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Purpose: To evaluate the five-year incidence of diabetic retinopathy (DR) and associated risk markers in patients with type 1 diabetes in the national Danish DR-screening programme., Methods: Based on national data, we included all 16 999 patients with type 1 diabetes in the Danish Registry of Diabetic Retinopathy, who attended the national screening programme in the period 2013-2018. According to the worse eye at first screening, DR was classified (levels 0-4) and linked with various national health registries to retrieve information on diabetes duration, systemic comorbidity, and medication., Results: At first screening, median age and duration of diabetes were 45.0 and 16.7 years, and 57.5% were males. The prevalence and five-year incidences for DR and progression to proliferative DR (PDR) were 44.2%, 8.9% and 2.0%, respectively. In multivariable Cox models, the incidence endpoints were associated with duration of diabetes (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.63-1.89, and HR 2.04, 95% CI 1.73-2.40 per 10 years), moderately low Charlson Comorbidity Index score (HR 1.27, 95% CI 1.10-1.47, and HR 2.80, 95% CI 2.23-3.51), and use of blood pressure lowering medication (HR 1.20, 95% CI 1.05-1.36, and HR 1.98, 95% CI 1.53-2.57)., Conclusion: In a study of all patients with type 1 diabetes from the Danish DR-screening programme, we identified duration of diabetes, systemic disease and use of anti-hypertensive treatment as consistent risk markers for incident and progressive DR., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Diabetic retinopathy (DR) is the most common complication in patients with diabetes, and screening for sight-threatening end-stages is indicated to avoid severe visual loss. Screening of DR is nationally implemented in Denmark according to evidence-based national guidelines, which includes the use of individualised screening intervals. Treatment is indicated for proliferative DR and diabetic macular oedema, and treatment modalities include retinal laser therapy, intravitreal angiostatic therapy, and vitrectomy. In this review, we summarise the current guidelines for screening and treatment of DR in Denmark., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Purpose: To investigate diabetic retinopathy (DR) as a potential marker of cardiovascular disease (CVD) in adults with type 1 diabetes attending the Danish DR-screening programme and non-diabetes adults., Methods: In this registry-based matched case-cohort study, we identified 16 547 adults with type 1 diabetes, who were registered in the Danish Registry of Diabetic Retinopathy (DiaBase). Each case was age- and sex-matched by five non-diabetes individuals (n = 82 399), and odds ratios (ORs) and hazard ratios (HRs) were estimated for incident and upcoming CVD in multivariable models., Results: Adults with type 1 diabetes (median age 44.5 years, 57.6% male) were more likely to have prevalent CVD (OR 1.29; 95% CI, 1.20-1.38) and to develop CVD within 5 years (HR 1.19; 95% CI, 1.08-1.30) as compared to non-diabetes control. However, adults without DR were less likely to develop CVD (HR 0.84; 95% CI, 0.72-0.97) compared to the reference population. For adults with type 1 diabetes, there was an increasing risk for incident CVD for increasing levels of DR (HR 1.33, 1.95, 1.71 and 2.39 for DR-levels 1-4, respectively). Patients with CVD at the time of the first screening had a higher risk to develop DR during follow-up (HR 1.23; 95% CI, 1.02-1.49)., Conclusion: In a nationwide matched case-cohort study adjusted for potential confounders, DR was identified as an independent marker of prevalent and incident CVD in type 1 diabetes with increasing risk demonstrated for higher levels of DR. Likewise, CVD also independently predicted the risk of incident DR., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: A number of algorithms have been developed to calculate screening intervals for diabetic retinopathy on the basis of individual risk factors. However, these approaches have not considered proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DME) as separate end points and death as competing risk., Methods: A multi-state survival model with death as competing risk was used to predict the screening interval for diabetic retinopathy based on information about all 2446 patients from a well-defined population who had started treatment for either PDR or DME during 25 years. The performance of the model was tested on the existing database and at seven screening sites on patients who had not developed a treatment requiring condition., Results: Testing on the existing database showed that at a risk level of 2% the algorithm could predict a screening interval with a success rate higher than 90% and a 1.75 times average prolongation of the screening interval without failing to detect the development of verified PDR og DME. The model was limited to a diabetes duration shorter than 40 years and depended on knowledge of relevant risk factors. At the other participating screening sites the algorithm predicted shorter intervals than the screener., Conclusions: Algorithms for individualised screening for diabetic retinopathy can prolong screening intervals without losing patients who develop a vision threatening condition. The calculation of screening intervals requires access to relevant risk factors and should be developed on large data sets that reflect the population in which the algorithm should be used., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Type 2 diabetes is a heterogeneous disease that can be subdivided on the basis of β-cell function and insulin sensitivity. We investigated the presence, incidence, and progression of diabetic retinopathy (DR) according to subtypes of type 2 diabetes. In a national cohort, we identified three subtypes of type 2 diabetes: classical, hyperinsulinemic, and insulinopenic type 2 diabetes, based on HOMA2 measurements. From the Danish Registry of Diabetic Retinopathy we extracted information on level of DR. We used several national health registries to link information on comorbidity, medications, and laboratory tests. We found individuals with hyperinsulinemic type 2 diabetes were less likely to have DR at entry date compared with those with classical type 2 diabetes, whereas individuals with insulinopenic type 2 diabetes were more likely to have DR. In multivariable Cox regression analysis, individuals with hyperinsulinemic type 2 diabetes had a decreased risk of both incidence and progression of DR compared to those with classical type 2 diabetes. We did not find any clear difference in risk of incident or progression of DR in individuals with insulinopenic compared to classical type 2 diabetes. These findings indicate that subcategorization of type 2 diabetes is important in evaluating the risk of DR., (© 2024 by the American Diabetes Association.)

Aims: Bariatric surgery is used to induce weight loss and glycemic stability in type 2 diabetes (T2D). It has been a concern that this may lead to early worsening of diabetic retinopathy (DR) due to a rapid decline in HbA1c. In this study, we evaluated the risk of short and long-term DR development and need for ocular intervention in an entire nation of individuals with T2D undergoing bariatric surgery., Methods: The study comprised a national, register-based cohort of individuals with T2D screened for DR. Cases were matched by age, sex and DR level at the date of surgery (index date) with non-bariatric controls. We extracted information on DR levels, in- and outpatient treatments, pharmaceutical prescriptions and laboratory values. We evaluated worsening of DR (incident and progressive DR) at follow-up (6 and 36 months)., Results: Amongst 238,967 individuals with T2D, who attended diabetic eye screening, we identified 553 that underwent bariatric surgery (0.2%) and 2677 non-bariatric controls. Median age was 49 years, and 63% were female. Cases had more comorbidities, lower HbA1c as well as more frequent use of glucose-lowering and antihypertensive medication than controls at index date. In a fully adjusted logistic regression model, the risk of DR worsening for cases was not significantly different compared to controls, neither short-term (OR 0.41 [CI 95% 0.13; 1.33], p = 0.14) nor long-term (OR 0.64 [CI 95% 0.33; 1.24], p = 0.18)., Conclusions: In this nationwide study, bariatric surgery did not associate with increased risk of short- or long-term DR worsening., (© 2023. The Author(s).)

Purpose: The Danish Registry of Diabetic Retinopathy includes information from >200 000 patients who attends diabetic retinopathy (DR) screening in Denmark. Screening of patients with uncomplicated type 2 diabetes is often performed by practicing ophthalmologists, while patients with type 1 and complicated type 2 diabetes attends screening at hospitals. We performed a clinical reliability study of retinal images from Danish screening facilities to explore the inter-grader agreement between the primary screening ophthalmologist and a blinded, certified grader., Methods: Invitations to participate were sent to screening facilities across Denmark. The primary grader uploaded fundus photographs with information on estimated level of DR (International Clinical Diabetic Retinopathy scale as 0 [no DR], 1-3 [mild, moderate or severe nonproliferative DR {NPDR}], or 4 [proliferative DR {PDR}]), region of screening, image style, and screening facility. Images were then regraded by a blinded, certified, secondary grader. Weighted kappa analysis was performed to evaluate agreement., Results: Fundus photographs from 230 patients (458 eyes) were received from practicing ophthalmologists (52.6%) and hospital-based grading centres (47.4%) from all Danish regions. Reported levels of DR by the primary graders were 66.8%, 12.2%, 13.1%, 1.3% and 5.5% for DR levels 0-4. The overall agreement between primary and secondary graders was 93% (κ = 0.83). Based on screening facility agreement was 96% (κ = 0.89) and 90% (κ = 0.76) for practicing ophthalmologists and hospital-based graders., Conclusion: In this nationwide study, we observed a high overall inter-grader agreement and based on this, it is reasonable to assume that reported DR gradings in the screening programme in Denmark, accurately reflect the truth., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Knowledge of visual health in the population is necessary for designing and implementing measures to handle visual handicap. The purpose of the FORSYN (Forekomst af synshandicap og synshjaelpemidler i Danmark) project was to study visual health in the Danish population 2020-2022 after implementation of the recent advances in the management of choroidal and retinal vascular disease. The present study reports visual acuity and causes of central visual loss from this study., Methods: A population-representative sample of 10 350 citizens living within 40 kilometres from Aarhus University Hospital were invited to answer a questionnaire about quality of life related to vision, measurement of visual acuity and a non-mydriatic examination of the eyes. The data were corrected for selection bias on the basis of demographic and socioeconomic factors so that the results could be projected to represent the adult Danish population., Results: Population-adjusted visual acuity in ETDRS letters (mean ± SD) differed significantly (p < 0.0001) among the worse eye (84.1 ± 0.25), the better eye (88.4 ± 0.11) and binocularly (89.2 ± 0.15). Social blindness affected 0.22% (95% CI: 0.14%-0.33%) of the population and was in none of the studied persons due to exudative age-related macular degeneration (AMD) or diabetic retinopathy. The most frequent causes of visual loss were atrophic AMD, neuro-ophthalmic disorders and other chorioretinal diseases., Conclusions: Recent advances in the therapy of chorioretinal vascular diseases have been paralleled with a reduction in central vision loss secondary to exudative AMD and diabetic retinopathy in Denmark. The demographic development can be expected to increase the demand for treatments of vision-threatening diseases that mainly affect older persons., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To investigate the level and localization of the multifunctional receptor sortilin in the diabetic retina, as well as the effect of sortilin inhibition on retinal neurodegeneration in experimental diabetes., Methods: The localization of sortilin and colocalization with the p75 neurotrophin receptor (p75NTR) and Müller cell (MC) markers were determined using immunofluorescence on retinal sections from human patients with diabetes and streptozotocin-induced diabetic C57BL/6J male mice. In the diabetic mice, levels were further quantified using Western blot and quantitative PCR. Therapeutic studies were performed on diabetic mice using intravitreally injected anti-sortilin antibodies. Neuroprotection was evaluated in vivo by optical coherence tomography and by quantification of retinal ganglion cells (RGCs) in flat mounts., Results: Increased levels of sortilin were observed in human and murine diabetic retinas compared with nondiabetic control retinas. Sortilin was highly localized to retinal MCs, and, notably, colocalization with p75NTR was only seen in diabetic retinas. A remarkable protective effect of sortilin inhibition on inner retinal cells was observed in diabetic mice. At eight weeks after diabetes induction, inner retinal thickness was reduced by 9.7% (-12.7%, -6.6%; P < 0.0001; n = 11-12) in the PBS-injected control group compared with the anti-sortilin injected group. Similarly, the count of RGCs was reduced by 20.5% (-30.8%, -10.2%; P = 0.0009) in the PBS-injected control group compared with the anti-sortilin-injected group., Conclusions: Sortilin is upregulated in the diabetic retina, and sortilin inhibition effectively protects against neuronal loss. Thus sortilin emerges as a novel pharmacological target in diabetic retinal neurodegeneration-an important early event in the pathogenesis of diabetic retinopathy.

Purpose: We aimed to investigate if diabetic retinopathy (DR), glaucoma and/or ocular hypertension (OHT) are prospectively linked, as previous studies have proposed cross-sectional associations, but longitudinal data from larger cohorts are lacking., Methods: We performed a bidirectional 5 years prospective, registry-based cohort study. We extracted data from national registers, including the Danish Registry of Diabetic Retinopathy, the Danish Civil Registration System, the Danish National Patient Register and the Danish National Prescription Registry. DR level was defined by the highest level of the two eyes. Glaucoma and/or OHT was defined by diagnostic codes (H40*) or at least three redeemed prescriptions of glaucoma medication (S01E*) within 1 year. We included 205 970 persons with diabetes and 1 003 170 age- and gender-matched non-diabetes controls. Exposures were level-specific DR (i) and glaucoma and/or OHT (ii), and outcomes were hazard ratios (HRs) for 5 years incident glaucoma and/or OHT (i) and DR (ii)., Results: Persons with diabetes were more likely to develop glaucoma and/or OHT (multivariable adjusted HR 1.11, 95% CI 1.06-1.15), but this did not depend on the level of DR. In persons with diabetes, those with glaucoma and/or OHT were more likely to develop DR (multivariable adjusted HR 1.12, 95% CI 1.03-1.23) within 5 years., Conclusion: In a national cohort, diabetes associated with a little higher risk of upcoming glaucoma and/or OHT, and, inversely, the presence of the latter predicted a higher risk of incident DR. Nevertheless, our data do not seem to justify including glaucoma evaluation in the national Danish DR-screening programme., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: The purpose of the study was to evaluate the prevalence and incidence of diabetic retinopathy (DR) along with associated markers in patients with type 2 diabetes in the Danish DR-screening programme., Methods: We included all persons with type 2 diabetes in the Danish Registry of Diabetic Retinopathy, who had attended at least one episode of DR screening in 2013-2018. DR was classified as levels 0-4 indicating increasing severity. Data were linked with various national health registries to retrieve information on diabetes duration, marital status, comorbidity and systemic medication., Results: Among 153 238 persons with type 2 diabetes, median age and duration of diabetes were 66.9 and 5.3 years and 56.4% were males. Prevalence and 5-year incidences of DR, 2-step-or-more progression of DR and progression to proliferative DR (PDR) were 8.8%, 3.8%, 0.7% and 0.2%, respectively. In multivariable models, leading markers of incident DR and progression to PDR were duration of diabetes (HR 1.98, 95% CI 1.87-2.09; HR 2.89, 95% CI 2.34-3.58 per 10 years of duration) and use of insulin (HR 1.88, 95% CI 1.76-2.01; HR 2.40, 95% CI 1.84-3.13), while the use of cholesterol-lowering medicine was a protecting marker (HR 0.87, 95% CI 0.81-0.93; HR 0.70, 95% CI 0.52-0.93). From 2013 to 2015, 3-year incidence rates of PDR decreased from 1.22 to 0.45 events per 1000 person-years., Conclusion: Nationally, among Danish individuals with type 2 diabetes attending DR screening, we identified duration of diabetes and use of insulin as the most important predictor for the development of DR, while cholesterol-lowering medicine was a protective factor., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Clustering of vision threatening diabetic retinopathy within specific families can be the result of similarities in life style but may also be due to a common genetic background. An evaluation of the role of heredity for the development of diabetic retinopathy may help adjusting control intervals in screening program to each patient's individual risk profile. Methods: Survival analysis was used to study whether family history of diabetes among men and women with type 1 or type 2 diabetes together with the degree of heredity could be added as risk factors to improve the prediction of the risk for developing proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). The study was conducted on data from 12,281 patients followed in the Aarhus area, Denmark, from 1 January 2003 to 1 July 2019. Results: The risk for developing PDR was significantly reduced 2-11 years after known onset of diabetes in the presence of female family members with type 1 diabetes, and the risk for developing DME significantly increased 4-24 years after onset of diabetes in the presence of family members with type 2 diabetes of any sex. These hereditary factors were independent of other studied risk factors such as previous cataract surgery, age of onset of diabetes, metabolic regulation and blood pressure. Conclusions: The presence of family members with diabetes affects the risk for developing vision threatening diabetic retinopathy and affects the risk for developing PDR and DME differently. This evidence may help individualizing the control intervals in screening programmes for diabetic retinopathy.

Purpose: To identify parameters that can predict the postoperative risk for progression of retinopathy to a vision-threatening stage after cataract surgery. This may optimize the timing of surgery and the postoperative follow-up strategy in diabetic patients., Methods: Multi-state survival analysis with death as competing risk was used to investigate how year of onset and age of onset of diabetes, gender, body mass index, HbA1c and blood pressure had affected the risk for developing diabetic macular oedema (DME) and proliferative diabetic retinopathy (PDR) among 2540 right eyes from 2797 diabetic patients operated for cataract on one or both eyes during 25 years until July 1. 2019., Results: Cataract surgery had been performed in 98.8% of patients reaching 90 years of age. The risk for developing both DME and PDR was increased by cataract surgery. The risk was highest during the first postoperative years and increased by pre-operative variability in HbA1c. The risk after more than 20 years postoperatively increased by increased cumulative HbA1c pre-operatively. The other studied risk factors contributed differently to the development of the two complications., Conclusions: Decision models for the timing of cataract surgery in diabetic patients should consider that the risk for developing vision-threatening retinopathy depends on follow-up time. Differences in the risk profiles for developing DME and PDR after cataract surgery support that the two complications should be regarded as separate late complications., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Proliferative diabetic retinopathy (PDR) can be treated by retinal photocoagulation, but in some cases, the treatment is initiated too late or is insufficient so that the disease advances to a stage requiring vitrectomy. There is a need to identify risk factors that can predict if patients with PDR will develop complications in need for vitrectomy., Methods: Survival analysis with death as competing risk was used to study systemic risk factors for PDR progression to a complication in need for vitrectomy in right eyes of all 1288 diabetic patients from the Aarhus area, Denmark, who had developed proliferative retinopathy in the right eye during the 25 years period from 1 July 1994 until 1 July 2019., Results: The overall cumulative incidence of reaching a vitrectomy end point in the right eye was 24.1% (n = 311). In 9.3% (n = 120) of the patients where vitrectomy had been performed together with the first photocoagulation, the age of onset of diabetes was significantly higher (p < 0.0001), the diabetes duration longer (p < 0.035) and BMI higher (p < 0.01) than in the patients who had been vitrectomized later than the first photocoagulation. The risk for vitrectomy was significantly increased by high variability of HbA1c before the development of PDR (p < 0.0001), but not by other parameters known to increase the risk for developing PDR., Conclusion: Increasing variability of HbA1c before the development of PDR increases the risk for progression to a complication in need of vitrectomy. The need for vitrectomy is unaffected by other risk factors known to increase the risk for developing PDR., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD)., Objective: To investigate diabetes and DR as a risk marker of present and incident AD., Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes., Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53)., Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.

Purpose: According to cross-sectional studies, oxygen saturation is elevated in retinal vessels in diabetic patients. We evaluated how retinal oxygenation (metabolic marker), vessel diameters and retinopathy grade (structural markers) change over time in diabetic patients., Design: Prospective cohort study following screening in a hospital setting., Methods: Retinal oximetry images were acquired in 214 patients with the Oxymap T1 oximeter. Imaging was repeated after a median of 3.0 years (range 0.76-6.8 years). Oxygen saturation and vessel diameters were measured in the right eye. Semiquantitative grading of retinopathy according to international guidelines and red lesion count were performed on fundus photographs., Results: Retinopathy grade according to the international semiquantitative grading system was unchanged. Arteriolar saturation increased by 0.75±0.15 percentage points per year of follow-up (p<0.0001). Venular saturation increased by 1.74±0.26 percentage points per year (p<0.0001) and arteriovenous difference decreased by 0.99±0.20 percentage points per year (p<0.0001). Arteriolar diameters decreased by 2.7±8.5μm (p<0.0001) between visits and venular diameters decreased by 2.4±9.1μm (p = 0.0002). Median increase in red lesion count between visits was 2 lesions (range -128 to 212 lesions, p<0.0001). The change in red lesion count and change in diameters did not correlate with the length of follow-up (p>0.44)., Conclusions: Oxygen saturation in larger retinal vessels can increase and arteriovenous difference can decrease over time in diabetic patients without any observable changes in retinopathy grade. The results suggest that changes in retinal oxygen saturation may precede progression of diabetic retinopathy or that oxygen saturation is more sensitive to disease progression than retinopathy grade., Competing Interests: Sveinn Hakon Hardarson and Einar Stefánsson have commercial interest in the company Oxymap ehf. They have stock in the company, are on its board and are listed on two patents related to retinal oximetry (Automatic registration of images US 7774036 B2, Temporal oximeter WO 2010143208 A3). This does not alter our adherence to PLOS ONE policies on sharing data and materials

Aims/hypothesis: The purpose of screening for diabetic retinopathy is to detect either of the two sight-threatening complications: proliferative diabetic retinopathy (PDR) or clinically significant diabetic macular oedema (DME). The aim of the study was to evaluate whether systemic risk factors affect the risk of developing these two complications differently., Methods: Survival analysis with death as a competing risk was used to describe the effect of sex, age and time of onset of diabetes, systolic (SBP) and diastolic (DBP) BPs, and the weighted exposure and CV of HbA 1c for the development of PDR and DME from all 2773 patients treated for diabetic retinopathy in a defined population from the Aarhus area, Denmark, between 1 July 1994 and 1 July 2019., Results: Increasing HbA 1c above normal increased the risk of developing both PDR and DME (p < 0.04), and values below normal increased the risk of developing PDR (p < 0.013). Increasing DBP increased the risk of developing both PDR and DME (p < 0.0001), whereas increasing SBP increased the risk of developing DME (p < 0.0001), but not PDR (p > 0.08). The risk of developing PDR increased with decreasing age of onset of diabetes (p < 0.0001), whereas the risk of developing DME was maximal for a known onset of diabetes at about 30 years of age and decreased significantly for both lower and higher ages of onset (p < 0.0001). The risk of developing both PDR and DME was lower in women than in men (p < 0.004) and was reduced with lower variability of repeated HbA 1c measurements (p < 0.0001)., Conclusions/interpretation: Systemic risk factors such as metabolic regulation, arterial BP and the age of onset of diabetes contribute differently to the development of PDR and DME. The overall risk of developing treatment-requiring diabetic retinopathy should be calculated from the risks of reaching each of the two complications separately.

Introduction: Diabetic retinopathy is defined as morphological lesions in the retina secondary to diabetes. The lesions may progress to a vision-threatening stage, which is more frequent in men and people with weak personal networks and a low psychosocial status. However, there is limited knowledge about the influence of other socio-economic factors on the development of treatment-requiring diabetic retinopathy., Methods: The number of patients from each postal district in the Aarhus County area who had been treated for diabetic retinopathy in the first eye between 1 July 1994 and 1 July 2019 was acquired. The standard information package "Key figures from postal districts" published 1 October 2019 by Statistics Denmark was used to study differences in treatment rates of diabetic retinopathy among postal districts and to explore to which extent such differences may be explained by population size, age, educational background and income., Results: During the study period of 25 years, 2,142 patients with home address in the former Aarhus County were treated for diabetic retinopathy. The treatment rate showed marked geographical variations and was inversely related to educational level, but was not independently related to either population size, age or income., Conclusions: Initiatives aiming to reduce the incidence of treatment-requiring diabetic retinopathy in Danish healthcare should include preventive measures especially adapted to citizens with a low educational background. FUNDNG: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Purpose: Diabetic maculopathy (DM) treated with photocoagulation may subsequently progress to proliferative diabetic retinopathy (PDR). However, there is insufficient knowledge about the incidence and risk factors for the development of PDR in patients previously treated for DM., Materials and Methods: Survival data was used to analyze prospectively collected epidemiological and clinical data to describe the incidence and risk factors for the occurrence of PDR in all 1,235 patients photocoagulation treated for DM in a defined population from the Aarhus area, Denmark, from January 1. 1993 until December 31. 2016., Results: Among 1,204 (97.5%) of the patients in whom the subsequent clinical history was known, 536 (44.5%) had died and 131 (10.9%) had received panretinal photocoagulation for PDR. The cumulative incidence of developing PDR after photocoagulation for diabetic maculopathy increased with time to reach a plateau around 13% after approximately 15 years. Earlier age at diagnosis of diabetes and higher HbA1c at the time of macular treatment were significant risk factors for the development of PDR, whereas gender, diabetes type, body mass index, known diabetes duration at the time of macular photocoagulation and blood pressure were not significant risk factors., Conclusions: In patients treated with retinal photocoagulation for DM, a tight metabolic control is accompanied with a reduced risk for subsequent progression to PDR. In the treated patients who do not develop PDR, the control interval can be gradually increased with time.

Background: Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown., Methods: The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture., Results: Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia., Conclusions: The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy., (© 2019 S. Karger AG, Basel.)

Purpose: Remote ischemic conditioning (RIC) implies that transient ischemia in one organ can affect blood flow and protect from ischemia in another remote organ such as the retina. The purpose of the present study was to investigate the effect of RIC on the diameter of retinal arterioles in patients with diabetic retinopathy and whether this effect differs among peripheral and macular vessels., Methods: In twenty type 1 diabetes patients aged 20-31 years, the Dynamic Vessel Analyzer (DVA) was used to measure diameters of peripheral and macular arterioles during rest, isometric exercise, and flicker stimulation. Measurements were obtained before, immediately after, and 1 h after RIC, and were compared to responses obtained from normal persons., Results: The reduced baseline diameter (p < 0.009) and contraction of peripheral retinal arterioles during isometric exercise (p = 0.025) observed immediately after RIC in normal persons were absent in the studied diabetic patients., Conclusions: RIC affects the diameter of peripheral but not macular arterioles in normal persons, but the response is abolished in diabetic patients., Trial Registration: NCT03906383.

Purpose: Diabetic retinopathy is characterized by disturbances in retinal blood flow mediated by capillary occlusion, intraretinal microvascular abnormalities (IRMAs), neovascularizations, and omega loops and reduplications. It is likely that the study of oxygen saturation in these abnormalities can provide knowledge about their role in the development of diabetic retinopathy., Methods: The oxygen saturation in IRMA vessels and venous loops and reduplications were studied in 40 diabetic patients with severe nonproliferative or proliferative diabetic retinopathy. The saturation values in the studied vascular abnormalities were compared to those of the larger retinal arterioles and venules., Results: There was a similar oxygen saturation (mean ± SD) in IRMAs observed to connect arterioles with venules (78.6% ± 11.8%, n = 22) and IRMAs connecting venules with venules (79.2% ± 9.0%, n = 12; P > 0.999). The saturation in IRMAs was significantly lower (P < 0.0002) than in arterioles (97.4% ± 5.2%, n = 40) and significantly higher (P < 0.0001) than the saturation in omega loops and reduplications (54.2% ± 19.3%, n = 6), which in turn showed no significant difference from the saturation in the venules (61.8% ± 6.8%, n = 40, P = 0.4)., Conclusions: The findings suggest that the oxygen saturation in vascular abnormalities in diabetic retinopathy depends on the extent of arteriovenous (A-V) shunting, with venous saturation due to no A-V shunting in venous loops and reduplications, and intermediate oxygen saturation due to moderate shunting in IRMAs. This may precede the development of neovascularizations with arterial oxygen saturation due to high A-V shunting.

Background: The oxygen saturation in larger retinal vessels has been shown to increase with increasing diabetic retinopathy (DR) grade and to help predict the effect of antivascular endothelial growth factor treatment in patients with diabetic maculopathy. However, it is unknown to what extent the increased oxygen saturation co-varies with other risk factors and whether it is an independent risk factor for the severity of DR., Methods: Seven hundred and twenty-two successive patients referred for specialist evaluation of diabetic retinopathy including retinal oximetry were studied. Multiple regression analysis was used to investigate whether oxygen saturation in the larger retinal arterioles and venules contributed to the severity of diabetic retinopathy, independently of gender, age, diabetes duration, diabetes type, body mass index, blood pressure, haemoglobin A1c, visual acuity and central retinal thickness., Results: The included parameters could explain less than 15% of the variation in retinopathy grade. Approximately, one-third of the explained variation was related to the retinal oxygen saturation., Conclusions: Prospective studies are needed to evaluate whether retinal oxygen saturation is predictive for the development of diabetic retinopathy and how it interacts with other biomarkers and risk factors over time., Competing Interests: Competing interests: ES is the shareholder and board member in Oxymap ehf. SHH is the shareholder in Oxymap ehf that produces retinal oximeters., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Retinal neovascularizations in proliferative diabetic retinopathy have been proposed to develop from larger retinal venules. However, angiographic evidence suggests that the new vessels may originate from both arterioles and venules, and the vitreous oxygen tension near retinal neovascularizations is similar to that of retinal arterioles. An assessment of the oxygen saturation in neovascularizations may help characterizing the vascular origin of these vessels in proliferative diabetic retinopathy., Methods: Dual wavelength oximetry was used to study the oxygen saturation in arterioles, venules, and retinal neovascularizations in 40 eyes from 40 patients with proliferative diabetic retinopathy., Results: The oxygen saturation was significantly lower in retinal venules than in arterioles and neovascularizations (P < 0.0001), and after a correction for the influence of vessel diameter, there was no significant difference between the oxygen saturation in retinal arterioles and neovascularizations (P = 0.71). Age at onset and duration of diabetes mellitus contributed significantly to the variation in oxygen saturation of the venules, whereas none of the clinical background parameters contributed to the variation in oxygen saturation in arterioles and neovascularizations., Conclusion: The oxygen saturation in retinal neovascularizations in proliferative diabetic retinopathy is similar to that of the arterioles. Neovascularizations may act as shunts to bypass areas of capillary occlusion.

Purpose: Diabetic retinopathy (DR) is among the leading causes of visual loss in the working-age population. It is generally accepted that screening of DR is cost-effective and can detect DR before it becomes sight-threatening to allow timely treatment., Methods: A group of retinal specialists was formed by the Danish Ophthalmological Society with the aim to formulate contemporary evidence-based guidelines for screening of DR in order to implement these in the Danish screening system., Results: We hereby present evidence for DR-screening regarding (1) classification of DR, (2) examination techniques, (3) screening intervals and (4) automated screening. It is our recommendation that the International Clinical Retinopathy Disease Severity Scale should be used to classify DR. As a minimum, mydriatic two-field disc- and macular-centred images are required. In the case of suspected clinically significant diabetic macular oedema, supplementary optical coherence tomography can increase the diagnostic accuracy. There is solid evidence to support a flexible, individualized screening regimen. In particular, it is possible to prolong screening intervals to 24-48 months for patients with no or mild nonproliferative diabetic retinopathy (NPDR), but it is also possible to use extended intervals of 12-24 months for patients with moderate NPDR given that these are well-regulated regarding glycaemic control (HbA1c ≤ 53 mmol/mol) and blood pressure (≤130/80 mmHg). Automated screening of DR is encouraging but is not ready for implementation at present., Conclusion: Danish evidenced-based guidelines for screening of DR support high-quality imaging and allow flexible, individualized screening intervals with a potential for extension to patients with low risk of DR progression., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Diabetic maculopathy can be treated with intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors. However, the therapy is not effective in all patients, and it would be desirable to have parameters for differentiating patients who will benefit from treatment from those who will not. Retinal fixation has been shown to be impaired in patients with low visual acuity (VA) secondary to macular disease, but the changes in fixational eye movements after anti-VEGF treatment for diabetic maculopathy have not been investigated., Methods: Retinal fixation was studied in 29 patients with diabetic macular oedema before three monthly anti-VEGF injections, and 1 and 4 months after the last injection. The change in VA was correlated with changes in area, frequency, amplitude and total number of fixational saccades., Results: During three monthly injections, best-corrected visual acuity (BCVA) increased from (mean ± SD) 74.0 ± 11.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters to 78.3 ± 9.8 ETDRS letters, (p = 0.003) and central retinal thickness (CRT) decreased from (mean ± SD) 441.7 ± 107.0 μm to 339.5 ± 74.2 μm, (p = <0.0001), which was followed by the opposite changes after treatment (BCVA reduced nonsignificantly to 77.5 ± 10.4 ETDRS letters (p = 0.06), and CRT increased to 393.0 ± 9.8 μm, p = <0.0001). Both improvement and worsening of BCVA correlated with the fixation area (r 2  = 0.28, p = 0.003 and r 2  = 0.14, p = 0.045, respectively), but only improvement of BCVA correlated with the frequency (r 2  = 0.15, p = 0.037) and total number of saccades (r 2  = 0.18, p = 0.02). BCVA showed no correlation with the amplitude and most frequently occurring saccade amplitude., Conclusion: Fixational eye movements may be used to monitor short-term effects of anti-VEGF treatment on diabetic macular oedema. Future studies should aim at investigating a possible predictive value of fixational eye movements for visual function in the long term., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Aims/hypothesis: Diabetic retinopathy is characterised by morphological lesions related to disturbances in retinal blood flow. It has previously been shown that the early development of retinal lesions temporal to the fovea may predict the development of treatment-requiring diabetic maculopathy. The aim of this study was to map accurately the area where lesions could predict progression to vision-threatening retinopathy., Methods: The predictive value of the location of the earliest red lesions representing haemorrhages and/or microaneurysms was studied by comparing their occurrence in a group of individuals later developing vision-threatening diabetic retinopathy with that in a group matched with respect to diabetes type, age, sex and age of onset of diabetes mellitus who did not develop vision-threatening diabetic retinopathy during a similar observation period., Results: The probability of progression to vision-threatening diabetic retinopathy was higher in a circular area temporal to the fovea, and the occurrence of the first lesions in this area was predictive of the development of vision-threatening diabetic retinopathy. The calculated peak value showed that the risk of progression was 39.5% higher than the average. There was no significant difference in the early distribution of lesions in participants later developing diabetic maculopathy or proliferative diabetic retinopathy., Conclusions/interpretation: The location of early red lesions in diabetic retinopathy is predictive of whether or not individuals will later develop vision-threatening diabetic retinopathy. This evidence should be incorporated into risk models used to recommend control intervals in screening programmes for diabetic retinopathy.

Occlusion of retinal vessels leads to retinal ischaemia and hypoxia, which induces vasodilatation in adjacent retinal areas in order to normalize retinal oxygenation. Previous studies have shown that NO and COX products are involved in hypoxia-induced dilatation of retinal arterioles in vitro and in vivo, and that this response is disturbed in patients with diabetes mellitus. However, it is unknown to what extent post-hypoxic recovery of the diameter of retinal arterioles depends on NO and COX products in normal persons and in diabetic patients. The Dynamic Vessel Analyzer (DVA) was used to study the post-hypoxic diameter changes of larger retinal vessels in 20 normal persons, 20 diabetic patients without diabetic retinopathy, and in 18 patients with diabetic maculopathy before and after inhibition of the synthesis of nitric oxide and COX products. In normal persons, the arterioles had re-constricted (p > 0.99) 2 minutes after termination of hypoxia in the absence of antagonists, but not after treatment with L-NMMA and diclofenac (p < 0.01 for all comparisons). In diabetic patients without retinopathy, the arterioles showed no diameter changes after termination of hypoxia during any of the interventions. In patients with diabetic maculopathy hypoxia had not dilated retinal arterioles (p > 0.1 for all comparisons) to allow the study of re-constriction. In all groups, the dilatation of venules remained significantly increased during the post-hypoxic observation period, both in the absence and in the presence of L-NMMA and diclofenac.Post-hypoxic constriction of retinal arterioles depends on NO and COX products, and is impaired in diabetic patients before the development of retinopathy. This disturbance may contribute to the development of diabetic retinopathy, and should be the target of future interventional studies aimed at preventing and treating the disease.ClinicalTrials.gov identifier: NCT01689090.

Mitochondrial dysfunction may predispose to the development of diabetes mellitus with the accompanying risk for developing diabetic retinopathy or may contribute directly to the diabetic metabolic dysregulation and thereby increase the risk of diabetic late complications including retinopathy. Diabetes mellitus in mitochondrial disease can lead to the development of vision threatening retinopathy, but visual acuity is often reduced secondary to neurological deficits resulting from the mitochondrial dysfunction. The relation between mitochondrial disease and diabetic retinopathy can be influenced by epigenetics where factors in the environment modify the expression of regulatory proteins coding for the elimination of reactive oxygen species., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Purpose of Review: The diameter of retinal vessels is an important source of information about retinal blood flow and metabolism. The purpose of the present study is to review how diameter changes of retinal vessels contribute to the development of diabetic retinopathy and may be a marker of the prognosis of the disease., Recent Findings: The early stages of diabetic retinopathy are accompanied with dilatation of the diameter of retinal vessels and reduced autoregulation. Diabetic retinopathy also shows regional differences in the macular area and the retinal periphery and accompanying differences in vascular reactivity in these areas. These differences may potentially become an important source of insight into the pathophysiology of the disease in the future. Diabetic retinopathy is accompanied with changes in the diameter regulation of retinal vessels. The potential of newly developed techniques for assessing retinal blood flow and metabolism, such as Doppler techniques, adaptive optics, and retinal oximetry, is promising and may potentially contribute to significant advances in our understanding of diabetic retinopathy which remains a major cause of visual impairment.

Background: Diabetic retinopathy is characterised by morphological lesions in the ocular fundus related to disturbances in retinal blood flow. The two vision threatening forms of retinopathy show specific patterns of distribution of retinal lesions with proliferative diabetic retinopathy (PDR) developing secondary to ischaemia and hypoxia in the retinal periphery and diabetic maculopathy (DM) developing secondary to hyperperfusion and increased vascular permeability in the macular area. These differences in the distribution of retinal lesions might be reflected in regional differences in oxygen saturation in the larger retinal vessels., Methods: Dual-wavelength retinal oximetry was performed in 30 normal persons, 30 patients with DM and 30 patients with PDR, and the oxygen saturation was measured in peripapillary vessels supplying the four retinal quadrants and in branches from the upper temporal arcades supplying, respectively, the macular area and the retinal periphery., Results: The overall oxygen saturation was significantly higher in diabetic patients than in normal persons and the arteriovenous (AV) saturation difference significantly lower in the patients with DM. The regional variation in oxygen saturation was similar in the three studied groups with a decreasing saturation from the upper nasal through the lower nasal, lower temporal and the upper temporal peripapillary vessels, and with a significantly higher oxygen saturation in venules draining the macular area than in venules draining the retinal periphery., Conclusions: The regional differences in retinal lesions in vision threatening diabetic retinopathy are not reflected in regional differences in the oxygen saturation of larger retinal vessels. The development of vision threatening diabetic retinopathy depends on other factors, such as, for example, regional differences in the retinal microcirculation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: It has previously been shown that the intervals between screening examinations for diabetic retinopathy can be optimized by including individual risk factors for the development of the disease in the risk assessment. However, in some cases, the risk model calculating the screening interval may recommend a different interval than an experienced clinician. The purpose of this study was to evaluate the influence of factors unrelated to diabetic retinopathy and the distribution of lesions for discrepancies between decisions made by the clinician and the risk model., Methods: Therefore, fundus photographs from 90 screening examinations where the recommendations of the clinician and a risk model had been discrepant were evaluated. Forty features were defined to describe the type and location of the lesions, and classification and ranking techniques were used to assess whether the features could predict the discrepancy between the grader and the risk model., Results: Suspicion of tumours, retinal degeneration and vascular diseases other than diabetic retinopathy could explain why the clinician recommended shorter examination intervals than the model. Additionally, the regional distribution of microaneurysms/dot haemorrhages was important for defining a photograph as belonging to the group where both the clinician and the risk model had recommended a short screening interval as opposed to the other decision alternatives., Conclusions: Features unrelated to diabetic retinopathy and the regional distribution of retinal lesions may affect the recommendation of the examination interval during screening for diabetic retinopathy. The development of automated computerized algorithms for extracting information about the type and location of retinal lesions could be expected to further optimize examination intervals during screening for diabetic retinopathy., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Treatment of diabetic maculopathy with vascular endothelial growth factor inhibitors is in some patients ineffective, and, therefore, parameters predicting visual outcome after treatment should be identified. It has been shown that fixational saccades are increased in patients with reduced visual acuity secondary to diabetic maculopathy, but it is unknown to what extent these saccades in an eye affected by diabetic maculopathy are influenced by the other eye during binocular fixation., Methods: In 57 eyes from 29 diabetic patients with clinically significant macular edema, fixational eye movements were recorded using the iView X™ video-based eye tracker, and quantitative measures of fixation with the worst eye obtained during monocular and binocular fixation were compared., Results: Fixational saccades during monocular fixation had a significantly higher frequency (p = 0.005), a larger amplitude (p = 0.03), and involved a larger retinal area (p = 0.02) than during binocular fixation. There was a significant negative correlation (r2 = 0.18, p = 0.02) between visual acuity and the area of fixation during monocular but not during binocular fixation (r2 = 0.007, p = 0.68)., Conclusion: Binocular fixation can reduce the area of fixation and the amplitude of fixational saccades in the worst eye of patients with diabetic maculopathy. Fixational saccades in diabetic maculopathy should be studied during monocular fixation., (© 2017 S. Karger AG, Basel.)

Purpose: Diabetic retinopathy is accompanied with changes in the diameter regulation and oxygenation of retinal vessels. Previous studies have shown that in normal persons and in diabetic patients without retinopathy hypoxia-induced vasodilatation is mediated by cyclo-oxygenase (COX) products and nitric oxide (NO). The purpose of the present study was to study whether these effects can be reproduced in patients with diabetic maculopathy., Methods: Eighteen patients with diabetic maculopathy aged 29-57 years were examined using the Dynamic Vessel Analyzer. The resting diameter and the diameter changes of retinal arterioles during isometric exercise and flicker stimulation were studied before and during breathing a hypoxic gas mixture. The examinations were also performed before and during intravenous infusion of the NOS inhibitor L-NMMA, and were repeated on a second day after topical administration of the COX-inhibitor diclofenac., Results: The diameter of retinal arterioles showed no significant change during hypoxia or L-NMMA infusion, or after topical application of diclofenac (p > 0.25 for all comparisons). The resting diameter of the venules was significantly increased during hypoxia (p = 0.003) and decreased during L-NMMA infusion (p < 0.0001). The diameter of retinal venules during isometric exercise increased significantly during hypoxia (p = 0.01). Flicker stimulation induced significant dilatation of the venules, which was significantly reduced during hypoxia and increased during L-NMMA infusion (p < 0.0001 for all comparisons)., Conclusion: Hypoxia-induced dilatation of retinal arterioles is severely reduced in patients with diabetic maculopathy. Future intervention studies aimed at normalizing the diameter regulation of retinal arterioles in diabetic patients should preferentially be conducted in the early stages of the disease where the potential for changing the vessel diameter is preserved. ClinicalTrials.gov identifier: NCT01689090.

Purpose: The advent of vascular endothelial VEGF antagonists has increased the therapeutic options for diabetic maculopathy considerably. However, there is a need to identify patients who respond favorably to the treatment from those in whom the treatment is less effective. The purpose of the present study was to test the hypothesis that the oxygen saturation in retinal vessels together with other risk factors can predict the effect of anti-VEGF treatment on diabetic maculopathy., Methods: In 73 eyes from 53 patients with center-involving diabetic macular edema, multiple linear regression was used to evaluate the predictive value of oxygen saturation in larger retinal vessels together with age, diabetes duration, diabetes type, hemoglobin A1c (HbA1c), mean arterial blood pressure (MAP), body mass index (BMI), previous retinal photocoagulation, visual acuity (VA), and central retinal thickness (CRT) before treatment as explanatory variables for VA and CRT after three monthly injections of anti-VEGF medication., Results: Anti-VEGF treatment induced a significant increase in VA and a significant decrease in CRT, but no significant changes in the overall oxygen saturation of larger retinal vessels. Visual acuity and CRT before treatment contributed significantly to predicting the same variable after treatment. Additionally, MAP and the oxygen saturation in retinal arterioles before treatment contributed significantly to predicting VA and CRT after treatment., Conclusions: The MAP and oxygen saturation in retinal arterioles might potentially be included as parameters in risk models predicting the effect of anti-VEGF treatment in patients with diabetic maculopathy.

Purpose: Diabetic retinopathy is diagnosed by fundus photography and optical coherence tomography (OCT) scanning. However, adaptive optics (AO) imaging can be expected to add new aspects to the knowledge of diabetic retinopathy because photographic resolution is improved by reducing the influence of optical aberrations on retinal imaging., Methods: Nineteen patients with diabetes mellitus were subjected to fundus photography, OCT scanning and AO imaging. The fundus photographs were scaled to the same magnification as that of the AO image, and qualitative aspects of AO images of each retinopathy lesion observed on fundus photographs and OCT scans were assessed., Results: All red lesions on fundus photographs appeared on AO images as dark hyporeflective elements, but it could not be verified whether lesions represented haemorrhages or microaneurysms. The smallest of these lesions were circular with a size corresponding to that of blood cells. Hard exudates had irregular surfaces with buddings of various sizes protruding from the lesions. Areas of retinal oedema observed by fundus imaging and OCT scanning resulted in blurring of AO images, but cystoid spaces observed by OCT could be seen on AO images to have a sharp delimitation with a darker hyporeflective rim at the internal lining of the cyst wall., Conclusion: AO imaging may potentially assist in detecting diabetic retinopathy at an earlier stage, may help elucidating the pathophysiology of the diseases and may be used for evaluating the effects of clinical interventions on diabetic retinopathy and other retinal vascular diseases., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies., Methods: Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were re-examined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened., Results: At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy., Conclusions: The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy.

Purpose: Diabetic retinopathy is characterized by retinal vascular impairment resulting in retinal hypoxia. The disease can be treated by retinal photocoagulation, but the mechanism of action of this treatment is unknown. Therefore, it is of interest to investigate whether the effects of retinal photocoagulation are related to changes in oxygen saturation., Methods: Retinal oximetry and diameter measurements were performed on larger retinal arterioles and venules in 220 eyes from 149 patients with diabetic maculopathy (DM) and proliferative diabetic retinopathy (PDR) before, immediately after, and 3 months after photocoagulation treatment., Results: Before treatment oxygen saturation was increased in retinal venules in DM patients to result in reduced arteriovenous (AV) saturation difference, and was increased in arterioles and venules in PDR patients to result in a normal AV saturation difference. Immediately after treatment the oxygen saturation in both groups was unchanged in retinal arterioles and increased in retinal venules resulting in a reduced AV saturation difference. Three months after treatment arterial and venous saturations were increased, but the AV saturation difference was not different from the pretreatment level. In both patient groups vascular diameters had decreased 3 months after treatment, which was significant for venules in the PDR group., Conclusions: The effects of retinal photocoagulation on diabetic retinopathy are not correlated with changes in oxygen saturation in larger retinal vessels., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: Diabetic retinopathy is characterized by morphological lesions in the retina secondary to disturbances in retinal blood flow which may influence the supply of oxygen to the retinal metabolism. Using retinal oximetry, it has been shown that the oxygen saturation is increased in retinal arterioles and venules from diabetic patients with retinopathy, but oxygenation before the development of retinopathy and possible differences in retinal oxygenation between diabetic maculopathy and proliferative diabetic retinopathy patients have not been evaluated., Methods: One-hundred and fifty-six consecutive patients referred for specialist evaluation of diabetic retinopathy, and eighty normal control persons were subjected to retinal oximetry of the larger retinal arterioles and venules. The diabetic patients were allocated to one of four groups with severity of retinopathy ranging from no retinopathy to vision-threatening retinopathy, and the oxygen saturation in arterioles and venules was compared between these groups., Results: Increasing severity of retinal changes from no retinopathy to diabetic maculopathy was accompanied with increasing oxygen saturation in retinal venules and decreasing oxygen extraction, whereas proliferative diabetic retinopathy showed increased oxygen saturation in both retinal arterioles and venules to result in a normal oxygen extraction., Conclusion: Prospective observational and interventional studies are needed to show whether changes in retinal oxygen saturation precede or follow the development of diabetic retinopathy. Additionally, studies of regional variations in haemodynamic parameters in patients with vision-threatening diabetic retinopathy might improve the understanding of the pathophysiology of diabetic retinopathy. This is a precondition for improving the prevention and treatment of the disease., (© 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To assess the effect of ruboxistaurin (RBX) on vision loss through a prospectively defined combined analysis of two phase 3 trials (MBDL and MBCU)., Methods: Patients in both of these 3-year randomized, placebo-controlled, double-masked trials had best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) ≥ 75 letters (∼20/32 Snellen), ETDRS retinopathy level 20 to 47D (MBDL) or 35B to 53E (MBCU), and no prior panretinal or focal photocoagulation in at least one eye at baseline. Patients received oral placebo (N = 508 total from both studies) or RBX 32 mg/d (N = 520 total). Best-corrected ETDRS VA was measured at 6-month intervals for 3 years (MBDL) or for 18 to 48 months (MBCU). Sustained moderate visual loss (SMVL) was defined as a 15-letter or more reduction from baseline in VA sustained for a patient's last 6 months of study participation., Results: In the combined studies (N = 1028 total), SMVL occurred in 4.4% of placebo- versus 2.3% of RBX-treated patients (P = 0.069). In patients with a minimum of 2 years of follow-up (N = 825 total), there was less SMVL in the RBX group (4.4% placebo versus 2.1% RBX, P = 0.045). Other VA-related measures (mean VA, contrast sensitivity, Visual Functioning Questionnaire 25 [VFQ-25]) either trended toward a benefit for RBX or were also statistically significant in favor of RBX. In contrast, diabetic macular edema (DME) morphology-related measures (occurrence of significant center of macula involvement, optical coherence tomography [OCT]-determined center of macula thickness, application of focal photocoagulation) did not show a consistent trend in favor of or against RBX., Conclusions: SMVL data in a prospectively defined combined analysis from these two phase 3 trials suggest a magnitude of effect of RBX on vision loss similar to that seen in two prior studies (approximately 50% reduction above standard care). However, event rates were low and statistical significance was not achieved. (ClinicalTrials.gov numbers, NCT00133952, NCT00090519.).

Purpose: Diabetic retinopathy is characterized by morphological changes in the retina secondary to disturbances in retinal blood flow. Vasomotion is a mechanism for regulating blood flow by spontaneous oscillations in the diameter of retinal resistance arterioles, and has been shown to be disturbed outside the eye in diabetic patients. Therefore, the purpose of the present study was to characterize spontaneous oscillations in the diameter of retinal arterioles in normal persons and in persons with different severity of diabetic retinopathy., Methods: Video recordings of the retina were performed in 19 normal persons and three matched groups of type 2 diabetic patients with no retinopathy, mild retinopathy, and diabetic maculopathy. Continuous recordings of a larger retinal arteriole during rest and during an increase in the arterial blood pressure induced by isometric exercise were subjected to power spectrum analysis of spontaneous oscillations in vessel diameter., Results: During rest the oscillations in the diameter of retinal arterioles with high frequencies were significantly reduced in patients with diabetic retinopathy. Increased arterial blood pressure did not change the oscillations in normal persons, but further reduced the oscillations in diabetic patients., Conclusions: Spontaneous high frequency oscillations in the diameter of larger retinal arterioles are reduced in type 2 diabetic patients, and are further reduced during an increase in the arterial blood pressure. The finding may reflect changes in the vascular walls of importance for diagnosing and predicting the visual prognosis in patients with diabetic retinopathy.

Purpose: Diabetic retinopathy is characterised by morphological lesions secondary to retinal vascular impairment, and it is assumed that changes in the diameter regulation of retinal arterioles are involved in the disease pathogenesis. It has previously been shown that prostaglandin F2α can constrict retinal arterioles in vitro. In the present study, we investigated whether a similar effect could be achieved by topical administration in diabetic patients with dilated retinal arterioles and retinopathy., Methods: Twenty-two type 1 diabetic patients with mild retinopathy and twenty-four matched normal controls were randomized to topical treatment with the prostaglandin F2α agonist latanoprost twice daily for 1 week, followed by similar treatment with the cyclo-oxygenase inhibitor diclofenac, or to receive the two medications in the reverse order. The Dynamic Vessel Analyzer was used to assess the effect of the interventions on the resting diameter of retinal vessels and on the diameter response of retinal arterioles to increased blood pressure (BP) induced by isometric exercise and flicker stimulation., Results: Latanoprost reduced the resting diameter of retinal arterioles significantly in patients with diabetes (p = 0.01), but had no effect on normal persons. Diclofenac had no effect on the resting diameter of arterioles in either of the groups. The diameter responses to increased BP and flicker stimulation were not significantly changed by any of the treatments., Conclusion: Long-term prospective studies are needed to study the effect of topical treatment with latanoprost on the consequences of retinal hyperperfusion in retinal vascular diseases such as diabetic retinopathy., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

Diabetic retinopathy frequently causes blindness, especially in patients with type 2 diabetes mellitus (T2D). The implementation of systematic screening can improve the visual prognosis significantly, and recently decision models that allow individualised determination of control intervals on the basis of known risk factors have been introduced. Current treatment of diabetic retinopathy with retinal photocoagulation has adverse effects with severe consequences for patients with T2D. However, recently intravitreal angiostatic therapy has been introduced as an effective new modality for the treatment of diabetic retinopathy.

Introduction: Screening programmes for diabetic retinopathy follow guidelines that ensure that vision-threatening complications are detected even when the disease progression is fast. This implies that patients with slow disease progression will be recommended examinations more often than needed., Method: On the basis of previously defined individual risk factors, multiple logistic regression was used to develop a model for individualized determination of the screening interval in diabetic retinopathy, while adjusting for the fact that in the data set used to construct the model, the screening interval acted as a time-dependent confounder. The model was tested on 1372 patients screened during year 2000., Results: It was possible to construct a model for calculating the optimal screening interval in low-risk patients in whom the recommended screening interval was longer than 12 months. When the probability of reaching a treatment requiring event was set to 0.5%, none of the patients reached a treatment end-point in a validation of the model, and the screening interval was prolonged on average 2.9 times in patients with type 1 diabetes and 1.2 times in those with type 2 diabetes. The predictive strength of the model depended on the number of variables included., Conclusions: It is possible to construct a model for optimizing the examination interval during screening for diabetic retinopathy in low-risk patients. The model can potentially be improved by identifying unknown or unmeasured confounders and by including knowledge of risk factors before and after the examination on the basis of which the prediction is made., (© 2010 The Authors. Acta Ophthalmologica © 2010 Acta Ophthalmologica Scandinavica Foundation.)

Objective: To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes., Research Design and Methods: A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20-79 years., Results: A total of 35 studies (1980-2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5-34.8) for any DR, 6.96% (6.87-7.04) for proliferative DR, 6.81% (6.74-6.89) for diabetic macular edema, and 10.2% (10.1-10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A(1c), and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes., Conclusions: There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.

Purpose: Diabetic retinopathy is characterized by morphological changes in the retina secondary to disturbances in retinal blood flow. It has been shown that antihypertensive treatment has a protective effect on the development of diabetic retinopathy, and evidence suggests that inhibitors of the renin-angiotensin system have a protective effect beyond the antihypertensive effect. The background for this additional effect is unknown but might be related to an effect on retinal autoregulation., Methods: In a double-blinded, two-way cross-over study, 25 normotensive patients with type 1 diabetes (T1D) aged 20.6-33.9 (mean 27.9) with mild retinopathy were randomized to receive either 5 mg of the calcium channel blocker (CCB) amlodipine for 14 days followed by a washout period and treatment with 10 mg of the angiotensin converting enzyme (ACE) inhibitor lisinopril for another 14 days or the two treatments in the reverse order. Using a Dynamic Vessel Analyzer (DVA), the diameter response of retinal arterioles during an acute increase in the blood pressure induced by isometric exercise, during flicker stimulation and during both stimulus conditions simultaneously was studied before and during the two treatments periods., Results: Amlodipine and lisinopril induced a similar non-significant decrease in the arterial blood pressure. At baseline, the arterial diameter decreased by 2.4 ± 0.9% (p = 0.004) during isometric exercise, increased by 2.2 ± 0.9% (p = 0.019) during flicker stimulation and increased by 1.8 ± 0.9% (p = 0.03) during the combined stimulus conditions. Neither of the antihypertensive drugs amlodipine (p = 0.76) or lisinopril (p = 0.11) changed the diameter response of retinal vessels significantly; however, the two treatments induced a different response in the veins during combined exercise and flicker (p = 0.021)., Conclusions: Short-term treatment with amlodipine and lisinopril had no significant effect on retinal autoregulation in young normotensive patients with T1D and mild retinopathy, and this lack of effect was similar for the two drugs. A possible normalizing effect of antihypertensive treatment on retinal autoregulation was not observed; however, it might take longer time to improve autoregulation than to reduce the arterial blood pressure., (© 2010 The Authors. Journal compilation © 2010 Acta Ophthalmol.)

Introduction: Diabetic retinopathy is screened by fundus photography and screening intervals are defined according to general rules to ensure that vision threatening complications are detected even if the progression of the disease is fast. The resulting superfluous examinations of patients with slow disease progression can be reduced by a more exact decision model that allows an adjustment of the screening interval to each patient's individual risk profile. This requires an identification of independent risk factors for reaching treatment end points for diabetic retinopathy., Methods: Clinical data from 5365 patients who had undergone 23 324 examinations at the Department of Ophthalmology, Århus University Hospital between Jan 1st 1994 and Dec 31st 2007 were used to identify independent risk factors for progression of treatment requiring retinopathy., Results: The risk of reaching a treatment end point was in both diabetes types independently affected by retinopathy grade and HbA1c. Furthermore, in type 1 diabetic patients the risk of reaching a treatment end point was independently affected by disease duration and by a recommended control interval of less than 3 months, in spite of correction for retinopathy grade and other studied confounders, whereas in type 2 diabetes this risk was affected by increasing age of diagnosis of the disease., Conclusions: Only a subset of known risk factors for development and progression of diabetic retinopathy should be used to construct a decision model for optimizing screening intervals for diabetic retinopathy., (© 2009 The Authors. Journal compilation © 2009 Acta Ophthalmol.)

Background: Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pressure autoregulation and metabolic autoregulation. The disease displays regional differences, with signs of hyperperfusion in the macular area and capillary occlusion with retinal ischemia in the peripheral retinal areas. It can be hypothesized that these regional differences in the occurrence of retinopathy lesions may reflect differences in the capacity of retinal arterioles to autoregulate the diameter of retinal arterioles., Methods: Seventeen normal persons and two matched groups of patients with respectively diabetic maculopathy and proliferative diabetic retinopathy were examined. The diameter change of a macular and a peripheral retinal arteriole during an increase in the arterial blood pressure induced by isometric exercise, during an increase in retinal metabolism induced by flicker stimulation, and during both stimulus paradigms simultaneously were studied using the dynamic vessel analyzer (DVA)., Results: During isometric exercise, the diameter response was reduced in both macular and peripheral retinal arterioles in the two groups of patients with diabetes mellitus. During flicker stimulation, the diameter response was significantly reduced in patients with proliferative diabetic retinopathy, but there was no significant difference between the responses of macular and peripheral arterioles. During simultaneous isometric exercise and flicker stimulation, there was no difference between the diameter response of macular arterioles in the three groups, whereas the diameter response of macular arterioles was significantly lower in normal persons and significantly higher in persons with proliferative diabetic retinopathy as compared to peripheral arterioles., Conclusions: Regional differences in the disturbances of the diameter response to increased blood pressure may contribute to the regional differences in the distribution of diabetic retinopathy lesions. In the central retinal areas, the diameter response to increased blood pressure and retinal metabolism interacted in a way that may potentially protect this area from ischaemia, whereas this protective mechanism was absent in the peripheral retinal arterioles. An elucidation of the mechanisms underlying diameter regulation to increased blood pressure and retinal metabolism, and the interaction between these two mechanisms, may help in understanding the pathophysiology of diabetic retinopathy.