Graefes Arch Clin Exp Ophthalmol DOI 10.1007/s00417-014-2682-7
RETINAL DISORDERS
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) M. L. Rasmussen & R. Broe & U. Frydkjaer-Olsen & B. S. Olsen & H. B. Mortensen & T. Peto & J. Grauslund
Received: 24 February 2014 / Revised: 1 May 2014 / Accepted: 20 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract 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 M. L. Rasmussen (*) : R. Broe : U. Frydkjaer-Olsen : J. Grauslund Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark e-mail: [email protected]
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.
M. L. Rasmussen : R. Broe : U. Frydkjaer-Olsen : T. Peto : J. Grauslund The Clinical Research Institute, University of Southern Denmark, Odense, Denmark
Keywords Diabetic retinopathy . Proliferative diabetic retinopathy . Microaneurysms . Risk factors . Type 1 diabetes mellitus . Population-based
R. Broe OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark
Introduction
B. S. Olsen : H. B. Mortensen Department of Pediatrics E, Herlev Hospital, Turkisvej 14, 2730 Herlev, Denmark B. S. Olsen : H. B. Mortensen Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark T. Peto The NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, 162 City Rd, London EC1V 2PD, UK
Type 1 diabetes mellitus (T1DM) is a systemic disease with onset usually in childhood or adolescence. In an earlier 25year follow-up study from Denmark, long-term incidence of diabetic retinopathy (DR) and blindness was 97 and 7.5 %, respectively [1, 2]. Consequently, early markers of DR are needed in order to identify patients at risk of sight-threatening complications. DR is characterized in the early clinical stages by microaneurysms (MAs). MAs are lesions caused by small out-pouchings of the capillary wall due to localized structural changes and weaknesses. The mechanisms for the formation
Graefes Arch Clin Exp Ophthalmol
of MAs are not completely understood, and a theory is that they are actually premature attempts of neovascularization [3]. They are dynamic lesions with a significant turnover less than 6 months [4, 5]. Furthermore, MAs are not uncommon in nondiabetic patients [6–8]. MAs have previously been thought to carry only a small risk of visual loss, but studies have found an association between increasing MAs and progression in DR [9–14]. However, these studies are few and without long-term reports. Moreover, studies have not included or included only a few young patients with T1DM. Amongst patients with type 2 diabetes mellitus (T2DM), the prevalence of hypertension and other cardiovascular diseases is higher and patients are older. Consequently the presence of MAs in these patients may have multiple origins. Therefore, the aim of this study was to examine the use of MA count as a predictor of long-term progression in DR in T1DM in a population-based cohort of young patients.
Patients and methods Study population Participants included in this study are part of the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987), which is a cohort of patients with T1DM established in 1987. The cohort has been described in details elsewhere [15–18]. The cohort was examined in 1995 where 339 participated and fundus photographs were taken. These 339 patients were invited to participate in a follow-up examination in 2011. Patients gave a written informed consent at both baseline and follow-up. Assessment of retinal photographs At 1995-baseline, two-field fundus photos were taken using 40–60° retinal cameras: a macular-temporal field and a discnasal field in accordance to the European Diabetes Study Group (EURODIAB) protocol [19]. The film slides containing the color images from 1995 were digitalized using DigitDia 5000 Filmscanner (Reflecta, Rottenburg, Germany). At follow-up a 3D OCT-2000 Spectral Domain Optical Coherence Tomography (SD-OCT), Topcon, Tokyo, Japan, was used to capture seven 45°, non-stereo color fundus photos in accordance with the Early Treatment Diabetic Retinopathy Study (ETDRS) standards [20]. Furthermore, SD-OCTs (3D macula and line scans) were taken using the same camera. All photos were analyzed in IMAGEnet i-base, version 3.10.5 (Topcon, Tokyo, Japan). All images (from 1995 to 2011) were graded by a single trained and certified grader (MLR) in accordance to the ETDRS protocol [21], allowing for non-standard photography
in 1995. Intragrader agreement and temporal drift analyses were performed. MAs at baseline were counted manually. MAs were defined according to the ETDRS protocol as “a red spot that is less than 1/12 the diameter of an average optic disc, or 125 μm in its longest dimension (approximately the width of an average major vein at the disc margin), and that has sharp margins” [21]. Any MA visible in both fields was only counted in the first image graded.
Clinical characteristics At baseline, sex, age, and diabetes duration were recorded. HbA1c, albumin excretion rate (AER), and systolic and diastolic blood pressure (BP) were determined. BP was measured using a digital BP meter (UA-751, Takeda Medical, Tokyo, Japan) with the patients in sitting and resting position. HbA1c was determined by an automated high-pressure liquid chromatography (HI-AUTO A1c, normal range 4.3–5.8, mean 5.3 %) and for determination of mean AER patients collected two consecutive overnight timed urine samples [16–18, 22].
Variables of interest Progression of DR was defined as a two-step or more increase on the ETDRS scale between baseline and follow-up, and progression to proliferative retinopathy (PDR) was defined as ETDRS level 61 or above in 2011. Incident DME was defined as current DME with characteristics of macular edema as per ETDRS. In addition, intraretinal fluid within 500 microns of the center of macula on SD-OCT or focal laser scarring on fundus images at follow-up were used.
Inclusion criteria For the purposes of this study, only participants with no DR and those with MAs only in at least one eye at baseline were included (ETDRS level 10/10, 10/20, or 20/20). For analyses for two-step progression and progression to PDR, the eye with the highest MA count at baseline was used. If an equal number of MAs was counted in both eyes, the right eye was chosen. For analyses on incident DME, the eye that developed DME was used, despite MA count or retinopathy (ETDRS 10 or 20) in the fellow eye. If both eyes had developed DME, the right eye was chosen. Analyses were adjusted for DR in the fellow eye to avoid confounding results [23]. The study was approved by the local scientific ethics committee and performed in accordance with the criteria of Helsinki II Declaration and good clinical practice.
Graefes Arch Clin Exp Ophthalmol
Statistical analyses Linear weighted kappa was used for intragrader agreement. Good and very good agreement was in accordance with Landis and Koch [24], considered to be Kappa >0.61–0.80 and Kappa >0.81, respectively. Categorical data are presented as percentages and continuous data are presented as means with standard deviations. Differences between groups were compared with the Mann–Whitney test for continuous data and Chi-squared test for categorical data. Multivariable logistic regression analyses were performed for MA count as a predictor of two-step progression, progression to PDR, and incident DME. Adjustments were made for potential baseline risk factors: sex, duration of T1DM, DR at baseline in the fellow eye, BP, HbA1c, and AER. MA count was treated as a continuous variable. For additional analysis, MA count was divided into four groups (no MAs [1], 1 MA [2], 2–4 MAs [3] and 5+ MAs [4]). Multivariable logistic regression using backwards selection was also performed for MA count below or at or above five MAs. For all statistics p-values ETDRS level 20 (n=47) Included in MA-analyses n=138
Fig. 1 Flow chart showing reasons of exclusion from 1995 baseline to the study on microaneurysm (MA) count
and diastolic blood pressure and a longer diabetes duration than patients without DR. Development in retinopathy For the 138 participants at follow-up, only five (3.6 %) had no DR, 79 (57.3 %) had mild non-proliferative retinopathy (NPDR) (ETDRS level 20–35), 24 (17.4 %) had moderatesevere NPDR (ETDRS level 43–53), and 30 participants (21.7 %) had PDR (ETDRS level 61 or above). At follow-up, two-step progression and progression to PDR was found in 52.9 % and 21.7 %, respectively. The 16year cumulative incidence of DME of the included participants was 10.1 % (n=14). Of these, 11 participants had received focal laser treatment and one participant had current DME on fundus photos and SD-OCT. Two participants had both focal laser scarring and current DME. None of the included participants regressed from DR of ETDRS level 20 to no DR (ETDRS level 10), and 25 participants remained stable (five at ETDRS level 10 and 20 at ETDRS level 20). MA count MA count at baseline ranged from 0 to 7 (mean=1.4±1.8). For participants who had MAs at baseline (ETDRS level 20), the mean MA count was 2.5±1.9 (range 1–7). For participants with only MAs in one eye (n=39), mean MA count was 1.3±
Graefes Arch Clin Exp Ophthalmol Table 1 1995 baseline characteristics of the included patients (n=138) and specified for patients with retinopathy (n= 80) and without retinopathy (n= 58) All patients (n=138)
Patients with retinopathy (n=80)
Patients without retinopathy (n=58)
N
Mean ± SD
Mean ± SD
Mean ± SD
p*
Age (years)
132
20.6±3.4
21.1±3.1
20.0±3.7
0.11
Duration of diabetes (years) HbA1c (%) HbA1c (mmol/mol) AER Systolic BP (mmHg) Diastolic BP (mmHg) MAs
133 131 131 131 133 133 138 N 75 80
12.9±3.1 9.5±1.6 79.9±17.5 11.0±27.0 123.4±12.3 73.4±8.2 1.42±1.9 % 54.4 58.0
13.4±3.2 9.8±1.7 83.4±19.0 10.3±18.9 124.6±12.2 74.7±8.0 2.4±1.7 % 55.0
12.3±2.9 9.1±1.3 75.5±14.3 11.9±35.0 121.9±12.4 71.6±8.1 0 % 53.5
RETINAL DISORDERS
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) M. L. Rasmussen & R. Broe & U. Frydkjaer-Olsen & B. S. Olsen & H. B. Mortensen & T. Peto & J. Grauslund
Received: 24 February 2014 / Revised: 1 May 2014 / Accepted: 20 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract 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 M. L. Rasmussen (*) : R. Broe : U. Frydkjaer-Olsen : J. Grauslund Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark e-mail: [email protected]
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.
M. L. Rasmussen : R. Broe : U. Frydkjaer-Olsen : T. Peto : J. Grauslund The Clinical Research Institute, University of Southern Denmark, Odense, Denmark
Keywords Diabetic retinopathy . Proliferative diabetic retinopathy . Microaneurysms . Risk factors . Type 1 diabetes mellitus . Population-based
R. Broe OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark
Introduction
B. S. Olsen : H. B. Mortensen Department of Pediatrics E, Herlev Hospital, Turkisvej 14, 2730 Herlev, Denmark B. S. Olsen : H. B. Mortensen Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark T. Peto The NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, 162 City Rd, London EC1V 2PD, UK
Type 1 diabetes mellitus (T1DM) is a systemic disease with onset usually in childhood or adolescence. In an earlier 25year follow-up study from Denmark, long-term incidence of diabetic retinopathy (DR) and blindness was 97 and 7.5 %, respectively [1, 2]. Consequently, early markers of DR are needed in order to identify patients at risk of sight-threatening complications. DR is characterized in the early clinical stages by microaneurysms (MAs). MAs are lesions caused by small out-pouchings of the capillary wall due to localized structural changes and weaknesses. The mechanisms for the formation
Graefes Arch Clin Exp Ophthalmol
of MAs are not completely understood, and a theory is that they are actually premature attempts of neovascularization [3]. They are dynamic lesions with a significant turnover less than 6 months [4, 5]. Furthermore, MAs are not uncommon in nondiabetic patients [6–8]. MAs have previously been thought to carry only a small risk of visual loss, but studies have found an association between increasing MAs and progression in DR [9–14]. However, these studies are few and without long-term reports. Moreover, studies have not included or included only a few young patients with T1DM. Amongst patients with type 2 diabetes mellitus (T2DM), the prevalence of hypertension and other cardiovascular diseases is higher and patients are older. Consequently the presence of MAs in these patients may have multiple origins. Therefore, the aim of this study was to examine the use of MA count as a predictor of long-term progression in DR in T1DM in a population-based cohort of young patients.
Patients and methods Study population Participants included in this study are part of the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987), which is a cohort of patients with T1DM established in 1987. The cohort has been described in details elsewhere [15–18]. The cohort was examined in 1995 where 339 participated and fundus photographs were taken. These 339 patients were invited to participate in a follow-up examination in 2011. Patients gave a written informed consent at both baseline and follow-up. Assessment of retinal photographs At 1995-baseline, two-field fundus photos were taken using 40–60° retinal cameras: a macular-temporal field and a discnasal field in accordance to the European Diabetes Study Group (EURODIAB) protocol [19]. The film slides containing the color images from 1995 were digitalized using DigitDia 5000 Filmscanner (Reflecta, Rottenburg, Germany). At follow-up a 3D OCT-2000 Spectral Domain Optical Coherence Tomography (SD-OCT), Topcon, Tokyo, Japan, was used to capture seven 45°, non-stereo color fundus photos in accordance with the Early Treatment Diabetic Retinopathy Study (ETDRS) standards [20]. Furthermore, SD-OCTs (3D macula and line scans) were taken using the same camera. All photos were analyzed in IMAGEnet i-base, version 3.10.5 (Topcon, Tokyo, Japan). All images (from 1995 to 2011) were graded by a single trained and certified grader (MLR) in accordance to the ETDRS protocol [21], allowing for non-standard photography
in 1995. Intragrader agreement and temporal drift analyses were performed. MAs at baseline were counted manually. MAs were defined according to the ETDRS protocol as “a red spot that is less than 1/12 the diameter of an average optic disc, or 125 μm in its longest dimension (approximately the width of an average major vein at the disc margin), and that has sharp margins” [21]. Any MA visible in both fields was only counted in the first image graded.
Clinical characteristics At baseline, sex, age, and diabetes duration were recorded. HbA1c, albumin excretion rate (AER), and systolic and diastolic blood pressure (BP) were determined. BP was measured using a digital BP meter (UA-751, Takeda Medical, Tokyo, Japan) with the patients in sitting and resting position. HbA1c was determined by an automated high-pressure liquid chromatography (HI-AUTO A1c, normal range 4.3–5.8, mean 5.3 %) and for determination of mean AER patients collected two consecutive overnight timed urine samples [16–18, 22].
Variables of interest Progression of DR was defined as a two-step or more increase on the ETDRS scale between baseline and follow-up, and progression to proliferative retinopathy (PDR) was defined as ETDRS level 61 or above in 2011. Incident DME was defined as current DME with characteristics of macular edema as per ETDRS. In addition, intraretinal fluid within 500 microns of the center of macula on SD-OCT or focal laser scarring on fundus images at follow-up were used.
Inclusion criteria For the purposes of this study, only participants with no DR and those with MAs only in at least one eye at baseline were included (ETDRS level 10/10, 10/20, or 20/20). For analyses for two-step progression and progression to PDR, the eye with the highest MA count at baseline was used. If an equal number of MAs was counted in both eyes, the right eye was chosen. For analyses on incident DME, the eye that developed DME was used, despite MA count or retinopathy (ETDRS 10 or 20) in the fellow eye. If both eyes had developed DME, the right eye was chosen. Analyses were adjusted for DR in the fellow eye to avoid confounding results [23]. The study was approved by the local scientific ethics committee and performed in accordance with the criteria of Helsinki II Declaration and good clinical practice.
Graefes Arch Clin Exp Ophthalmol
Statistical analyses Linear weighted kappa was used for intragrader agreement. Good and very good agreement was in accordance with Landis and Koch [24], considered to be Kappa >0.61–0.80 and Kappa >0.81, respectively. Categorical data are presented as percentages and continuous data are presented as means with standard deviations. Differences between groups were compared with the Mann–Whitney test for continuous data and Chi-squared test for categorical data. Multivariable logistic regression analyses were performed for MA count as a predictor of two-step progression, progression to PDR, and incident DME. Adjustments were made for potential baseline risk factors: sex, duration of T1DM, DR at baseline in the fellow eye, BP, HbA1c, and AER. MA count was treated as a continuous variable. For additional analysis, MA count was divided into four groups (no MAs [1], 1 MA [2], 2–4 MAs [3] and 5+ MAs [4]). Multivariable logistic regression using backwards selection was also performed for MA count below or at or above five MAs. For all statistics p-values ETDRS level 20 (n=47) Included in MA-analyses n=138
Fig. 1 Flow chart showing reasons of exclusion from 1995 baseline to the study on microaneurysm (MA) count
and diastolic blood pressure and a longer diabetes duration than patients without DR. Development in retinopathy For the 138 participants at follow-up, only five (3.6 %) had no DR, 79 (57.3 %) had mild non-proliferative retinopathy (NPDR) (ETDRS level 20–35), 24 (17.4 %) had moderatesevere NPDR (ETDRS level 43–53), and 30 participants (21.7 %) had PDR (ETDRS level 61 or above). At follow-up, two-step progression and progression to PDR was found in 52.9 % and 21.7 %, respectively. The 16year cumulative incidence of DME of the included participants was 10.1 % (n=14). Of these, 11 participants had received focal laser treatment and one participant had current DME on fundus photos and SD-OCT. Two participants had both focal laser scarring and current DME. None of the included participants regressed from DR of ETDRS level 20 to no DR (ETDRS level 10), and 25 participants remained stable (five at ETDRS level 10 and 20 at ETDRS level 20). MA count MA count at baseline ranged from 0 to 7 (mean=1.4±1.8). For participants who had MAs at baseline (ETDRS level 20), the mean MA count was 2.5±1.9 (range 1–7). For participants with only MAs in one eye (n=39), mean MA count was 1.3±
Graefes Arch Clin Exp Ophthalmol Table 1 1995 baseline characteristics of the included patients (n=138) and specified for patients with retinopathy (n= 80) and without retinopathy (n= 58) All patients (n=138)
Patients with retinopathy (n=80)
Patients without retinopathy (n=58)
N
Mean ± SD
Mean ± SD
Mean ± SD
p*
Age (years)
132
20.6±3.4
21.1±3.1
20.0±3.7
0.11
Duration of diabetes (years) HbA1c (%) HbA1c (mmol/mol) AER Systolic BP (mmHg) Diastolic BP (mmHg) MAs
133 131 131 131 133 133 138 N 75 80
12.9±3.1 9.5±1.6 79.9±17.5 11.0±27.0 123.4±12.3 73.4±8.2 1.42±1.9 % 54.4 58.0
13.4±3.2 9.8±1.7 83.4±19.0 10.3±18.9 124.6±12.2 74.7±8.0 2.4±1.7 % 55.0
12.3±2.9 9.1±1.3 75.5±14.3 11.9±35.0 121.9±12.4 71.6±8.1 0 % 53.5
