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Purpose: The retinal vasculature is the only part of the microcirculation that can be directly studied by non-invasive imaging. Based on the hypothesis that the systemic circulation is reflected in retinal vessels, we investigated if coronary artery bypass grafting (CABG) is related to changes in retinal vascular oxygen saturation (rSatO2). Methods: Retinal metabolism was evaluated by Oxymap T1, which simultaneously captures two retinal images at different wavelengths measuring the retinal arteriolar (raSatO2) and venular (rvSatO2) oxygen saturation. Three to 4 days after surgery, we measured the median rSatO2 after CABG in 38 patients and in 39 healthy controls (operated for cataract). Results: Coronary artery bypass grafting patients had higher raSatO2 (median ± standard deviation 93.1 ± 6.7% versus 90.5 ± 11.2%, p = 0.001) and rvSatO2 (57.4 ± 8.3% versus 53.5 ± 15.4%, p = 0.048) compared to healthy controls. In multivariable linear regression models, raSatO2 independently associated with CABG (coefficient + 3.6% in CABG patients, p = 0.007), and rvSatO2 correlated with gender (coefficient + 9.4% for females, p = 0.001) and CABG (coefficient + 8.2% in patients with CABG, p = 0.001). Conclusions: Comparing patients with and without cardiovascular disease, raSatO2 and rvSatO2 positively and independently associated with CABG, suggesting their potential as non-invasive markers for coronary large artery disease.

Cognitive impairment; Diabetes mellitus; Diabetic retinopathy Discapacidad cognitiva; Diabetes mellitus; Retinopatía diabética Discapacitat cognitiva; Diabetis mellitus; Retinopatia diabètica 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. This work was supported by VELUX FONDEN (grant number 00028744) and Odense University Hospital PhD Foundation (grant number 4339).

PurposeAngiostatic agents have proven effective in the treatment of macular oedema in patients with branch retinal vein occlusion (BRVO). However, treatment is inconvenient and expensive, and novel treatment regimens are warranted. We aimed to evaluate if combination treatment of navigated central retinal laser and aflibercept lowered the treatment burden in these patients.MethodsTreatment-naïve patients with BRVO and macular oedema were included at two centres and randomized 1:1 to three monthly injections of 2.0 mg aflibercept with (Group A) or without (Group B) navigated central laser, followed by aflibercept as needed from month 4 through 12. Re-treatment need was evaluated, and secondary endpoints included functional and anatomical outcomes and safety evaluated by retinal microperimetry.ResultsWe evaluated 41 eyes of 41 patients with a mean age of 69.6 years. Baseline median best-corrected visual acuity (BCVA) was 70.0 letters, and median central retinal thickness (CRT) was 502 μm with no difference between Groups A (n = 21) and B (n = 20). Percentage of patients needing re-treatment after month three was 71% and 80% (p = 0.72). At month 12, groups did not differ in number of injections after loading (1 versus 2, p = 0.43), change in BCVA (+12.8 versus +15.1 letters, p = 0.48), CRT (−195 versus −181 μm, p = 0.82), or retinal sensitivity (+3.3 versus +4.1 dB, p = 0.67).ConclusionIn treatment-naïve BRVO patients, addition of navigated central laser to aflibercept did not lower treatment burden or affect functional or anatomical outcomes. A low number of intravitreal injections were needed for successful outcome in both treatment arms.

Diabetic retinopathy (DR) is the most common microvascular complication in diabetes and may cause severe visual impairment. Until late stages of DR, treatment options are limited. The aim of the present review was to investigate whether changes of DR might be influenced by topical treatment with eye drops. This systematic review included both randomized and non-randomized human clinical studies on the subject. A systematic search of PubMed Medline, Embase and Scopus databases yielded 710 studies. No inclusion criteria regarding classification of DR were defined. Reference lists as well as first authors were screened for the inclusion of additional studies. Potential bias of the randomized studies was assessed using the Cochrane Risk of Bias tool. Nineteen studies suitable for inclusion were identified. Seven studies were randomized trials. These examined 11 different pharmacological groups of drugs in DR. A favourable effect of corticosteroid eye drops in diabetic macular oedema (DMO) was reported in four studies, and another study reported a positive trend. Eye drops with non-steroidal anti-inflammatory drugs were also reported to have a favourable effect in DMO, but not in non-center involving DMO. Application of neuroprotective agents was found effective in patients with pre-existing neurodegeneration in three studies. The remaining studies of DMO and DR were heterogeneous in both designs and results. Studies on treatment of DR with topical eye drops vary with regards to patient population, interventional drugs, study design, and outcome measures. Treatment of DR with eye drops was found effective in the aforementioned cases, but there is still a need for further investigations of long-term, randomized controlled trials in any of the reported pharmacological group.

The incidence of diabetes continues to increase across the world. As the number of patients rises, so does the need for educated health care professionals. Diabetic retinopathy (DR) remains one of the primary complications in diabetes, and screening has proved to be a cost-effective measure to avoid DR-related blindness. Denmark has an established screening programme, but no formal training of the people responsible for analysing retinal images.We here present an online learning platform that offers a diabetic eye screening course for health care professionals undertaking screening responsibility in the Region of Southern Denmark. The course is divided into lectures, each focussed on identifying different levels of DR or detecting related lesions. The course is free to use on-demand, contains instructional videos, interactive tests and exercises, and it is concluded with a certification test. The tools on the platform can in addition be used to generate data for research purposes, such as comparing users or experts in detection of lesions or annotating data for the development of machine learning models.More than 150 participants have so far completed the course, and the platform is being adopted for education in other regions of Denmark.

BACKGROUND: Osteogenesis imperfecta (OI) is a hereditary disease caused by affected collagen type 1. Collagen type 1 is an important structural component of the eye. Ocular manifestations in OI are described in literature, but little is known about the risk of eye diseases in OI.OBJECTIVE: To investigate the risk of eye diseases in OI.DESIGN: A Danish nationwide register-based cohort study based on data from the Danish National Patient Register.PARTICIPANTS: All patients registered with an OI diagnosis between January 1977 and December 2018 matched 1:5 with a reference population on gender and birth month and birth year.MEASUREMENTS: Incidence rates (IR) per 1000 patient years and sub-hazard ratio (SHR) for any eye disease, corneal diseases, cataract, refraction disorders, vitreous haemorrhage, retinal detachment, retinopathy, angiopathy, retinal haemorrhage, retinal degeneration, retinal changes, optic nerve disorders, and traumatic eye lesions.RESULTS: We identified 907 OI patients (493 women) and 4535 persons (2465 women) in the reference population. The IR for any eye disease was 4.07 [95% CI 3.41-4.85] in the OI cohort and 1.96 [95% CI 1.89-2.12] in the reference cohort. The two diseases with highest incidence was cataract (2.41 [95%CI 1.93-3.03] vs 1.29 [95% CI 1.12-1.47], SHR 1.76 [95% CI 1.34-2.33]) and glaucoma (1.08 [95% CI 0.77-1.51] vs 0.42 [95% CI 0.33-0.54], SHR 2.33 [95% CI 1.55-3.53]). The absolute risk of most other eye diseases was low, but the SHR indicated a higher risk in the OI cohort compared to the reference group showing statistically increased risk of refractive disorders, vitreous haemorrhage, retinal detachment or ruptures, other retinal diseases (i.e., retinopathy, angiopathy, retinal haemorrhage, degeneration, retinal changes), and optic nerve disorders. Corneal diseases and traumatic eye lesions were not statistically significantly increased in OI-patients.CONCLUSION: Patients with OI have a higher risk of cataract, refractive disorders, glaucoma, vitreous haemorrhages, retinal detachment/ruptures, retinal diseases, and optic nerve disorders.

Purpose: We aimed to develop and test a deep-learning system to perform image quality and diabetic macular ischemia (DMI) assessment on optical coherence tomography angiography (OCTA) images. Methods: This study included 7,194 OCTA images with diabetes mellitus for training and primary validation and 960 images from three independent data sets for external testing. A trinary classification for image quality assessment and the presence or absence of DMI for DMI assessment were labeled on all OCTA images. Two DenseNet-161 models were built for both tasks for OCTA images of superficial and deep capillary plexuses, respectively. External testing was performed on three unseen data sets in which one data set using the same model of OCTA device as of the primary data set and two data sets using another brand of OCTA device. We assessed the performance by using the area under the receiver operating characteristic curves with sensitivities, specificities, and accuracies and the area under the precision-recall curves with precision. Results: For the image quality assessment, analyses for gradability and measurability assessment were performed. Our deep-learning system achieved the area under the receiver operating characteristic curves .0.948 and area under the precision-recall curves .0.866 for the gradability assessment, area under the receiver operating characteristic curves .0.960 and area under the precision-recall curves .0.822 for the measurability assessment, and area under the receiver operating characteristic curves .0.939 and area under the precision-recall curves .0.899 for the DMI assessment across three external validation data sets. Grad-CAM demonstrated the capability of our deep-learning system paying attention to regions related to DMI identification. Conclusion: Our proposed multitask deep-learning system might facilitate the development of a simplified assessment of DMI on OCTA images among individuals with diabetes mellitus at high risk for visual loss.

Dry eye disease (DED) has a prevalence of between 5 and 50%, depending on the diagnostic criteria used and population under study. However, it remains one of the most underdiagnosed and undertreated conditions in ophthalmology. Many tests used in the diagnosis of DED rely on an experienced observer for image interpretation, which may be considered subjective and result in variation in diagnosis. Since artificial intelligence (AI) systems are capable of advanced problem solving, use of such techniques could lead to more objective diagnosis. Although the term 'AI' is commonly used, recent success in its applications to medicine is mainly due to advancements in the sub-field of machine learning, which has been used to automatically classify images and predict medical outcomes. Powerful machine learning techniques have been harnessed to understand nuances in patient data and medical images, aiming for consistent diagnosis and stratification of disease severity. This is the first literature review on the use of AI in DED. We provide a brief introduction to AI, report its current use in DED research and its potential for application in the clinic. Our review found that AI has been employed in a wide range of DED clinical tests and research applications, primarily for interpretation of interferometry, slit-lamp and meibography images. While initial results are promising, much work is still needed on model development, clinical testing and standardisation.

Dry eye disease (DED) has a prevalence of between 5 and 50%, depending on the diagnostic criteria used and population under study. However, it remains one of the most underdiagnosed and undertreated conditions in ophthalmology. Many tests used in the diagnosis of DED rely on an experienced observer for image interpretation, which may be considered subjective and result in variation in diagnosis. Since artificial intelligence (AI) systems are capable of advanced problem solving, use of such techniques could lead to more objective diagnosis. Although the term ‘AI’ is commonly used, recent success in its applications to medicine is mainly due to advancements in the sub-field of machine learning, which has been used to automatically classify images and predict medical outcomes. Powerful machine learning techniques have been harnessed to understand nuances in patient data and medical images, aiming for consistent diagnosis and stratification of disease severity. This is the first literature review on the use of AI in DED. We provide a brief introduction to AI, report its current use in DED research and its potential for application in the clinic. Our review found that AI has been employed in a wide range of DED clinical tests and research applications, primarily for interpretation of interferometry, slit-lamp and meibography images. While initial results are promising, much work is still needed on model development, clinical testing and standardisation.

Purpose: To investigate whether pretraining of basic skills in virtual vitreoretinal surgery affected the performance curve when proceeding to procedure-specific modules. Methods: This study was a prospective, randomized, controlled, two-centre study. Medical students were randomized into two groups: Group 1 pretrained basic psycho-motor skills (Navigation Training level 2 and Bimanual Training level 3) until they reached their performance curve plateau. Hereafter, both groups trained on the procedure-specific modules (Posterior Hyaloid level 3 and ILM Peeling level 3) until they reached their performance curve plateau. Plateau was defined as three consecutive sessions with the same score with an acceptable variation. The primary outcome was time used to reach performance curve plateau in the procedure-specific modules. Results: A total of 68 medical students were included, and equally randomized into two groups. The participants in Group 1 used a median time of 88 minutes to reach plateau in the basic skills modules but did not differ from Group 2 in time to reach plateau on the procedure-specific modules (183 min versus 210 min, p = 0.40) or in the amplitude of plateau. Group 1 and 2 differed significantly in the starting score of ILM peeling level 3 (0 (0-0) versus 3.5 (0-75), p = 0.03). Conclusion: We were not able to show positive skill transfer from basic skills training to the procedure-specific modules in time, starting score or amplitude of plateau. Thus, we recommend that aspiring vitreoretinal surgeons proceed directly to simulation-based training of procedures instead of spending valuable training time on basic skills training.

Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, and an association between diabetic retinopathy and Parkinson’s disease has been proposed. In this nationwide register-based cohort study, we investigated the prevalence and incidence of Parkinson’s disease among patients screened for diabetic retinopathy in a Danish population-based cohort. Cases (n = 173 568) above 50 years of age with diabetes included in the Danish Registry of Diabetic Retinopathy between 2013 and 2018 were matched 1:5 by gender and birth year with a control population without diabetes (n = 843 781). At index date, the prevalence of Parkinson’s disease was compared between cases and controls. To assess the longitudinal relationship between diabetic retinopathy and Parkinson’s disease, a multivariable Cox proportional hazard model was estimated. The prevalence of Parkinson’s disease was 0.28% and 0.44% among cases and controls, respectively. While diabetic retinopathy was not associated with present (adjusted odds ratio 0.93, 95% confidence interval 0.72–1.21) or incident Parkinson’s disease (adjusted hazard ratio 0.77, 95% confidence interval 0.56–1.05), cases with diabetes were in general less likely to have or to develop Parkinson’s disease compared to controls without diabetes (adjusted odds ratio 0.79, 95% confidence interval 0.71–0.87 and adjusted hazard ratio 0.88, 95% confidence interval 0.78–1.00). In a national cohort of more than 1 million persons, patients with diabetes were 21% and 12% were less likely to have prevalent and develop incident Parkinson’s disease, respectively, compared to an age- and gender-matched control population without diabetes. We found no indication for diabetic retinopathy as an independent risk factor for incident Parkinson’s disease., In this register-based cohort study investigating the association between diabetic retinopathy and Parkinson’s disease, Larsen et al. report that diabetic retinopathy does not increase the risk of having or developing Parkinson’s disease; on the contrary, diabetes per se seems to have a protective effect., Graphical Abstract Graphical Abstract

PURPOSE: Genetic and epidemiologic studies have shown that lipid genes and High Density Lipoproteins (HDL) are implicated in age-related macular degeneration (AMD). We studied circulating lipid levels in relation to AMD in a large European dataset, and investigated whether this relationship is driven by certain sub fractions. DESIGN: (Pooled) analysis of cross-sectional data. PARTICIPANTS: 30,953 individuals aged 50+ participating in the E3 consortium; and 1530 individuals from the Rotterdam Study with lipid sub fraction data. METHODS: In E3, AMD features were graded per eye on fundus photographs using the Rotterdam Classification. Routine blood lipid measurements were available from each participant. Data on genetics, medication and confounders such as body mass index, were obtained from a common database. In a subgroup of the Rotterdam Study, lipid sub fractions were identified by the Nightingale biomarker platform. Random-intercepts mixed-effects models incorporating confounders and study site as a random-effect were used to estimate the associations. MAIN OUTCOME MEASURES: early, late or any AMD, phenotypic features of early AMD, lipid measurements. RESULTS: HDL was associated with an increased risk of AMD, corrected for potential confounders (Odds Ratio (OR) 1.21 per 1mmol/L increase (95% confidence interval[CI] 1.14-1.29); while triglycerides were associated with a decreased risk (OR 0.94 per 1mmol/L increase [95%CI 0.91-0.97]). Both were associated with drusen size, higher HDL raises the odds of larger drusen while higher triglycerides decreases the odds. LDL-cholesterol only reached statistical significance in the association with early AMD (p=0.045). Regarding lipid sub fractions: the concentration of extra-large HDL particles showed the most prominent association with AMD (OR 1.24 [95%CI 1.10-1.40]). The CETP risk variant (rs17231506) for AMD was in line with increased-HDL levels (p=7.7x10-7); but LIPC risk variants (rs2043085, rs2070895) were associated in an opposite way (p=1.0x10-6 and 1.6x10-4). CONCLUSIONS: Our study suggests that HDL-cholesterol is associated with increased risk of AMD and triglycerides negatively associated. Both show the strongest association with early AMD and drusen. Extra-large HDL sub fractions seem to be drivers in the relation with AMD, variants in lipid genes play a more ambiguous role in this association. Whether systemic lipids directly influence AMD or represent lipid metabolism in the retina remains a question to be answered.

PURPOSE: To detect pre- and postoperative retinal changes in fundus autofluorescence (AF) and spectral domain optical coherence tomography (SD-OCT) and to correlate these with functional outcome in patients with primary rhegmatogenous retinal detachment (RRD).METHODS: A prospective, 30-month study of patients operated with 25-gauge vitrectomy for primary RRD. Patients were examined preoperatively and after 6 and 30 months, using ultrawide-field AF images (UWFI) (Optos 200Tx) and SD-OCT (Topcon 3D OCT-2000) imaging.RESULTS: Of 84 patients (84 eyes) included at baseline, 100.0 and 86.9% were re-examined at month 6 and 30, respectively. Preoperative findings such as macular attachment, detachment > 750 μm from foveola, lack of intraretinal separation, and subfoveal elevation ≤ 500 μm were all associated with better BCVA at months 6 and 30. Postoperative disruption of the photoreceptor layer was associated with poor BCVA at month 6 (p CONCLUSION: Fundus AF and SD-OCT is able to identify retinal reestablishment up to 30 months after primary RRD, with good correlation to BCVA. These findings emphasize the importance of long-term studies for final visual recovery.

Background/aimsAssociations between retinal vein occlusion (RVO) and subsequent cardiovascular disease (CVD) or mortality have not been evaluated in a recent cohort, after novel therapeutic options have increased referrals for treatment of the condition. We aimed to evaluate overall and subtype-stratified risk of CVD and all-cause mortality following RVO and assess any alterations after the introduction of angiostatic therapy in Denmark in 2011.MethodsThis nationwide, registry-based cohort study from 1998 to 2018 evaluated 4 194 781 individuals. Hazard ratios (HRs) were reported for RVO as an overall measure and subclassified as branch and central RVO.ResultsPatients with RVO (n=15 665) were median 71.8 years old at the time of exposure and 50.7% were women. RVO associated with incident CVD (adjusted HR 1.13, 95% CI 1.09 to 1.17) but not mortality (adjusted HR 1.00, 95% CI 0.97 to 1.03). Almost similar risks of CVD were found for patients with branch and central RVO (adjusted HRs 1.14, 95% CI 1.03 to 1.25, and 1.12, 95% CI 1.00 to 1.25, respectively), but only patients with central RVO exhibited increased mortality (adjusted HR 1.12, 95% CI 1.04 to 1.21). Risk of CVD, especially non-ischaemic, was higher for patients diagnosed after 2011 (adjusted HRs 1.24, 95% CI 1.15 to 1.33 vs 1.06, 95% CI 1.01 to 1.12).ConclusionIn a cohort of the Danish population aged 40 years or more, patients with RVO had a 13% increased risk of incident CVD compared with unexposed individuals. Risk of CVD was increased after 2011, when intravitreal angiostatic treatment was introduced and referral practices altered.

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.

ObjectiveWe examined the hypothesis that baseline retinal vascular geometry in patients with proliferative diabetic retinopathy (PDR) predicts disease activity 6 months after panretinal photocoagulation (PRP).Methods and analysisWe included 47 eyes from 40 patients with treatment-naïve PDR in a 6-month prospective study. Diagnosis of PDR and disease activity was evaluated by wide-field fluorescein angiography (Optomap, Optos, Dunfermline, Scotland, UK). At baseline and 6-month follow-up, the retinal vessel geometry was measured on optic disc centred images using semiautomated software Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE, Dundee, Scotland).ResultsAt baseline, mean age and duration of diabetes was 51.6 and 21.4 years, and 62.5% were men. Seventeen eyes (36.2%) had progression of PDR during follow-up. At baseline, we found higher retinal arteriolar calibre (31.3±0.8 vs 28.8±0.8 pixels, p=0.02) and venous fractal dimension (FD) (1.257±0.011 vs 1.222±0.011, p=0.02) in eyes with progression of PDR as compared with eyes with non-progression. In a multiple logistic regression model, both higher retinal arteriolar calibre (OR 1.34, 95% CI, 1.09 to 1.64, pD (OR 1.15, 95% CI, 1.04 to 1.27, pConclusionOur prospective study showed that arteriolar calibre and venular FD at baseline were predictive of disease activity 6 months after PRP treatment in patients with treatment-naïve PDR.

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.

Purpose: Metabolic and structural microvascular retinal alterations are essential components in diabetic retinopathy (DR). The present study aimed to measure changes at different stages of non-proliferative DR (NPDR) and to explore interactions of imaging-based metrics. Methods: This cross-sectional, cohort study included 139 eyes from 80 diabetic patients. Each patient underwent dilated fundal examinations including colour fundus photography, retinal oximetry and optical coherence tomography angiography (OCTA), analysed by semi-automated and automated software. Diabetic retinopathy (DR) severity was classified according to the International Clinical Diabetic Retinopathy (ICDR) Severity Scale, ranging from no DR to severe NPDR (level 0–3). Retinal metabolism was evaluated by oximetry as retinal arteriolar (raSatO2) and venular oxygen saturation (rvSatO2), and macular microvascular structure was measured by OCTA as the area of foveal avascular zone (FAZ), vessel density (VD), vessel diameter index (VDI), FAZ circularity and fractal dimension (FD) in the superficial and deep retinal capillary plexus. Results: A trend for increasing rvSatO2 was found with increasing DR severity (51.3%, 53.3%, 54.2%, 59.8%, p = 0.02). Increasing severity of DR associated with decreasing FD in the superficial and deep plexus (p 2, rvSatO2 and VDI, but only in the deep capillary plexus (p

Asteroid hyalosis is a benign degenerative condition of the vitreous that is often asymptomatic. Our purpose with this narrative review is to provide a current overview of asteroid hyalosis from a clinical perspective. We review the epidemiology and risk factors, the clinical diagnosis and differential diagnoses, clinical challenges in eyes with asteroid hyalosis, and the treatment of asteroid hyalosis. Many clinical questions remain unanswered, and the current evidence to guide clinical practice is largely based on anecdotal evidence and clinical experience. More studies on asteroid hyalosis from a clinical perspective are warranted.

Topic: To examine the potential role of systemic neurodegeneration, this study aimed to provide an overview of the available evidence on the relationship between diabetic retinopathy (DR) and systemic neurodegeneration. Clinical Relevance: The association between DR and systemic neurodegeneration is inconsistent in the literature. A summary estimate on the measures of association is important to establish whether DR may be used as a risk marker of systemic neurodegeneration. Methods: We searched the literature databases PubMed/MEDLINE, EMBASE, and Cochrane Library on October 3, 2020, for all observational studies on humans evaluating the association between DR and systemic neurodegenerative diseases. Two authors conducted the literature search, study selection, and data extraction in an independent fashion. Studies were reviewed qualitatively in text and quantitatively in meta-analyses. Heterogeneity was evaluated with Cochran's Q and I2, and Funnel plot was used to investigate for skewed results and possible publication bias. Results: We identified 27 eligible studies with a total of 1 398 041 patients with diabetes. Diagnosis of DR was made using fundus photography or examination (n = 20), health registries (n = 4), was self-reported (n = 1), or was not disclosed in the remaining studies. Neurodegenerative conditions studied were cognitive impairment (n = 23), Alzheimer's disease (n = 3), and Parkinson's disease (n = 1). In cross-sectional and longitudinal studies, respectively, presence of any DR was associated with present (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.02–2.43, P = 0.043) and incident (OR, 2.36; 95% CI, 1.50–3.71, P = 0.00021) systemic neurodegeneration, but severity of DR was not associated with differences in systemic neurodegeneration (OR, 0.98; 95% CI, 0.45–2.15, P = 0.96). Conclusions: In this systematic review, DR appears to be a marker of systemic neurodegeneration. Further studies are warranted to better elucidate the clinical practical implications of this relationship.

The aim of this systematic review was to compare certain side-effects [visual fields (VF), dark adaptation, colour vision (CV) and contrast sensitivity (CS)] of conventional panretinal photocoagulation (PRP) with those of other treatments in proliferative diabetic retinopathy (PDR). A systematic literature search was conducted on 30 November 2018 in PubMed and Embase. The search comprised the keywords ‘proliferative diabetic retinopathy’, ‘laser’, ‘treatment’ and ‘anti-vegf’. We included prospective studies and randomized controlled trials that investigated certain side-effects (VF, dark adaptation, CV, CS) in treatment of PDR (primary outcome). In total, 1867 articles were screened, and 10 studies were included (2176 eyes of 2086 patients examined in the VF studies and 1360 eyes of 1360 patients examined in the CV and CS studies). Visual fields (VF) were investigated in 10 studies, CV in one study and CS in one study. Treatment modalities included conventional PRP, other modalities of laser treatment and vascular endothelial growth factor (VEGF) inhibitors. Four studies demonstrated a worse VF impact of PRP than VEGF inhibitors. Seven studies reported of an overall worsening in VF after laser with no differences between different laser approaches. No differences were found in CV or CS. Overall, we found a trend, confirmed in four large studies, towards VEGF inhibitors causing less harm to VF compared to conventional PRP. Whilst VF was generally depressed after laser, it did not differ between different treatment approaches. Furthermore, it was not possible to make certain conclusions of CV or CS, with only one study in each field.

BACKGROUND: Screening for diabetic retinopathy (DR) is recommended to detect sight-threatening complications prior to visual loss. Early Treatment Diabetic Retinopathy Study (ETDRS) seven standard field (7SF) retinal imaging has traditionally been regarded the gold standard for DR classification, but other methods are often preferred clinically. The purpose of this systematic review was to determine whether 7SF is the most optimal screening method for DR grading, or if similar results can be achieved by other methods using a smaller field of view (METHODS: Based on Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two independent reviewers initially identified 7167 publications in PubMed, Cochrane and Embase databases. Of these, 16 publications were included based on predefined inclusion criteria.RESULTS: 7SF was used as reference standard in 12 studies (compared with < 7SF in five studies and UWF in seven studies), and four studies compared other reference standards. Compared to 7SF, studies using < 7SF and UWF images both reported of similar agreement. A lower rate of ungradable images was reported for mydriatic and non-mydriatic UWF as compared to non-mydriatic < 7SF modalities.CONCLUSION: Retinal imaging of

Background The purpose of this study was to evaluate the area of retinal neovascularization in patients with treatment-naïve proliferative diabetic retinopathy (PDR) as measured by optical coherence tomography angiography (OCT-A) as a marker of subsequent treatment response after panretinal photocoagulation (PRP), and to examine if this area correlated with area of retinal neovascularization as measured by fluorescein angiography (FA). Methods En face OCT-A scans (4.5 × 4.5 mm) of neovascularizations were obtained at baseline (BL) before PRP and at month (M) 3 and M6 after treatment. Progression of PDR were defined as lesion growth (assessed by ophthalmoscopy and wide-field fundus photo) or increasing leakage by Optos ultra-widefield FA, and patients were divided into two groups; progression or non-progression. Mann–Whitney U test and Wilcoxon signed-rank test were used to analyse differences between groups and between time points. Areas of retinal neovascularizations (OCT-A and FA) were calculated by algorithms developed in Python (version 3.6.8, The Python Software Foundation, USA). Results Of 21 eyes included, 14 had progression of disease. Median OCT-A area did not differ between the two groups (progression vs. non-progression) at BL (76.40 ± 162.03 vs. 72.62 ± 94.15, p = 0.43) but were statistically significantly larger in the progression group at M6 (276.69 ± 168.78 vs. 61.30 ± 70.90, p = 0.025). Median FA area did not differ in the progression vs. the non-progression group at BL (111.42 ± 143.08 vs. 60.80 ± 54.83, p = 0.05) or at M6 (200.12 ± 91.81 vs. 123.86 ± 162.16, p = 0.62). Intraclass correlation between area by OCT-A and FA was −5.99 (95% CI: −35.28–0.993), p = 0.71. Conclusions In this study of patients with treatment-naïve PDR, we showed that increasing area of retinal neovascularizations measured by OCT-A at M6 indicated progression of disease after PRP treatment. Our results suggest that area by OCT-A reflects disease activity and that it can be used as an indicator to monitor the progression of PDR over time, and to evaluate treatment response six months after PRP. Trial registrationhttps://clinicaltrials.gov (identifier: NCT03113006). Registered April 13, 2017.

In a variety of corneal and retinal diseases, ocular ischaemia mediates vascular endothelial growth factor (VEGF) expression, which in turn causes angiogenesis and increased vascular permeability. Consequently, VEGF-inhibitory treatment has been introduced in different ocular diseases. Hypoxia-inducible factor (HIF)-1α is an upstream regulator of VEGF-A, and increased HIF-1α expression has been established in ocular animal models. Upcoming translational studies are expected to increase our understanding of the complex balance between pro- and anti-angiogenic factors in the eye.

Objective To evaluate retinal oxygen metabolism by retinal oximetry for ocular and CNS diseases in a cross-sectional study of sarcoidosis. Methods Overall 201 eyes from 103 biopsy-verified sarcoidosis patients were included and divided into four groups depending on the organ affection: (i) sarcoidosis without ocular or CNS affection, (ii) ocular sarcoidosis, (iii) CNS sarcoidosis, and (iv) combined ocular and CNS sarcoidosis. Retinal oximetry was obtained and analysed, with the mean retinal arteriolar and venular saturation as well as arteriovenous difference as principal outcomes. Comparison between groups was done in a multi linear regression model adjusted for age, sex, duration of sarcoidosis, best corrected visual acuity and retinal oximetry quality. Results Mean (s.d.) age was 50.5 (13.4) (95% CI: 47.9, 53.1) years and 52.2% were males. Eyes of the combined Ocular/CNS group had a higher retinal arteriovenous difference than eyes of the Non-ocular/no-CNS group (42.1% vs 37.7%, P = 0.012) but did not differ between other groups. Eyes in the four groups (Non-ocular/no-CNS, Ocular, CNS and Ocular/CNS) did not differ according to retinal arterial (94.5%, 93.5%, 93.5% and 94.5%, respectively) or venular (57.5%, 56.4%, 55.0% and 52.5%, respectively) oxygen saturation. Conclusions The results of this study suggest that eyes of sarcoidosis patients with combined ocular and CNS affection have an altered oxygen metabolism indicating a subclinical eye affection that is not recognized by conventional screening methods.

This was a pilot study, where we demonstrated comparable efficacy and side effects of less extensive versus standard panretinal photocoagulation in patients with treatment-naive proliferative diabetic retinopathy. Panretinal laser photocoagulation (PRP) is considered the standard treatment of PDR 1 , but given the invasive nature of the treatment, side-effects like loss of visual fields (VF) 2 and night vision 3 as well as diabetic macular edema (DME) 4 can be expected.

Purpose: To examine the efficacy of intravitreal aflibercept and navigated laser as compared to intravitreal aflibercept and conventional laser in diabetic macular oedema (DME) treatment. Methods: In 12-month randomized clinical trial, 48 eyes of 37 patients with centre-involved DME at Odense University Hospital were randomized 1:1 to receive three monthly injections of aflibercept followed by navigated (group A) or conventional (group B) focal/grid laser. From month four through twelve, patients were examined monthly, and additional injections were given pro re nata (PRN) (central retinal thickness [CRT]>20% from lowest measurement or loss in visual acuity [VA]>5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters compared with baseline). Outcome measures; (1) percentage of eyes that needed additional injections after laser in group A and B, (2) mean number of injections in group A and B, and (3) mean change in VA and CRT in group A and B. Results: In the PRN phase, 60.5% of patients needed additional injections without differences between groups A and B (58.3 versus 63.2%, p > 0.99). The mean number of injections between baseline and month 12 was 4.4 (4.2 versus 4.6, p = 0.41). From baseline to month 12, VA improved by 8.4 ETDRS letters, and CRT was reduced by 97.4 μm (+9.4 versus +7.1 letters, p = 0.17, and −83.2 versus −115.4 μm, p = 0.21). Conclusion: No difference in need for retreatment was detected between treatment arms of aflibercept and navigated versus conventional laser.

Eye screening is mandatory in diabetes, but treatment is only indicated at the sight-threatening stages of diabetic retinopathy (DR). Treatments include intravitreal injections, laser photocoagulation and vitrectomy, which are all invasive options. In order to prevent or delay DR, it is important to investigate earlier, non-invasive managements prior to sight-threatening DR. The aim of this study is to evaluate the effect of systemic treatment on incident and progressive DR. The search in this systematic review was performed in PubMed and Embase using the keywords 'diabetic retinopathy' AND 'systemic therapy'. Two independent researchers identified 619 studies; 26 duplicates were removed, 579 articles were excluded based on title and abstract, and six were removed after full-text assessment. Five articles were added from reference screening, resolving in a total of 13 eligible articles. These were quality-assessed using the Cochrane Risk of Bias tool. Twelve randomized control trials and one follow-up study were included. Intensive glycaemic control (IGC), antihypertensive and lipid-lowering treatments were some of the main interventions tested in the studies. Three studies found statistically significant reduction of progression of DR by IGC, three by antihypertensive, and two by the lipid-lowering drug fenofibrate. Systemic intervention appears important in different stages of DR. While IGC seems effective in relation to incident and progressive DR, antihypertensive treatments may be valuable in the early stages of DR, as opposed to fenofibrate, which could benefit at a later stage.

Purpose: We aimed to investigate the effect of four distracting factors on surgical performance in virtual vitreoretinal surgery. Methods: Nineteen novice surgeons completed a validated training programme on the Eyesi surgical simulator (VRmagic GmbH, Manheim, Germany; software version 2.9.2) until a calculated target score was reached. The training programme consisted of four modules: navigation level 2 (Nav2), bimanual training level 3 (BimT3), posterior hyaloid level 3 (PostH3) and internal limiting membrane peeling level 3 (ILMP3). When properly trained, the participants completed the training programme once without distraction to generate reference scores and times. Next, they conducted the training programme under the influence of each of the following: auditory distraction, 12 hr of fasting, interrupted sleep and 24 hr of sleep deprivation. Wilcoxon signed-rank test was used to compare the distraction-induced results to the participants’ reference scores and times. Results: As compared to reference score (328), a lower performance was found for all four distractions: auditory distraction (289, p = 0.0012), fasting (302, p = 0.02), sleep interruption (304, p = 0.02) and sleep deprivation (300, p = 0.0006). In particular, PostH3 performance was influenced by all four interventions. (86 versus 50, p = 0,0012, 65, p = 0.05, 72, p = 0.05, 54, p = 0.0007 respectively). Conclusions: Virtual vitreoretinal surgery is an important tool for practicing complex surgical skills without compromising patient safety. In this study, deleterious effects on surgical performance were induced by four independent distracting factors. This knowledge is useful to optimize surgeons’ work conditions and ensuring the best possible treatment of patients.

Purpose: The purpose of this study was to evaluate the association between retinal laser burden and vascular oxygen saturation in patients with proliferative diabetic retinopathy (PDR) treated with different extent of retinal laser. Methods: The study was a prospective, interventional study of patients with treatment-naïve PDR. Patients were treated with navigated retinal laser (Navilas®, OD-OS GmbH, Teltow, Germany) in different doses. Retinal oximetry was obtained at baseline (BL) prior to laser and after 6 months (M6). Patients were divided into three groups according to total laser spots applied: 2000 spots (Group 3). Results: We included 33 eyes of 28 patients with treatment-naïve PDR. The groups did not differ according in BL characteristics. Between BL and M6, retinal arteriolar oxygen saturation did not change but retinal venular oxygen saturation (median with interquartile range) decreased in Groups 1 and 2 (1: 65.5 ± 8.8% versus 60.5 ± 9.5%, p = 0.04; 2: 65.3 ± 7.3% versus 63.0 ± 13.5%, p = 0.04). Focal retinal venular oxygen saturation, located to quadrants with retinal neovascularization, decreased in Group 2 from BL to M6 (67.5 ± 13.3% versus 61.5 ± 8.8%, p = 0.04). Retinal venular diameter decreased from BL to M6 in Group 1 (174.5 ± 15.3 μm versus 165.1 ± 28.7 μm, p = 0.01). Conclusions: In this study of patients with treatment-naïve PDR, we showed that a less extensive laser treatment caused a reduction in retinal venular oxygen saturation and diameter 6 months after treatment. Our results suggest that less extensive laser treatment may be sufficient to improve the retinal metabolic environment conducive to PDR regression.

We aimed to evaluate whether macular laser still has a role in the treatment of macular oedema (MO) caused by branch retinal vein occlusion (BRVO) and provide an overview of recent studies on commonly available treatment options. A literature search was last conducted in PubMed on 26 February 2019, limited to human randomized controlled trials published in English since 2008. Seventeen articles addressing 13 trials were included in this assessment. In trials evaluating intravitreal corticosteroid and macular laser, triamcinolone was non-inferior to laser in regard to visual acuity (VA) and central retinal thickness (CRT) outcomes. Combination treatment of dexamethasone and laser resulted in better VA and lower CRT after 6 months. In trials evaluating vascular endothelial growth factor (VEGF) inhibitors versus macular laser treatment, or sham and rescue laser, better VA and CRT of VEGF inhibition treatment was consistently reported. Results of combination treatment versus VEGF inhibition monotherapy were inconsistent, with four of six studies reporting comparable outcomes and injection burden. Study comparison was affected by considerable differences in study design and inadequate reporting of laser protocol and rescue laser. Studies evaluating angiostatic treatment as monotherapy largely report the use of rescue laser, indicating that some patients would benefit from supplemental laser treatment even in the era of intravitreal therapy. Thus, we suggest further studies on optimal design of combination therapy prioritizing longer follow-up time to sufficiently evaluate the delayed effect of laser.

Purpose: The Danish Excellence Centre in Ophthalmic Epidemiology (DECODE-EYE) is a national research collaboration formed in order to study the real-life interaction between ocular and systemic disease based on the entire Danish population. Here, we aim to describe the study design and the methodology, which will be used. Methods: We will extract data from various healthcare registers and databases including the Danish Civil Registration System (unique personal identifier), the Danish National Patient Register (inpatient and outpatient visits), the Danish National Prescription Registry (redeemed prescription drugs), the National Health Service Register (data on health services in primary health care), the Danish Register of Cause of Death (data on cause of death), Statistics Denmark (demographic and socioeconomic data), the Danish Registry of Diabetic Retinopathy (level of diabetic retinopathy (DR) in diabetes patients) and the database of the Danish Association of the Blind (date and cause of blindness). Relevant registers will be linked by the unique personal identifier, and associations will be examined cross-sectional and/or longitudinally, in principle in 1:5 age- and gender-matched case–control cohort studies. Conclusion: Denmark has a strong tradition in register-based healthcare research, given a high number of validated national registers and databases. DECODE-EYE will provide Danish, large-scale data on associations between ocular and systemic disease. With a target population of 5.8 million individuals, twelve separate studies (Protocols A–L) have initially been designed to be studied in the upcoming years. These will provide novel data on interactions between systemic disease and relevant ophthalmological end-points like blindness, DR, glaucoma, corneal disease, retinal vascular disease, cataract and intravitreal angiostatic treatment.

Purpose: To attribute data on changes in diabetic retinopathy (DR) severity during treatment of diabetic macular edema (DME) with vascular endothelial growth factor inhibitors (anti-VEGF), this study aimed to (1) examine the correlation between oxygen saturations in retinal vessels and the number of DR lesions on ultra-wide field color fundus photographs prior to anti-VEGF treatment and (2) compare changes in oxygen saturations in retinal vessels with changes in the number of DR lesions after a loading dose of three monthly intravitreal injections of 2.0 mg of aflibercept. Methods: This 3-month prospective study included 37 eyes of patients with DME and varying severity of peripheral DR lesions. DR lesions were graded on wide field images and retinal oxygen saturations were evaluated by retinal oximetry. Patients were then treated with three monthly intravitreal injections of 2 mg aflibercept and wide field imaging and retinal oximetry were repeated 4 weeks after the last injection. Patients with proliferative DR or previous panretinal photocoagulation were excluded. Results: Baseline retinal arteriolar oxygen saturation increased with increasing DR severity and numbers of microaneurysms, hemorrhages, and cotton wool spots (p = 0.03, 0.01, 0.03, and p = 0.44; 62.9 vs. 64.5%, p = 0.08; 32.5 vs. 31.4%, p = 0.33). Conclusion: This study demonstrated that structural DR lesions correlate with retinal arteriolar oxygen saturation in patients with DME prior to anti-VEGF treatment and that improvement in the severity of DR lesions can occur without corresponding changes in retinal oxygen metabolism during intravitreal therapy. Our results suggest that DR severity on color fundus photographs should be interpreted with caution once intravitreal therapy is initiated.

Retinal microaneurysms (MAs) are the earliest signs of diabetic retinopathy (DR) whichis the leading cause of blindness among the working aged population in the western world.Detection of MAs present a particular challenge as MA pixels account for less than 0.5% ofthe retinal image. In deep neural networks the learning process can be adversely affectedby imbalance which introduces a bias towards the most well represented class. Recently, anumber of objective functions have been proposed as alternatives to the standard Crossentropy (CE) loss in efforts to combat this problem. In this work we investigate the influenceof the network objective during optimization by comparing Residual U-nets trained forsegmentation of MAs in retinal images using six different objective functions; weighted andunweighted CE, Dice loss, weighted and unweighted Focal loss and Focal Tversky loss. Wealso perform test with the CE objective using a more complex model. Three networks withdifferent seeds are trained for each objective function using optimized hyper-parametersettings on a dataset of 382 images with pixel level annotations for MAs. Instance levelMA detection performance is evaluated with the average free response receiver operatorcharacteristic (FROC) score calculated as the mean sensitivity at seven average false positives per image thresholds on 80 test images. The image level MA detection performanceand detection of low levels of DR is evaluated with bootstrapped AUC scores on the sameimages and a separate test set of 1287 images. Significance test for image level detectionaccuracy (α = 0.05) is performed using Cochran’s Q and McNemar’s test. Segmentationperformance is evaluated with the average pixel precision (AP) score. For instance leveldetection and pixel segmentation we perform repeated measures ANOVA with Post-Hoctests. Results: Losses based on the CE index perform significantly better than the Diceand Focal Tversky loss for instance level detection and pixel segmentation. The highestFROC score of 0.5448 (±0.0096) and AP of 0.4888 (±0.0196) is achieved using weightedCE. For all objectives excluding the Focal Tversky loss (AUC = 0.5) there is no significantdifference for image level detection accuracy on the 80 image test set. The highest AUC of0.993 (95% CI: 0.980 - 1.0) is achieved using the Focal loss. For detection of mild DR on theset of 1287 images there is a significant difference between model objectives (p = 2.87e−12).An AUC of 0.730 (95% CI: 0.683 - 0.745 is achieved using the complex model with CE.Using the Focal Tversky objective we fail to detect any MAs on both instance and image level. Conclusion: Our results suggest that it is important to benchmark new lossesagainst the CE and Focal loss functions, as we achieve similar or better results in our testusing these objectives.

Corneal refractive surgery disrupts corneal integrity and reduces biomechanical stability in consequence of the beneficial refractive alteration. The minimal invasive cap-based refractive procedure, small-incision lenticule extraction (SMILE), has been proposed to affect corneal integrity less than flap-based procedures, due to the fibre-sparing incision of the strong anterior corneal lamellae. Flap-based procedures include laser-assisted in situ keratomileusis (LASIK), femtosecond laser-assisted in situ keratomileusis (FS-LASIK) and femtosecond lenticule extraction (FLEx). The purpose of this systematic review was to evaluate corneal biomechanical changes by noncontact air pulse tonometry after treatment of myopia/myopic astigmatism with SMILE compared to flap-based refractive surgery. A total of 220 publications were identified through a systematic search in PubMed and Embase. Two levels of screening identified nine studies (three randomised controlled trials (RCT) and six nonrandomised clinical trials) eligible for the review. All the nonrandomised clinical trials were graded to have an overall serious risk of bias. Measurements with the Corvis ST were not included in any of the eligible studies. The RCTs found no statistical significant differences between SMILE or flap-based procedures concerning corneal hysteresis (CH) or corneal resistance factor (CRF), as measured with the Ocular Response Analyzer. However, a greater reduction in CRF and CH was found in the flap-based group in five and two of the nonrandomised studies, respectively. The findings in this review illustrate that the presumed biomechanical advantages of a cap-based small incision could not be demonstrated in existing studies and by commercially available technology. However, studies with lower levels of evidence suggest less affection of corneal viscoelastic properties after SMILE when evaluating corneal stability by noncontact tonometry.