Proliferative diabetic retinopathy (PDR) is a leading cause of vision loss in patients with diabetes mellitus, resulting in 12,000 to 24,000 new cases of blindness each year in the United States.1 PDR is characterized by the growth of new abnormal vessels on the retina or optic disc that can result in sight-threatening complications such as vitreous hemorrhage and tractional retinal detachment (Figures 1-3). Without treatment, nearly 50% of patients with high-risk PDR experience severe vision loss within five years.2 This article briefly reviews current advances in both medical and surgical management of PDR, as well as emerging therapies.
ADVANCES IN MEDICAL MANAGEMENT: RECENT TRIALS
Panretinal photocoagulation (PRP) has been the standard treatment for PDR for over four decades and reduces the risk of severe visual loss by 50%.2 However, PRP can cause permanent peripheral visual field loss, decreased night vision and may exacerbate diabetic macular edema (DME). Even with timely PRP treatment, about 5% of eyes with PDR develop severe vision loss.1
Anti-VEGF agents have been shown to cause short-term new vessel regression and reduce the risk of diabetic retinopathy becoming worse, making these agents a potentially viable PDR treatment. Bevacizumab (Avastin, Genentech Inc.), ranibizumab (Lucentis, Genentech Inc.) and aflibercept (Regeneron) have been studied in PDR.3 Two large randomized clinical trials have shown the benefits of anti-VEGF compared with PRP — the U.S. Diabetic Retinopathy Clinical Research (DRCR) Network Protocol S and the UK CLARITY trial.4 The DRCR.net showed that compared to PRP, patients in the ranibizumab arm had less visual field loss, better visual acuity over two years, and fewer vitrectomies.5
The CLARITY trial showed that at one year, patients taking aflibercept had an improved outcome compared to PRP. Anti-VEGF agents also have a disease-modifying effect in terms of improvement in both DME and diabetic retinopathy severity score (DRSS).6, 7 This is important because DRSS improvement correlates with both functional and anatomic improvement.
The long-term benefits and risks of anti-VEGF treatment for PDR are unknown to us. CLARITY is a one-year study and Protocol S only has published data through two years. The five-year follow-up data of Protocol S should show us whether the beneficial effects anti-VEGF over PRP are maintained over that period, how many injections are needed to maintain these effects, and whether patients experience worsening of neovascularization.8
The major concerns about the widespread implementation of anti-VEGF treatment include cost (particularly with ranibizumab or aflibercept) and the visit burden to patients.7 Weighing the relative benefits of PDR treatment with PRP vs. with anti-VEGF injections could be influenced by whether DME is present since anti-VEGF would treat both.5 For patients without DME, PRP is far more cost-effective than ranibizumab or aflibercept.9
A patient’s acceptance of a highly burdensome anti-VEGF treatment regimen may be low among patients with PDR.8 These patients often have other medical comorbidities and the treatment burden of repeated anti-VEGF injection visits may be onerous, especially given the frequent visits to other medical providers. The effect of missed injections is unknown and may place individuals at greater risk for long-term, vision-threatening complications. It is important to discuss with your patient the importance of compliance before considering anti-VEGF treatment.8
ROLE OF ANTI-VEGF INJECTIONS IN PDR WITH VITREOUS HEMORRHAGE
There is a role for anti-VEGF injections in patients with vitreous hemorrhage (VH) in the setting of PDR. Parikh et al. recently showed that a proportion of these patients may be treated with anti-VEGF injections only. The rate of pars plana vitrectomy (PPV) at 2 years (27.9%) suggested that some patients may potentially be managed nonsurgically.10 It is very important, however, to try to ensure that these eyes do not have significant traction prior to anti-VEGF, as a retinal detachment could develop underneath the VH.
SURGICAL MANAGEMENT OF PDR
Despite adequate risk factor management and early treatment with full PRP, up to one-third of PDR eyes continue to show new vessel growth, and ~4.5% require PPV.11, 12 The 1990 Diabetic Retinopathy Vitrectomy study (DRVS defined the classic role of surgery for diabetic retinopathy.13 Twenty-seven years later, the major indications for surgery remain NCVH, severe fibrovascular proliferation, tractional retinal detachment (TRD) or combined tractional-rhegmatogenous detachments (Figure 6).14
The earliest indication for PPV in PDR is a non-clearing VH, which occurs due to the contraction of fibrovascular membranes surrounding new vessel growth.4 The DRVS first showed that type I diabetic patients and monocular patients with severe VH had a greater chance of recovering good visual acuity when treated with PPV within 1 month of onset. However, surgery does not preclude the possibility of recurrent VH.15
Most vitreoretinal surgeons worldwide have now transitioned to using small gauge 23-, 25- or 27-G minimally invasive vitrectomy surgery (MIVS) platforms.16 This transition has also driven refinements in vitreous cutter safety, valved cannulas, improved fluidics and performance that has enhanced the cutter’s versatility as a multifunctional tool. Newer techniques, such as cutter segmentation and foldback delamination, have decreased reliance on scissors and other ancillary instruments for removal of proliferative tissue.17
Today, vitreoretinal traction is the most common indication for surgical intervention in PDR.18 Contraction of fibrovascular tissue adherent to both the retina and vitreous body may lead to a TRD and subsequent severe vision loss that is often irreversible. Not all TRDs, however represent an indication for PPV; only 15% of peripheral or mid-peripheral TRDs progress to involve the macula,19 and many surgeons choose to observe TRDs not involving the macula. Current practice patterns reserve PPV for those cases in which the macula is either involved or threatened by an adjacent progressive TRD.14
The mixed 23-27 mixed gauge vitrectomy, which utilizes the versatility of MIVS platforms, involves the passage of narrower gauge instruments through wider gauge cannulas.20 Initially, the larger 23-g probe is introduced and used to release anteroposterior traction and perform the core vitrectomy. The higher flow rate facilitates more efficient removal of the vitreous bulk.
The smaller 27-g probe is then introduced during the dissection of fibrovascular proliferation. It can be maneuvered more easily within tight dissection planes, especially the newer probe designs with a beveled tip (ULTRAVIT 10k probe, Alcon) which can act as a surrogate scissor with simultaneous active aspiration making it efficient for dissecting midperipheral and peripheral membranes in TRD (Figures 4-6).
Emerging technologies such as intraoperative OCT and heads-up 3D visualization systems such as the NGENUITY 3D Visualization System (Alcon) provide more detailed visualization of the anatomy and provide dynamic feedback of micro-architectural tissue alterations and instrument–vitreous-retina interface interactions (see “Heads up? A new way to perform retina surgery,” page 46 and “Update on intraoperative OCT,” page 50). There is also a role for removal of the internal limiting membrane to relieve traction in DME that has been recalcitrant to pharmaceutical therapy.21
Preoperative planning is crucial in diabetic vitreous surgery taking into considering glycemic and blood pressure control, hemodialysis schedule, use of anticoagulants and judicious use of preoperative pharmacotherapy, such as intravitreal steroids or anti-VEGF medications.
As with all surgical procedures, PPV carries risk of complication including recurrent vitreous hemorrhage, endophthalmitis, retinal tear, retinal detachment, cataract formation and neovascular glaucoma.22, 23 Favorable prognostic factors for improved visual acuity after PPV include age <40 years, preoperative visual acuity ≥5/200, lack of iris neovascularization and prior PRP.24 Unfavorable prognostic factors include a macular-involving retinal detachment and previously failed vitrectomy in the fellow eye.25
Current therapies for PDR target the later proliferative stages of the disease process, but there is growing interest in targeting the earlier microvascular manifestations. Earlier detection of disease mandates improved retinal imaging modalities, which have undergone significant advancements over the past decade. Advances in OCT angiography and widefield fluorescein angiography reveal new insights to detect diabetic microvascular changes earlier and more accurately in the retinal periphery. Although still under investigation, early treatment of nonperfusion or abnormal perfusion — especially in peripheral retina — may prove to be beneficial in halting the progression of proliferative changes.
ADVANCES IN LASER THERAPY
Retinal pigment epithelium (RPE) targeting lasers, such as subthreshold diode micropulse laser photocoagulation, may limit damage to the neurosensory retina by using short duration laser pulses focused at the RPE.26 Initial studies have shown micropulse to reduce the progression of severe nonproliferative- to PDR and to be effective for DME.27
FUTURE OF MEDICAL THERAPY
Novel molecules such as designed ankyrin repeat proteins (DARPins); (abicipar pegol) platelet-derived growth factors and fibroblast growth factor in addition of VEGF, angiopoietin-2 (AKB-9778, Aerpio Therapeutics), interleukins including intravitreal IL-6 antibody (EBI-029, Eleven Biotherapeutics), chemokine inhibitors (CCR2/CCR5, Pfizer), integrin inhibitors (integrin antagonist, Luminate, ALG-1001, Allegro Ophthalmics) and encapsulated cells, inhibitors of multiple growth factors are all being investigated for PDR. These agents may have a higher potency and longer half-life.28
Sustained release delivery systems are useful in reducing the treatment burden and providing more consistent therapeutic drug levels in chronic diseases such as PDR. Several approaches in this direction include bio-erodible implants and microspheres, nonbiodegradable long-term drug delivery implants and encapsulated cells; gene therapy is under investigation.29
Several new tools are available to manage PDR complications and improve patient outcomes. But while anti-VEGF is emerging as a frontline tool against PDR, cost, long-term efficacy, treatment burden and compliance remain major challenges with unanswered questions.
Several advances are on the horizon to help us treat this potentially blinding condition, including improved imaging technologies, new pharmaceutical molecules and more precise surgical techniques. OM
- Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012;366:1227-1239.
- Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981;88:583-600.
- Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab for proliferative diabetic retinopahy: Results From the Pan-American Collaborative Retina Study Group (PACORES) at 24 Months of Follow-up. Retina. 2017;37:334-343.
- Sivaprasad S, Prevost AT, Vasconcelos JC, et al. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet. 2017;389(10085):2193-2203.
- Writing Committee for the Diabetic Retinopathy Clinical Research N, Gross JG, Glassman AR, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015;314:2137-2146.
- Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 100-Week Results From the VISTA and VIVID Studies. Ophthalmology. 2015;122(:2044-2052.
- Ip MS, Zhang J, Ehrlich JS. The Clinical Importance of Changes in Diabetic Retinopathy Severity Score. Ophthalmology. 2017;124:596-603.
- Glassman AR. Results of a Randomized Clinical Trial of Aflibercept vs Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Is It Time to Retire Your Laser? JAMA Ophthalmol. 2017.
- Hutton DW, Stein JD, Bressler NM, et al. Cost-effectiveness of Intravitreous Ranibizumab Compared With Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Secondary Analysis From a Diabetic Retinopathy Clinical Research Network Randomized Clinical Trial. JAMA Ophthalmol. 2017;135:576-584.
- Parikh RN, Traband A, Kolomeyer AM, et al. Intravitreal Bevacizumab for the Treatment of Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy. Am J Ophthalmol. 2017;176:194-202.
- Doft BH, Blankenship G. Retinopathy risk factor regression after laser panretinal photocoagulation for proliferative diabetic retinopathy. Ophthalmology. 1984;91:1453-1457.
- Flynn HW, Jr., Chew EY, Simons BD, Barton FB, Remaley NA, Ferris FL, 3rd. Pars plana vitrectomy in the Early Treatment Diabetic Retinopathy Study. ETDRS report number 17. The Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1992;99:1351-1357.
- Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol. 1990;108:958-964.
- Smiddy WE, Flynn HW, Jr. Vitrectomy in the management of diabetic retinopathy. Surv Ophthalmol. 1999;43:491-507.
- Steel DH, Connor A, Habib MS, Owen R. Entry site treatment to prevent late recurrent postoperative vitreous cavity haemorrhage after vitrectomy for proliferative diabetic retinopathy. Br J Ophthalmol. 2010;94:1219-1225.
- Sharma S, Hariprasad SM, Mahmoud TH. Surgical management of proliferative diabetic retinopathy. Ophthalmic Surg Lasers Imaging Retina. 2014;45(3):188-193.
- Charles S. Vitrectomy techniques for complex retinal detachments. Taiwan J Ophthalmol. 2012;2:81-84.
- Machemer R, Blankenship G. Vitrectomy for proliferative diabetic retinopathy associated with vitreous hemorrhage. Ophthalmology. 1981;88:643-646.
- Charles S, Flinn CE. The natural history of diabetic extramacular traction retinal detachment. Arch Ophthalmol. 1981;99:66-68.
- Walter SD, Mahmoud TH. Hybrid-gauge and Mixed-gauge Microincisional Vitrectomy Surgery. Int Ophthalmol Clin. 2016;56:85-95.
- Nakajima T, Roggia MF, Noda Y, Ueta T. Effect of internal limiting membrane peeling during vitrectromy for diabetic maculr edema: Systematic Review and Meta-analysis. Retina. 2015;35:1719-1725.
- Schachat AP, Oyakawa RT, Michels RG, Rice TA. Complications of vitreous surgery for diabetic retinopathy. II. Postoperative complications. Ophthalmology. 1983;90:522-530.
- Itakura H, Kishi S, Kotajima N, Murakami M. Persistent secretion of vascular endothelial growth factor into the vitreous cavity in proliferative diabetic retinopathy after vitrectomy. Ophthalmology. 2004;111:1880-1884.
- de Bustros S, Thompson JT, Michels RG, Rice TA. Vitrectomy for progressive proliferative diabetic retinopathy. Arch Ophthalmol. 1987;105:196-199.
- Blankenship GW. Preoperative prognostic factors in diabetic pars plana vitrectomy. Ophthalmology. 1982;89:1246-1249.
- Luttrull JK, Musch DC, Spink CA. Subthreshold diode micropulse panretinal photocoagulation for proliferative diabetic retinopathy. Eye (Lond). 2008;22:607-612.
- Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review. Curr Diabetes Rev. 2012;8:274-284.
- Smithwick E, Stewart MW. Designed Ankyrin Repeat Proteins: A look at their evolving use in medicine with a focus on the treatment of chorioretinal vascular disorders. Antiinflamm Antiallergy Agents Med Chem. 2017.
- Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration. 2017; http://www.clinicaltrials.gov identifier/: NCT02510794 Accessed June 13, 2017.