PEER REVIEWED

Proliferative Diabetic Retinopathy: A Brief Review of Medical and Surgical Management

GIAN PAOLO GIULIARI, MD

Diabetes mellitus is a significant cause of blindness worldwide, and its prevalence is projected to increase.^1,2 Diabetic macular edema (DME) and proliferative diabetic retinopathy are the most sight-threatening ocular diseases associated with diabetes. Panretinal and macular photocoagulation were established as the gold standard of treatment, supported by the data of the Early Treatment Diabetic Retinopathy Study (ETDRS)³ and the Diabetic Retinopathy Study (DRS).⁴

Diabetic retinopathy conforms to a very broad spectrum of manifestations in the retina — especially in the retinal vasculature. Diabetic retinopathy can be classified by the clinical presentation of the disease either as nonproliferative diabetic retinopathy or proliferative diabetic retinopathy (PDR).

A number of molecular mechanisms connect hyperglycemia to the vascular damage, such as accumulation, advanced glycation end-product formation, general oxidative stress elevation with concomitant free radical generation, and pathological activation of protein kinase C (PKC), which promotes the already elevated expression of vascular endothelial growth factor (VEGF).^5-11

The development of fibrovascular proliferation is due, in great extent, to the secretion of many factors by the ischemic retina, such as VEGF, which stimulates the formation of new blood vessels.¹² This is where most of the new therapies have been targeted.

SYSTEMIC CONTROL

Substantial benefits in reducing the long-term risk of sight-threatening complications have been demonstrated with the control of not only of blood glucose but also systemic blood pressure. The Diabetes Control and Complications Trial (DCCT) found a reduction in the progression to severe retinopathy in almost 50% in patients with intensive glucose control.¹³

The United Kingdom Prospective Diabetes Study (UKDPS) showed the positive effect of blood pressure control.¹⁴ On the other hand, in the past years, new trials have provided further insights into the benefits and limitations of systemic control as management for diabetic retinopathy. The Action in Diabetes and Vascular Disease (ADVANCE) study showed for the first time that reducing the glycosylated hemoglobin to 6.5% or lower, as well as lowering — by a mean of 5.6 mm Hg and 2.2 mm Hg — the systolic and diastolic pressures, respectively, did not alter the 4-year incidence or progression of diabetic retinopathy.^15,16 However, the Diabetic Retinopathy Candesartan Trials (DIRECT) provided more promising results. The use of 32 mg of candesartan (an angiotensin 2 receptor blocker) showed a reduced incidence and progression of diabetic retinopathy; this effect was more pronounced in patients with type 2 diabetes.^17,18 The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study provided even more encouraging new findings. In this study, the use of lipid-lowering fenofibrate demonstrated a reduction in the need for laser photocoagulation in both DME and PDR. Fenofibrate also reduced the overall risk for cardiovascular and renal diseases.¹⁹

RETINAL PHOTOCOAGULATION

The goal of panretinal photocoagulation (PRP) is to prevent further damage and to induce regression of the present retinal neovascularization. Panretinal and macular photocoagulation were established as the gold standard of treatment, supported by the data of the ETDRS and DRS.⁴ The early application of PRP is recommended for patients with PDR, especially in the presence of high-risk features.²⁰

Laser photocoagulation can be delivered through a slit-lamp system, an indirect ophthalmoscope, or an endolaser probe. Usually topical anesthesia is sufficient, although peribulbar or retrobulbar anesthesia may be needed in some situations. The DRS protocol specified 800 to 1600 spots of 500 μm in size, which should be placed 1 to 1.5 burn widths apart. The duration varies from 0.1 to 0.2 second. There are no significant long-term differences in single-session PRP vs multiple-session treatment, although 1 study found fewer transient choroidal and exudative retinal detachments with multiple sessions.²¹

Even though PRP can reduce the risk of severe vision loss in diabetic retinopathy, it is an anatomically destructive treatment unavoidably associated with an increased risk of moderate adverse effects that have a negative impact on visual function and quality of life in some patients.^22-24

VITRECTOMY

In PDR, pars plana vitrectomy (PPV) is an important procedure used to relieve traction on the retina and to resolve a nonclearing vitreous hemorrhage. As PPV became more common, its indications increased and it was offered earlier in the course of the disease. Currently it is used in cases of nonclearing vitreous hemorrhage, tractional retinal detachment (macular detachment), anterior hyaloidal fibrovascular proliferation, active and severe neovascular or fibrovascular proliferation, massive premacular hemorrhage, hemolytic glaucoma, and DME associated with posterior hyaloid traction.

The Diabetic Retinopathy Vitrectomy Study (DRVS) evaluated the risks and benefits on performing an early PPV vs conventional treatment for vitreous hemorrhage and very severe PDR, demonstrating a better outcome in patients who underwent early surgical intervention.²⁵

Recently, there have been some reports concerning the merits of smaller-gauge instrumentation;²⁶ however, no significant data that favor one over the other has been found. The surgeon should choose the instrument with which he or she feels most comfortable — taking into consideration the complexity of the case and available instrumentation.

To achieve a better outcome during the surgery, it is fundamental to have a vast knowledge of the physiopathology of the PDR. It is extremely important to remove as much vitreous and fibrovascular tissue as possible; eyes with complete posterior vitreous detachment rarely develop posterior neovascularizations.

As opposed to epiretinal membranes in nondiabetic eyes — in which the tissue grows on the retinal surface without infiltrating the retina and a surgeon could peel them without significant risk of producing tears in the retina — diabetic membranes commonly grow from the retinal vessels, having tight connections with them. An attempt to peel these membranes may very easily create retinal tears. The surgeon should choose one of the different techniques described to peel these membranes such as the segmentation and/or delamination techniques, among others. In the segmentation technique, relief of the antero-posterior traction is made first, followed by segmentation with vertical scissors into islands of the neovascular proliferations. These islands can them be easily trimmed with the vitrector. Conversely, in the delamination and in the en-bloc resection, there is no previous relief of the antero-posterior traction. Instead, this traction is used to facilitate the dissection of the posterior vitreous.^27-29

As mentioned in the PRP section above, retinal coagulation is a hallmark in the treatment of PDR. Therefore, eyes undergoing PPV commonly receive additional photocoagulation with the use of endolaser.

CORTICOSTEROIDS

Due to the better understanding of the pathophysiology of DME, and the discovery of the critical role played by the inflammatory cascade, it is no surprise that many physicians have decided to use corticosteroids to treat this disease. Corticosteroids have an inhibitory effect on inflammatory reactions and angiogenesis by reducing the migration and activation of inflammatory cells. They also have the ability to block the pathways of selections integrins, intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), and monocyte chemo-attractive protein-1 (MCP-1) at various levels. And they have a direct angiostatic effect by upregulating the extracellular-matrix protein plasminogen activator inhibitor 1.³⁰ This characteristic could provide a better benefit compared to other drugs that block just a single molecule. Corticosteroids can also suppress group 2 phospholipase A2, blocking the inflammatory response at the top of the cascade.³¹ In 1 study.³² corticosteroids demonstrated to reduce the expression of aquaporin-4, a substance that promotes leakage, edema, and cell disorganization in a retina model of ischemia-induced retinal edema.³³

Figure 1. Color fundus photograph and fluorescein angiogram (A,B) of an eye with active PDR showing active and significant PVD, with multiple retinal and preretinal hemorrhages, venous beading, and retinal ischemia.

Intravitreal triamcinolone acetonide has shown positive results in the treatment of DME. However, steroid-induced complications, such as cataracts and increment in the intraocular pressure, are frequently reported side effects.³⁴ New efforts have been made in the development of intravitreal or retinal implants, facilitating extended drug delivery.

Such therapies include an intravitreal implant for the delivery of fluocinolone acetonide, which has shown improvement in visual acuity in patients with DME.³⁵ A biodegradable, implantable, extended-release product that delivers dexamethasone directly to the posterior segment has also shown positive visual outcomes.³⁶

ANTIANGIOGENIC THERAPY

A strong relationship has been found between VEGF and the development of PDR. Laboratory experiments have confirmed the development of the pathologic changes seen in diabetic retinopathy after the intravitreal injection of VEGF.^37-39 Increased levels of VEGF have been found in patients with PDR when compared with patients with the nonproliferative form of the disease — which decreased after panretinal laser photocoagulation treatment (PRP).^40-43 These findings have lead to the use of molecules that block VEGF in the treatment of PDR.

■ Selective Anti-VEGF Blockade. The first drug of this category to be used in the eye was pegaptanib sodium (Macugen, [OSI] Eyetech, Inc.), an anti-VEGF RNA aptamer that binds selectively to VEGF₁₆₅⁴⁴ and was first approved by the US Food and Drug Administration for the treatment of neovascular age-related macular degeneration (AMD).^45,46 Recent data suggests that intravitreal pegaptanib may inhibit the pathological neovascularization consequent to the ischemia present in this disease, without compromising physiological retinal vascularization.⁴⁷

There have not been many studies that report the off-label use of intravitreal pegaptanib sodium for the treatment of PDR and DME. A phase 2 double-masked, multicenter, randomized, dose-ranging controlled trial was performed to assess the viability of pegaptanib as a novel treatment for DME.⁴⁸ Data analysis indicated intravitreal pegaptanib to be more efficacious than sham injection. Subjects injected with pegaptanib exhibited improved vision, decreased retinal thickness, and a lessened need for laser therapy.

Gonzalez and colleagues⁴⁹ recently finished the analysis of the final results from an independent pilot study in which a direct comparison was made between the efficacies of intravitreal pegaptanib vs PRP in the treatment of patients with active PDR. This study included 16 subjects with active PDR. Subjects were randomly assigned in a 1:1 ratio to receive treatment in 1 eye either with intravitreal pegaptanib (0.3 mg) every 6 weeks for 30 weeks or with PRP laser. The final analysis of this small population suggested that intravitreal pegaptanib produces marked and rapid regression of diabetic retinal neovascularization. This result was maintained throughout the study and at the final visit. Even though these results were promising, further studies with larger populations and longer follow-ups are undoubtedly necessary to make any conclusive statements regarding the need for prolonged intravitreal pegaptanib therapy in eyes with PDR. Other studies have also shown benefits with the use of intravitreal pegaptanib;⁵⁰ however, Krishnan and colleagues⁵¹ presented 2 patients who developed progression of a previously stable retinal detachment after the intravitreal injection of pegaptanib.

■ Pan–anti-VEGF Blockade. Bevacizumab (Avastin, Genentech) is a potent monoclonal antibody that blocks all VEGF isoforms. Bevacizumab was the first anti-VEGF therapy approved by the FDA for the treatment of colorectal, breast, and lung cancer.⁵² After the success of preliminary studies with a similar molecule, ranibizumab (Lucentis, Genentech), in the treatment of AMD, researchers and clinicians were motivated to use off-label bevacizumab, both systemically and intravitreally, to treat AMD, as well as other forms of choroidal neovascular membranes.^45,53-58

Given the prominence of diabetes, there has been an interest in treating PDR with bevacizumab. Several studies have shown the potential of bevacizumab as a monotherapy for diabetic NV secondary to PDR.^59,60 More recently, the 1-year results of an open label, uncontrolled, multicenter, interventional case series from Latin America showed that repeated intravitreal injections of either 1.25 mg or 2.5 mg of bevacizumab in different ocular pathologies appear to be safe and well tolerated during the first year.⁶¹ On the other hand, in 7 eyes, after a rapid regression of retinal neovascularization, the resulting fibrous scar tissue led to the development or progression of tractional retinal detachment (TRD). This progression to TRD has been found in other studies as well.⁶²

Intravtireal bevacizumab has shown benefits in patients undergoing PPV. Romano and colleagues showed that preoperative treatment with bevacizumab reduced the thickness of fibrovascular proliferation, and ultimately decreased surgery time by facilitating the dissection and reducing transoperative bleeding.⁶³

ENZYMATIC VITREOLYSIS

Several diseases, such as macular hole, macular edema, and diabetic retinopathy, may arise from a pathological vitreoretinal interface. Surgery might be required in many of these cases to liberate the vitreous adhesions and traction. A complete posterior vitreous detachment facilitates vitreous retinal surgery. However, a mechanical PVD during the surgery carries the risk of retinal tears and nerve fiber damage.^64,65

Figure 2. Color fundus photograph of (A) an eye with active PDR showing active and significant PVD, with multiple retinal and preretinal hemorrhages; and (B) the same eye after panretinal photocoagulation, showing regression of the PVD.

Pharmacologic vitreolysis has the potential to induce a PVD by producing liquefaction of the vitreous gel and a detachment of vitreous from the retinal surface, thereby eliminating the substrate into which the fibrovascular tissue grows in eyes with diabetic retinopathy.

In the last few years, different enzymes, such as chondroitinase, hyaluronidase, and dispase, have been studied showing variable results.^66,67 More recently, a study by Chen and colleagues⁶⁸ demonstrated the effectiveness of intravitreal 1.5 units of microplasminogen in induction of complete PVD in animal models.

CONCLUSION

The glycemic control associated with normal blood pressure is the cornerstone for an optimal treatment of patients with diabetic ocular and systemic complications. PRP and focal/grid laser remains the gold standard of treatment for PDR and DME and has been the only proved therapeutic option that offers long-term control.

Blockage of the VEGF-A molecule appears to be safe and efficacious for the treatment of ocular proliferative diseases. We can only hope that, with the use of these new therapeutic modalities, we may be able to diminish the need for extensive PRP treatment, which would reduce the side effects associated with laser photocoagulation. Nonetheless, in most cases there will be a recurrence of proliferative changes after discontinuation of intravitreal therapy. Whether the realm of anti-VEGF therapy will continue to expand remains unclear. However, coadjuvant treatment with more selective PRP, confined to the areas of retinal ischemia, may lead to a stabilization of the retinal disease and reduce the need for additional treatments, though further studies should be performed to better assess this.

Recently, new treatments with the use of PKC inhibitors are undergoing clinical trials. Ruboxistaurin, a specific inhibitor of PKC-b, and PKC 412, has been shown to reduce visual loss in diabetic patients.^69-71 Growth hormone inhibitors have also been studied in the treatment of diabetic retinopathy. Grant et al.⁷² showed a reduction in the requirement for laser photocoagulation and reduced incidence of ocular disease progression in patients with octreotide (long-acting somatostatin analogue).

Despite all the effective treatments available for PDR and DME, diabetic retinopathy continues to be an important cause of vision loss worldwide. The growing understanding of the biochemical pathways in its pathophysiology, as well as the ongoing clinical trials with the new therapeutic agents, will eventually bring newer hopes in the treatment of this sometimes refractory disease. RP

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