Colin S. Tan
SriniVas R. Sadda
Incorporating current trials and technology into clinical practice
Ultra-widefield (UWF) imaging has made a significant impact on the practice of ophthalmology in recent years, especially among retina specialists. Devices such as the Optos 200Tx (Optos, Dunfermline, U.K.) now allow imaging of up to 200° of the posterior pole in a single field of view1,2 (Figures 1 and 2). In contrast, the fields of view in conventional imaging devices are limited to between 30° and 55° of the posterior pole. Montages of several fields, such as those used in ETDRS seven-field imaging, have significant limitations, including inconvenience to patients as well as artifacts at the borders of the overlapping images.
Widefield fluorescein angiogram taken using the Optos 200Tx (Optos, Dunfermline, U.K.). Despite extensive panretinal photocoagulation, areas of capillary nonperfusion are seen together with several areas of hyperfluorescence caused by leakage from retinal neo-vascularization at the optic disc and elsewhere.
(A) Widefield (102°) fluorescein angiogram taken using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Ger-many). Photocoagulation scars are seen throughout the periphery, with several regions of capillary dropout throughout the posterior pole. There is also leakage from macular edema. (B) Grading diagram of the same eye, with areas of perfused retina (orange) and capillary dropout (blue).
Several imaging modalities are available to ophthalmologists using UWF devices, including pseudo-color images, fluorescein angiography (FA), and fundus autofluorescence (FAF). These have been shown to be of relevance to many diseases including diabetic retinopathy,3–5 retinal vein occlusion,6 age-related macular degeneration (AMD),2 uveitis, and retinal dystrophies. For example, the pattern of peripheral FAF abnormalities has been shown to vary among patients with neovascular and non-neovascular AMD, and it is possible that the presence of a particular type of abnormality may be a prognostic indicator for progression of the disease.2
Diabetic retinopathy (DR) is a common complication of diabetes mellitus, affecting up to 93 million people worldwide, and is estimated to be responsible for up to 17% of total blindness.7,8 Diabetic macular edema (DME) is a common cause of vision loss among diabetics9 and has been shown to have considerable impact on patients’ quality of life.10 In the United States, DME occurs in 30% of adult diabetics who have had the disease for more than 20 years.11 The prevalence varies with the severity of diabetic retinopathy: 3% among those with mild nonproliferative DR, 38% among those with moderate to severe nonproliferative DR, and increasing to 71% for those with proliferative diabetic retinopathy.11
Because the clinical features of DR occur throughout the posterior pole, UWF imaging is of particular importance managing this disease. Silva et al5 recently reported that the severity of DR assessed using widefield imaging and ETDRS photography matched in 80% of eyes and remained within 1 level in 94.5% of eyes (weighted kappa 0.74). Even more importantly, in 10% of eyes, UWF FA has been shown to demonstrate additional peripheral pathology such as nonperfusion and retinal neovascular-ization that would have been missed on corresponding ETDRS seven-field imaging (Figure 1).
Even though DME occurs at the macula and is adequately imaged using conventional devices, recent studies suggest that UWF imaging may play an important role in assessing and managing patients with DME. Several studies have demonstrated an association between peripheral retinal nonperfu-sion and the occurrence of both neovascularization and DME.3,4 This is believed to be mediated by the production of vascular endothelial growth factor (VEGF). We know that retinal ischemia stimulates VEGF production. VEGF is a potent vasodilator that weakens the walls of the capillaries at the macula, which enhances vascular permeability and causes leakage of proteins, lipids, and fluid, resulting in the formation of DME. It has been shown that retinal photocoagulation reduces the levels of VEGF in the eye,12 and it is possible that laser photocoagulation may have a beneficial effect on control of DME.13
A study by Wessel et al4 found that 26.3% of eyes with peripheral ischemia on UWF FA had DME, compared to 8.7% among eyes without ischemia (P < .001). Moreover, eyes with ischemia had 3.75 times higher odds of having DME compared to those without ischemia. Patel et al reported that among a cohort of 76 patients (148 eyes) with recalcitrant DME, the mean ischemic index — the amount of retinal nonperfusion expressed as a percentage of the total area of visible retina — was 47%, with a range of 0% to 100%.3 The extent of the peripheral nonperfusion varied with the cohort, being 0% for those with mild nonproliferative DR and ranging from 53% to 65% among patients with proliferative DR. Patients with larger areas of non-perfusion had more recalcitrant DME and required a larger number of macular photocoagulation treatments. Patients in cohort 4, defined as active proliferative DR with or without prior panretinal pho-tocoagulation, experienced the smallest decrease in central macular thickness (7.2%) after treatment and required an average of 5.7 macular photocoagu-lation treatments.3 Patel et al also reported differences among patients with focal and diffuse DME. The mean ischemic index was higher for eyes with diffuse compared to focal DME (ischemic index 64% vs 41%). In addition, 69% of eyes with untreated nonperfusion had diffuse DME, while the remaining 31% manifested with focal DME.
Not all studies, however, have found a relationship between peripheral nonperfusion and macular edema. Sim et al14 reported no relationship between DME and either peripheral ischemia or peripheral leakage. Wessel et al also reported no correlation between the presence of peripheral nonperfusion and central macular thickness on optical coherence tomography.4 The authors suggested that perhaps only a small amount of retinal ischemia is required to cause DME and that macular thickening may be related to local, structural, and anatomical factors rather than the amount of VEGF present.4 These findings, while requiring further study and validation, are interesting because they suggest that not all regions of peripheral nonperfusion contribute equally to DME. Additional studies are required to determine which regions of the retina may contribute more significantly to the formation of macular edema and whether it is possible to distinguish these regions reliably using current imaging modalities.
The results of recent studies have generated proposals on new ways to treat DME. Patients with recalcitrant DME may benefit from targeted retinal photocoagulation to areas of retinal nonperfusion.3 This would theoretically address the major underlying driver of the DME and perhaps reduce the frequency of anti-VEGF injections or macular laser photocoagulations required, while sparing areas of peripheral retina that remain perfused. Another proposal is the use of combination therapy: using anti-VEGF injections to block existing VEGF molecules, while performing targeted retinal photocoagulation to reduce VEGF production from areas of nonperfu-sion.3 It is possible that such combination therapy may enhance the durability of treatments and reduce the number of treatments that patients require.
While there is still much to be learned, it seems clear that UWF imaging, in particular UWF angiography, is of considerable importance to assess retinal pathology among patients with DR and DME and indeed other retinal vascular disorders such as retinal vein occlusion.
- Heussen FM, Tan CS, Sadda SR. Prevalence of peripheral abnormalities on ultra-widefield greenlight (532 nm) autofluorescence imaging at a tertiary care center. Invest Ophthalmol Vis Sci. 2012;53:6526–6231. doi:10.1167/iovs.12-9909 [CrossRef]
- Tan CS, Heussen F, Sadda SR. Peripheral autofluorescence and clinical findings in neovascular and non-neovascular age-related macular degeneration. Ophthalmology. 2013;120:1271–1277. doi:10.1016/j.ophtha.2012.12.002 [CrossRef]
- Patel RD, Messner LV, Teitelbaum B, et al. Characterization of isch-emic index using ultra-widefield fluorescein angiography in patients with focal and diffuse recalcitrant diabetic macular edema. Am J Oph-thalmol. 2013;155:1038–1044. doi:10.1016/j.ajo.2013.01.007 [CrossRef]
- Wessel MM, Nair N, Aaker GD, et al. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol. 2012;96:694–698. doi:10.1136/bjophthalmol-2011-300774 [CrossRef]
- Silva PS, Cavallerano JD, Sun JK, et al. Nonmydriatic ultrawide field retinal imaging compared with dilated standard 7-field 35-mm photography and retinal specialist examination for evaluation of diabetic retinopathy. Am J Ophthalmol. 2012;154:549–559. doi:10.1016/j.ajo.2012.03.019 [CrossRef]
- Singer M, Tan CS, Bell D, Sadda SR. Area of peripheral retinal non-perfusion and treatment response in branch and central retinal vein occlusion. Retina. In press.
- World Health Organization. Global Initiative for the Elimination of Avoidable Blindness: Action Plan 2006e2011. Geneva, Switzerland: World Health Organization, 2007.
- Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–564. doi:10.2337/dc11-1909 [CrossRef]
- Klein R. Diabetic retinopathy. Annu Rev Public Health. 1996;17:137–158. doi:10.1146/annurev.pu.17.050196.001033 [CrossRef]
- Hariprasad SM, Mieler WF, Grassi M, et al. Vision-related quality of life in patients with diabetic macular oedema. Br J Ophthalmol. 2008;92:89–92. doi:10.1136/bjo.2007.122416 [CrossRef]
- Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984;91:1464–1474. doi:10.1016/S0161-6420(84)34102-1 [CrossRef]
- Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–1487. doi:10.1056/NEJM199412013312203 [CrossRef]
- Gardner TW, Eller AW, Friberg TR. Reduction of severe macular edema in eyes with poor vision after panretinal photocoagulation for proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1991;229:323–328. doi:10.1007/BF00170689 [CrossRef]
- Sim DA, Keane PA, Rajendram R, et al. Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography. Am J Ophthalmol. 2014;158:144–153. doi:10.1016/j.ajo.2014.03.009 [CrossRef]
Colin S. Tan, MBBS, FRCSEd (Ophth), MMed (Ophth), can be reached at National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Level 1, TTSH Medical Centre, 11 Jalan Tan Tock Seng, Singapore 308433; email:
SriniVas R. Sadda, MD, can be reached at Doheny Eye Institute-DEI 3623, 1450 San Pablo Street, Los Angeles, CA 90033; email:
Seenu M. Hariprasad, MD, can be reached at the Department of Ophthalmology and Visual Science, University of Chicago, 5841 S. Maryland Avenue, MC2114, Chicago, IL 60637; 773-795-1326; email:
Supported in part by the National Healthcare Group Clinician Scientist Career Scheme Grant CSCS/12005 (Dr. Tan).
Disclosures: Dr. Tan receives travel support from Bayer, Heidelberg Engineering, and Novartis. Dr. Sadda has served as a consultant to Alcon, Allergan, Carl Zeiss Meditec, Genentech, and Optos. Dr. Hariprasad is a consultant or on the speakers bureau for Alcon, Allergan, Bayer, Clearside Biomedical, Optos, Ocular Therapeutix, OD-OS, and Regeneron.