Article

Management of proliferative DR

The latest on our pharmaceutical and surgical options.

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.

Figure 1. Proliferative diabetic retinopathy: Ultra-widefield fluorescein angiogram (UWFFA) (B) shows the near 360° extent of neovascularization surrounding the posterior pole and the extensive peripheral nonperfusion, which is not apparent on the color fundus photograph (A).

Figure 2. Proliferative diabetic retinopathy with subhyaloid hemorrhage and vitreous hemorrhage: Color photograph (A) shows severe neovascularization at the disc and elsewhere along with vitreous hemorrhage and subhyaloid hemorrhage. There is blockage from the hemorrhage on the UWFFA (B) and leakage from neovascularization at the disc and elsewhere, along with extensive peripheral nonperfusion.

Figure 3. Progression of PDR to a tractional retinal detachment despite panretinal photocoagulation (A), with UWFFA showing neovascularization and staining of peripheral panretinal photocoagulation scars (B). Widefield OCT (C) shows the tractional retinal detachment involving the macula with subretinal fluid and overlying fibrovascular proliferative tissue.

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.

ANTI-VEGF CAVEATS

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

Figure 6. PDR with combined tractional-rhegmatogenous retinal detachment (A and B). Postoperative OCT following vitrectomy surgery shows re-attachment of the macula with restoration of the retinal architecture (C).

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).

Figure 4. Preoperative OCT showing extensive traction in the macula with overlying fibrovascular tissue (A, yellow arrow), hyperechoic opacities in the vitreous consistent with vitreous hemorrhage (blue arrow) and subretinal fluid in the inferior macula showing a limited tractional retinal detachment (red arrow). Following pars plana vitrectomy (B), there is release of traction, a significant portion of the fibrovascular tissue has been removed, there is improvement in the retinal anatomy and architecture and resolution of the tractional retinal detachment.

Figure 5. Intraoperative photographs of 23-27 mixed gauge microincision vitrectomy using the beveled cutter probe which illustrates the versatility of the vitreous cutter in removal of the fibrovascular proliferation (FVP). Sequential intraoperative photographs show segmentation and removal of FVP using the cutter both simultaneously for cutting as a scissor and aspiration.

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

FUTURE THERAPIES

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

CONCLUSION

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

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