Non-proliferative Retinopathy Research Articles

Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients

This study aimed to evaluate the prevalence of retinopathy in long-surviving type 1 diabetic patients. It also investigated the 25 year incidence of proliferative retinopathy and associated risk factors in a Danish population-based cohort. A population-based cohort of 727 type 1 diabetic patients from Fyn County, Denmark, was identified in 1973. In 1981-1982, baseline retinopathy was graded and other risk factors were assessed in 573 patients. Twenty-five years later, 308 patients were still alive. Of these, 201 (65.3%) were re-examined at follow-up in 2007-2008. The median age and duration of diabetes at follow-up were 58.8 and 43 years, respectively. At follow-up, the prevalence of diabetic retinopathy was 97.0%. Non-proliferative retinopathy was found in 45.8%, and 51.2% had proliferative retinopathy. The 25 year incidence of proliferative retinopathy was 42.9% among patients at risk. In a multivariate analysis, baseline HbA(1) (OR 2.14 per 1% increase, 95% CI 1.06-4.31) and non-proliferative retinopathy (OR 4.61, 95% CI 1.94-11.0) were the only risk factors for incident proliferative retinopathy. The long-term incidence of proliferative retinopathy was not associated with baseline duration of diabetes, proteinuria, smoking, body mass index, maculopathy or systolic or diastolic blood pressure. Retinopathy among long-surviving type 1 diabetic patients is almost universal. Proliferative retinopathy was found in half of these patients. In addition, the 25 year incidence of proliferative retinopathy was high. Baseline glycaemic regulation and non-proliferative retinopathy were identified as risk factors for incident proliferative retinopathy.

Corneal Subbasal Nerves Changes in Patients with Diabetic Retinopathy: An In Vivo Confocal Study

To study the subbasal corneal plexus (SCP) in patients with diabetic retinopathy (DR) treated or nontreated with panretinal Argon laser photocoagulation (ALP). Fifty consecutive patients with DR and 50 age- and sex-matched normal control subjects were examined with retinal tomography by a masked evaluator. The following subbasal plexus nerves parameters were considered: number per frame, tortuosity, and reflectivity. Diabetic patients were divided into two groups, according to the presence of proliferative versus nonproliferative retinopathy, according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. The number of fibers per frame and reflectivity were significantly lower in diabetic patients compared with control subjects (2.4 +/- 1 vs. 2.9 +/- 0.8, P = 0.01 and 2.3 +/- 0.9 vs. 2.6 +/- 0.9, P = 0.04, respectively). Tortuosity was significantly higher in diabetic patients (2.5 +/- 0.9 vs. 2.0 +/- 0.8, P = 0.002). Number per frame and reflectivity were significantly lower in diabetic patients with proliferative diabetic retinopathy (PDR; respectively, 2.0 +/- 0.9 vs. 2.9 +/- 0.9, P = 0.001, and 2.0 +/- 0.8 vs. 2.6 +/- 0.7, P = 0.003). Tortuosity was significantly higher in the PDR group (2.2 +/- 0.8 vs. 2.8 +/- 0.9, P = 0.008). The PDR group treated with ALP had significantly lower subbasal nerves number compared with the nontreated group (P = 0.01). DR may induce substantial changes in the SCP. There is a difference between proliferative and nonproliferative retinopathy and in the former group between ALP treated and nontreated patients.

Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study

Aims/hypothesisThis long-term study was designed to further characterise the retinal safety profile of insulin glargine and human neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes mellitus.MethodsAn open-label, 5 year, randomised (1:1), multicentre, stratified, parallel-group study conducted in the USA and Canada enrolled individuals with type 2 diabetes and either no or non-proliferative retinopathy (less than severe; Early Treatment Diabetic Retinopathy Study [ETDRS] level less than 53 in both eyes) who were treated with oral hypoglycaemic agents (OHAs) alone, insulin alone or OHAs with insulin for ≥3 months prior to study entry and a baseline HbA1c level of 6.0–12.0%. Patients were randomised by the investigator according to the centralised interactive voice response system to receive twice-daily NPH insulin (n = 509) or once-daily basal insulin glargine (n = 515). The investigator was not blinded to the treatment group to which each participant had been assigned. The main objective of this study was to compare the progression of diabetic retinopathy between treatment groups by analysing the percentage of patients with three or more step progression in the ETDRS retinopathy patient-level severity scale after treatment with either basal insulin. Masked, centralised grading of seven-field stereoscopic fundus photographs was used.ResultsSimilarly sustained glycaemic control was observed in both the insulin glargine and NPH insulin treatment groups. Despite a slightly greater severity of diabetic retinopathy for the insulin glargine group at baseline, three or more step progression in ETDRS score from baseline to end-of-study was similar between treatment groups (14.2% [53/374] of insulin glargine-treated patients vs 15.7% [57/363] of NPH-treated patients); the difference in the incidence of progression was −1.98% (95% CI −7.02, 3.06%). Other measures of retinopathy—the development of proliferative diabetic retinopathy and progression to clinically significant macular oedema—occurred to a similar degree in both treatment groups. No other safety issues, such as unexpected adverse events for either insulin emerged during the 5 year study. However, NPH insulin treatment was associated with a higher incidence of severe hypoglycaemia compared with insulin glargine.Conclusions/interpretationThis study shows no evidence of a greater risk of the development or progression of diabetic retinopathy with insulin glargine vs NPH insulin treatment in patients with type 2 diabetes mellitus.Trial registrationClinicalTrials.gov NCT00174824FundingThis study was sponsored by sanofi-aventis.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1415-7) contains supplementary material, which is available to authorised users.

Photographic detection of retinopathy in insulin-treated diabetes. A population study in the city of Tartu, Estonia.

To perform a cross-sectional baseline investigation of diabetic retinopathy prevalence and metabolic control. Using a register of insulin-dependent diabetes mellitus in Tartu (pop. 104,791), 175 patients were invited to fundus photography; 149 (89%) participated, 99 of them diagnosed with diabetes before the age of thirty. Four Kodachrome 64 photographs per eye were taken with a Canon CR4 - 45NM camera through tropicamide-dilated pupils; slides were projected and systematically graded. Capillary blood samples (n = 132) for HbA1c determination were mailed on filter paper. Following cysteine buffer elution, Mono S ion exchange chromatography was performed (reference range 3.7 to 5.3%). Any diabetic retinopathy was found in 114 patients (76.5%; 95% confidence interval, CI, 70 to 83%); mild to moderate non-proliferative retinopathy in 59 (40%; 95% CI 32 to 48%); severe non-proliferative retinopathy in 29 (19.5%; 95% CI 13 to 26%); proliferative retinopathy in 26 (17%; 95% CI 11 to 24%); 47 patients (32%) needed laser photocoagulation. Vitreous haemorrhage was observed in 9 (6%) of subjects. In patients diagnosed with diabetes before the age of 30 years, prevalence of any retinopathy was 82% (95% CI 73 to 89%) and of proliferative retinopathy 23% (95% CI 15 to 33%). Median HbA1c was 9.7% for women and 8.6% for men (95% CI for difference 0.7 to 2.1%). Retinopathy prevalences (76-82%) are the highest reported from population-based studies. Glycaemia levels were very high and should be gradually lowered. Methods capable of validation can be successfully introduced for population-based assessment of hyperglycaemia and retinopathy prevalences.

Visual fields at different stages of diabetic retinopathy.

Available studies on visual field disturbances in diabetic retinopathy have shown conflicting results, obtained with different and often non-comparable techniques. We have studied visual fields at different stages of diabetic retinopathy with modern sensitive computerized technique taking precautions to limit disturbing effects of random field variation and lack of perimetric experience. Sixty-three diabetic patients, insulin-dependent and non-insulin dependent, were each subject to three test sessions using the 30-2 full threshold program of the Humphrey perimeter. Retinopathy levels ranged from 10 to 65 in the ETDRS Final scale. In eyes without retinopathy or with very mild and mild disease (levels 10-35) mean deviation values exceeding the p < 5% level occurred in only 4% of eyes in trained sessions, and the number of test points with significantly reduced sensitivity did not exceed that expected in normal eyes. In moderate and moderately severe diabetic retinopathy (level 43-47) and in severe non-proliferative and proliferative retinopathy (levels 53-65) there was clear evidence of field loss, however, with significantly reduced mean deviation values in 44% of the eyes and 6.5% of tested points showing reproducible loss of sensitivity. Thus, there was no evidence of field loss in eyes with mild disease, but clear field defects in eyes with more advanced disease. Significantly reduced sensitivity was often correlated with retinal non-perfusion and there was seen a tendency towards more correlation in the midperiphery than paracentrally.

Diabetic retinopathy, PAI-1 4G/5G and −844G/A polymorphisms, and changes in circulating PAI-1 levels in Tunisian type 2 diabetes patients

Aim The association of altered plasminogen activator inhibitor (PAI)-1 levels and PAI-1 polymorphisms (4G/5G and −844G/A) with diabetic retinopathy (DR) was investigated in 856 type 2 diabetes (T2D) patients, of whom 383 presented with (DR group), and 473 presented without (DWR group), retinopathy. Methods PAI-1 4G/5G and −844G/A genotyping were done by PCR-RFLP, and PAI-1 levels were measured by ELISA testing. Results The genotype distribution of 4G/5G and −844G/A polymorphisms did not deviate from the Hardy-Weinberg equilibrium model among healthy subjects. Higher frequencies of the 4G/4G genotype, and lower frequencies of the −844A allele, −844G/A and −844A/A genotypes, were seen in DR patients, conferring disease susceptibility and protection, respectively. While PAI-1 levels were significantly elevated in the 4G/4G compared with other PAI-1 genotypes, significant differences in PAI-1 levels between DR and DWR patients were seen in the 4G/−844A, 4G/−844G and 5G/−844A haplotype carriers among DR patients. However, comparable distributions of 4G/5G and −844G/A alleles, genotypes and haplotypes, and similar PAI-1 levels, were seen in the proliferative retinopathy (PR) and non-proliferative retinopathy (NPR) patients, indicating that neither PAI-1 variants nor changes in PAI-1 levels were linked to DR severity. Multivariate analyses identified 4G/−844A and 4G/−844G haplotypes as negatively and positively associated, respectively, with DR, but not with DR severity (PR vs NPR) after adjusting for a number of covariates. Conclusion The present study identifies changes in PAI-1 levels and genetic variations at the PAI-1 locus as risk factors for DR, but not DR severity, that may serve as useful markers of increased DR susceptibility.

Compliance with the quality standards of National Diabetic Retinopathy Screening Committee

Aims The National Diabetic Retinopathy Screening Committee has recommended 19 standards for quality assurance of screening programmes in the United Kingdom. Five of the standards apply to the care provided by ophthalmology departments. This study assesses the quality assurance of the eye care provided by the Wakefield and North Kirklees Screening programme. Methods A retrospective audit of case notes of patients for 12 consecutive months in 2007. The outcomes were compared with the five quality standards. Results Out of a total number of 15,080 patients screened for diabetic retinopathy (DR), 479 (3.17%) required referral to ophthalmology department (screen-positive). Of these, 352 (2.33% of total screened) were referred for diabetic retinopathy. Forty-three patients (13%) were referred for proliferative retinopathy (R3), 279 (79%) for maculopathy (M1), 24 (7%) for non-proliferative retinopathy (R2), and 4 (1%) for a history of previous photo-coagulation (P1). Fifty-eight patients (16%) failed to attend. A timely consultation was achieved in 33% of R3 and 77% of M1 patients. Only 31% of R3 and 8% of M1 at screening were listed at their first visit to ophthalmology clinic and received laser treatment in stipulated time. Conclusion Significant progress is required for timely consultation and management of screen-positive patients. In order to achieve these targets efficiently, it may be appropriate to re-define M1 so that a significant proportion of patients with M1 may be referred to and better managed by primary care physicians or diabetologists.

Association of homozygous SDF-1 3′A genotype with proliferative diabetic retinopathy

Stromal cell-derived factor 1 (SDF-1) is involved in the development of experimental proliferative retinopathy. Since little data are available on the genetic predisposition or on biomarkers predicting the development of proliferative retinopathy, we assessed the distribution of the SDF-1 3'A genotype in 130 diabetic patients with retinopathy. In patients with proliferative retinopathy, the frequency of the homozygous SDF-1 3'A genotype was significantly higher than in patients with non-proliferative retinopathy (10.9% of PDR vs. 0 of NPDR, P = 0.01). This association was confirmed when type 2 diabetes patients were analysed separately (10.3% of PDR vs. 0 of NPDR, P = 0.03). The finding that homozygous carriers of the SDF-1 3'A genotype are more frequent in diabetes patients with proliferative retinopathy suggests a possible role of this genotype in the development of sight-threatening diabetic retinopathy.

Computer-Assisted Microaneurysm Turnover in the Early Stages of Diabetic Retinopathy

Purpose: To assess the reliability of microaneurysm turnover, computed from color fundus photographs, in evaluating diabetic retinopathy in patients with type 2 diabetes and nonproliferative retinopathy. Methods: A new method (MA-Tracker) was developed to count microaneurysms by mapping their locations through image co-registration. To compute the reliability of microaneurysm turnover, 3 different graders were asked to earmark microaneurysms on the same set of color fundus photographs. Results: The total numbers of microaneurysms earmarked in each of 5 visits suggest that microaneurysms remain stable over time (p ≥ 0.138). However, an analysis of each microaneurysm showed that only 29.4% remained at the same location. By computing the formation and disappearance rates of microaneurysms (2.3 and 1.7 microaneurysms/year, respectively), a significant turnover of microaneurysms was found. Conclusions: The formation and disappearance rates of microaneurysms obtained from color fundus photographs using MA-Tracker show very good agreement between different graders, and can be used as indicators of microaneurysm turnover in the initial stages of diabetic retinopathy.

Microaneurysm Turnover Is a Biomarker for Diabetic Retinopathy Progression to Clinically Significant Macular Edema: Findings for Type 2 Diabetics with Nonproliferative Retinopathy

Purpose: To examine the relationship between microaneurysm turnover (formation rate), using a new semi-automatic method (MA-Tracker) based on color fundus photographs, and diabetic retinopathy (DR) progression to clinically significant macular edema (CSME). Methods: In total, 113 patients/eyes with nonproliferative DR (NPDR) were followed up every 6 months for 2 years as controls of the DR clinical trials, and by conventional general and ophthalmological care for the next 8 years (over a total of 10 years’ follow-up). Microaneurysm turnover for the 2 first years was computed using the MA-Tracker. Results: The 17 patients that developed CSME over the 10 years of follow-up presented a microaneurysm formation rate of 9.2 ± 18.2 microaneurysms/year (mean ± SD) during the first 2 years, which was statistically higher than the eyes that did not develop CSME (0.5 ± 1.2 microaneurysms/year, p < 0.001). These 17 patients also presented higher HbA_1C levels at baseline (8.5 ± 1.2%) compared to the patients who did not develop CSME (7.3 ± 1.2%, p = 0.001). Conclusions: A high microaneurysm formation rate on color fundus photographs appears to be a good biomarker for DR progression to CSME in type 2 diabetic patients with NPDR.

Ability of Retinopathy to Predict Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus

It is important identify patients with very high cardiovascular risk to intensify their therapy. Our aim was to assess the association between retinopathy and incident cardiovascular events (cardiovascular disease [CVD]) in patients with type 2 diabetes mellitus (DM). Patients were included if they had type 2 DM and a visible fundus. Baseline clinical and biochemical variables, including urinary albumin excretion rate, were collected. Clinical end points were nonfatal or fatal cardiovascular events (unstable angina including revascularization, nonfatal or fatal myocardial infarction, transient ischemic attack, nonfatal or fatal stroke, lower-leg amputation, terminal chronic heart failure, sudden death). Cox multivariate regression models were used to evaluate the risk associated with each variable and the independent contribution of baseline retinopathy. A total of 458 patients were included, with mean follow-up time of 6.7 +/- 2.6 years. Incident CVD rates were 30.7 per 1,000 patient-years in patients with a normal fundus, 56.7 in patients with nonproliferative retinopathy, and 90.7 in patients with proliferative retinopathy (p <0.0001). In multivariate analysis, nonproliferative retinopathy (hazard ratio 1.71, 95% confidence interval 1.1 to 2.66, p = 0.017) and proliferative retinopathy (hazard ratio 2, 95% confidence interval 1.1 to 3.56, p = 0.019) were significantly associated with incident CVD. In conclusion, retinopathy proved to be an independent risk marker for CVD in patients with type 2 DM.

Diabetes and Obesity

Diabetes and Obesity

Plaque Radiotherapy for Juxtapapillary Choroidal Melanoma Overhanging the Optic Disc in 141 Consecutive Patients

To evaluate tumor control with plaque radiotherapy for juxtapapillary choroidal melanoma that overhangs the optic disc. Retrospective medical record review of 141 consecutive patients with data on complications of treatment, final visual acuity, visual loss, enucleation, tumor recurrence, metastasis, and death. The median patient age was 61 years. Presenting symptoms included reduced visual acuity in 72 eyes (51%), photopsia in 14 (10%), and visual field defect in 18 (13%); 35 patients (25%) were asymptomatic. The median tumor basal diameter was 11 mm and the median thickness was 5.2 mm. The tumor overhung 50% or less of the disc in 88 eyes (62%) and more than 50% of the disc in 53 eyes (38%). In 19 cases (13%), the tumor overhung the entire disc. All patients were treated with plaque radiotherapy, using a notched design in 126 eyes (89%) and a round design in 14 eyes (10%), with iodine 125 in 132 eyes (94%) and cobalt 60 in 9 eyes (6%). The median radiation dose to the tumor apex was 8500 cGy. Adjuvant transpupillary thermotherapy was used in 54 eyes (39%). During a mean follow-up of 56 months, complications included nonproliferative retinopathy in 61 eyes (51%), proliferative retinopathy in 26 (22%), maculopathy in 44 (37%), papillopathy in 57 (48%), neovascular glaucoma in 23 (19%), and vitreous hemorrhage in 48 (40%). A final visual acuity of 20/200 or worse was measured in 72 eyes (77%), and visual loss of more than 5 Snellen lines occurred in 59 eyes (63%). Enucleation was necessary in 27 eyes (23%). Tumor recurrence was found in 12 eyes (10%). Metastasis developed in 15 patients (13%) and death in 4 cases (3%). Using plaque radiotherapy for choroidal melanoma overhanging the optic disc, local tumor control was achieved in 90% of cases. Tumor and radiation effects led to poor visual acuity in 77% of eyes. The metastatic rate was 13% and the mortality rate was 3%.

In early-stage diabetic retinopathy, risk of cardiac events after implantation of sirolimus-eluting stent is higher than after coronary artery bypass surgery

Patients with diabetic retinopathy (DR) have an increased risk of death from coronary heart disease and myocardial infarction. The purpose of this study was to compare the outcomes of revascularization strategies (sirolimus-eluting stent [SES] and coronary artery bypass surgery [CABG]) in patients with DR according to the stage of retinopathy: non-proliferative retinopathy (NPDR) and proliferative retinopathy (PDR). From April 2004 until February 2007, 627 patients including 51 NPDR and 62 PDR patients underwent SES implantation. For each retinopathy group, a historical comparison group at the same stages of retinopathy undergoing CABG was selected. Cardiac events were defined as a composite of cardiac death, myocardial infarction, and repeat revascularization. The average follow-up from the time of the initial revascularization was 27.7 ± 8.5 months for NPDR-SES patients, 69.6 ± 36.6 months for NPDR-CABG patients, 26.4 ± 9.7 months for PDR-SES patients, and 68.3 ± 44.2 months for PDR-CABG patients; and Kaplan-Meier estimates of the percentages of events at 24 months were 47.0%, 22.8%, 28.5%, and 26.0%. Kaplan-Meier curves for cardiac events differed significantly between the SES group and the CABG group in NPDR patients (p = 0.04), whereas the curves did not differ significantly between the two groups of PDR patients. The adjusted hazard ratio of SES implantation for cardiac events in the entire group of DR patients was 1.75 (95% confidence interval [CI] 1.02-3.00, p = 0.04). SES implantation is not a suitable method of revascularization in DR patients, especially in NPDR patients. CABG may become the first-choice revascularization technique for these patients.

Risk markers for progression of mild nonproliferative retinopathy to clinically significant macular edema in type 2 diabetic patients

Abstract Purpose To determine risk markers for the development of clinically significant macular edema (CSME) needing photocoagulation treatment in type 2 diabetic patients with mild nonproliferative retinopathy (NPDR), during a 7‐year period. Methods Fifty‐one type 2 diabetic patients with mild NPDR, followed‐up for 2 years as controls of diabetic retinopathy clinical trials, were selected. Patients underwent ophthalmological examinations every 6 months, including stereoscopic color fundus photography, fluorescein angiography and vitreous fluorophotometry, and were metabolically controlled. These patients were thereafter followed‐up for the next 5 years by conventional general and ophthalmological care. Results At the end of the 7‐year follow‐up period, 8 patients developed CSME, needing photocoagulation treatment. These patients presented a higher microaneurysm (MA) formation rate at the first year of follow‐up (p&lt;0.001), a higher blood‐retinal barrier (BRB) permeability value (p=0.042), an abnormal foveal avascular zone (FAZ) contour on fluorescein angiography (p=0.009) and a higher HbA1C level at baseline (p=0.001). Conclusion Microaneurysm formation rate higher or equal to 3 MA/year, BRB permeability values over or equal to 4.0 nm.s‐1, evidence of abnormalities in the FAZ, and hemoglobin A1C levels at baseline, are risk markers for progression of NPDR to CSME in patients with type 2 diabetes.

Intravitreal pegaptanib sodium (Macugen®) for radiation retinopathy following episcleral plaque radiotherapy

Editor, A 63-year-old woman was referred to our department with a best-corrected visual acuity (BCVA) of 20/25 in her right eye and 20/20 in her left eye. She presented with a posterior uveal mass of her right eye; this was diagnosed as choroidal melanoma, involving the superonasal quadrant. The tumour sizes were 12.54 mm (base) and 4 mm (height). The patient underwent episcleral plaque radiotherapy with a notched Ruthenium 106 plaque. Fourteen months after plaque treatment, the patient developed early radiation retinopathy involving the fovea – consisting of capillary changes, retinal haemorrhages and retinal exudation (non-proliferative radiation retinopathy) – and was therefore offered sector laser photocoagulation to prevent progression of radiation retinopathy (Finger 1997). Three months later, the patient developed disc neovascularization (proliferative radiation retinopathy) and massive retinal exudation involving the fovea, as evaluated by fundus biomicroscopy, fluorescein angiography (FA) (Fig. 1A) and optical coherence tomography (OCT-3; Humphrey-Zeiss, San Leandro, California, USA) (Fig. 1B); BCVA dropped to 20/200. After discussing adjunctive treatment options and being presented with the option of intravitreal pegaptanib sodium [Macugen®; (OSI) Eyetech and Pfizer Inc., Melville, New York, USA], the patient requested that the treatment be given. Intravitreal pegaptanib sodium 0.3 mg was administered without complication. At the 1-month follow-up, BCVA improved to 20/40; fundus biomicroscopy, FA and OCT revealed almost total resolution of the retinal and macular exudation and partial regression of disc neovascularization. At the time of writing, 6 months after the injection, the patient’s BCVA remained 20/40, with no recurrence of retinal and macular exudation as well as partial regression of disc neovascularization, as evaluated by fundus biomicroscopy, FA (Fig. 1C) and OCT (Fig. 1D). Fluorescein angiography frame (A) and OCT-3 scan (B) of the right eye showing disc neovascularization and massive retinal exudation involving the fovea 3 months after sector scatter laser photocoagulation. Fluorescein angiography frame (C) and OCT-3 scan (D) of the right eye showing partial regression of disc neovascularization and resolution of the retinal and macular exudation 6 months after intravitreal injection of pegaptanib sodium. Closure of blood vessels is the central effect of ionizing radiation. FA after radiation therapy of choroidal melanomas reveals closure of blood vessels within and around the tumour (the tissues surrounding the targeted zone). The histopathology of radiation-induced ischaemic vasculopathy shows the destruction of the endothelial cells and pericytes that maintain blood-vessel walls (Archer et al. 1991). These changes, induced by hypoxia, alter blood flow patterns and produce alternative channels with thickened and fenestrated walls (Archer et al. 1991). Vascular endothelial growth factor (VEGF) is induced by hypoxia and it has been implicated in the development of iris and retinal neovascularization in ischaemic retinopathies. In addition or in association with its role in inducing neovascularization, VEGF may contribute to blood–retinal barrier breakdown in a variety of ocular disorders, and blockage of VEGF signalling may help to reduce some types of macular oedema. Pegaptanib sodium is an anti-VEGF, developed to bind and block the activity of extracellular VEGF (aptamer), specifically the 165-amino-acid isoform (VEGF 165); it is used effectively in the treatment of neovascular age-related macular degeneration (Gragoudas et al. 2004). Given that blockage of VEGF signalling may help to reduce some types of macular oedema (Vinores et al. 1997) and seems to induce short-term reduction of fluorescein leakage from persistent active retinal new vessels (Jorge et al. 2006), we decided to inject 0.3 mg of pegaptanib sodium into the vitreous cavity of our patient. One month after the intravitreal injection of pegaptanib sodium, BCVA improved to 20/40; fundus biomicroscopy, FA and OCT revealed almost total resolution of the retinal and macular exudation and partial regression of disc neovascularization. In addition, there has been no recurrence and no complications from the intravitreal injection of pegaptanib sodium, even at the 6-month follow-up. Similar results have been reported recently using intravitreal bevacizumab, a non-specific anti-VEGF (Finger & Chin 2007). Based on our findings, intravitreal pegaptanib sodium associated with sector scatter laser photocoagulation seems to induce short-term regression of retinal and macular exudation and partial regression of disc neovascularization, with improvement of visual acuity. Further investigations are required to confirm our results. Given that recurrences could be possible and should require additional therapy, we believe that not only more treated cases but also a longer follow-up are needed.

Correlation of Different Circulating Endothelial Progenitor Cells to Stages of Diabetic Retinopathy: First In Vivo Data

To investigate vasculogenic circulating progenitor cells (CPCs), endothelial progenitor cells (EPCs), and mature EPCs in patients with type 1 diabetes mellitus (T1DM) with or without diabetic retinopathy (DR). A case-control study comparing 90 patients with T1DM with and without DR was performed. Patients were studied and staged for retinopathy according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification. Ninety patients were included: 30 without DR (control [CO]), 30 with mild nonproliferative DR (mNPDR), 10 with moderate-severe NPDR (msNPDR), 10 with mild-moderate proliferative diabetic retinopathy (mmPDR), and 10 with high-risk PDR (hrPDR). CPCs (CD34/CD133), EPCs (CD34/CD133/CD309), and mature EPCs (CD34/CD133/CD309/CD31) were enumerated by flow cytometry. EPCs were reduced in mNPDR (114 +/- 66; P < 0.001) and msNPDR (77 +/- 40; P = 0.042) compared with CO (244 +/- 115). In contrast, EPCs were unchanged in mmPDR (248 +/- 155) compared with CO. Strikingly, EPCs were augmented in hrPDR (389 +/- 124) compared with all other stages. Numbers of undifferentiated progenitor cells (CPCs) did not differ among CO, mmPDR, and hrPDR. Augmentation (3x) of mature EPCs in hrPDR (325 +/- 118; P < 0.001) compared with CO (100 +/- 49) but against all other stages of DR was observed. The percentage of mature EPCs/EPCs was augmented in an ETDRS classification-dependent manner. In patients with T1DM with DR, EPCs undergo stage-related regulation. In nonproliferative retinopathy, a reduction of EPCs was observed, and in proliferative retinopathy, a dramatic increase of mature EPCs was observed.

Direct medical costs for type 2 diabetes mellitus complications in the US commercial payer setting

Medical complications are the key drivers of the direct medical costs of treating patients with type 2 diabetes mellitus. However, the published literature shows great variability across studies in the number and type of sources from which these costs for diabetes are obtained. To provide to researchers a set of costs for type 2 diabetes complications, originally developed for input into an established diabetes model, that are empirically based, clearly and consistently defined and applicable to a large segment of managed care patients in the US. Patients with 1 of 24 diabetes-related complications between 1 January 2003 and 31 December 2004 and with evidence of type 2 diabetes were identified using a nationally representative US commercial insurance claims database. Therapy utilization and complication cost data were extracted for all patients for the 12 months following the first identified complication; data for months 13-24 were obtained for a subset of patients with at least 24 months of follow-up enrollment. Medical costs included both the amounts charged by medical providers and the health plan contracted allowed amounts. Costs were expressed as $US, year 2007 values. A total of 44 021 patients with a minimum of 12 months of continuous follow-up enrollment were identified, with a mean age of 56 years; a subset of 32 991 patients with at least 24 months of continuous health-plan enrollment was also identified. Among the aggregate sample, 74% of patients were receiving oral antidiabetics, 26% were receiving insulin, 43% were receiving ACE inhibitors and 50% were receiving antihyperlipidaemics/HMG-CoA reductase inhibitors (statins) during the first 12 months following the index complication. The majority of patients had at least one physician office visit (99.8%), laboratory diagnostic test (96.2%) and other outpatient visit (97.5%). Six complications (angina pectoris, heart failure, peripheral vascular disease, renal disease, nonproliferative retinopathy and neuropathy) had a prevalence of at least 10%. Allowed amounts for most complications were 30-45% of charges. Myocardial infarction, heart failure and renal disease had the greatest fiscal impact because of the total number of patients experiencing them (7.2%, 14.0% and 11.0%, respectively) and their associated costs; 12-month mean allowed amounts were $US 14,853, $US 11,257 and $US 13,876, respectively, and 12-month mean charged amounts were $US 41,695, $US 30, 066 and $US 34,987, respectively. Similarly, in the subset of 32 991 patients, these three complications had higher allowed and charged amounts over months 13-24 compared with the majority of other complications of interest. These costing results provide an important resource for economic modelling and other types of costing research related to treating diabetes-related complications within the US managed care system.

Evaluation of N ε-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy

Recent studies suggest that oxidative stress should be monitored alongside HbA(1c) to identify subgroups of diabetic patients at high risk of initiation or progression of retinopathy. The acrolein-derived advanced lipoxidation end-product (ALE), [Formula: see text]-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine), is a useful biomarker that reflects the cumulative burden of oxidative stress over long periods of time. The purpose of the present study was to investigate whether serum and haemoglobin levels of FDP-lysine are associated with the severity of diabetic retinopathy in type 1 and type 2 diabetic patients. Serum and haemoglobin levels of FDP-lysine were measured by competitive ELISA in 59 type 1 and 76 type 2 diabetic patients with no retinopathy, non-proliferative retinopathy or proliferative retinopathy (mean age [+/-SEM] 54.3 +/- 1.3 years), and in 47 non-diabetic control individuals (mean age 51.9 +/- 2.1 years). Serum and haemoglobin levels of FDP-lysine were significantly increased in diabetic patients compared with control individuals (p = 0.04 and p = 0.002, respectively). However, no significant association was found between levels of serum FDP-lysine and the severity of diabetic retinopathy (p = 0.97). In contrast, increased haemoglobin FDP-lysine levels were observed in patients with proliferative retinopathy compared with patients without retinopathy and with non-proliferative retinopathy (p = 0.04). The relationship of FDP-lysine with proliferative retinopathy was unaltered after adjustment for HbA(1c), or other clinical parameters. Our data suggest that haemoglobin FDP-lysine may provide a useful risk marker for the development of proliferative diabetic retinopathy independently of HbA(1c), and that elevated intracellular ALE formation may be involved in the pathogenesis of this sight-threatening complication of diabetes.

Prevalence and Risk Factors for Diabetic Retinopathy: The Singapore Malay Eye Study

To describe the prevalence and risk factors of diabetic retinopathy in Asian Malays. Population-based cross-sectional study. Persons with diabetes of Malay ethnicity aged 40 to 80 years in Singapore. Diabetes mellitus was defined as random glucose of 11.1 mmol/l or more, use of diabetic medication, or a physician diagnosis of diabetes. Retinal photographs taken from both eyes were graded for diabetic retinopathy using the modified Airlie House classification system. Any diabetic retinopathy, retinopathy grades, macular edema, or vision-threatening retinopathy. Of the 3261 persons who participated in this study, 757 (23.1%) had diabetes and gradable retinal photographs. In persons with diabetes, the overall prevalence of any retinopathy was 35.0% (95% confidence interval [CI], 28.2-43.4), the overall prevalence of macular edema was 5.7% (95% CI, 3.2-9.9), and the overall prevalence of vision-threatening retinopathy was 9.0% (95% CI, 5.8-13.8). Compared with men, women had significantly higher proportions with more severe diabetic retinopathy, moderate (12% vs. 4%) and severe (3% vs. 0.2%) nonproliferative retinopathy, proliferative retinopathy (7% vs. 2%), and vision-threatening retinopathy (13% vs. 3%). In multiple logistic regression, independent risk factors for any retinopathy were longer diabetes duration (odds ratio [OR], 1.07; 95% CI, 1.04-1.09, per year increase), higher hemoglobin A1(c) (OR, 1.21; 95% CI, 1.10-1.33, per % increase), hypertension (OR, 1.85; 95% CI, 1.04-3.30), and higher pulse pressure (OR, 1.34, 95% CI, 1.19-1.51, per 10-mmHg increase); older age (OR, 0.73; 95% CI, 0.57-0.93, per decade increase) and higher total cholesterol levels (OR, 0.75; 95% CI, 0.63-0.89, per 1-mmol/l increase) were protective of any retinopathy. Vision-threatening retinopathy additionally was associated with previous stroke (OR, 3.74; 95% CI, 1.24-11.26), cardiovascular disease (OR, 2.23; 95% CI, 1.08-4.62), and chronic kidney disease (OR, 4.45; 95% CI, 2.18-9.07). Female gender was not an independent risk factor for diabetic retinopathy after adjusting for metabolic and socioeconomic risk factors. One in 10 Malay adults with diabetes in Singapore has vision-threatening diabetic retinopathy. Risk factors for retinopathy in this population are largely similar to white populations elsewhere, suggesting that control of these risk factors may reduce both the prevalence and impact of retinopathy.