Proliferative diabetic retinopathy is a leading cause of severe vision impairment. Untreated, almost half of patients with high risk PDR will develop severe visual loss within five years.
Over the last few years, major studies have challenged conventional wisdom on the management of proliferative diabetic retinopathy (PDR). At the forefront of this paradigm shift has been debate revolving around the role of intravitreal anti-vascular endothelial growth factor (VEGF) agents for PDR. Globally, 8.5 per cent (422 million people) of the adult population suffer from diabetes mellitus (DM), a four-fold increase since the 1980s.1 This trend relates to the positive correlation between DM and ageing. There is also a growing trend of adolescents developing DM due to obesity.
In Australia, the prevalence of DM has doubled from 2.4 per cent (400,000 people) in 1995 to approximately 5.1 per cent (1.2 million people) in 2014-15, with a daily rate of over 270 Australians being newly diagnosed with diabetes.2,3 The prevalence differs between location and demographics, with a higher frequency in remote areas (6.7 per cent) than in major cities (4.7 per cent) and triple the rate in the indigenous Australian population.2,4 The Australian Diabetes, Obesity and Lifestyle (AusDiab) study predicts that the prevalence of DM will continue to rise to 11.4 per cent by 2025.5
In patients presenting with PDR but no DMO, the recommended management is less clear
Diabetic retinopathy (DR) places a significant burden on the Australian economy, with an indirect cost of AU$2 billion per year from DR related vision loss.2 In Australia, DR affects 24.5 per cent of people with known DM, with proliferative DR (PDR) accounting for 2.1 per cent of those with DM.6 Proliferative diabetic retinopathy is a leading cause of severe vision loss in patients with DR.7 Without treatment, almost half of patients with high risk PDR will develop severe visual loss within five years.8
The correlation between the pathogenesis of DR with chronic hyperglycemia, hypertension and hyperlipidemia is well established.9 There are several pathways implicated with early DR, observed as changes in the cellular composition and structure of the microvasculature.9 Damage to endothelial cells and retinal pericytes leads to a break down of the blood-retinal barrier. Progressive ischemia induces vascular endothelial growth factor (VEGF) which in turn stimulates the growth of new abnormal blood vessels, the hallmark of PDR. At any stage of DR, diabetic macular oedema (DMO) can occur.
Diabetic retinopathy can be classified by the International Clinical Disease Severity Scale for DR (Table 1).10
The hallmark of PDR is the presence of neovascularisation.10-12 These abnormal blood vessels are stimulated by increased levels of VEGF in diabetic eyes and can develop at the optic nerve neovascularisation of the disc, NVD, Figure 1), retina (neovascularisation elsewhere, NVE, Figure 2) or in the anterior segment (neovascularisation of the angle, NVA; neovascularisation of the iris, NVI). In the fundus, these vessels grow on top of the retina (pre-retinal), and often along the posterior hyaloid face and into the vitreous. This ‘elevation’ and their fine, lacy appearance can help distinguish nevoascularisation from intraretinal microvascular abnormalities (IRMAs). Gonioscopy is important to identify NVA and should be performed in patients at risk for PDR or with elevated intraocular pressures.
In themselves, neovascular vessels are usually asymptomatic. This can give patients a false sense of security as the absence of symptoms is discordant with the severity of their retinopathy. Examination of the peripheral fundus is necessary as eyes with mainly peripheral DR lesions have five times the risk of progressing to PDR13,14 and peripheral NVE can easily be missed. Neovascular vessels become symptomatic if they bleed into the pre-retinal space or vitreous. Any pre-retinal blood (which will obscure retinal blood vessels) warrants a careful examination for neovascularisation. Neovascular vessels can also fibrose and contract, leading to tractional and rhegmatogenous retinal detachments. Those in the angle can cause rubeotic glaucoma or hyphema. Independent to the proliferative process, diabetic patients can lose vision due to DMO or foveal ischaemia.
The severity of retinopathy at baseline is the predominant risk factor for the progression of DR to high risk PDR.15 Other risk factors include poor glycaemic control, systemic hypertension, dyslipidaemia, anemia, pregnancy, cataract surgery, diabetic neuropathy, low serum albumin, younger age, and Type 1 DM.15
All patients with diabetic retinopathy require systemic investigations performed in conjunction with their general practitioner and/or endocrinologist. These include fasting blood sugar level, HbA1c, systemic blood pressure, full blood count (for anemia), urea/electrolytes/creatinine (for diabetic nephropathy) and serum lipids. The presence of DR is a sign of widespread end-organ microcirculatory damage, and patients with DR have triple the risk of developing coronary artery disease and stroke, independent of cardiovascular risk factors.16
Although the presence of neovascularisation can usually be diagnosed clinically, fundus fluorescein angiography (FFA) is useful for confirming the presence of new vessels. Such vessels will demonstrate hyperfluorescent leakage in the late phases of the angiogram. Fundus fluorescein angiography is also useful in documenting areas of capillary nonperfusion and ischaemia, which are not easily identifiable with clinical examination alone. Such areas can be targeted when performing pan-retinal photocoagulation. Rarely, anterior segment angiography can be performed to identify NVI.
Traditionally, seven-field montages captured with 30-50 degree cameras were the gold standard for fundus imaging in diabetic retinopathy.17 More recently, ultrawidefield imaging systems have allowed for a field of view up to 200 degrees, and are thought to improve the detection of peripheral lesions and accuracy of classification (Figure 3).17 Disadvantages of fluorescein angiography are its invasive nature and 5 per cent risk of developing an adverse reaction. This can range from mild (e.g. nausea, vomiting, pruritus, rash) to severe (e.g. local tissue necrosis, syncope, bronchospasm, anaphylaxis and cardiogenic shock).18 Furthermore, recent evidence has shown that FFA may underestimate the vascular features of the retina by 50 per cent when compared to histological assessment.19
Optical Coherence Tomography Angiography
Optical coherence tomography (OCT) is the most important investigative tool for identifying DMO, but is not very effective in detecting proliferative disease other than cross-sectional characterisation of already identified neovascular lesions. OCT angiography (OCTA) is a newer technique based on OCT technology that produces ‘en face’ images. It detects variation (decorrelation) in reflectivity, phase shift or phase variance to identify blood flow within retinal vessels. Its basis is the principle that the only difference between sequentially obtained OCT cross sectional scans can be attributed to motion of erythrocytes (red blood cells) through retinal and choroidal blood vessels.21
Its advantages include an ability to visualise the retinal layers in segments (‘en face’), identification of vascular complexes invisible to FFA (such as the deep capillary plexus and radial peripapillary capillary network), its high resolution, and the avoidance of an intravenous dye.20
Disadvantages include image artefacts such as from movement, masking and projection, its longer acquisition time than conventional FFA, smaller field of view, inability to show leakage and difficulties in interpreting this new technology.22 OCT-A has been shown to be able to objectively stage DR.23 Neovascular vessels do not ‘leak’ as they do in fluorescein angiography, but have two distinct morphologies: an irregular proliferation of fine vessels (‘exuberant vascular proliferation’) or pruned vascular loops.24 Currently, the application of OCT-A in detecting proliferative diabetic retinopathy is limited by its small field of view.
Management of all diabetic retinopathy begins with systemic control of blood sugar levels25,26 and systemic hypertension.27 There is evidence that a 1 per cent decrease in glycated haemoglobin (HbA1c) can decrease progression to vision threatening retinopathy by 25 per cent.28 Similarly, control of blood pressure helps reduce the risk of DR, with every 10mmHg decrease in blood pressure associated with a 15 per cent risk reduction in PDR.29 Treatment with fenofibrates may also reduce the progression of diabetic retinopathy and the need for laser, although whether this result is through its lipid lowering effect is debateable.30,31
Laser (Panretinal Photocoagulation)
For forty years, panretinal laser photocoagulation (PRP) has been the gold standard treatment for PDR since the publication of two landmark clinical trials, the Diabetic Retinopathy Study (DRS)8,32 and the Early Treatment Diabetic Retinopathy Study (ETDRS).33 The aim of panretinal laser photocoagulation (PRP) is to elicit thermal damage in ischaemic extra-macular peripheral retina to reduce VEGF production and thus the neovascular drive (Figure 4).
Diabetic Retinopathy Study
The Diabetic Retinopathy Study (DRS) was a randomised controlled trial (RCT) that included 1,758 patients from 15 centres with PDR or severe bilateral non-proliferative diabetic retinopathy (NPDR). The two year incidence of severe visual loss (SVL; ie. visual acuity less than 6/240 at two or more consecutive four month follow up visits) was reduced by over half in patients with PDR receiving PRP. The authors recommended PRP in eyes with ‘high-risk’ PDR; ie NVD or NVE associated with pre-retinal or vitreous haemorrhage, or NVD (within 1 disc diameter of the optic disc) with an area of at least one quarter to one third of the disc.
Early Treatment of Diabetic Retinopathy Study The Early Treatment of Diabetic
Retinopathy Study (ETDRS) randomised 3,711 patients with DR from 22 clinical centres. One eye from each patient was randomly assigned to early laser photocoagulation (mild or full), and the other eye did not receive laser. Full scatter laser photocoagulation consisted of 1,200-1,600 moderately intense white burns with a spot size of 500 microns and duration of 0.1s. Early photocoagulation was associated with a small reduction in the incidence of severe visual loss (visual acuity less than 6/240 at two consecutive visits), although the five-year rates of this were low in both groups (2.6 per cent in the laser arm, 3.7 per cent in the deferred laser arm).33 Like DRS, ETDRS recommended prompt laser in patients with ‘high risk’ PDR.
Side Effects of Panretinal Photocoagulation
Both the DRS and ETDRS recognised that PRP is not without side effects, which can include: reduced peripheral vision, nyctalopia, reduced accommodation, pain, exacerbation of DMO, choroidal effusion, inadvertent foveal burn and late choroidal neovascularisation following an excessive burn. For this reason, PRP was not recommended for patients with mild or moderate NPDR.8,33,34 The DRS found less side effects with argon compared to xenon laser photocoagulation.8
Newer Laser Photocoagulation Techniques
A recent Cochrane review compared conventional PRP described in the ETDRS (midperipheral scatter, moderate intensity PRP with 0.1 second pulse duration) with modern laser techniques (double frequency Nd: YAG laser; diode laser; longer laser pulse; less intense laser burns).35 A total of 11 RCTs were included with best corrected visual acuity as the primary outcomes. The study found limited evidence for the efficacy and safety of these modern laser techniques compared to conventional PRP as described by the ETDRS.35 The main limitation of the included RCTs was the high risk of bias and small study size – nine out of 11 studies had 50 or fewer subjects.
Intravitreal Anti-VEGF Therapy
Intravitreal anti-VEGF is an emerging treatment for PDR, with animal studies36 and clinical trials7,37,38 showing its efficacy in reducing retinal neovascularisation due to ischemia.
Diabetic Retinopathy Clinical Research Network Protocol S
The Diabetic Retinopathy Clinical Research Network (DRCRnet) Protocol S was a RCT of 394 PDR study eyes in 305 patients across 55 US clinical sites. It evaluated the intravitreal anti-VEGF agent ranibizumab against PRP with mean VA change at two years as the primary outcome.7 Eyes with DMO could be included in either arm, and treatment with ranibizumab was allowed. Ranibizumab was found to be non-inferior to PRP with a mean VA improvement of +2.8 letters compared with +0.2 letters in the PRP group. In addition, eyes receiving ranibizumab had less visual field loss and were three times less likely to undergo vitrectomy or develop DMO.7However, the treatment regimen was intensive with a mean of seven anti-VEGF injections and monthly visits during the first year of the trial, while PRP was completed within one to three visits.
The CLARITY study was a single-blinded RCT comparing another anti-VEGF agent (aflibercept) with PRP in 232 patients with PDR but no DMO across 22 UK clinical sites.37 Aflibercept was both non-inferior and superior to PRP, with mean best-corrected VA of 3.9 letters achieved and a median of four injections over one year. The aflibercept group had a significantly lower incidence of developing vitreous haemorrhage compared with the PRP group (9 per cent vs 21 per cent), but the proportion of patients requiring vitrectomy were small and not statistically significant between groups.37
Differences in the study design may explain why CLARITY showed superiority of anti-VEGF injection over PRP, while DRCRnet Protocol S did not. Aflibercept used in CLARITY has a higher binding affinity to VEGF than ranibizumab, and blocks VEGF-A, VEGF-B and placental growth factor (ranibizumab only blocks VEGF-A). CLARITY included patients with less severe PDR, no baseline DMO and 46 per cent had previous PDR treatment. On the other hand, DRCRnet Protocol S patients had a higher initial mean grade of retinopathy, 22-23 per cent had DMO at baseline and no patients had prior PRP.
The PROTEUS study was a recent prospective, multi-centre RCT of 87 patients with high risk PDR comparing intravitreal ranibizumab plus PRP versus PRP alone.38 A higher percentage of patients treated with ranibizumab plus PRP (92.7 per cent) had a reduction in ‘neovascularisation total’ (any decrease in the area of NV) compared with patients treated with PRP alone (70.5 per cent) at one year.38 Furthermore, the mean number of PRP laser burns received in the ranibizumab plus PRP group was significantly lower than in the PRP alone group.38
Panretinal Photocoagulation vs Intravitreal Anti-VEGF
There is ample evidence that intravitreal anti-VEGF is an effective treatment for DMO.39-44 For this reason, for most patients presenting with PDR and DMO, anti-VEGF is first-line treatment. In patients presenting with PDR but no DMO, the recommended management is less clear.
Although CLARITY and PROTEUS suggest a benefit with anti-VEGF therapy, the disadvantages of intravitreal therapy (patient visits, cost, complications including endophthalmitis and systemic anti-VEGF exposure) must also be considered.7,45Intravitreal anti-VEGF can also be associated with acutely increased fibrosis and regression of the vascular component of fibrovascular proliferation, leading to tractional retinal detachment. In Australia, both ranibizumab and aflibercept are listed by the pharmaceutical benefits scheme for treatment of vision-affecting DMO, but not for PDR alone. Interestingly, there is emerging evidence that intravitreal anti-VEGF therapy may not only be useful in treating PDR and DMO, but may have a disease modifying effect by improving Diabetic Retinopathy Severity Scores.46,47
Beside anti-VEGF, other biochemical pathways underlying PDR are being investigated. A recent pilot study by Chang et al.48 showed that the epiretinal membrane formation in PDR has a higher level of endothelin-1 levels compared to non-diabetic tissues via immunohistochemistry. Endothelin is a potent vasoconstrictor and ability to promote fibrosis is extensively studied in pulmonary studies.48 Thus endothelin-1 can be a potential therapeutic target to prevent fibroblastic transition in PDR. Other promising targets include erythropoietin. Erythropoietin is produced in response to retinal ischemia with increased intraocular levels observed in PDR.49 Animal studies have shown inhibition of erythropoietin decreases retinal neovascularisation.49
Vitrectomy surgery for PDR may need to be considered in the following situations:
- Non-clearing vision impairing vitreous haemorrhage
- Non-clearing vision impairing premacular haemorrhage (Figure 5)
- Tractional retinal detachment threatening the macula (Figure 6)
- Combined tractional and rhegmatogenous retinal detachment
- Visually significant epiretinal membrane
The aims of diabetic vitrectomy surgery are to clear vitreous and pre-macular haemorrhage, relieve retinal traction by segmentation and delamination, repair rhegmatogenous retinal detachment and remove visually significant epiretinal membranes. Separation of the posterior hyaloid of the vitreous from the retina removes the scaffold for proliferation of retinal new vessels. Supplemental PRP can often be added by endolaser, and in some cases silicone oil tamponade may be required for retinal detachment.
The indications and timing of vitrectomy for the management of advanced DR was assessed by the Diabetic Retinopathy Vitrectomy Study (DRVS) in 1985.50 This RCT included a total of 616 eyes with severe (VA 6/240 or less) non-clearing (at least one month) diabetic vitreous haemorrhage and found that patients with Type 1 DM were more likely to recover desirable VA when vitrectomy was performed early (within several days of randomisation) rather than deferred (until one year after the onset of haemorrhage). Since the DRVS, modern small-gauge minimally invasive vitrectomy surgery (MIVS) has significantly reduced the morbidity and complication rates of vitrectomy surgery, and thus the threshold for intervention has also reduced. The intraoperative complication rates for diabetic vitrectomy surgery have been reported at 13.5 per cent without delamination and 30.4 per cent with delamination.51 Overall, over 60 per cent of patients achieve ‘visual success’ (an improvement in vision of 0.3 logMAR or more, six to 12 months after surgery).51
PDR is a leading cause of severe vision impairment in patients with DM. Fundus fluorescein angiography, in particular with ultrawide field imaging systems, is a useful adjuvant investigation to clinical examination. Although PRP laser photocoagulation has been the gold standard for treatment of PDR, recent studies have shown intravitreal anti-VEGF to be at least non-inferior to PRP. Factors other than efficacy, including patient access, cost and complications may also need to be considered when individualising treatment. Vitrectomy surgery should be considered for non-clearing vitreous haemorrhage and tractional retinal detachment threatening the macula.
Associate Professor Adrian Fung, MBBS, MMed (Clin Epi), MMed (Ophthal Sci), FRANZCO is a specialist in Vitreoretinal Surgery and Medical Retina Diseases. He is Co-Director of the Westmead Hospital Vitreoretinal Fellowship, and works at Macquarie University Hospital, Retina & Macula Specialists and Retina Associates in Sydney. A/Prof. Fung is active in research and teaching and has published over 50 international peer-reviewed journal articles and seven book or book chapters, including ‘Ophthalmic Clinical Examination’ and ‘Vitreoretinal Surgery for Trainees’. He is a member of RANZCO, AAO, ANZSRS, ASRS, APVRS, ISOO, IntRis and the Vit Buckle Society and regularly lectures nationally and internationally. He is a chief investigator of the NHMRC funded Bionic Eye Project and teaches training ophthalmology registrars and fellows at Westmead Hospital. A/Prof. Fung is the course convenor for Ophthalmology Updates!, an annual ophthalmology conference. He sits on the Sydney Eye Hospital Alumni Committee, Ophthalmic Research Institute of Australia Research Committee and RANZCO Clinical Standards Committee. A/Prof Fung has no financial disclosures relevant to the subject matter. www.dradrianfung.com.au
Dr. Michelle Hui, BMed, MD, completed medical school at the University of New South Wales in 2015. She is currently working as a senior resident and has experience in ophthalmic research and publications. She is interested in pursuing a career in ophthalmology.
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