Imaging


turnover in successive visits during a one- or two-year period. We have demonstrated that it is possible to use microaneurysm turnover computed from non-invasive colour fundus photographs as a biomarker to identify patients at risk of progression to clinically significant macular oedema (CSME).2


A microaneurysm formation rate


of at least two microaneurysms per eye in eyes with mild NPDR and diabetes type 2 also appears to identify patients at risk for progression to CSME. In one recent study, with a 10-year follow-up of 113 eyes/patients, the percentage of false negatives (eyes that developed CSME with a low microaneurysm formation rate) was 29.4 % (5/17) and the percentage of false positives (eyes that did not develop CSME with a high microaneurysm formation rate) was 8.3 % (8/96), resulting in a sensitivity in predicting CSME development of 70.6 %. The high negative predictive value for CSME (94.6 %, 88/93) indicates that a low microaneurysm turnover, i.e. fewer than two microaneurysms per year, identifies particularly well the eyes that are not expected to progress to CSME within a 10-year period.


Differences between successive visits using microaneurysm counts are less reliable than microaneurysm formation rates, which take into account newly formed microaneurysms and give more accurate information on activity of the retinopathy.11


Furthermore, we have also


found much better agreement between graders when determining microaneurysm turnover than in microaneurysm counting alone.1


Recently, Sharp et al.12 found that the microaneurysm turnover varied


widely among eyes of the same retinopathy level; this is consistent with our findings. Microaneurysm turnover has been shown in our studies to vary among eyes classified with the same retinopathy level.13


of NPDR: microaneurysms, alteration of the blood–retinal barrier and capillary closure.


Microaneurysms are a sign of vascular disease and their formation and disappearance, i.e. their turnover rate, appear to be the best indicators of disease activity. In the initial stages of NPDR a microaneurysm formation rate of two or more per year is a predictor of progression and the development of macular oedema.15


Capillary closure is a relevant step in the retinal vascular disease process that leads to progressive ischaemia and formation of preferential channels inducing remodelling of the retinal circulation. The presence of ischaemia is a necessary condition in the development of proliferative retinopathy. The development of capillary closure may be identified using colour fundus photography by determining the rate of microaneurysm disappearance or by changes in the same eye in the branching pattern of the arterioles and their density in the macula.


Alterations of the blood–retinal barrier cannot be identified by colour fundus photography but may be identified using another non-invasive method, optical coherence tomography (OCT).16


Measurements of


retinal thickness and changes in the retinal extracellular space resulting from focal alterations of the blood–retinal barrier occurring in the initial stages of NPDR can be performed and show the degree of breakdown of the blood–retinal barrier and its change over time. Work in progress in another group is also focusing on the ganglion cell layer using OCT to determine ganglion cell loss as an indicator of ischaemia.17


Particularly relevant and of major interest is the finding that patients who have higher microaneurysm turnover values go on to develop CSME and show more rapid retinopathy progression, particularly in association with poor metabolic control demonstrated by higher haemoglobin A1c values. Therefore, microaneurysm turnover appears to be a distinctive characteristic that indicates activity of disease and rapid progression in eyes with apparently similar retinopathy level.


A more recent study, using automated analysis of digital fundus photographs with the RetmarkerDR software, confirms our initial observations and demonstrates that automated analysis of fundus digital images is extremely promising in determining DR progression. Furthermore, it is an easy to use non-invasive tool to predict development of CSME. In the Caldiret study, co-ordinated by Munich University, a group of 290 eyes were followed by fundus photography for five years. It was possible to compare the 49 eyes that did develop CSME over the study period with the 241 eyes that did not develop CSME in the same five-year period.14


In this study, an increased microaneurysm


formation rate was confirmed to be clearly associated with the development of CSME. Values of microaneurysm formation rate greater than two per year in this early stage of retinopathy were present in 71.4 % of the eyes that developed CSME. In clear contrast, the eyes that did not develop CSME during the period of the study showed a microaneurysm formation rate of less than two per year in 71.8 % of the cases.


Identification of Risk Profiles Using Non-invasive Procedures


To evaluate progression of NPDR it is necessary to be able to closely follow any significant changes in the three major features


106


Incorporating information about progression risk can be difficult in clinical practice but is an objective that must be pursued if we want to improve management of DR and prevent the development of the major complications of DR: macular oedema and proliferative retinopathy.


Creation of a progression profile starts with establishing an adequate baseline. The first step is clinical assessment and documentation of patients with diabetes, identifying the presence of NPDR in its initial stage (equivalent to Wisconsin classification <43). This baseline should include digital fundus photography with at least two fields, one centred on the fovea and the other on the optic disk and OCT with central retinal thickness measurements and an optical density baseline and best corrected visual acuity obtained, preferably using Early Treatment Diabetic Retinopathy Study (ETDRS) procedures.


Subsequent testing should include the same procedures after six or 12 months and repeated again 24 months after the collection of the baseline. Automated computer-aided analysis of the fundus photographs will give the rate of progression of retinal vascular disease. The rate of formation of new microaneurysms indicates activity of retinal disease with the rate of disappearance of microaneurysms indicating the occurrence of capillary closure. Changes in OCT will monitor alteration of the blood–retinal barrier and how the retinal vessels are responding to changes of metabolic control in an individual eye. The next step is to develop a risk profile based on the patient’s ocular phenotype of progression and non-ocular risk factors.


Determination of the activity of the retinal disease and individual risk profiles using non-invasive procedures are expected to contribute decisively to better personalised management of diabetic retinopathy and prevent vision-threatening complications – macular oedema and proliferative retinopathy.


EUROPEAN OPHTHALMIC REVIEW


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