As retinopathy progresses, capillary damage and nonperfusion increase. Worsening retinal ischemia leads to release of vasoproliferative factors and the subsequent development of retinal neovascularization. VEGF is 1 of the major proangiogenic factors isolated from the vitreous of patients with PDR. This factor can stimulate neovascularization of the retina, optic nerve head, or anterior segment.
Extraretinal fibrovascular proliferation, which defines PDR, progresses through 3 stages:
Neovascular proliferation is categorized by its location: either on or within a disc diameter of the disc (NVD, neovascularization of the disc) or elsewhere (NVE, neovascularization elsewhere).
Patients may receive treatment at any stage of PDR; however, treatment is usually considered mandatory once an eye has developed high-risk characteristics. PDR with high-risk characteristics is defined as having any of the following findings:
Treatment may be deferred in eyes that have not developed high-risk characteristics or in eyes that have peripheral neovascularization outside the 7 standard ETDRS fields without accompanying hemorrhage; these cases can be watched closely until the PDR worsens. However, eyes at especially high risk for diabetic retinopathy progression due to patient nonadherence or poor systemic control should be treated promptly.
Management of Proliferative Diabetic Retinopathy and Its Complications
The goal of management of PDR is to control ischemia and reduce ocular VEGF levels so that neovascularization can involute or regress. This management can be accomplished with intravitreal administration of anti-VEGF drugs or with ablation of ischemic retina via laser photocoagulation. Because of the contraction of fibrovascular tissue, treatment may be followed by increased vitreoretinal traction, recurring vitreous hemorrhage, tractional retinal detachment, and/or combined tractional and rhegmatogenous retinal detachment. Complications from PDR or its treatment—vitreous hemorrhage and tractional retinal detachment—can be addressed with vitreoretinal surgical interventions, when appropriate.
Nonsurgical management of proliferative diabetic retinopathy
Anti-VEGF and steroid drugs Multiple studies, including phase 3 trials of anti-VEGF drugs for the treatment of DME, have demonstrated that intravitreal administration (see the section Intravitreal Injections in Chapter 20 of this volume for a discussion of the injection procedure) of anti-VEGF drugs is highly effective at regressing retinal neovascularization in eyes with PDR. Anti-VEGF therapy leads to regression of diabetic neovascular complexes in both newly diagnosed cases and chronic, refractory disease. Potential complications from the use of anti-VEGF drugs in the management of PDR include tractional retinal detachments, retinal tears, and combined tractional and rhegmatogenous retinal detachments that are related to the induced rapid contracture of the fibrovascular tissue.
Figure 5-5 Fundus photograph of a left eye demonstrates neovascularization of the disc (NVD, arrow) with a small amount of vitreous hemorrhage. Even without vitreous hemorrhage, this degree of NVD is the lower limit of moderate NVD and is considered high-risk PDR.
(Standard photograph 10A, courtesy of the Diabetic Retinopathy Study [DRS].)
Figure 5-6 Fundus photograph of a right eye shows cotton-wool spots and moderate neovascularization elsewhere (NVE) with preretinal hemorrhage.
(Standard photograph 7, courtesy of the DRS.)
Because of its effectiveness in regressing intraocular neovascularization and its generally favorable safety profile, anti-VEGF therapy is a reasonable first-line treatment alternative to panretinal photocoagulation (PRP) for many eyes with PDR. The DRCR.net Protocol S study randomized eyes with active PDR to treatment with either standard-care prompt PRP or intravitreal ranibizumab and deferred PRP. At 2 years, visual outcomes were equivalent between the PRP and anti-VEGF treated groups. However, ranibizumab treatment was associated with multiple benefits over PRP, including better average vision over the 2 years, reductions in peripheral visual field loss, reduced rates of vitrectomy surgery, and fewer cases of DME onset. Ranibizumab was well tolerated; no substantial differences in rates of major cardiovascular adverse events were found between the treatment groups. Longer-term follow-up through the full 5-year study duration will determine whether anti-VEGF treatment burden decreases over time and whether the anti-VEGF effect endures after treatments are halted. (For more on DRCR.net studies, see the sidebar Selected Diabetic Retinopathy Clinical Research Network Studies at the end of this chapter.)
Although ranibizumab is effective for PDR treatment and offers some advantages over PRP, whether to use anti-VEGF versus PRP should be based on individual patient circumstances. Patients receiving anti-VEGF need to be able to adhere to near monthly follow-up visits throughout the first 1–2 years of treatment. For patients who have a high likelihood of nonadherence due to medical instability or other limitations, treatment with PRP is the most appropriate option.
Anti-VEGF drugs also cause involution of anterior segment neovascularization and have been successfully used to treat neovascular glaucoma. In addition, when administered preoperatively, these drugs may be helpful as an adjunct to vitrectomy to manage complications of PDR.
Although steroid agents are not used for primary treatment of PDR, they do reduce PDR-related outcomes in diabetic eyes. Combined rates of vitreous hemorrhage, need for PRP, and development of neovascularization, as viewed on fundus photographs or during a clinical examination, are reduced in eyes receiving intravitreal steroid therapy for non-PDR indications, such as DME.
Surgical management of proliferative diabetic retinopathy
Laser surgery Over the past 4 decades, until the recent advent of anti-VEGF therapy, the mainstay of treatment for PDR was thermal laser photocoagulation in a panretinal pattern to induce regression of neovascularization. Treatment indications are still largely based on findings from the Diabetic Retinopathy Study (DRS) (Clinical Trial 5-4). For patients with high-risk PDR, PRP treatment in eyes not already receiving anti-VEGF therapy is almost always recommended. PRP destroys ischemic retina, which produces growth factors, such as VEGF, that promote disease progression. PRP also increases oxygen tension in the eye via 2 mechanisms: (1) decreasing oxygen consumption overall as a result of the purposeful retinal destruction, and (2) increasing the diffusion of oxygen from the choroid in the areas of the photocoagulation scars. Collectively, these changes result in the regression of existing neovascular tissue and prevent progressive neovascularization.
Treatment may be accomplished in a single session or over multiple sessions. The DRCR.net found no long-term vision benefit of multiple-session over single-session laser administration. After the initial PRP, additional therapy can be applied incrementally in an attempt to achieve complete regression of persistent or recurrent neovascularization. Some clinicians combine anti-VEGF therapy with PRP with the rationale that initial anti-VEGF therapy will regress neovascularization quickly, whereas the effect of the PRP will endure over subsequent years, without the need for long-term intravitreal injections.
Full PRP, as used in the DRS (see Clinical Trial 5-4) and ETDRS (see Clinical Trial 5-3), included 1200 or more 500-μm burns using argon green or blue-green lasers, separated from each other by one-half burn width (Fig 5-8). The use of automated pattern scan laser systems has been increasing in recent years; however, uncontrolled studies have suggested that pattern scan laser treatments may not be equivalent in their treatment effect on a burn-for-burn comparison; the burn-count target for equivalent treatment effect with pattern scan laser treatment may need to be higher.
Adverse effects of scatter PRP include choroidal detachment as well as decreases in night vision, color vision, contrast sensitivity, peripheral vision, and, in rare cases, pupillary dilation. Some patients may experience a transient loss of 1 or 2 lines of visual acuity or increased glare following treatment. Other transient adverse effects include loss of accommodation, loss of corneal sensitivity, and photopsias. Macular edema may also be precipitated or worsened by PRP. Sparing the horizontal meridians, that is, the path of the long ciliary vessels and nerves, protects accommodation pupillary function and corneal innervation. Heavy treatment, when necessary, should be performed in areas of the retina where vision loss is less noticed by patients or in areas that are associated with lower rates of morbidity. Great care must be taken to avoid foveal photocoagulation, especially when using image-inverting lenses.
Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22): 1480–1487.
Figure 5-8 Fundus photograph shows an eye that has undergone panretinal photocoagulation (PRP) treatment. Laser scars are characterized by either chorioretinal and retinal pigment epithelium (RPE) atrophy or RPE hyperpigmentation.
(Courtesy of Jennifer K. Sun, MD, MPH.)
Chew EY, Ferris FL III, Csaky KG, et al. The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy: the early treatment diabetic retinopathy follow-up study. Ophthalmology. 2003; 110(9):1683–1689.
Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report number 8. Ophthalmology. 1981;88(7):583–600.
Gross JG, Glassman AR, Jampol LM, et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314(20): 2137–2146.
Silva PS, Cavallerano JD, Sun JK, et al. Proliferative diabetic retinopathy. In: Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P, eds. Ryan’s Retina. 6th ed. Philadelphia: Elsevier/Saunders; 2018:1091–1121.
Management of neovascularization of the iris or anterior chamber angle
Small, isolated tufts of neovascularization at the pupillary border are relatively common in eyes of patients with diabetes mellitus. Treatment can be withheld in eyes with these tufts in favor of careful monitoring, with relatively short intervals between slit-lamp and gonioscopic examinations. Treatment should be considered for eyes that have contiguous neovascularization of the pupil and iris collarette, with or without inclusion of the anterior chamber angle, and if wide-field FA reveals widespread nonperfusion or peripheral neovascularization. Treatment usually consists of PRP; intravitreal injection of anti-VEGF drugs can be used as a temporizing measure to reduce neovascularization until definitive PRP is administered.
Vitrectomy surgery for complications of diabetic retinopathy
Indications for pars plana vitrectomy in patients with PDR are
nonclearing vitreous hemorrhage
significant recurring vitreous hemorrhage, despite use of maximal PRP
dense premacular subhyaloid hemorrhage
tractional retinal detachment involving or threatening the macula
combined tractional and rhegmatogenous retinal detachment
red blood cell–induced (erythroclastic) glaucoma and “ghost cell” glaucoma
anterior segment neovascularization with media opacities preventing PRP
The Diabetic Retinopathy Vitrectomy Study (DRVS) was an early prospective, randomized clinical trial that investigated the role of vitrectomy in the management of eyes with severe PDR. Benefits of early (1–6 months after onset of vitreous hemorrhage) versus late (1 year after onset) vitrectomy were evaluated. Eyes of patients with type 1 diabetes mellitus and severe vitreous hemorrhage clearly demonstrated a benefit from earlier vitrectomy, whereas eyes of patients with type 2 or mixed diabetes did not.
If PRP has not been performed previously, earlier intervention is usually recommended. Patients with previous, well-placed, complete PRP who have vitreous hemorrhage secondary to PDR may be observed for a longer period prior to initiating intervention. Frequent echography (ultrasound) studies are necessary to monitor for retinal detachment in patients with dense, nonclearing vitreous hemorrhages. If a retinal detachment is discovered, the timing for the vitrectomy depends upon the characteristics of the detachment. Patients with bilateral severe vitreous hemorrhage should undergo vitrectomy in 1 eye as soon as possible for vision rehabilitation. Recent advances in vitreoretinal surgery, including smaller-gauge instrumentation facilitating faster operating times and fewer complications, have led to earlier intervention for nonclearing vitreous hemorrhage.
Recchia FM, Scott IU, Brown GC, Brown MM, Ho AC, Ip MS. Small-gauge pars plana vitrectomy: a report by the American Academy of Ophthalmology. Ophthalmology. 2010; 117(9):1851–1857.
Simunovic MP, Maberley DA. Anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy: a systematic review and meta-analysis. Retina. 2015;35(10): 1931–1942.
Tractional retinal detachment
Complications from PDR may be exacerbated by vitreous attachment to and traction on fibrovascular proliferative tissue, often causing secondary tractional retinal detachments. Partial posterior vitreous detachment frequently develops in eyes with fibrovascular proliferation, resulting in traction on the new vessels and vitreous or preretinal hemorrhage. Tractional complications such as vitreous hemorrhage, retinal schisis, retinal detachment, or macular heterotopia may ensue, as well as progressive fibrovascular proliferation. Contraction of the fibrovascular proliferation and vitreous may result in retinal breaks and subsequent combined tractional and rhegmatogenous retinal detachment. The presence of chronic retinal detachment in eyes with PDR contributes to retinal ischemia and may account for the increased risk of anterior segment neovascularization in such eyes.
Tractional retinal detachment that does not involve the macula may remain stable for many years. When the macula becomes involved or is threatened, prompt vitrectomy is generally recommended. Combined tractional and rhegmatogenous retinal detachment may progress rapidly; urgent surgery should be considered for these patients.
A more extensive discussion of the surgical management of tractional retinal detachments secondary to PDR appears in the section Vitrectomy for Complications of Diabetic Retinopathy in Chapter 20 of this volume.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.