Diabetic Retinopathy Classification: ETDRS 7-fields vs Widefield Imaging (ClarusDR)

Study Overview
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Brief Summary
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The goal of this observational study is to analyse and compare Diabetic Retinopathy severity level using 30º ETDRS 7-fields and Wide-field Imaging techniques using Clarus 500 (Carl Zeiss Meditech Inc., Dublin, USA) and Optos (Optos, Dunfermline, UK) in diabetic patients with mild to moderate diabetic retinopathy. The main questions it aims to answer are: 1. To compare the Clarus 500TM wide-field imaging technique with the ETDRS 7-fields method in the assessment of DR severity level using the ETDRS DRSS.2. To compare the two wide-field imaging techniques (Clarus 500TM vs OptosTM) in the assessment of DR severity level using the ETDRS DRSS.3. To evaluate the peripheral area imaged by the wide-field Clarus 500TM and OptosTM to characterize DR lesions distribution (predominantly observed within or outside the ETDRS 7-fields) and severity (according to the ETDRS standard photos).4. To determine the relevance and frequency of DR PPL, located outside the ETDRS 7-fields area, and to explore PPL occurrence in different DR severity levels. Participants will undergo a non-invasive ophthalmological examination, which includes BCVA, 7-fields CFP and UWF FP to assess ETDRS DRSS level.

Detailed Description
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Diabetic Retinopathy (DR) remains a significant cause of blindness in working-age populations across the world. The gold-standard method for assessing its severity is the modified Airlie House classification developed for the Early Treatment Diabetic Retinopathy Study (ETDRS), still used by clinical trials for developing of DR therapeutic and management guidelines. ETDRS Diabetic Retinopathy Severity Score (DRSS) is based on the identification of DR lesions on colour fundus photography's (CFP) obtained in different locations of the retina. The photography acquisition protocol consists in acquiring seven stereoscopic pairs of overlapping 30° fields images of the ocular fundus to map out the macula and mid-peripheral retina. Photographers and fundus camera systems usually need training and certification by external reading centres to guarantee proper images quality and fields definition in a process that can be challenging with a considerable learning curve. Patient collaboration to follow a fixation point in different locations and withstand intense flashes of light, a good dilation of eye pupil and the difficulty to obtain well focused images in peripherical gaze positions are some of the main difficulties for obtaining gradable images using this 7-fields acquisition protocol. On the other side, the grading process of ETDRS 7-fields images can be extremely labour-intensive and strongly dependent on the quality of the images, presence of artifacts and the definition of the peripherical fields, requiring well-trained people to identify and recognise features that can be very subtle or easily get unnoticed. Moreover, the retinal area documented with the ETDRS 7-fields protocol represents approximately only 35% of the retina surface. Substantial diabetic retinal pathology can exist in the retinal periphery located outside this area which is being emphasized by advanced retinal imaging technology. Predominantly Peripheral Lesions (PPL) like the presence of venous beading, new-vessels, haemorrhages and microaneurysms in the extreme periphery have been correlated with peripheral non-perfusion, neurodegenerative changes and consequent increase of DR progression. Recent instrumentation like OptosTM (Optos, Dunfermline, UK) or Clarus 500TM (Carl Zeiss Meditech Inc., Dublin, USA) allow wide-field acquisitions that document up to 90% of the retina surface in just one or two images decreasing patients tiredness and discomfort and overcoming most of the quality and fields definition issues described above. OptosTM equipment can acquire almost 200º of the retina in just one picture without the need for pupil dilation and using ultra-widefield scanning laser ophthalmoscopy (SLO) technology. Its final image is based on the superimposition of two images acquired with 2 different laser wavelengths: a green and a red wavelength, giving a semirealistic colour image that despite its high contrast and sharpness, gives the retina a greenish and unreal aspect. Also, its 200º field amplitude is usually disturbed by artifacts caused by the presence of eyelashes or eyelids, that mainly obscure the peripherical area of the retina. On the other hand, Clarus 500 TM equipment uses an imaging technique called Broad Line Fundus Imaging that is a hybrid of confocal SLO (cSLO) and traditional fundus photography. This technology provides higher resolution images with more accurate coloration of the fundus. A single image capture with this system obtains 133-degrees of view but with the acquisition of just two pictures (a temporal and nasal image of the retina), a 200-degree of view can be achieved. Several studies have suggested moderate to substantial agreement between Optos ultra-wide field (UWF) and ETDRS 7-fields imaging and have shown that DR occurs in areas peripheral to the ETDRS fields in up to 40% of eyes, which may imply a more severe level of DR in 9% to 15% of eyes. However, there is only limited data regarding the validity of DR assessment using Clarus 500TM imagine technique obtained in cross-sectional studies with few patients. On this basis, the aim of this work is to identify and compare the ETDRS severity level of diabetic patients using 3 different images modalities: the 30º ETDRS 7-fields colour fundus photography's protocol, the 2 wide-field images technique with Clarus 500 TM and the 1 wide-field image of OptosTM, in a prospective, longitudinal, and randomized study. The ETDRS 7-fields area will be superimposed on both wide-field equipment's images so equivalent retinal areas will be analysed. Our goal is to demonstrate that ETDRS severity level can be accurately evaluated using only two Clarus 500TM high quality images with wider amplitude, decreasing the effort and collaboration skills that are required in older techniques, while improving the quality and identification capability of key disease features with less artifacts than other wide-field systems. Additionally, peripheral retina outside the ETDRS 7-fields area will also be analysed to assess the presence of PPL and evaluate its relevance and association with disease severity level and progression. Finally, the investigators expect to evaluate patients' opinion about their experience in each imaging modality, evaluating their discomfort and satisfaction degree while submitted to each procedure.

Official Title
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Diabetic Retinopathy Classification: ETDRS 7-fields vs Widefield Imaging (Clarus 500 and Optos California)

Conditions
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Retinopathy, Diabetic

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: DM type 2 according to 1985 World Health Organization (WHO) criteria Age between 35 and 80 years BCVA ≥ 75 letters (20 /32) Refraction with a spherical equivalent less than 5 Diopters NPDR levels 35 and 43-47 (based on the ETDRS criteria - 7 fields CFP) Exclusion Criteria: Cataract or other eye disease that may interfere with fundus examinations Glaucoma Other retinal vascular disease than DR Refractive errors > to + or - 5 Diopters Pupil diameter of less than 5 mm Poor quality images due to artifacts, movements, or media opacities

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ETDRS severity level according to the Early Treatment Diabetic Retinopathy Study - Diabetic Retinopathy Severity Scale (ETDRS-DRSS). | Compare DR severity level between the ETDRS 7-fields imaging and the wide-field imaging techniques: Clarus 500TM and OptosTM. The ETDRS - DRSS goes from level 10 - no presence of DR to level 75 - Severe proliferative DR | 12 months | 
| One or more than 2-steps change on ETDRS - DRSS severity level | Compare ETDRS -DRSS between the two imaging techniques and evaluate the presence of 1 step or more than 2 steps difference between ETDRS 7-fields imaging and the wide-field imaging techniques: Clarus 500TM and OptosTM | 12 months | 
| Peripheral DR lesions characterization | Investigate the peripheral area and analyze the presence, distribution, and severity of peripheral DR lesions, in wide-field images: Clarus 500TM and OptosTM. Presence and distribution of lesions in the periphery will be evaluated as 1) Not observed; 2) predominantly observed outside ETDRS fields; 3) Uniformly distributed within and outside ETDRS fields. 4) Ungradable. Severity of the peripheral lesions will be evaluated using the same ETDRS-DRSS scale described above and will vary between level 35 and level 65. Also, it will then be compared with the ETDRS 7-field area and graded as less, equivalent or greater than the observed inside ETDRS 7-fields area. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Images quality in each imaging modality. | Images from each modality (7-fields, Clarus 500 and Optos TM) will be analysed according to 1) presence of artifacts like eyelashes, halos, eyelids, cataract opacities, etc; 2) Presence of unfocused areas 3) % of area occupied by those artifacts. | 12 months | 
| Evaluation of Patients satisfaction about each imagining modality. | To evaluate patient's experience and degree of satisfaction in each imaging modality, a questionnaire will be developed with qualitative and quantitative questions covering all aspects of the experience. | 12 months | 
| Correlate and analysed DR findings in each imaging technique with disease severity | To characterize the study population, demographic, and systemic characteristics, as well as visual function (BCVA), will be collected and analysed to correlate DR findings in each imaging technique with disease severity | 12 months |