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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.

Purpose: Previous studies have shown that the retinal oxygen saturation in central retinal vein occlusion treated with anti-VEGF compound has no predictive value for visual outcome after 12 months. It is of interest to evaluate whether this conclusion is similar for patients with branch retinal vein occlusion among whom only some patients are treated. Methods: Retinal oxygen saturation, visual acuity and central retinal thickness were studied at the time of referral and after six and 12 months in 111 patients successively referred to the Department of Ophthalmology, Aarhus University Hospital, with a venous occlusion affecting branches peripheral from the central retinal venule. The predictive value of the oxygen saturation at referral was investigated in treated and untreated patients. Results: Seventy-three patients with visual acuity between 35 and 70 ETDRS letters at referral were treated with intravitreal injection of anti-VEGF compound. Over 12 months, the venous oxygen saturation improved in parallel with central retinal thickness and visual acuity but had no predictive value for visual outcome. In 12 untreated patients with visual acuity >70 ETDRS letters, younger age and high oxygen saturation at the time of referral were positive predictors for the visual outcome after 12 months. Conclusion: Oxygen saturation, visual acuity and central retinal thickness improve in parallel during treatment of branch retinal vein occlusion with intravitreal anti-VEGF medication. Retinal oximetry at referral cannot predict visual acuity after 12 months in treated patients but may perhaps become a tool for predicting the visual prognosis in a subgroup of patients where treatment is omitted because of a too high visual acuity at the time of diagnosis of the disease.

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.

BACKGROUND AND AIMS: Attenuated retinal vasoreactivity in patients with type 2 diabetes preceding diabetic retinopathy development has been proposed to reflect local endothelial dysfunction. Whether retinal vessel reactivity is associated with peripheral endothelial dysfunction and large artery stiffness in patients with type 2 diabetes remains to be elucidated.METHODS: Twenty patients with type 2 diabetes without retinopathy and 20 sex- and age matched controls (diabetes duration: 9.9 years (range 6.0;12.4), 40% male, age: 66.5 ± 7.3 (diabetes) and 65.2 ± 7.6 years (controls)) were included. Endothelial function was assessed using EndoPAT. Arterial stiffness was assessed by carotid-femoral pulse wave velocity using the SphygmoCor. Retinal blood supply regulation was examined by retinal arteriolar diameter change during 1) isometric exercise (hand-weight lifting), 2) exposure to flickering lights, and 3) a combined stimulus of 1) + 2) using the Dynamic Vessel Analyzer.RESULTS: No significant differences were observed in retinal vessel reactivity in T2DM patients compared to controls. Endothelial function was associated with mean arteriolar diameter change during only the combination intervention, (Beta = 0.033 [0.0013;0.064], p = 0.042) in the overall population of patients and controls. When groups were analyzed separately, the associations was statistically significant only in controls. However, formal test for interaction was not statistically significant, p = 0.40. No association was observed between pulse wave velocity and retinal arteriolar %-diameter change in patients or controls.CONCLUSION: Peripheral endothelial function was associated with retinal arteriolar diameter change in the combined sample. The association seemed to be driven primarily by the controls. Our findings indicate that peripheral endothelial function is reflective of endothelial function in the retina mainly in subjects without T2DM, whereas an association in T2DM without retinopathy was not observed. Further studies are needed in T2DM patients with more advanced retinopathy.

Background: The neurotransmitter adenosine has been proposed to be involved in the pathogenesis of diabetic retinopathy, which may be due to the vasoactive properties of the compound. Previous studies have shown that adenosine can affect the tone of retinal arterioles in vitro to induce dilatation mediated by A2A and A2Breceptors and constriction mediated by A1 and A3 receptors. Purpose: To investigate effects of intravenous administration of the adenosine A2A receptor agonist regadenoson on the diameter of retinal vessels in vivo. Method: The diameter responses of larger retinal arterioles and venules were evaluated using the dynamic vessel analyser in 20 normal persons (age 22–31 years) after intravenous administration of the adenosine A2A receptor agonist regadenoson during exposure to systemic normoxia and hypoxia. Results: The diameter of retinal arterioles and venules increased significantly during stimulation with flickering light (p < 0.0001). Regadenoson reduced the flicker-induced dilatation of venules during normoxia (p = 0.0006), but otherwise had no effect on vessel diameters (p > 0.08 for all comparisons). Conclusions:Intravenous administration of the adenosine A2A receptor agonist regadenoson had no significant effect on the diameter of retinal arterioles. Future studies should investigate differential effects of intra- and extravascular administration of adenosine receptor agonists on retinal vessels.

Purpose: The purpose of this study was to develop a porcine model for photocoagulationinduced choroidal neovascularization (CNV) with high success rate and minimalthermic damage to the neuroretina.Methods: Experimental CNV was induced by laser photocoagulation in both eyes of 16domestic pigs. In the left eyes, photocoagulation was preceded by subretinal injectionof saline to protect the neuroretina from thermic damage, whereas the right eyes weretreated with photocoagulation only. The development of the CNV after 3, 7, 14, 28, and42 days was evaluated by optical coherence tomography (OCT) scanning, fluoresceinangiography, and OCT angiography, and by histology after enucleation.Results: From day 7 after the photocoagulation, OCT showed subretinal density in alllesions of 14 alive animals, and either fluorescein or OCT angiography confirmed CNVformation in 11 of 14 of the eyes that had received photocoagulation alone and thosein which photocoagulation had been preceded by subretinal injection of saline. In allcases pretreated with subretinal saline, the neuroretina was protected from immediatethermic damage. The formation of CNVs were confirmed by histology. For both groups,the largest lesions were observed within 14 days after photocoagulation.Conclusions: Injection of subretinal saline can protect the retina fromthermic damageinduced by retinal photocoagulation without reducing the success rate in producingexperimental CNV. The effect of interventional studies aimed at reducing photocoagulationinduced experimental CNV in pigs can be evaluated within 2 weeks after photocoagulation.Translational Relevance: This model provides a fundament to develop and evaluatenovel treatment methods for neovascular retinal diseases.

PURPOSE. Convergence insufficiency (CI) is characterized by abnormal vergence eye movement frequently accompanied by abnormal accommodation and subjective symptoms, such as headache, blurred vision, and diplopia. CI is treated with vergence and accommodation exercises that are integrated so that the relative contributions of vergence and accommodation exercises to the outcome are concealed. The purpose of the present study was to determine the individual contributions of vergence and accommodation exercises for the treatment of CI in school children. METHODS. In a prospective crossover study 44 children aged 9 to 13 years with CI were randomized to perform either vergence exercises followed by accommodation exercises each for 6 weeks or the 2 treatment regimes in the reverse order. The outcome measures were recovery from CI and the parameters vergence facility, positive fusional vergence, near point of convergence, monocular amplitude, and facility of accommodation. RESULTS. After the first 6-week period, full recovery from CI was significantly more frequent in the group commencing vergence exercises than in the group commencing monocular accommodation exercises (p = 0.01), whereas there was no significant difference between these proportions after the second 6-week period (p = 0.45). Vergence facility and positive fusional vergence improved significantly more after the period with vergence exercises than after the accommodation exercises, whereas there was no significant difference between the effects of the two types of exercises on the other studied parameters. CONCLUSIONS. Vergence treatment induces a faster recovery of CI than accommodation treatment in school children. This may be used to improve compliance and success rate of the treatment.

PURPOSE. Recent evidence suggests that the smaller retinal vessels are significantly involved in the regulation of retinal blood flow and that this regulation may differ among the macular area and the retinal periphery. An alternative to studying blood flow regulation in smaller retinal vessels that are difficult to resolve is to assess the metabolic consequences of changes in the microcirculation using oximetry. METHODS. In 20 normal persons aged (mean ± SD, range) 30.1 ± 3.8 (24-37) years, the oxygen saturation and diameter of retinal arterioles and venules to the macular area and the retinal periphery were studied before and during an increase in the arterial blood pressure induced by isometric exercise. RESULTS. The isometric exercise increased the mean arterial blood pressure by (mean ± SEM) 10.0 ± 1.1 mm Hg but induced no significant changes in the diameter of the arterioles (P = 0.83). The isometric exercise had no significant effect on the oxygen saturation in the arterioles supplying the macular area and the retinal periphery (P > 0.42 for both comparisons). However, there was a significant increase in the oxygen saturation in venules draining the retinal periphery to reduce the oxygen extraction from (mean ± SEM) 36.0% ± 2.3% to 30.6% ± 2.1% (P = 0.002) but no significant change in the preexisting low oxygen extraction in the macular area that changed from (mean ± SEM) 18.2% ± 3.0% to 16.2% ± 1.9% (P = 0.37). CONCLUSIONS. Minor changes in the arterial blood pressure can induce changes in retinal rheology with significant regional variation. The finding may help explain regional variations in manifestations of retinal vascular disease such as hyperpermeability in the macular area and capillary occlusion in the retinal periphery.

Purpose: Central retinal vein occlusion (CRVO) entails retinal hypoxia that often causes visual impairment. It has been shown that oxygen saturation in larger retinal vessels correlates with the visual acuity at the time of diagnosis of CRVO but has no predictive value for the visual outcome in patients treated with anti-VEGF medication after 3 months. However, assessing the predictive value of retinal oxygen saturation after 12 months is essential because this is when the main restitution after CRVO occurs. Methods: Retinal oximetry was performed in 117 patients referred with CRVO to three European centres. The correlation between oxygen saturation and visual acuity at baseline and the predictive value of oxygen saturation in larger retinal vessels for the 12-month visual outcome after treatment with anti-VEGF medication were studied. Results: In the affected eye, the oxygen saturation was significantly higher in the arterioles, significantly lower in the venules, and the arterio-venous (A-V) significantly higher than in the unaffected eye (p

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.

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.

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 = 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.

Toke Bek, Sidsel Ehlers Klug Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark Purpose: Randomized clinical trials studying the effects of VEGF inhibition on wet age-related macular degeneration (wAMD) are designed so that the effects of individually varying risk factors on the treatment response are eliminated. The influence of these risk factors can be studied in large data sets from real-life experience.Patients and methods: All 2,255 patients diagnosed with wAMD requiring anti-VEGF treatment in at least one eye over more than 9 years in a defined Danish population with 0.9million inhabitants were studied. The predictive value of eye laterality, sex, current smoking status, type of anti-VEGF compound, membrane position, membrane type, leakage area, number of injections, number of visits, age, time to follow-up, visual acuity, and central retinal thickness (CRT) at baseline on change in CRT after three monthly injections with anti-VEGF compound followed by treatment pro re nata for up to 12 months was assessed.Results: After 12 months, 67 patients had died, 903 had had stable CRT for at least 6 months, and 1,285 patients had not achieved stable CRT. The reduction in CRT was -84.8±118.3 µm, whereas the increase in visual acuity was 2.2±14.7 Early Treatment Diabetic Retinopathy Study letters. The risk factors included contributed to 64% of the variation in CRT reduction. High age and high CRT at baseline predicted high CRT reduction, whereas more injections, treatment with ranibizumab, and male sex predicted a low CRT reduction.Conclusion: Age, sex, and type of anti-VEGF medication can be used to plan treatment and inform patients about the expected response of anti-VEGF treatment in wAMD. Keywords: wet AMD, anti-VEGF treatment, risk factors, real-life experience&nbsp

Aims/hypothesis\ud 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.\ud \ud Methods\ud 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.\ud \ud Results\ud 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.\ud \ud Conclusions/interpretation\ud 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.

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.

BackgroundThe 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.MethodsSeven 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.ResultsThe 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.ConclusionsProspective 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.

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.

Retinal oximetry imaging of retinal blood vessels measures oxygen saturation of hemoglobin. The imaging technology is non-invasive and reproducible with remarkably low variability on test-retest studies and in healthy cohorts. Pathophysiological principles and novel biomarkers in several retinal diseases have been discovered, as well as possible applications for systemic and brain disease. In diabetic retinopathy, retinal venous oxygen saturation is elevated and arteriovenous difference progressively reduced in advanced stages of retinopathy compared with healthy persons. This correlates with pathophysiology of diabetic retinopathy where hypoxia stimulates VEGF production. Laser treatment and vitrectomy both improve retinal oximetry values, which correlate with clinical outcome. The oximetry biomarker may allow automatic measurement of severity of diabetic retinopathy and predict its response to treatment. Central retinal vein occlusion is characterized by retinal hypoxia, which is evident in retinal oximetry. The retinal hypoxia seen on oximetry correlates with the extent of peripheral ischemia, visual acuity and thickness of macular edema. This biomarker may help diagnose and measure severity of vein occlusion and degree of retinal ischemia. Glaucomatous retinal atrophy is associated with reduced oxygen consumption resulting in reduced arteriovenous difference and higher retinal venous saturation. The oximetry findings correlate with worse visual field, thinner nerve fiber layer and smaller optic disc rim. This provides an objective biomarker for glaucomatous damage. In retinitis pigmentosa, an association exists between advanced atrophy, worse visual field and higher retinal venous oxygen saturation, lower arteriovenous difference. This biomarker may allow measurement of severity and progression of retinitis pigmentosa and other atrophic retinal diseases. Retinal oximetry offers visible light imaging of systemic and central nervous system vessels. It senses hypoxia in cardiac and pulmonary diseases. Oximetry biomarkers have been discovered in Alzheimer's disease and multiple sclerosis and oxygen levels in the retina correspond well with brain.

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.

White matter hyperintensities of presumed vascular origin are frequently observed on magnetic resonance imaging in normal aging. They are typically found in cerebral small vessel disease and suspected culprits in the etiology of complex age- and small vessel disease-related conditions, such as late-onset depression. White matter hyperintensities may interfere with surrounding white matter metabolic demands by disrupting fiber tract integrity. Meanwhile, risk factors for small vessel disease are thought to reduce tissue oxygenation, not only by reducing regional blood supply, but also by impairing capillary function. To address white matter oxygen supply–demand balance, we estimated voxel-wise capillary density as an index of resting white matter metabolism, and combined estimates of blood supply and capillary function to calculate white matter oxygen availability. We conducted a cross-sectional study with structural, perfusion- and diffusion-weighted magnetic resonance imaging in 21 patients with late-onset depression and 21 controls. We outlined white matter hyperintensities and used tractography to identify the tracts they intersect. Perfusion data comprised cerebral blood flow, blood volume, mean transit time and relative transit time heterogeneity—the latter a marker of capillary dysfunction. Based on these, white matter oxygenation was calculated as the steady state cerebral metabolic rate of oxygen under the assumption of normal tissue oxygen tension and vice versa. The number, volume and perfusion characteristics of white matter hyperintensities did not differ significantly between groups. Hemodynamic data showed white matter hyperintensities to have lower blood flow and blood volume, but higher relative transit time heterogeneity, than normal-appearing white matter, resulting in either reduced capillary metabolic rate of oxygen or oxygen tension. Intersected tracts showed significantly lower blood flow, blood volume and capillary metabolic rate of oxygen than normal-appearing white matter. Across groups, lower lesion oxygen tension was associated with higher lesion number and volume. Compared with normal-appearing white matter, tissue oxygenation is significantly reduced in white matter hyperintensities as well as the fiber tracts they intersect, independent of parallel late-onset depression. In white matter hyperintensities, reduced microvascular blood volume and concomitant capillary dysfunction indicate a severe oxygen supply–demand imbalance with hypoxic tissue injury. In intersected fiber tracts, parallel reductions in oxygenation and microvascular blood volume are consistent with adaptations to reduced metabolic demands. We speculate, that aging and vascular risk factors impair white matter hyperintensity perfusion and capillary function to create hypoxic tissue injury, which in turn affect the function and metabolic demands of the white matter tracts they disrupt., Magnetic resonance imaging-defined white matter hyperintensities may emerge in regions with poor oxygenation and disrupt the function of fibers they intersect. Dalby et al. report reduced microvascular density and blood supply in white matter hyperintensities and to a lesser extent in the affected tracts, possibly as an adaption to lower metabolic demands., Graphical Abstract Graphical Abstract

The clinical presentation of the most frequent vision threatening retinal diseases is dominated by lesions indicating that disturbances in retinal blood flow are involved in the pathogenesis of these diseases. The present review describes the experience from a translational strategy pursued to investigate retinal vascular diseases with diabetic retinopathy as the main object. The normal regulation of retinal blood flow is investigated in porcine retinal vessels in vitro and ex vivo. Subsequently, the in vitro findings are translated to clinical studies in normal persons in vivo, and it is investigated whether the mechanisms are disturbed in retinal vascular disease. This is followed by clinical intervention studies on these diseases. The approach has been used to investigate pressure autoregulation, metabolic autoregulation and vasomotion in retinal vessels. The investigations have shown that retinal vascular tone can be regulated by receptor-specific agonists and antagonists to vasoactive compounds such as purines, prostaglandins and nitric oxide synthesis and that the vasoactive effects can be modulated by the concentration and the mode of administration of these compounds. Additionally, it has been shown that retinal precapillary arterioles and capillaries not visible by ophthalmoscopy may play an important role for the pathophysiology of retinal vascular disease and its treatment. Future studies should focus on investigating normal and pathological regulation of retinal blood flow in these smaller vessels.

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.

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 (p0.44). 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.

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.

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.

Aim: Whether or not Roux-en-Y gastric bypass (RYGB) and the derived metabolic improvements are beneficial to diabetic retinopathy is controversial. We aimed to determine the presence and development of retinopathy in individuals with obesity and Type 2 diabetes treated by RYGB compared with non-operated controls, and to determine the role of diabetes remission. Methods: We graded fundus photography using the Wisconsin Epidemiologic Study of Diabetic Retinopathy in 96 individuals with obesity and Type 2 diabetes treated by RYGB 6 years after surgery compared with 48 non-operated controls. In a subsample, we investigated the development of retinopathy over time. In the secondary analysis, we divided the RYGB group according to diabetes remission. Results: RYGB surgery was not statistically associated with less retinopathy [relative risk (RR) 0.82, 95% CI 0.59 to 1.14], when adjusted for diabetes duration, sex, age and BMI. During 5.9 years of follow-up, retinopathy grading in the RYGB group was unchanged, whereas the control group displayed worse grading by 0.69 steps (95% CI 0.18 to 1.19). The RYGB group with diabetes remission (52%) showed a trend towards less retinopathy [adjusted RR (aRR) 0.45; 95% CI 0.19 to 1.06] than controls, and less retinopathy (aRR 0.33; 95% CI 0.11 to 0.94) than the RYGB group without remission in the cross-sectional data. Conclusions: In a cross-sectional setting, individuals with Type 2 diabetes treated by RYGB showed a tendency towards less retinopathy than non-operated controls, in particular diabetes remission following RYGB was associated with less retinopathy. Moreover after 5.9 years, retinopathy in the RYGB group had progressed less than in the control group. (Clinical Trial Registry No: NCT02625649).

Background: Coats’ disease is characterized by vascular hyperpermeability, oedema and accumulation of exudates related to impairment of retinal vascular function. The background for the development of the disease is unknown, but it is likely that the study of diameter changes of retinal vessels may contribute to understanding the pathophysiology of the disease. Methods: In seven patients with unilateral Coats’ disease (mean age = 34.7 years, range: 11–69 years), the baseline diameter and reactivity of retinal vessels during an increase in the arterial blood pressure by isometric exercise and in the metabolism by flicker stimulation were measured on video recordings of the retina obtained with the Dynamic Vessel Analyzer. Results: The baseline diameter of retinal vessels was larger in the affected than in the unaffected eyes which was significant for the arterioles (p = 0.02), but not for the venules (p = 0.15). During an increase in the arterial blood pressure induced by isometric exercise, the normal contraction of arterioles was absent in both eyes (p > 0.7), whereas there was a significant dilatation of the venules in the unaffected eyes (p = 0.04). Stimulation with flickering light induced normal dilatation of retinal vessels in both affected and unaffected eyes. Conclusion: Unilateral Coats’ disease is accompanied by vasodilatation in the affected eye but impaired pressure autoregulation in both eyes. A further investigation of the disease should include an elucidation of the background for dilatation of retinal vessels in affected eyes and whether impaired pressure autoregulation can be found in vessels elsewhere in the body.

Vascular endothelial growth factor A (VEGFA) is involved in the pathogenesis of vasoproliferative retinal diseases, such as exudative age-related macular degeneration (AMD). The objective of this study was to investigate whether dual-acting therapy based on the simultaneous expression of anti-VEGFA microRNAs (miRNAs) and the secreted, antiangiogenic protein pigment endothelial-derived factor (PEDF) delivered by adeno-associated virus (AAV) vectors provides improved protection against choroidal neovascularization (CNV). To investigate this, a multigenic AAV vector allowing retina pigment epithelium (RPE)-specific expression of anti-VEGFA miRNAs and PEDF was engineered. Robust expression of PEDF, driven by the RPE-specific vitelliform macular dystrophy 2 promoter, was observed in human cells and in mouse retina. A significant reduction in CNV was observed in a laser-induced CNV mouse model 57 days post-injection of the AAV5 particles conveying either anti-VEGFA miRNA and PEDF dual therapy or anti-VEGFA miRNA monotherapy. Overall, CNV reduction was most prominent in animals receiving dual-acting therapy. In both cases, the reduction in CNV was accompanied by a significant attenuation of VEGFA. In conclusion, the presented data reveal that gene therapy targeting VEGFA via multigenic AAV vectors displays combined efficacy, suggesting that dual-acting therapy is an important tool in future eye gene therapy for the treatment of neovascular ocular diseases, including AMD. Keywords: vascular endothelial growth factor A, age-related macular degeneration, adeno-associated virus, choroidal neovascularization, retina pigment epithelium, dual-acting therapy

PURPOSE: The epidemiology, risk factors, and the effect of anti-VEGF treatment on neovascular age-related macular degeneration (nAMD) have primarily been studied in the first eye developing the disease. The understanding of pathophysiology and planning of follow-up examinations can be improved by knowledge of incidence and risk factors for development of the disease in the fellow eye.METHODS: In a prospective observational cohort study, epidemiological and clinical risk factors for the development of nAMD in the fellow eye among 2516 patients consecutively diagnosed with the disease from a population of 0.9 million citizens during a period of more than 10 years were studied.RESULTS: nAMD had been diagnosed in the fellow eye of 541 (21.5%) of the patients. The incidence of fellow-eye involvement increased from approximately 5% in patients initially presenting with bilateral disease to approximately 28% more than 6 years after the diagnosis in the first eye. Visual acuity (VA) was higher and central retinal thickness (CRT) was lower in fellow eyes with nAMD diagnosed later than the first eye. Male gender, increasing leakage area, and peripapillary location of the subretinal neovascular membrane in the first eye reduced the risk of developing disease in the fellow eye.CONCLUSIONS: The planning of follow-up examinations of patients diagnosed with nAMD in one eye should consider that the risk of fellow-eye involvement is higher within the first 6 years, in women, and when the leakage area in the first eye is small and not located peripapillary.

Objectives Steroid treatment can accelerate visual recovery in patients with optic neuritis (ON), but it is unknown whether the timing of the start of treatment influences the outcome. The main purpose of this observational study was to assess the effect of early onset steroid treatment of ON on visual prognosis and retinal morphology. Methods Forty‐nine patients with acute mild/moderate (n = 21) or severe (n = 28) ON, and an equal number of healthy controls were enrolled. Patients with severe ON either received early onset steroid treatment (initiated within 1 week of presentation with visual loss) (n = 9), late‐onset treatment (initiated after 1 week) (n = 13), or no treatment (n = 6). Visual function and retinal morphology was studied after 6 and 12 months. Results All measures of visual function had improved after 6 months (p ≤ 0.03) in the three groups with severe ON. This was not the case for Rayleigh match setting range (SR) in the nontreated group (p = 0.24), or for SR (p = 0.08) and latency to P100 of visual evoked potential (p = 0.08) in the late‐onset treated group. After 12 months, further improvement occurred in the nontreated and late‐treated groups, but not in the early treated group. Macular retinal nerve fiber layer (mRNFL) and ganglion cell plus inner plexiform layer had decreased significantly (p ≤ 0.001) in all three groups with severe ON after 6 months. After 12 months, only mRNFL had further significantly decreased and only in the late‐onset treated group (p = 0.02). Conclusion The beneficial effects of early onset steroid treatment of ON is limited to a few months whereas the long‐term prognosis is independent of the timing of treatment.

Objectives Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) may be misdiagnosed as multiple sclerosis. The aim of this study was to (i) to measure AQP4-IgG in patients who fulfilled the clinical and radiological criteria of NMOSD in the Central Denmark Region and (ii) to estimate the incidence of NMOSD in the region, according to both the 2006 Wingerchuk criteria and the 2015 International Panel for NMO Diagnosis criteria. Materials and methods Medical records of all patients diagnosed with a demyelinating disorder in the region from 1 January 2012 to 31 December 2013 were reviewed. Patients were classified as having (i) "NMO" if the 2006 criteria were met, (ii) "NMOSD with AQP4-IgG" or (iii) "NMOSD without/unknown AQP-IgG" if the new 2015 NMOSD criteria were met. Patients with core symptoms were invited to provide a blood sample for AQP4-IgG analysis with an enzyme-linked immunosorbent assay and a cell-based indirect immunofluorescence assay. Results In 191 patients with core symptoms, one met the 2015 NMOSD with AQP4-IgG criteria. Two patients met the 2006 NMO and 2015 NMOSD without/unknown AQP4-IgG criteria. Among 108 patients providing a blood sample, all were seronegative. The estimated incidence of NMO (2006 criteria) and NMOSD (2015 criteria) was 0.08 and 0.12 per 100 000 person-years, respectively. Conclusion NMO/NMOSD is a rare disease in the Central Denmark Region, with a considerably lower incidence rate than previously estimated in a neighbouring region.

Purpose: Remote ischemic conditioning (RIC) implies that transient ischemia in a limb can affect perfusion in a target organ elsewhere in the body. The changes in perfusion can be assumed to be paralleled by changes in the vessel diameters in the target organ. It remains to be elucidated whether the diameter of normal retinal vessels can be used as a marker of RIC in vivo.Methods: In 20 normal persons aged 20 to 31 years the Dynamic Vessel Analyzer (DVA) was used to measure the resting diameter and diameter changes during isometric exercise and flicker stimulation before, immediately after, and 1 hour after RIC induced by transient ischemia in the left arm.Results: The baseline diameter of retinal venules was reduced nonsignificantly immediately after (P = 0.07) and significantly 1 hour after RIC (P = 0.009), whereas the baseline diameter of arterioles was unaffected by the intervention (P = 0.61). Arterial constriction induced by isometric exercise was significantly reduced immediately after RIC (P = 0.04), but not 1 hour after RIC (P = 0.99). None of the other diameter responses were affected by RIC (P = 0.22 for all comparisons).Conclusions: The diameter of retinal vessels might potentially be a marker of ischemic conditioning in the body in general. The effect of RIC on retinal vascular diseases where ischemia is a part of the pathogenesis should be investigated.

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.

SummaryPurpose To determine factors of importance for quantitating retinal blood flow in patients with diabetic retinopathy using bi-directional Doppler OCT. Methods Retinal blood flow was measured by bi-directional Doppler OCT in 20 diabetic patients with different diabetes type, age and retinopathy stage. Results It appeared that age above 40 years was a significant limiting factor for obtaining suitable signals to measure retinal blood flow, which was due to lens opacities and insufficient mydriasis. Quantitative measures of blood flow in the studied patients below the age of 40 years will be reported. Conclusion Bi-directional Doppler OCT offers a new principle for quantitating retinal blood flow, but the principle has not yet been fully developed to be suitable for routine clinical practise.

Purpose:Remote ischemic conditioning (RIC) implies that repeated episodes of ischemia in one organ can protect another remote organ from the adverse consequences of ischemia. It remains to be elucidated whether the diameter response in retinal vessels can be used as a marker of RIC in general and whether the response can be used to predict the effect of RIC on the visual prognosis in diseases characterized by retinal ischemia.Methods:In twenty normal persons aged 20–31 years the Dynamic Vessel Analyzer (DVA) was used to measure the resting diameter and diameter changes during isometric exercise and flicker stimulation before, immediately after, and one hour after RIC induced by transient ischemia in the left arm.Results:The baseline diameter of retinal venules was reduced non-significantly immediately after (p = 0.07) and significantly one hour after RIC (p < 0.009), whereas the baseline diameter of arterioles was unaffected by the intervention (p > 0.61). Arterial constriction induced by isometric exercise was significantly reduced immediately after RIC (p < 0.04), but not one hour after RIC (p > 0.99). None of the other diameter responsese were affected by RIC (p > 0.22 for all comparisons).Conclusions:The diameter of large retinal vessels is affected one hour after controlled transient ischemia in the left arm. This indicates that the diameter response of retinal vessels could be a potential marker of ischemic conditioning in the body in general. The potential of remote ischemic conditioning as an intervention on vision threatening retinal diseases where ischemia is a part of the pathogenesis should be investigated.

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.

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.

Purpose: Biomarkers for several eye and brain diseases are reviewed, where retinal oximetry may help confirm diagnosis or measure severity of disease. These include diabetic retinopathy, central retinal vein occlusion (CRVO), retinitis pigmentosa, glaucoma, and Alzheimer's disease.Methods: Retinal oximetry is based on spectrophotometric fundus imaging and measures oxygen saturation in retinal arterioles and venules in a noninvasive, quick, safe manner. Retinal oximetry detects changes in oxygen metabolism, including those that result from ischemia or atrophy.Results: In diabetic retinopathy, venous oxygen saturation increases and arteriovenous difference decreases. Both correlate with diabetic retinopathy severity as conventionally classified on fundus photographs. In CRVO, vein occlusion causes hypoxia, which is measured directly by retinal oximetry to confirm the diagnosis and measure severity. In both diseases, the change in oxygen levels is a consequence of disturbed blood flow with resulting tissue hypoxia and vascular endothelial growth factor (VEGF) production. In atrophic diseases, such as retinitis pigmentosa and glaucoma, retinal oxygen consumption is reduced and this is detected by retinal oximetry. Retinal oximetry correlates with visual field damage and retinal atrophy. It is an objective metabolic measure of the degree of retinal atrophy. Finally, the retina is part of the central nervous system tissue and reflects central nervous system diseases. In Alzheimer's disease, a change in retinal oxygen metabolism has been discovered.Conclusions: Retinal oximetry is a novel, noninvasive technology that opens the field of metabolic imaging of the retina. Biomarkers in metabolic, ischemic, and atrophic diseases of the retina and central nervous system have been discovered.

PURPOSE: Fixational eye movements are necessary for maintaining normal vision by preventing a stabilized image on the retina that would result in visual fading. The movements can be divided into tremor, drifts and saccades that may be related to movements of gaze and to fixation. It has previously been shown that the frequency of fixational saccades with an amplitude larger than 3° depends on age. The purpose of this study was to investigate whether other parameters describing fixational saccades also depend on age which necessitates age correction in studies of fixation during visual development.METHODS: Fixational eye movements were recorded in 36 normal children aged 5-16 years. Parameters describing fixational saccades were characterized using a standardized algorithm and were correlated with age.RESULTS: There was a significant linear relation between the amplitude and duration of fixational saccades (r(2) = 0.37, p < 0.0001). The relation between the number of saccadic movements and the amplitude was unimodal and showed no correlation with age. However, the number of saccades per examination with an amplitude larger than 1° showed a negative correlation with age (r(2) = 0.23, p = 0.003).CONCLUSIONS: The overall frequency and amplitude of fixational saccades show no correlation with age that necessitates correction in clinical studies of visual development. The decreasing frequency of large saccadic eye movements with increasing child age may be due to improved attention.

PURPOSE: To estimate the risk of developing rhegmatogenous retinal detachment (RRD) in the fellow eye in patients with RRD in the first eye and to identify potential risk factors.METHODS: We used the Danish National Patient Registry to identify all surgeries performed for RRD in Denmark in the period from January 2000 to July 2011.RESULTS: In 11,451 cases of RRD in the study period, 8,553 cases in 8,081 patients were identified as primary RRD with an annual incidence of 13.7 per 100,000 citizens. There was a significant increase in the number of cases with RRD during the study period that was mainly explained by an increase of cataract surgeries. Four hundred and seventy-one of 7,941 patients with primary RRD on one eye and no other previous eye disease developed an additional RRD in the fellow eye with an overall incidence of 1% per year. Cox analysis revealed male gender, surgery on the lens, and young age as significant risk factors (P < 0.0001).CONCLUSION: Patients with RRD on the first eye have a 100 times greater risk of developing RRD on the second eye, and the risk increases with male gender and surgery on the lens but decreases with age.

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.

Prostaglandin analogues and adrenergic drugs are used to reduce the intraocular pressure in glaucoma, which may partly be due to an effect on the tone of the intraocular arteries supplying the ciliary body. The aim of the present study was to investigate the interaction between prostaglandins and autonomic nervous activity induced by electrical stimulation of the tone in these ciliary vessels. The intraocular part of porcine ciliary arteries were isolated and mounted in a microvascular myograph for isometric tension recordings, and the effect of prostaglandin E 2 on electrically induced contractions was studied in the presence of selective EP receptor antagonists. PGE 2 induced concentration-dependent inhibition of electrically induced contractions of intraocular ciliary arteries which depended on the presence of the vascular endothelium. The effect of PGE 2 was blocked by an EP 4 receptor antagonist but not by an EP 1 receptor antagonist. The neurogenic contractions were partially inhibited by an α 2 -adrenoceptor antagonist and totally inhibited by a NPY 1 receptor antagonist. The effect of these antagonists was similar when contraction was induced by noradrenaline and NPY. Neurogenic contractions in intraocular porcine arteries are mediated by α 2 -adrenoceptors and NPY 1 receptors and can be inhibited by PGE 2 acting on prejunctional EP 4 receptors. This contributes to a further understanding of the role of the autonomic nervous system and prostaglandins for regulating blood flow to the anterior segment of the eye.

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.