Understanding retinal vascular disease with UWF angiography

October 15, 2018

Increasingly, UWF imaging is becoming standard practice in diabetic retinopathy and retinal vein occlusion, as well as providing important insights into the management of retinopathy of prematurity and rare hereditary retinal vascular conditions.

Increasingly, UWF imaging is becoming standard practice in diabetic retinopathy and retinal vein occlusion, as well as providing important insights into the management of retinopathy of prematurity and rare hereditary retinal vascular conditions.

Fundus photography and fluorescein angiography are well-established tools in the diagnosis and management of retinal vascular disease. In particular, the seven-standard fields (7SF) developed in the Early Treatment Diabetic Retinopathy Study (ETDRS) have been widely employed; many treatment algorythms derived from multicenter studies are based on this 75˚-imaging technique.

The development of ultra-widefield (UWF) imaging provides significantly more information for clinicians and researchers. The widest available field of view currently from a single image is that provided by the Optos devices, which combine a scanning laser ophthalmoscope and an ellipsoidal mirror. These UWF devices produce a 200° field of view (roughly 82.5% of the total retinal surface area) in a single image capture.

Increasingly, the use of UWF imaging is becoming standard practice in diabetic retinopathy (DR) and retinal vein occlusion (RVO), as well as providing important new insights into the management of retinopathy of prematurity and rare hereditary retinal vascular conditions.

Diabetic retinopathy

Patients with DR typically have ischemic changes in the central field that are visible with conventional imaging. However, recent studies suggest UWF imaging may lead to more accurate classification of the disease because it can reveal significantly more retinal vascular pathology than 7SF imaging, including 3.9 times more nonperfusion and 1.9 times more neovascularization. (Figures 1 and 2A,B).1 In about 10% of patients, UWF angiography leads to a diagnosis of DR that would have been missed entirely by 7SF.1

The improved retinal visualization of UWF imaging may also influence follow-up and treatment. For example, while we know that panretinal photocoagulation (PRP) reduces ischemia in the retina and is widely accepted as appropriate treatment for proliferative DR, it also has significant morbidity (in the form of macular edema, loss of peripheral vision, and decreased night vision) that we would rather avoid. Through better visualization of the periphery with UWF, it is possible to identify areas of non-ischemic retina that could be avoided during PRP to preserve the areas of healthier retinal tissue.

In addition, close evaluation of UWF angiography in high-risk diabetic patients who do not yet have neovascularization and capillary dropout may help to identify predictors of proliferative DR. Identification of the extent of retinal nonperfusion area and calculation of the nonperfusion index using UWF fluorescein angiography has been shown to be highly correlated with severity of DR and the presence of predominantly peripheral lesions, themselves a risk factor for progression of DR.2 Recent evidence suggests that late angiographic posterior and peripheral vascular leakage (LAPPEL) or PVL (peripheral vessel leakage) may be a marker of inflammation and a precursor of capillary dropout.3 Perivascular leakage, as demonstrated by UWF imaging, is associated with neovascularization and possibly with macular edema.4,5 The use of UWF to detect LAPPEL or PVL could allow us to treat at-risk patients with intravitreal anti-VEGF before these complications occur, thereby postponing or avoiding PRP and its associated damage.

We are also using UWF to increase the efficiency of laser surgery in patients with DR. When patients undergo surgery to treat a non-clearing vitreous hemorrhage or tractional retinal detachment, we treat the far periphery initially, but it is difficult to know how centrally to draw the borders.

My current approach is to use UWF imaging to guide my secondary laser treatment of the remaining ischemic areas several weeks postoperatively.

Future protocols for DR will continue to change dramatically thanks to insights gained from UWF angiography.

Retinal vein occlusion

Historically, vein occlusions have been classified as ischemic or nonischemic based on the amount of retinal nonperfusion. UWF imaging now provides the opportunity to visualize greater areas of peripheral nonperfusion, which should lead to more accurate classification of RVO. Some researchers are already using UWF angiography to develop an ischemic index that better represents the amount of nonperfused to total visualized retina to aid in this classification.

Further exploration of UWF imaging may also help to explain the considerable variability we see in nonperfusion among patients with RVO. In turn, better understanding of this variability and its relationship to the extent and location of vein occlusion may prompt more robust analysis of risk factors for ischemic progression.

There has been considerable debate over whether PRP of the ischemic areas in RVO can reduce the burden of intravitreal injections; to date, the available literature is inconclusive. It is not clear whether previous studies have failed to show a reduction in injections because the laser treatment was ineffective generally or because the laser treatment was not appropriately targeted as would now be possible with UWF imaging to guide treatment. We are currently recruiting patients for the PEARL study, which will evaluate whether laser treatment of peripheral ischemic areas specifically identified by UWF angiography affects intravitreal injection outcomes.

Hereditary vitreoretinal pathology

In many patients with genetic vitreoretinal pathologies such as familial exudative vitreoretinopathy (FEVR) or Norrie disease, the condition is related to defects in the development of retinal vessels and, in particular, to immature development of the peripheral vasculature, similar to what we see in retinopathy of prematurity (ROP).

These conditions range from mild (with no clinical symptoms or visual deterioration) to quite severe cases in which there may be a full retinal detachment. Imaging of the peripheral vasculature is required for diagnosis (Fig 3A,B). Early detection is critical because laser treatment in the earlier stages of the disease can improve outcomes. We are finding that in children with severe vitreoretinal pathology, imaging of their parents or other family members often aids in diagnosis.

In one case, we examined a young child with severe FEVR. The child’s mother had no symptoms and completely normal central angiography, but UWF angiography revealed peripheral pathology in the mother’s eyes, and further testing showed she had the same genetic variant or single nucleotide polymorphism (SNP) as the child.

We know that four SNPs [FZD4 (frizzled-4), NDP (Norrie disease pseudoglioma), LRP5 (low-density lipoprotein receptor-like protein 5), and TSPAN12 (tetraspanin 12)] are responsible for nearly 50% of FEVR cases.6 However, there can be significant variation in the clinical presentation of patients with the same genetic variation, as in the case described above.

In another case, a child had been diagnosed with severe ROP. Although he had been born pre-term, at 26 weeks, he needed minimal oxygen after birth and had no other risk factors for ROP, so the severity of the condition was surprising. We performed UWF angiography of the whole family and found both parents also had abnormal peripheral vasculature not associated with any known disease. We believe they may have a new variant of hereditary silent protein disease that contributed to what appeared to be ROP.

It is entirely possible that this genetic mutation may have been a risk factor not just for retinopathy but for the child’s prematurity in the first place. Previously published work has shown that in patients with severe ROP there is a higher rate of Norrie disease mutations and that FZD4 gene mutation may be a risk factor for retinopathy and pre-term birth.7,8

It seems clear that there are probably quite complex interrelationships among FEVR, Norrie disease, retinopathy of prematurity, and other conditions, such as Coats' disease. We have a lot to learn about how to use this genetic information in combination with imaging. We are currently looking at phenotype/genotype correlations and hoping that UWF imaging can help to identify patients at risk.  

In other rare genetic retinal vascular pathologies UWF imaging is already leading to new treatment protocols. In a recent study involving subjects with Eales disease, UWF angiography led to immediate changes in the treatment plans of one-third of the patients because of peripheral changes picked up in the UWF imaging that had not previously been visible.9

These are very exciting times. With UWF imaging we have a chance of detecting pathology before complications occur and potentially guiding treatment more effectively for a variety of disease states. Moreover, beyond just providing us with broader visualization of well-understood diseases, UWF imaging is changing our fundamental understanding of these retinal vascular conditions.

Disclosures:

Prof Armin Wolf e: armin.wolf@med.uni-muenchen.de
Prof Armin Wolf is consultant and vice director in the Department of Ophthalmology at Ludwig Maximilians University’s Klinikum der Universität München in Munich, Germany.

References:

1. Wessel MM, Aaker GD, Parlitsis G, et al. Ultra wide-field angiography improves the detection and classification of diabetic retinopathy. Retina 2012;32(4):785-91.

2. Silva PS, Dela Cruz AJ, Ledesma MG, et al. Diabetic retinopathy severity and peripheral lesions are associated with nonperfusion on ultrawide field angiography. Ophthalmology 2015;122(12):2465-72.

3. Thanos A, Todorich B, Trese MT. A novel approach to understanding pathogenesis and treatment of capillary dropout in retinal vascular diseases. Ophthalmic Surg Lasers Imaging Retina 2016;47(3):288-92.

4. Oliver SC, Schwartz SD. Peripheral vessel leakage (PVL): a new angiographic finding in diabetic retinopathy identified with ultra wide-field fluorescein angiography. Semin Ophthalmol 2010;25(1-2):27-33.

5. 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;96:694-8.

6. Kondo H. Complex genetics of familial exudative vitreoretinopathy and related pediatric retinal detachments. Taiwan J Ophthalmol 2015;5(2):56-62.)

7. Dailey WA, Gryc W, Garg PG, Drenser KA. Frizzled-4 variations associated with retinopathy and intrauterine growth retardation: A potential marker for prematurity and retinopathy. Ophthalmology 2015;122(9):1917-23.

8. Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Molecular Vision 2006;11:501-8.

9. Kumar V, Chandra P, Kumar A. Ultra-wide field angiography in the management of Eales disease. Indian J Ophthalmol 2016;64(7):504-7.