Non-invasive structural and metabolic retinal markers of disease activity in non-proliferative diabetic retinopathy
This study will try to determine if macular ischaemia and the retinal venular oxygen saturation correlates with the level of DR along the entire DR-spectrum. It will also try to assess, if structural and metabolic changes are tightly associated at all levels of non-proliferative diabetic retinopathy (NPDR) and if non-invasive measurements of macular ischaemia and retinal venular oxygen saturation are able to predict progression of DR.
Diabetic retinopathy (DR) is the most common complication in diabetes and a leading cause of blindness in the working-age population of developed countries. In order to avoid vision loss, regular eye screening by retinal fundus photography is cost-effective and fully implemented in Denmark. Eye screening aims to identify sight-threatening DR - in particular proliferative diabetic retinopathy (PDR) - at an asymptomatic stage prior to irreversible visual loss. Many patients are seen annually regardless of disease activity. Individualized screening intervals could relieve the screening-burden put on patients and the health care system, but besides the level of DR there are no well-established retinal markers to identify patients at high risk of progression. To be implemented in a screening-setup, such markers should be based on fast and non-invasive retinal imaging techniques.
Optical coherence tomography angiography (OCTA) is a novel, non-invasive marker of the retinal vasculature. Motion contrast images are used to image high-resolution blood flow in order to generate angiographic images in a matter of seconds. The retinal microvasculature has traditionally been visualized by fluorescein angiography, but this is an invasive procedure with potential side effects, and it is only used in high-risk patients. Likewise, it is not able to separate the various layers of the retinal vasculature. As an alternative, OCTA enables the clinician for the first time to visualize the 3-dimensional structure of the retinal microvasculature, previously only visible with histologicalexaminations.
A variety of quantitative metrics can be obtained from OCTA including foveal avascular zone dimensions, a circularity index, and axis ratio which appear useful for quantifying the degree of central retinal ischemia and remodelling. In a cross-sectional study, Ting et al demonstrated that the retinal microvasculature in patients with proliferative diabetic retinopathy varied considerably from patients with no DR, but no information was given of the structure of the retinal
microvasculature in the intermediary levels of DR which are those most relevant for screening.
The retinal oximeter is a non-invasive measurement of the retinal metabolism. It is based on the principle that the colour of blood depends on the oxygen saturation of haemoglobin. A two-wavelength technique is used to estimate the haemoglobin oxygen saturation, and a colour map delineates the oxygen saturation of the retinal vessels.
In a pivotal study, Jorgensen et al described higher retinal venular oxygen saturation for patients with more advanced levels of DR, a finding which has recently been confirmed in a systematic review. However, it is not known if the increment in the retinal venular oxygen saturation happens gradually along the DR-spectrum, or if it is triggered at a certain level by structural damage in the retinal microvasculature.
This study aims to evaluate the association between microstructural and metabolic retinal changes along the DR-spectrum, and determine if such changes could predict progression of DR in a well-characterized population of diabetic patients from the Funen Diabetes Database.
Description of the cohort
Two hundred patients will be recruited from the Funen Diabetes database (FDDB) at the Department ofophthalmology at Odense University University Hospital (OUH). The FDDB was established in 2003 on the island of Funen, Denmark, which has approximately 473,000 inhabitants. The FDDB contains data of over 22,000 patients with diabetes. It is continuously updated on an individualized level and contains information of age, sex, type and duration of diabetes, glycaemic regulation, blood pressure, body mass index, blood pressure, blood tests, and levels of microvascular complications including level of DR. In FDDB, the level of DR is determined according to the International Clinical
Diabetic Retinopathy scale (ICDR). Categories include no DR (level 0), mild NPDR with microaneurysm(s) only (level 1), moderate NPDR (level 2) with more changes than mild NPDR, but less than severe NPDR (level 3). Severe NPDR is present for eyes with more than 20 intralretinal haemorrhages in all 4 retinal quadrants, or definite venous beading in more than 2 quadrants, or prominent intra-retinal
microvascular abnormalities more than 1 quadrant. Finally, PDR is categorized as level 4. The present study will include one eye in 200 patients without PDR equally distributed among levels 0-3 (n=50 in each group).
Data and biological material
The main study will be a cross-sectional examination including fundus 7-field 45 degree imaging to confirm the level of DR. OCTA imaging (Heidelberg Spectralis, Heidelberg Engineering Inc, Franklin, Massachusetts, USA) of macular ischaemia is analysed by semiautomatic software measurements of the capillary density index and fractal dimension at the superficial and deep retinal vascular plexus. Likewise, the retinal arteriolar and venular oxygen saturation will be measured at the optic disc and macula by Oxymap T1 using the Oxymap Analyzer software (Oxymap, Reykjavik, Iceland). Additional data (including age, sex, type and duration of diabetes, glycaemic regulation, blood pressure, body mass index, blood pressure, blood tests, and levels of microvascular complications) will be extracted from the FDDB.
Collaborating researchers and departments
Department of Ophthalmology, Odense University Hospital (OUH)
- Undergraduate student Gwen Weisner
- Principal supervisor Professor Jakob Grauslund
- PhD student Søren Blindbæk
Department of Ophthalmological research, Queen's University, Belfast, Northern-Ireland
Department of Ophthalmological research, University of Reykjavik, Iceland
- Professor Einar Stefansson
Department of Endocrinology, Odense University Hospital (OUH)
- Associate Professor Jan Erik Henriksen