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Aims Neurodegeneration and glial activation are primary events in the pathogenesis of diabetic retinopathy. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are biomarkers of underlying neuroinflammatory and neurodegenerative disease processes. The aim of the present study was to assess the usefulness of these serum biomarkers for the identification and monitoring of retinal neurodysfunction in subjects with type 2 diabetes. Methods A case–control study was designed including 38 patients from the placebo arm of the EUROCONDOR clinical trial: 19 with and 19 without retinal neurodysfunction assessed by multifocal electroretinography. GFAP and NfL were measured by Simoa. Results Serum levels of GFAP and NfL directly correlated with age ( r  = 0.37, p  = 0.023 and r  = 0.54, p  < 0.001, respectively). In addition, a direct correlation between GFAP and NfL was observed ( r  = 0.495, p  = 0.002). Serum levels of GFAP were significantly higher at baseline in those subjects in whom neurodysfunction progressed after the 2 years of follow-up (139.1 ± 52.5 pg/mL vs. 100.2 ± 54.6 pg/mL; p  = 0.04). Conclusions GFAP could be a useful serum biomarker for retinal neurodysfunction. Monitoring retinal neurodysfunction using blood samples would be of benefit in clinical decision-making. However, further research is needed to validate this result as well as to establish the best cutoff values.

To compare non-mydriatic, mydriatic and steered mydriatic widefield retinal images with mydriatic 7-field Early Treatment Diabetic Retinopathy Study (ETDRS)-standards in grading diabetic retinopathy (DR). We examined 95 patients (190 eyes) with type 1 diabetes. A non-mydriatic, a mydriatic and four steered mydriatic 200° widefield retinal images were captured (Optos 200Tx, Optos plc, Dunfermline, Scotland) and compared to mydriatic 7-field 45° ETDRS images (Topcon 3D OCT-2000, Topcon, Tokyo, Japan). Images were graded for DR according to ETDRS-protocol by a trained and certified grader masked to the results of the corresponding grading. For agreement kappa-statistics were used. Exact level agreement with 7-field images was found in 76.3%, 76.1% and 70.7% for non-mydriatic, mydriatic and steered mydriatic widefield images, respectively. Corresponding values for one-level agreement were 99.0%, 98.9% and 99.5%, respectively. Non-mydriatic matched mydriatic widefield images almost fully with exact and one-level agreement of 96.8% and 100.0%, respectively. Mydriatic steered images resulted in higher grading in 24 eyes. Widefield images matched 7-field images favorably. Widefield images can be captured without pupil-dilation and only one image is needed. However, because of overlapping eyelashes and distortion some lesion might be missed. Mydriatic steered images in selected cases may solve some of these problems.

The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain–optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

Background To report tumour pathology, surgical procedure, complication rates and overall outcome of periocular basal cell carcinoma (BCC) in the Department of Ophthalmology at Sygehus Lillebaelt, Southern Denmark Region over a 5-year period. Methods Medical records for all patients who underwent surgery for periocular BCC between January 2016 and December 2020 were reviewed. All tumours were excised with a 3 mm margin beyond the clinically apparent delimitation of the tumour and analysed by frozen section histological examination. Paraffin sections were subsequently examined for a final histopathological diagnosis. Patient age, gender, date of resection, former cancer history, referring unit and follow-up time were recorded. Furthermore, histological subtypes identified from biopsy and resection, lesion location, lesion diameter, free margin after the first operation, lacrimal punctum involvement, reconstructive techniques and complications were also recorded. Results A total of 242 surgical excisions from 237 patients were recorded. The mean age was 69.7 ± 12.6 with women significantly predominant compared to men (1.8:1, p  < 0.0001, binomial test). The mean tumour diameter was 4.29 mm (range 0.5–20 mm). The most common location and histological subtype was the lower eyelid and nodular BCC respectively (64.9% and 74.0% of cases). In 17.4% of the patients, the initial resection margin on the frozen section histology was not free of tumour cells and the risk was significantly greater for BCC subtypes considered aggressive in terms of growth pattern (morphea form, infiltrative and micronodular features) as compared to non-aggressive BCC subtypes (nodular and superficial) ( p  = 0.002, X 2 ). In 239 (98.8%) of the patients, the BCC was found to be radically removed after final histopathological examination. The sensitivity of identification of aggressive subtypes of periocular BCC in biopsies was 47.7%. No recurrences were found during the 5-year period. Conclusion This study demonstrated a tendency towards more women than men being diagnosed with periocular BCC. The initial biopsy performed for all patients underestimated the aggressiveness of BCC in almost half of the cases while aggressive BCC subtypes were more likely to need further resection after frozen section compared to non-aggressive subtypes.

The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes.

Aims/hypothesis Fractal analysis of the retinal vasculature provides a global measure of the complexity and density of retinal vessels summarised as a single variable: the fractal dimension. We investigated fractal dimensions as long-term predictors of microvasculopathy in type 1 diabetes. Methods We included 180 patients with type 1 diabetes in a 16 year follow-up study. In baseline retinal photographs (from 1995), all vessels in a zone 0.5–2.0 disc diameters from the disc margin were traced using Singapore Institute Vessel Assessment-Fractal image analysis software. Artefacts were removed by a certified grader, and fractal dimensions were calculated using the box-counting method. At follow-up (in 2011), diabetic neuropathy, nephropathy and proliferative retinopathy were assessed and related to baseline fractal dimensions in multiple regressions adjusted for sex and baseline age, diabetes duration, HbA 1c , BP, BMI, vibration perception threshold, albuminuria, retinopathy and vessel diameters. Results Mean baseline age and diabetes duration were 21.0 and 13.4 years, respectively, and of patients 50.0% were males. The mean fractal dimension was 1.3817. The 16 year incidences of neuropathy, nephropathy and proliferative retinopathy were 10.8%, 8.0% and 27.9%, respectively. Multiple regression analyses showed a lower fractal dimension to significantly predict incident neuropathy (OR 1.17 per 0.01 fractal dimension decrease [95% CI 1.01, 1.36]), nephropathy (OR 1.40 per 0.01 fractal dimension decrease [95% CI 1.10, 1.79]) and proliferative retinopathy (OR 1.22 per 0.01 fractal dimension decrease [95% CI 1.09, 1.37]). Conclusions/interpretation The retinal vascular fractal dimension is a shared biomarker of diabetic microvasculopathy, thus indicating a possible common pathogenic pathway. Retinal fractal analysis therefore is a potential tool for risk stratification in type 1 diabetes.

Purpose To examine differences in structural and functional neurodegenerative measurements between patients with no and early diabetic retinopathy (DR). Methods In this cross-sectional study, we examined 103 patients with type 2 diabetes mellitus. In 7-field fundus photographs acquired with Topcon TRC-NW6S, a single, certified grader determined the presence of DR according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral domain optical coherence tomography (OCT) and by a RETI-scan multifocal electroretinography (mf-ERG) system in rings 1–6. Results Median age and duration of diabetes were 63.6 and 10 years, respectively, and 46% were men. Median HbA1c was 50 mmol/mol (6.7%), and ETDRS levels were 10 (41.7%, n  = 43), 20 (35.0%, n  = 36), and 35 (23.3%, n  = 24). The duration of diabetes increased with higher levels of DR ( p  = 0.04), but patients with different level of DR did not differ according to age, sex, blood pressure, HbA1c, and mf-ERG or OCT parameters. In a multiple logistic regression model, macular ganglion cell layer thickness was associated with the presence of DR (OR 1.73 per 5 μm increase, 95% CI 1.06–2.85, p  = 0.03). Conversely, retinal nerve fibre layer thickness at optic disc was inversely related to DR (OR 0.69 per 5 μm increase, 95% CI 0.51–0.95, p  = 0.02). There were no associations between DR and mf-ERG outcomes. Conclusion In patients with type 2 diabetes, structural neurogenic characteristics were associated with DR. If confirmed by larger prospective studies, these results may indicate that a complex neurovascular interaction is an early event in the pathogenesis of DR.

The aim was to investigate the long-term incidence of proliferative diabetic retinopathy (PDR), and progression and regression of diabetic retinopathy (DR) and associated risk factors in young Danish patients with Type 1 diabetes mellitus. In 1987–89, a pediatric cohort involving approximately 75 % of all children with Type 1 diabetes in Denmark <19 years of age was identified ( n  = 720). In 1995, 339 (47.1 %) were re-studied with retinopathy graded and all relevant diabetic parameters assessed. Of those, 185 (54.6 %) were evaluated again in 2011 for the same clinical parameters. All retinal images were graded using modified early treatment of DR study for 1995 and 2011. In 1995, mean age was 21.0 years and mean diabetes duration 13.5 years. The 16-year incidence of proliferative retinopathy, 2-step progression and 2-step regression of DR was 31.0, 64.4 and 0.0 %, respectively, while the incidence of DR was 95.1 %. In a multivariate logistic regression model, progression to PDR was significantly associated with 1995 HbA 1c (OR 2.61 per 1 % increase, 95 % CI 1.85–3.68) and 1995 diastolic blood pressure (OR 1.79 per 10 mmHg increase, 95 % CI 1.04–3.07). Two-step progression of DR was associated with male gender (OR 2.37 vs. female, 95 % CI 1.07–5.27), 1995 HbA 1c (OR 3.02 per 1 % increase, 95 % CI 2.04–4.48) and 1995 vibration perception threshold (OR 1.19 per 1 Volt increase, 95 % CI 1.02–1.40). In conclusion, one in three progressed to PDR and two in three had 2-step progression despite young age and increased awareness of the importance of metabolic control. After 30 years duration of diabetes, the presence of DR is almost universal.