European Association for the Study of Diabetic Eye Complications

Annual Meeting Rome 26-27th May 2007

Poster Abstract 1

BASELINE DATA OF THE ÅRHUS PROSPECTIVE STUDY OF AUTOREGULATION IN DIABETIC RETINOPATHY. T Bek, ST Knudsen, P Løgstrup, CE Mogensen, O Schmitz, P Jeppesen. Dept. of Ophthalmology, Aarhus, Denmark.

Purpose: To study autoregulation of retinal arterioles in type 2 diabetic patients with mild diabetic retinopathy at baseline, and after 2 and 5 years to correlate changes in autoregulation with changes in retinopathy.
Methods: Sixty-five type 2 diabetic patients (mean age 57.2y, range: 43.9y - 65.3y) were examined. All patients had mild (1 to 4 dot and blots haemorrhages alone) retinopathy in at least one eye, had no other known systemic vascular or ocular diseases. All patients underwent a general ophthalmological examination including measurement of visual acuity, intraocular pressure, slit lamp examination, and fundoscopy. Subsequently, the Retinal Vessel Analyzer was used to measure the diameter response of a retinal arteriole at rest and during isometric exercise by lifting a hand weight. The systemic blood pressure was measured on the upper left arm at rest and during exercise.
Results: The visual acuity of the examined eye ranged between 0.6 and 1.2 (mean = 0.97). The mean intraocular pressure and mean blood glucose was 17.0 ±0.4 mmHg and 11.5 ±0.6 mmol/l. The mean systemic arterial blood pressure at rest was 101.7 ±1.4 mmHg and a significant increase of 24.8 ±1.8% was observed during isometric exercise (p<0.0001). The mean blood vessel diameter at rest was 116.8 ±1.9 AU (AU = arbitrary unit which approx. is equal to microns) and exercise induced a non-significant change in diameter of 0.1 ±0.4% (p=0.79). A considerable variation was observed in the diameter response among the patients (var = 9.6). However no significant correlation was found between the change in diameter and the change in MAP (p=0.18).
Conclusion: Type 2 diabetic patients with mild diabetic retinopathy have a diminished autoregulatory response in the retinal vessels, indicating that autoregulation is disturbed early in the disease process. Follow-up examination of the cohort to observe whether a further development of diabetic retinopathy is paralleled in changes in autoregulation will indicate whether these two parameters are related causally.

Poster Abstract 2

CONNECTIVE TISSUE GROWTH FACTOR (CTGF) IS NOT INVOLVED IN ANGIOGENESIS IN KNOCK OUT MOUSE MODELS
RJ van Geest,1 EJ Kuiper,¹ C Ehlken,² V Lambert,³ H Bloys,⁴ KM Lyons,⁵ H-J,T Agostini,² J-M Rakic,³ I Klaassen,¹ CJF van Noorden,¹ R Goldschmeding,⁶ RO Schlingemann.^1
1Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam - The Netherlands
²Department of Ophthalmology, University of Freiburg, Freiburg - Germany
³Laboratory of Tumor and Development Biology and Department of Ophthalmology, University Hospital Liège, Sart Tilman, Liège - Belgium.

Purpose: Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing and fibrosis. It has also been implicated to play a role in angiogenesis besides vascular endothelial growth factor (VEGF). In the eye, angiogenesis and subsequent fibrosis are the main cause of blindness in diabetic retinopathy.
Methods: We have applied 3 different models of angiogenesis to homozygous CTGF-/- and heterozygous CTGF+/- mice to establish involvement of CTGF in neovascularisation. CTGF-/- mice die around birth. Therefore, embryonic CTGF-/-, CTGF+/- and CTGF+/+ bone explants were used to study in vitro angiogenesis and neonatal and mature CTGF+/- and CTGF+/+ mice were used in models of oxygen-induced retinopathy and laser-induced choroidal neovascularisation (CNV).
Results: Angiogenesis in vitro was independent of the CTGF genotype both in the presence and absence of VEGF. Oxygen-induced vascular pathology in the retinas as determined semi-quantitatively and laser-induced CNV as determined quantitatively were not affected by the CTGF genotype either.
Conclusions: Our data strongly suggest that down-regulation of CTGF levels does not affect neovascularisation in the eye and support that VEGF is the major inducer of angiogenesis under diabetic conditions.

Poster Abstract 3

RETINAL VESSEL SIGNS AND EARLY RETINOPATHY IN TYPE 1 DIABETES. JP Kytö,^1,2 M Rosengård-Bärlund,² J Fagerudd,² K Hietala,^1,2 C Forsblom,² M Lindström-Karjalainen,¹ P-H Groop,² PA Summanen.
¹ Ophthalmology, Helsinki Univ Central Hospital, Helsinki, Finland
² Diabetes Genetics, Folkhälsan Research Center, Helsinki, Finland.

Purpose: To evaluate and grade arteriolosclerotic retinal vessel signs in the ocular fundus and to study their association with early DR in T1D.
Methods: This preliminary cross-sectional IDEAL substudy of the collaborative multicenter FinnDiane study comprised of 76 consecutive patients (58% men) aged 26 (SD 6), with T1D duration of 9 (2) yrs and age at onset 17 (SD 6). One macula and one optic disc centered 50-60º red-free fundus image was digitized. In patients with DR (45%) the more affected eye and in patients without DR a randomly selected eye was graded by J.P.K. and P.A.S. unaware of the patient characteristics.
The grading focused on: 1) arteriolar signs, 2) venular signs, 3) arteriovenous nickings (AVN: remoteness, arching, banking, compression and deviation) according to a classification based on early literature of vascular signs, 4) DR (a modified ETDRS classification), 5) AVN signs summed as the AVN risk sum (ANR), 6) all arteriolar, venular and nicking signs expressed as the arteriolosclerotic risk burden (ARB).
Results: Thirty-one patients (41%) had minimal to mild and 3 (4%) moderate DR. Arteriolar signs (sinusoidal elongation 74% (n=56), generalised 45% (n=34), and focal narrowing 3% (n=2), pronounced light streak 40% (n=30), straightening 1% (n=1) as well as venular signs (tortuosity 65% (n=49), minimal tortuosity 51% (n=39), tortuosity in macula 57% (n=43) and local narrowing 1% (n=1) were common in all 76 eyes. At least one AVN occurred in 96% of patients. ANR and ARB did not differ between patients with and without DR, although there was a trend of higher ARB in patients with DR (p=0.064). In a univariate regression analysis, ANR was associated with duration (r=0.263, p=0.022). ARB was associated with duration (r=0.262, p=0.022) and HDL cholesterol (r= 0.241, p=0.036).
Conclusions: These preliminary data show that early arteriolar and venular signs are common in T1D with short duration.

Poster Abstract 4

POSSIBLE INCREASED SEVERITY OF RETINAL VEIN OCCLUSION IN DIABETIC SUBJECTS. M Paques, H Klifi, JF Girmens, J-A Sahel. Ophthalmology Department of the Fondation Rothschild and of the Centre Hospitalier National des Quinze-Vingts, Pierre-et-Marie-Curie University, Paris, France

Purpose: To report the evolution of retinal vein occlusion (RVO) in diabetic subjects.
Methods: The charts of 16 cases of RVO (10 central RVO, 6 branch RVO) in diabetic subject are reported.
Results: 11 patients developed chronic macular oedema. 4 patients developed new vessels, either preretinal or on the disc. Three of them had preretinal fibrovascular proliferation, which is highly uncommon in nondiabetic RVO. 14 had no or minimal diabetic retinopathy (DR) in the fellow eye.
Conclusion: RVO in diabetic patients appears associated with a high rate of chronic macular oedema and capillary nonperfusion. Moreover, diabetic-like complications such as fibrovascular proliferation may develop even in the absence of underlying DR, suggesting a reciprocal aggravation of diabetes and RVO. These findings may aid the understanding of microvascular remodelling following both RVO and DR, and the management of patients.

Poster Abstract 5

EFFECT OF LUTEIN IN THE RETINA OF DIABETIC MICE. M Muriach,¹ M Miranda,¹ E Arnal,¹ F Bosch-Morel,^1,2 FJ Romero.^1,2 Dept. Fisiología, Universidad CEU-Cardenal Herrera,¹ Fundación Oftalmológica del Mediterraneo,² Moncada, Valencia, Spain.

Purpose: Oxidative stress markers and functional tests were studied to evaluate early biochemical and functional changes in retina of diabetic mice after different periods of time. We also tested the effects of lutein treatment compared to insulin therapy.
Methods: Mice were rendered diabetic by alloxan injection and divided into subgroups: control, control + lutein, diabetic, diabetic + lutein, diabetic + insulin and diabetic + insulin + lutein. Treatments started on day 4 after alloxan injection and animals were sacrificed on days 7, 14 or 21. MDA concentration and GPx activity were measured as oxidative stress markers. Electroretinogram (ERG) was carried out to evaluate retinal function.
Results: We observed an increase in MDA concentration and a decrease of GPx activity in the retina after 7 days of diabetes induction. This oxidative stress situation is better established after 2 and 3 weeks of diabetes. We also observed an impairment of retinal function since the first week of diabetes. This alteration was more evident after 3 weeks of diabetes induction. Lutein prevented all these changes even under hyperglycaemic conditions.
Conclusions: Although a proper glycaemic control is desirable to prevent the development of diabetic complications, it is not sufficient to prevent them completely. Therefore, lutein, a natural antioxidant without hypoglycaemic properties, could be an appropriate coadjuvant treatment for the changes observed in this study.
This work was supported by projects PI03/1710 from Fondo de Investigación Sanitaria and PRUCHB06/09 from Universidad CEU-Cardenal Herrera.

Poster Abstract 6

EFEECT OF DIABETES IN RAT RETINA AND LENS. TREATMENT WITH LUTEIN. E Arnal,¹ M Miranda,¹ M Muriach,¹ F Bosch-Morel,^1,2 FJ Romero.^1,2
Dept. Fisiología, Universidad CEU-Cardenal Herrera,¹ Fundación Oftalmológica del Mediterraneo,² Moncada, Valencia, Spain.

Purpose: As oxidative stress may play an important role in the pathogenesis of diabetes complications, the aim of this study was to study the status of the antioxidant defences in the retina and lens of diabetic rats after 3 months of hyperglycemia. We also investigated retinal function and assayed a treatment with the natural antioxidant lutein.
Methods: Rats were rendered diabetic by streptozotocin injection and divided into subgroups: control, control + lutein, diabetic, diabetic + lutein, diabetic + insulin and diabetic + insulin + lutein. Treatments started on day 4 after streptozotocin injection and were administered daily until the end of the experiment, 3 months of after diabetes induction. Antioxidant defences: GSH concentration and GPx activity were measured, and electroretinogram (ERG) was carried out to evaluate retinal function.
Results: GSH concentration was decreased in the retina and lens after 3 months of diabetes, in contrast, GPx activity was decreased in the retina but not in lens. We observed an impairment in the ERG of diabetic animals when compared to controls. The administration of insulin and lutein together was the only treatment able to recover to control values all the alterations observed, being the most efficient treatment.
Conclusions: Although a proper glycaemic control is desirable to prevent the development of diabetic complications, it is not sufficient to prevent them completely. Therefore, lutein, a natural antioxidant without hypoglycaemic properties, could be an appropriate coadjuvant treatment for the changes observed in this study.
This work was supported by projects PI03/1710 from Fondo de Investigación Sanitaria and PRUCHB06/09 from Universidad CEU-Cardenal Herrera.

Poster Abstract 7

MIXED MACULAR PATHOLOGY IN A DIABETIC PATIENT. M Niskopoulou, T Peto, JG Dowler, GE Holder. Moorfields Eye Hospital NHS Trust, London, UK.

Purpose: We present a rare case of co-existing pathology of diabetic and bull's eye maculopathy. To our knowledge, only one similar case has been reported in the literature before.
Results: A 55 year old male was reviewed in the Medical Retinal clinic with bilateral moderate diabetic retinopathy and bilateral diabetic maculopathy with clinically significant macular oedema in the right eye. Visual acuities at the time were 6/6 bilaterally and the patient was asymptomatic. Fluorescein angiography (FA) revealed marked hypofluorescence in the central macula in both eyes and significant angiographic macular oedema in the right eye. The initial interpretation of the FA was enlarged foveal avascular zone in both eyes. Macular grid laser for the right eye was entertained but the patient was not keen to proceed. In further follow up, autofluorescence was performed which showed a distinct ring of increased autofluorescence surrounding an area of decreased autofluorescence. Electrodiagnostic tests were requested. Results revealed undetectable pERGs, diagnosing severe macular dysfunction.
Conclusions: Caution has to be taken when interpreting the clinical picture and fluorescein angiography in a diabetic patient, as coexisting pathology may go unnoticed. The fact that the bull's eye maculopathy acted as a barrier in the expansion of diabetic oedema in the fovea in this patient, is of interest and possible explanations are discussed in this paper.

Poster Abstract 8

REFRACTION IN PEOPLE WITH AND WITHOUT DIABETES OVER A 10 YEAR PERIOD.
BL Justesen, N Løgstrup, KO Kyvik, A Green, AK Sjølie. Department of Ophthalmology, Vejle Hospital, Denmark.

Purpose: To examine the changes in refraction and refractive components for people with and without diabetes over a 10 year follow-up period.
Methods: A longitudinal study of 21 twin pairs with at least one twin with Type 1 diabetes at baseline was performed in 1993 and 2003. At baseline, patients were from 12-39 years old. Refractometer- and keratometer-measurements were performed in cycloplegia. The spherical equivalent of refraction (refraction) and the radius of corneal curvature (CC) were calculated. Axial length (AL), anterior chamber depth (ACD) and lens thickness (LT) were measured with ultrasound biometry.
Results: Refraction shifted in a myopic direction in both people with and without diabetes. The mean difference in refraction over 10 years was -0.40 D in people with diabetes (p=0.001) and -0.22 D for people without diabetes (p=0.069). Lens thickness increased with 0.52mm (p<0.001) and 0.44 mm (p<0.001) in people with and without diabetes, respectively, and a corresponding decrease in anterior chamber depth of -0.20 mm (p<0.001) and -0.14mm (p=0.018) was found. Axial length increased with 0.05mm (p=0.161) and 0.12mm (p=0.044). Corneal curvature radius increased with 0.05mm (p<0.001) and 0.03mm (p=0.045). The differences in change between the groups with and without diabetes were not statistically significant in any of the parameters mentioned.
Conclusions: This study suggests that the myopic changes in refraction over time regardless of diabetic status may be caused by increased thickness of the lens. In addition, the duration of diabetes might enhance these myopic changes in the lens. An important perspective of this study is the evaluation of anterior chamber depth when examining patients with diabetes, to examine whether an increased risk of angle-closure glaucoma is present.

Poster Abstract 9

EFFECT OF THE ORAL PROTEIN KINASE C β; INHIBITOR RUBOXISTAURIN ON VISUAL ACUITY IN THE PKC-DRS2 STUDY. A Girach, LP Aiello, MD Davis, RC Milton, MJ Sheetz, X Zhi, L Vignati for the PKC-DRS2 Study Group.

Purpose: Patients with advanced nonproliferative diabetic retinopathy (NPDR) are at increased risk of vision loss. We explored the impact of Ruboxistaurin, an oral PKC β; inhibitor, on different visual acuity outcome measures, and the need for focal photocoagulation(PC), compared to placebo, in addition to standard of care.
Methods: The PKC-DRS2 study was a 36-month, double-masked, parallel, multi-center, phase 3 study. Patients were randomized to placebo (n=340) or 32 mg/d ruboxistaurin (RBX, n=345). Participants had moderately severe to very severe NPDR (ETDRS retinopathy score ≥47A and <53E), no prior panretinal photocoagulation, and a best-corrected visual acuity (VA) of ≥45 letters (~20/125, 0.16 or 6/40 Snellen) in a study eye. The primary objective was to assess the effect of RBX on the reduction of sustained moderate visual loss (SMVL: ≥15 ETDRS letter loss sustained over the last 6 months of the study).
Results: In the PKC-DRS2 study, 5.5% of RBX patients experienced SMVL, compared to 9.1% of placebo patients (40% risk reduction, p=0.034). RBX eyes were more likely to gain 15 letters of VA (4.9% vs. 2.4% placebo; p=0.027) and less likely to lose 15 letters (6.7% RBX vs. 9.9% placebo, p=0.044). Compared to placebo, RBX also reduced sustained loss of 10 letters (9.9% vs. 14.1%, p=0.043) and 5 letters (20.3% vs. 26.5%, p=0.033). From baseline-to-endpoint (last observation carried forward), the mean change in VA was -0.8 vs. -2.6 letters for the RBX and placebo groups, respectively (p=0.014). In eyes without focal PC prior to randomization, fewer RBX eyes required application of focal PC during the study (28.0%, RBX, vs. 37.9% placebo; p=0.008).
Discussion: In the PKC-DRS2 study, oral RBX reduced visual acuity loss and improved visual acuity more frequently than placebo over 36 months of treatment. RBX was also associated with less need for application of focal photocoagulation. These beneficial outcomes were evident in addition to standard of care.