Attendance in a national screening program for diabetic retinopathy: a population-based study of 205,970 patients.

AIMS: A nationwide diabetic retinopathy (DR) screening program has been established in Denmark since 2013. We aimed to perform an evaluation of adherence to DR screenings and to examine whether non-adherence was correlated to DR progression. METHODS: The population consisted of a register-based cohort, who participated in the screening program from 2013 to 2018. We analyzed age, gender, marital status, DR level (International Clinical DR severity scale, none, mild-, moderate-, severe non-proliferative DR (NPDR) and proliferative DR (PDR)), comorbidities and socioeconomic factors. The attendance pattern of patients was grouped as either timely (no delays > 33%), delayed (delays > 33%) or one-time attendance (unexplained). RESULTS: We included 205,970 patients with 591,136 screenings. Rates of timely, delayed and one-time attendance were 53.0%, 35.5% and 11.5%, respectively. DR level at baseline was associated with delays (mild-, moderate-, severe NPDR and PDR) and one-time attendance (moderate-, severe NPDR and PDR) with relative risk ratios (RRR) of 1.68, 2.27, 3.14, 2.44 and 1.18, 2.07, 1.26, respectively (P < 0.05). Delays at previous screenings were associated with progression to severe NPDR or PDR (hazard ratio (HR) 2.27, 6.25 and 12.84 for 1, 2 and 3+ delays, respectively). Any given delay doubled the risk of progression (HR 2.28). CONCLUSIONS: In a national cohort of 205,970 patients, almost half of the patients attended DR screening later than scheduled or dropped out after first screening episode. This was, in particular, true for patients with any levels of DR at baseline. DR progression in patients with delayed attendance, increased with the number of missed appointments.

Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

Fundus autofluorescence and spectral domain optical coherence tomography as predictors for long-term functional outcome in rhegmatogenous retinal detachment.

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 < 0.001) but not at month 30. At baseline, AF-demarcation of RRD was demonstrated by a hyperfluorescent edge in 92.0% and was associated with visual impairment at months 6 (p = 0.003) and 30 (p = 0.003). Visual outcome at month 30 was good (≤ 0.3 logMAR (≥ 20/40 Snellen)), regardless of the preoperative, macular status. However, with significantly better visual outcome in patients with macula attachments versus partly or totally macular detachments (p < 0.001). 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.

Retinal vascular diameters in relation to physical activity in Danish children - The CHAMPS Eye Study.

Our objective was to determine associations between retinal vascular caliber and physical activity (PA) in a school-based child cohort. In a prospective study, we created a childhood cumulative average PA-index using objectively measured PA (accelerometry) assessed at four periods between 2009 and 2015. Cumulative exposure to PA intensities was estimated. Cross-sectional examinations on biomarkers, anthropometry, and ophthalmological data including retinal fundus photographs were performed in 2015. Semi-automated measurements of retinal vascular diameters were performed and summarized into central retinal arteriolar and venular equivalents (CRAE, CRVE). We included 307 participants. Mean age in 2015 was 15.4 years (0.7). The mean CRAE and CRVE were 156.5 µm (2.8) and 217.6 µm (7.7), respectively. After adjusting for age, gender, and axial length, more time in PA was independently related to thinner retinal venules (ß-coefficient = -1.25 µm/%, 95% confidence interval = -2.20, -0.30, P < .01). Sedentary time was associated with wider venules (P < .01). Furthermore, birthweight (ß-coefficient = 0.56 µm/%, 95% confidence interval = 0.18, 0.95, P < .01) was associated with CRVE. Blood pressure was associated with thinner retinal arterioles (ß-coefficient = -0.19 µm/mmHg, 95% confidence interval = -0.36, -0.01, P = .04). We concluded that children with higher PA in childhood had thinner retinal venular caliber. Our results suggest that PA during childhood positively impacts the retinal microcirculation and that retinal vascular analysis may be a possible assessment to detect microvascular impairments in children with an increased risk of future cardiovascular disease.

Magnetic resonance imaging findings at the first episode of acute optic neuritis.

BACKGROUND: Optic neuritis (ON) is a focal demyelinating event, which may evolve into multiple sclerosis (MS). OBJECTIVE: To study MRI characteristics in the acute phase of the first ON episode. METHODS: A prospective population-based study was performed on 31 patients with a first episode of acute ON with a one year follow-up. MRI, clinical evaluation, and detection of aquaporin-4 (AQP4)-IgG and myelin oligodendrocyte glycoprotein (MOG)-IgG was undertaken. For lesion characterization on MRI the optic nerves were divided into three segments: intra-orbital (IO), canalicular (CAN) and chiasmal (CHI). RESULTS: Lesions of the optic nerve were observed in 80.6%(25/31), with IO location in 48%(12/25), CAN in 8% (2/25) and both IO and CAN in 44%(11/25). Patients who converted to MS had lesions located at IO in 77%(10/13), whereas the group with isolated ON had IO and CAN in 73% (8/11), p = 0.003. Brain lesions were observed in 84% (21/25) at onset of ON; 62%(13/25) progressed to MS with more frequent location in brainstem (p = 0.030) and lesions in periventricular areas (p = 0.015). Spinal cord lesions were detected only in patients who progressed to MS (p = 0.002). MOG-IgG was detected in one patient with an optic nerve lesion located at IO and CAN. Serum AQP4-IgG was detected in none. Follow-up MRI showed progression in optic nerve lesions in 55% (11/20) patients. CONCLUSIONS: Specific location of optic nerve and brain lesions and the presence of spinal cord lesions in the acute phase of the first ON episode facilitated an MS diagnosis. The extension of optic nerve lesions following ON suggests a long-term progressive degeneration as an important element of ON pathology.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Association between microfibrillar-associated protein 4 (MFAP4) and micro- and macrovascular complications in long-term type 1 diabetes mellitus.

AIMS: To evaluate microfibrillar-associated protein 4 (MFAP4) as a marker of micro- and macrovascular complications in patients with type 1 diabetes. METHODS: This cross-sectional study included 203 persons with a long duration of type 1 diabetes from a population-based cohort ascertained in the former Funen County, Denmark. Detection of plasma-MFAP4 (pMFAP4) was performed by the AlphaLISA Technique. Diabetic retinopathy (DR) was graded in accordance with the Early Treatment Diabetic Retinopathy Study adaptation of the modified Airlie House classification. A monofilament test was used to test for neuropathy, and nephropathy was evaluated in a single spot urine sample. Data describing macrovascular disease were obtained from the Danish National Patient Register. RESULTS: Median age and duration of diabetes were 58.7 and 43 years, respectively, and 61% were males. High levels of pMFAP4 were found in participants of old age, in women and in non-smokers (p < 0.05). In a multiple logistic regression model, patients with high levels of pMFAP4 were more likely to have diabetic neuropathy (OR 2.47 for quartile 4 versus quartile 1, 95% CI 1.01-6.03). No association was found between pMFAP4 and proliferative diabetic retinopathy, nephropathy or macrovascular disease. CONCLUSIONS: No association between pMFAP4 and macrovascular vascular complications was found. However, high levels of pMFAP4 correlated independently with diabetic neuropathy. Further studies on the predictive value of increased circulating MFAP4 in diabetic neuropathy are warranted.

Increased mortality in a Danish cohort of young people with Type 1 diabetes mellitus followed for 24 years.

AIM: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. METHODS: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. RESULTS: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). CONCLUSION: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.

Retinal vascular geometry and its association to microvascular complications in patients with type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

PURPOSE: To examine associations between retinal vascular geometry (tortuosity, branching coefficient [BC] and length-diameter ratio [LDR]) and diabetic proliferative retinopathy (PDR), nephropathy, and peripheral neuropathy in patients with type 1 diabetes mellitus (T1DM). METHODS: A cohort of patients with T1DM participated in a clinical examination in 2011. Blood and urine analyses were done and retinal images taken. PDR was defined as Early Treatment Diabetic Retinopathy Study level 61 or above, nephropathy as albumin-creatinin ratio ≥300 mg/g, and neuropathy as vibration perception threshold >25 Volt. Retinal vessel parameters were measured using semi-automated software. Multiple logistic regressions were performed to investigate correlations between retinal vascular parameters and outcomes. Models were adjusted for other variables (sex, age, duration of diabetes, systolic and diastolic blood pressure, HbA1c, and presence of microvascular complications). Odds ratios were given per standard deviation in retinal vascular parameter. RESULTS: Retinal vascular analyses were performed in 181 patients. Mean age and duration of diabetes were 37.0 years and 29.4 years respectively, and 50.8% were male. Prevalence of PDR, nephropathy, and neuropathy were 26.5%, 6.8%, and 10.1% , respectively. Patients with increased arteriolar BC had a higher risk of nephropathy (OR: 3.10, 95% CI: [1.01-9.54]). Patients with increased venular BC had a higher risk of neuropathy (OR: 2.11, 95% CI: [1.11-4.03]). No associations were found in patients with PDR. CONCLUSIONS: By analyzing the retinal vascular tree in patients with T1DM, we found a higher risk of complications in kidneys and nerves when BC was increased. This might indicate a suboptimal construction of the vascular tree in these patients.

Long-term incidence of vitrectomy and associated risk factors in young Danish patients with Type 1 diabetes: the Danish Cohort of Paediatric Diabetes 1987.

AIMS: To examine the long-term incidence of vitrectomy in young people with Type 1 diabetes. METHODS: We prospectively studied 324 people with Type 1 diabetes who participated in baseline examinations in 1995. Surgical history was obtained from the Danish National Patient Registry in April 2012. RESULTS: During the 17-year study period, 39 people (12.0%) underwent vitrectomy at least once. The mean age and diabetes duration at first vitrectomy were 29.8 and 22.9 years, respectively, and 64.1% of the participants were men. In multivariable Cox regression analysis, baseline age (hazard ratio 0.81 per 1 year increase), BMI (hazard ratio 1.21 per 1 kg/m(2) increase), HbA1c (hazard ratio 1.72 per 1% increase) and diabetic retinopathy (hazard ratio 2.85 and 6.07 for mild and moderate/severe diabetic retinopathy vs none, respectively) were independent predictors of vitrectomy (P < 0.05 for all variables). CONCLUSIONS: Vitrectomy is a relatively common procedure in young people with Type 1 diabetes, with poor glycaemic control being the strongest modifiable risk factor.

Microaneurysm count as a predictor of long-term progression in diabetic retinopathy in young patients with type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

PURPOSE: To investigate microaneurysm (MA) count as a predictor of long-term progression of diabetic retinopathy (DR) in young patients with type 1 diabetes mellitus (T1DM). METHODS: We examined 185 patients with T1DM at baseline (1995) and at follow-up (2011). At baseline, mean age and duration of diabetes were 20.6 and 12.9 years, respectively. Two-field (1995) and seven-field (2011) fundus photographs were taken in accordance with the European Diabetes Study Group (EURODIAB) and the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. DR was graded in accordance to the ETDRS protocol, allowing for non-standard photography at baseline. Baseline MAs were counted; patients without DR and those with MAs only were included. Multivariable logistic regressions were performed to investigate MA-count as a predictor of two-step progression, progression to proliferative DR (PDR), and incident diabetic macula edema (DME). RESULTS: We included 138 patients (138 eyes). Of these, 58 had no retinopathy and 80 had MAs only. At follow-up, rates of two-step progression of DR, progression to PDR and incident DME were 52.9, 21.7, and 10.1 %, respectively. In logistic regression models, MA count was able to predict progression to PDR (OR: 1.51 per MA; 95 % CI: [1.04-2.20]) and DME (OR: 1.69 per MA; 95 % CI: [1.05-2.77]), but not two-step progression (OR 0.91 per MA, 95 % CI: [0.64-1.31]). CONCLUSIONS: In younger patients with T1DM, MA count predicts long-term incidence of PDR and DME. This demonstrates that early DR is a warning sign of late retinopathy complications and that the number of MAs is an important factor for long-term outcome.

Plasma osteoprotegerin concentrations in peripheral sensory neuropathy in Type 1 and Type 2 diabetic patients.

AIMS: Osteoprotegerin (OPG) has been linked to different diabetes complications, including cardiovascular disease, and new findings have indicated a specific role in diabetic peripheral neuropathy, but the exact mechanism is unknown. To investigate a possible association between OPG and diabetic peripheral sensory neuropathy, we therefore analysed plasma OPG in Type 1 and Type 2 diabetic patients with and without peripheral neuropathy. SUBJECTS AND METHODS: Two hundred Type 1 diabetes mellitus (T1DM) patients and 305 Type 2 diabetes mellitus (T2DM) patients participated in the study. Plasma OPG was measured with a sandwich immunoassay. Peripheral neuropathy was assessed by the Semmes-Weinstein monofilament test. RESULTS: In T2DM, plasma OPG concentrations were significantly higher in the peripheral neuropathy group (P < 0.001). Furthermore, there was a significant relationship between the presence of neuropathy in T2DM and plasma OPG levels on logistic regression (P = 0.006). However, when investigated in a full multiple regression model including other long-term diabetes complications, the association became insignificant (P = 0.092). In T1DM, the difference in plasma OPG between groups did not reach significance (P = 0.066). However, plasma OPG significantly correlated to peripheral neuropathy in this group also (P = 0.022), although this correlation was not significant in a multiple linear regression model (P = 0.051). CONCLUSION: Plasma OPG levels are related to peripheral neuropathy in both Type 1 and Type 2 diabetes, although with the strongest relationship in T2DM. Before understanding the significance of this, the pathological mechanism involved and, speculatively, a possible use of plasma OPG as a peripheral sensory neuropathy marker, a larger prospective study is needed.

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

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

Retinal vessel calibre and micro- and macrovascular complications in type 1 diabetes.

AIMS/HYPOTHESIS: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients. METHODS: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics. RESULTS: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications. CONCLUSIONS/INTERPRETATION: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

Proliferative retinopathy and proteinuria predict mortality rate in type 1 diabetic patients from Fyn County, Denmark.

AIMS/HYPOTHESIS: We evaluated the effect of diabetic retinopathy on 25 year survival rate among a population-based cohort of type 1 diabetic patients from Fyn County, Denmark. METHODS: In 1973 all diabetic patients from Fyn County, Denmark with onset before the age of 30 years as of 1 July 1973 were identified (n=727). In 1981, only 627 patients were still alive and resident in Denmark. Of these, 573 (91%) participated in a clinical baseline examination, in which diabetic retinopathy was graded and other markers of diabetes measured. Mortality rate was examined in a 25 year follow-up and related to the baseline examination. RESULTS: Of the 573 patients examined at baseline in 1981 and 1982, 297 (51.8%) were still alive in November 2006. Of the others, 256 (44.7%) had died, three (0.5%) had left Denmark and 17 (3%) were of unknown status. Age- and sex-adjusted HRs of mortality rate were 1.01 (95% CI 0.72-1.42) and 2.04 (1.43-2.91) for patients with non-proliferative and proliferative retinopathy respectively at baseline compared with patients with no retinopathy. After adjusting for proteinuria, HR among patients with proliferative retinopathy lost statistical significance, but still remained 1.48 (95% CI 0.98-2.23). The 10 year survival rate of patients who had proliferative retinopathy as well as proteinuria at baseline was 22.2% and significantly lower (p<0.001) than in patients with proteinuria only (70.3%), proliferative retinopathy only (79.0%) or neither (86.6%). CONCLUSIONS/INTERPRETATION: Proliferative retinopathy and proteinuria predict mortality rate in a population-based cohort of type 1 diabetic patients. In combination they act even more strongly. Non-proliferative diabetic retinopathy did not affect survival rate.