaging techniques with the recommendation that these must be utilized to discover and evaluate the injury earlier in the disease process, even in the prediabetic state. This would allow earlier therapy with ocular as well as systemic pharmacologic treatments that lower the and neuro-inflammatory processes within eye and brain. This also may include newer, micropulsed laser therapy that, if applied during the earlier cascade, should result in improved and often normalized retinal function without the adverse treatment effects of standard photocoagulation therapy.

Diabetes mellitus associated neurovascular lesions in the retina and brain: A review.

Diabetes mellitus (DM) is now recognized as a system-wide, autoimmune, inflammatory, microvascular disorder, which, in the retina and brain results in severe multifocal injury now recognized as a leading cause, world-wide, of progressive vision loss and dementia. To address this problem, resulting primarily from variations in glycemia in the prediabetic and overt diabetic states, it must be realized that, although some of the injury processes associated with diabetes may be system wide, there are varying responses, effector, and repair mechanisms that differ from organ to organ or within varying cell structures. Specifically, within the retina, and similarly within the brain cortex, lesions occur of the "neurovascular unit", comprised of focal microvascular occlusions, inflammatory endothelial and pericyte injury, with small vessel leakage resulting in injury to astrocytes, Müller cells, and microglia, all of which occur with progressive neuronal apoptosis. Such lesions are now recognized to occur before the first microaneurysms are visible to imaging by fundus cameras or before they result in detectable symptoms or signs recognizable to the patient or clinician. Treatments, therefore, which currently are not initiated within the retina until edema develops or there is progression of vascular lesions that define the current staging of retinopathy, and in the brain only after severe signs of cognitive failure. Treatments, therefore are applied relatively late with some reduction in progressive cellular injury but with resultant minimal vision or cognitive improvement. This review article will summarize the multiple inflammatory and remediation processes currently understood to occur in patients with diabetes as well as pre-diabetes and summarize as well the current limitations of methods for assessing the structural and functional alterations within the retina and brain. The goal is to attempt to define future screening, monitoring, and treatment directions that hopefully will prevent progressive injury as well as enable improved repair and attendant function.

Slowed Progression of Age-Related Geographic Atrophy Following Subthreshold Laser.

PURPOSE: To determine the effect of panmacular low-intensity/high-density subthreshold diode micropulse laser (SDM) on age-related geographic atrophy (ARGA) progression. METHODS: The retinal images of all eyes with ARGA in a previously reported database, consisting of all eyes with dry age-related macular degeneration (AMD) active in a vitreoretinal practice electronic medical record (EMR), were identified and analyzed to determine the velocity of radial linear ARGA progression during observation and after panmacular SDM. RESULTS: Sixty-seven eyes of 49 patients with ARGA, mean age of 86 years were identified as having follow-up both before and after initiation of SDM treatment. All were included in the study. These eyes were followed a mean 910 days (2.5 years) prior to SDM treatment and a mean 805 days (2.2 years) after. Measurement masked to treatment vs observation found the radius of ARGA lesions progressed 1 to 540 µm per year (mean 137µm, SD 107) prior to treatment (controls); and -44 to 303 µm per year (mean 73µm, SD 59) after initiation of periodic panmacular SDM laser. Thus, the velocity of radial linear progression decreased 47% per year following panmacular SDM (p<0.0001). There were no adverse treatment effects. CONCLUSION: In cohort of eyes with high-risk dry AMD, panmacular SDM slowed linear radial ARGA progression velocity 47% per year (p<0.0001) without adverse treatment effects. Validated, these findings would constitute an important advance in the prevention of age-related visual loss and a benchmark for future therapies.

Diabetic Retinopathy-An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes.

Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic ß-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.

Low incidence of choroidal neovascularization following subthreshold diode micropulse laser (SDM) in high-risk AMD.

PURPOSE: To determine the incidence of new choroidal neovascularization (CNV) in eyes with dry age-related macular degeneration (AMD) following subthreshold diode micropulse laser (SDM). METHOD: In an observational retrospective cohort study, the records of all patients active in the electronic medical records database were reviewed to identify eyes with dry AMD treated with SDM. Identified eyes were classified by simplified AREDS categories, and analyzed for the primary endpoint of new CNV after treatment. RESULTS: The EMR revealed SDM was offered to 373/392 (95%) patients with dry AMD and elected by 363/373 (97%) between 2008-2017. Follow up was available for 354/363 patients (547 eyes, 98%) (range 6-108 mos., avg. 22). CNV risk factors included age (median 84 years, 67% > 80); reticular pseudodrusen (214 eyes, 39%); AREDS category (78% category 3 and 4); and fellow eye CNV (128 eyes, 23%). New CNV developed in 9/547 eyes (1.6%, annualized rate 0.87%). Visual acuity was unchanged. There were no adverse treatment effects. SUMMARY: In a review of a large group of eyes with exceptionally high-risk AMD, SDM was followed by a very low incidence of new CNV. If confirmed by further study, SDM would offer a new and highly effective treatment to reduce the risk of vision loss from AMD.

Safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in eyes with good visual acuity.

PURPOSE: To determine the safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema. METHODS: The records of all patients treated with transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in two retina clinics were reviewed. The eligibility included fovea-involving diabetic macular edema by spectral domain optical coherence tomography and pretreatment visual acuity of 20/40 or better. RESULTS: Thirty-nine eyes of 27 patients aged 50 years to 87 years (mean, 69 years) were included. Postoperative follow-up ranged from 3 months to 36 months (mean, 11 months). Fourteen patients were insulin dependent, and 19 had nonproliferative retinopathy. The preoperative visual acuity was 20/20 (10 eyes), 20/25 (10 eyes), 20/30 (8 eyes), and 20/40 (11 eyes). No eye had evidence of laser-induced macular damage by any imaging means postoperatively. There were no adverse treatment effects. Logarithm of the minimum angle of resolution visual acuity was improved on average of 0.03 units at 4 months to 7 months of follow-up (P = 0.0449, paired t-test) and otherwise stable. The central foveal thickness was improved at 4 months to 7 months (P = 0.05, paired t-test) and 8 months to 12 months, postoperatively (P = 0.04, mixed model accounting). Maximum macular thickness was improved at 4 months to 7 months postoperatively (P = 0.01, paired t-test and mixed model accounting). CONCLUSION: In a small retrospective series, transfoveal subthreshold diode micropulse laser was safe and effective for the treatment of fovea-involving diabetic macular edema in eyes with good preoperative visual acuity that were not the candidates for conventional photocoagulation or intravitreal injection. Further study is warranted.

Anti-VEGF effects of intravitreal erythropoietin in early diabetic retinopathy.

In the present study, a single intravitreal erythropoietin (EPO) to diabetic rats produced therapeutic effects on blood-retinal barrier (BRB) function and neuronal survival at different time courses of retinopathy. In parallel, the hypoxia-inducible factor 1 alpha (HIF-1 alpha) pathway has been quantitatively studied, including VEGF-A, endogenous EPO, EPO receptor (EpoR), prolyl hydroxylases (PHD1-3) and von Hippel-Lindau tumor suppressor (VHL). The mRNA levels of HIF-1 alpha, VEGF-A, endogenous EPO, PHD1-3 and VHL are all up-regulated in the diabetic retina, and suppressed by exogenous EPO. The increased protein levels of HIF-1 alpha, VEGF-A, and endogenous EPO found in diabetic retinas also have been down-regulated by exogenous EPO. The results demonstrate that the HIF-1 pathway is activated in the retina in early diabetes, but is negatively regulated by a feedback loop following the administration of exogenous EPO. Exogenous EPO at pharmacologic levels leads to suppression of VEGF and in turn, restoration of the normal functions of BRB in a time-dependent manner. In the diabetic retina, the same level of exogenous EPO that inhibits VEGF also exerted neuronal protection.

Effects of intravitreal erythropoietin therapy for patients with chronic and progressive diabetic macular edema.

BACKGROUND AND OBJECTIVE: To determine the effects of intravitreal injections of erythropoietin in eyes with severe, chronic diabetic macular edema, 5 eyes of 5 patients underwent injections of rHuEPO alpha (EPO). PATIENTS AND METHODS: All eyes had progressive vision loss and persistent or worsening edema with prior multi-modal treatment. EPO (5U/50 microL) was injected intravitreally every 6 weeks for three doses and followed for an additional 6 weeks with complete ocular examinations, fluorescein angiography, optical coherence tomography (OCT), and central field acuity perimetry. RESULTS: Visual acuity of all patients was subjectively improved by 3 or more lines in 3 eyes and 1 line in 2 eyes. Visual acuity improved to a larger extent than anatomic improvement by OCT. Clearing of hard exudates but only minor improvement in leakage on fluorescein angiography was observed. Improvement in vision occurred within 1 week after the first injection and was maintained until the end point of the current case series (at 18 weeks after the first injection). CONCLUSION: This case series seems to show a short-term positive response to EPO for a specific group of patients with chronic diabetic macular edema who were unresponsive to currently available therapies.

Screening athletes with Down syndrome for ocular disease.

BACKGROUND: Persons with Down syndrome are well known to have a high prevalence of vision and eye health problems, many of which are undetected or untreated primarily because of infrequent ocular examinations. Public screening programs, directed toward the pediatric population, have become more popular and commonly use letter or symbol charts. This study compares 2 vision screening methods, the Lea Symbol chart and a newly developed interactive computer program, the Vimetrics Central Vision Analyzer (CVA), in their ability to identify ocular disease in the Down syndrome population. METHODS: Athletes with Down syndrome participating in the European Special Olympics underwent an ocular screening including history, auto-refraction, colour vision assessment, stereopsis assessment, motility assessment, pupil reactivity, and tonometry testing, as well as anterior segment and fundus examinations to evaluate for ocular disease. Visual acuity was tested with the Lea chart and CVA to evaluate these as screening tests for detecting ocular disease as well as significant, uncorrected refractive errors. RESULTS: Among the 91 athletes that presented to the screening, 79 (158 eyes) were sufficiently cooperative for the examination to be completed. Mean age was 26 years +/-10.8 SD. Significant, uncorrected refractive errors (>/=1.00 spherical equivalent) were detected in 28 (18%) eyes and ocular pathology in 51 (32%) eyes. The Lea chart sensitivity and specificity were 43% and 74%, respectively, for detecting ocular pathology and 58% and 100% for detecting uncorrected refractive errors. The CVA sensitivity and specificity were 70% and 86% for detecting pathology and 71% and 100% for detecting uncorrected refractive errors. CONCLUSION: This study confirmed the findings of prior studies in identifying a significant presence of uncorrected refractive errors and ocular pathology in the Down syndrome population. Screening with the Lea symbol chart found borderline sufficient sensitivity and specificity for the test to be used for screening in this population. The better sensitivity and specificity of the CVA, if adjusted normative values are utilized, appear to make this test sufficient for testing Down syndrome children for identifying both refractive errors and ocular pathology.

ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD.

PURPOSE: To characterize the neuroprotective mechanisms of erythropoietin (EPO) against the stress of glyoxal-advanced glycation end products (AGEs) in retinal neuronal cells. METHODS: Rat retinal organ culture, primary retinal neuron culture, and retinal cell line (R28 cell) culture under glyoxal-AGEs insult were used as in vitro models. Exogenous EPO was applied to these models. Retinal neuronal cell death was assessed by TUNEL, ethidium bromide/acridine orange staining, and cell viability assay. R28 cell proliferation was evaluated by BrdU incorporation and propidium iodide staining. Real-time RT-PCR and Western blot analysis were used to detect Bcl-xL, Bcl-2, Bax, BAD, and products of extracellular signal regulated kinase (ERK) and Akt pathways. Specific inhibitors and plasmids were used to pinpoint the roles of ERK and Akt pathways. Results. EPO protected the retinal cells from glyoxal-AGE-induced injury in a time- and dose-dependent fashion. The protective function of EPO was proved to be antiapoptotic, not pro-cell proliferative. Glyoxal upregulated Bax expression but suppressed Bcl-xL expression and BAD phosphorylation. In contrast, EPO enhanced BAD phosphorylation and Bcl-xL expression but downregulated Bax. The regulation of these apoptosis-related proteins by EPO was through ERK and Akt pathways. CONCLUSIONS: These data demonstrate that exogenous EPO significantly attenuates the retinal neuronal cell death induced by glyoxal-AGEs by promoting antiapoptotic and suppressing apoptotic proteins. EPO/EPO receptor signaling through ERK and Akt pathways is pivotal in EPO neuroprotective mechanisms.

Entoptic phenomenon following pars plana vitrectomy caused by retained preretinal gel.

A patient who underwent pars plana vitrectomy for vitreous floaters is described. At the time of surgery, the posterior hyaloid was avulsed and stripped from the posterior retinal surface. Postoperatively, the patient described filamentous and "sea-fan" entoptic phenomena scattered throughout the periaxial vision that were in focus, attached, and "waving" with movement that was counter to the direction of gaze pursuit and demonstrated after movement. The authors believe these structures represent vitreous gel retained at the retinal surface, even though the structures could not be demonstrated by optical coherence tomography or indocyanine green staining at later vitrectomy surgery. This case should raise caution when considering vitrectomy surgery that requires posterior hyaloid stripping in patients with good vision.

Pharmacokinetic and toxicity study of intravitreal erythropoietin in rabbits.

AIM: To study the pharmacokinetics and toxicity of intravitreal erythropoietin (EPO) for potential clinical use. METHODS: For toxicity study, 4 groups (60 rabbits) with intravitreal injection (IVit) of EPO were studied (10 U, 100 U, or 1,000 U) per eye for single injection and 0.6 U/eye (the designed therapeutic level in rabbits) for monthly injections (6X). Eye examination, flash electroretinogram (ERG), and fluorescein angiography (FA) were carried out before and after injection. The rabbits were killed for histological study at different intervals. For the pharmacokinetic study, after IVit of 5 U EPO into left eyes, 44 rabbits were killed at different intervals, and the EPO levels in vitreous, aqueous, retina and serum were analyzed by enzyme-linked immunosorbent assay. RESULTS: At all of the time points examined, the eyes were within normal limits. No significant ERG or FA change was observed. The histology of retina remained unchanged. The pharmacokinetic profile of EPO in ocular compartments was summarized as follows. The half-life times of EPO in vitreous, aqueous and serum were 2.84, 3.24 and 2.12 d, respectively; and Cmax were 4615.75, 294.31 and 1.60 U/L, respectively. EPO concentrations in the retina of the injected eye peaked at 1.36 U/g protein at 6 h following injection, with the half-life observed to be 3.42 d. CONCLUSIONS: IVit of EPO in a wide range is well tolerated and safe for rabbit eyes. At doses up to 10-fold higher than therapeutic levels, EPO has a pharmacokinetic profile with faster clearance, which is favorable for episodic IVit.

Intravitreal injection of erythropoietin protects both retinal vascular and neuronal cells in early diabetes.

PURPOSE: To explore and evaluate the protective effect of erythropoietin (EPO) on retinal cells of chemically induced diabetic rats after EPO was injected intravitreally at the onset of diabetes. METHODS: Diabetes was induced in Sprague-Dawley rats by intraperitoneal injection of streptozotocin (STZ). At the onset of diabetes, a single intravitreal injection of EPO (0.05-200 ng/eye) was performed. In the following 6 weeks, the blood retinal barrier (BRB) was evaluated by Evans blue permeation (EBP). Retinal cell death in different layers was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The retinal thickness and cell counts were examined at the light microscopic level. Electron microscopy (EM) was used to scrutinize retinal vascular and neuronal injury. Neurosensory retinas of normal and diabetic rats were used as the sources of reverse transcription-polymerase chain reaction (RT-PCR) and Western blot for the detection of EPO, EPO receptor (EpoR), and products of the extracellular signal-regulated kinase (ERK) and the signal transducers and activators of transcription 5 (STAT5) pathways. The distribution of EpoR in retinal layers was demonstrated by immunohistochemistry (IHC). RESULTS: In the diabetic rats, BRB breakdown was detected soon after the onset of diabetes, peaked at 2 weeks, and reached a plateau at 2 to 4 weeks. The number of TUNEL-positive cells increased in the neurosensory retina, especially, the outer nuclear layer (ONL) at 1 week after diabetes onset and reached a peak at 4 to 6 weeks. The retinal thickness and the number of cells in the ONL were reduced significantly. EM observations demonstrated vascular and photoreceptor cell death starting soon after the onset of diabetes. All these changes were largely prevented by EPO treatment. Upregulation of EpoR in the neurosensory retina was detected at both the transcriptional and protein levels 4 to 8 weeks after the onset of diabetes, whereas, the endogenous EPO levels of neurosensory retinas were essentially unchanged during the same period observed. In EPO-treated diabetic groups, EpoR expression remained at upregulated levels. Within 2 weeks of the onset of diabetes, activation of the ERK but not the STAT5 pathway was detected in the diabetic retina treated with EPO. CONCLUSIONS: These data demonstrate that apoptosis is an major contributor to neuronal cell death in the early course of diabetic retinopathy (DR). The upregulation of EpoR may be a compensatory response of retinal cells and tissue to diabetic stresses. The EPO/EpoR system as a maintenance-survival mechanism of retinal neurons responds to the insults of early diabetes other than ischemia. The protective function of EPO/EpoR at the least acts through the EpoR-mediated ERK pathway. Exogenous EPO administration by intravitreal injection in early diabetes may prevent retinal cell death and protect the BRB function. Therefore, this is a novel approach for treatment of early DR.

Diabetic retinopathy: the unmet needs for screening and a review of potential solutions.

Diabetic retinopathy remains the leading cause of severe vision loss and blindness in the developed world, in spite of recognized ocular treatments that are successful at reducing the rate of vision impairment. Retinal photography appears a promising method to perform screening in such a setting utilizing new 45 degrees + retinal cameras that do not require pupil dilation and can be operated by a trained, nonophthalmic technician. Certain developments may make the photography more successful including the conversion to electronic chip camera sensors that allow each picture as it is taken to be immediately projected onto a monitor for evaluation and assessment. Utilizing a nonmydriatic camera, studies of single-field photography through a dilated pupil have demonstrated superior or equal sensitivity to fundus examination by an ophthalmologist in a number of studies. However, photography without pupil dilation, especially in the older age group may result in poor-quality photographs owing to intense bilateral pupil constriction after the first images and also due to the presence of cataracts. Computer analysis of the retinal images allows extraction of quantitative data, not only of the diabetic lesions but also of vascular changes that, up until now, have been impossible by human grading and potentially allows a much more detailed and quantitative evaluation of the progression of retinopathy over time. When success of image processing algorithms is demonstrated for a large number of images taken under screening conditions, the benefits of retinal photography and image processing to provide timely, reliable, quantitative and cost-effective results, will make this the preferred method over physician examination or human grader evaluation of the images.

Diabetic retinopathy: treating systemic conditions aggressively can save sight.

To control diabetic retinopathy, we need not only to detect it promptly, but also to manage common systemic comorbid conditions such as hypertension, hyperlipidemia, anemia, obstructive sleep apnea, and smoking--all of which tend to accelerate its course and increase its severity.

The internist's role in managing diabetic retinopathy: screening for early detection.

Although laser treatment keeps vision damaged by diabetic retinopathy from becoming worse, it only rarely improves vision. If primary care physicians wait until the patient complains of blurred vision, it is too late--there is already permanent retinal injury, and the lost vision almost never can be restored. Unfortunately, only half of patients with diabetes undergo an appropriate examination every year. Only by teamwork between primary care physician and ophthalmologist can blindness from diabetic retinopathy be reduced.