nerve may result in permanent mydriasis and loss of accommodation.208 Profound visual field loss may

be caused by high-density, high-intensity PRP.67,152,164 Even with standard PRP visual com-

plications may include decreased acuity, visual field, color vision, and contrast sensitivity.185

9.2.4 Outcome

The ETDRS demonstrated that immediate full scatter (PRP) decreased the rate of development of high-risk proliferative diabetic retinopathy by approximately 50% over a 2-year period.67 Even in the group with poorest prognosis (severe nonproliferative diabetic retinopathy with macular edema) the 5-year rate of severe visual loss (<5/200) was only 6.5% with immediate PRP.67 Risk factors for poor visual out-

come include poor baseline vision, more severe PDR at baseline, and presence of DME. 67,187,209

9.3Intraocular Pharmacological Therapy

Subsequent to the completion of the ETDRS and DRVS, a number of pharmacological agents have been used with increasing frequency in an effort to improve outcome in the management of PDR.210 In general, the risks of intravitreal injection include vitreous hemorrhage, endophthalmitis (0.02–0.87%), pseudo-endophthalmitis, and transient extreme ele-

vation of intraocular pressure following injec- tion.211–215 Individual agents are discussed below

with attendant benefits and risks.

Triamcinolone acetonide: Triamcinolone acetonide (TA) has anti-inflammatory, anti-angiogenic,

and anti-fibrotic effects making it an appealing pharmacological choice to treat the complications of PDR and short-term adverse consequences of laser and vitrectomy.211 Its mechanism of action in reducing neovascular proliferation may include

lowering vascular endothelial growth factor (VEGF) and promotion of apoptosis of NV.216,217

Corticosteroids stabilize the blood–retinal barrier and may protect the neurosensory retina against apoptosis.211 Intravitreal triamcinolone acetonide (IVT) has been used in PDR to prevent or treat loss of vision from macular thickening and inflammation after panretinal laser and vitrectomy, as well

as to treat serous macular detachment following PRP.218–221 IVT appears to decrease early post-

operative ciliary body thickening and anterior chamber angle narrowing after vitrectomy.222 IVT induces regression of neovascularization of the

retina and iris in PDR and NVG, respec- tively.223–227 The aqueous half-life of 1.5 mg intra-

vitreally injected TA is 18.6 days in the non-vitrec- tomized human eye and 3.2 days in the vitrectomized human eye, in which there is a greater

probability of dispersion of TA throughout the vitreous cavity and into the anterior chamber.228,229

Clinically, the duration of effect of a single intravitreal injection is 2–4 months for a 4 mg intravitreal injection and 6 months to 1.5 years for a 20–25 mg injection.223,229 The particulate size of TA crystals varies from one preparation to another and this difference may account of variable rates of clearance and durations of action among commercially available preparations.229 There is no significant evidence of therapeutic systemic levels of triamcinolone following IVT.229 The benefits, however, must be weighed against the adverse effects of cataract (51%), ocular hypertension/glaucoma (21–53%), cytomegalovirus retinitis, reactivation of herpes

simplex keratitis, central serous retinopathy, and others.211,223,229–235 Additionally, concerns have

been raised regarding the potential toxicity of triam-

cinolone acetonide or its preservative on the retina.236–238 In one study of several, commercially

produced preparations of TA using a rabbit model, there was no evidence of toxicity found with a commonly used preparation (Kenalog1).239 Clinical reports to date suggest that triamcinolone acetonide is useful in select cases of PDR.211 Readers are directed to Chapter 7 for discussion of triamcinolone acetonide in nonproliferative diabetic retinopathy.

Anti-VEGF Therapy: Intravitreal anti-VEGF drugs offer many advantages of triamcinolone acet-

onide without the steroid-associated risks of cataract and glaucoma.240–243 By blocking the effect of

vascular endothelial growth factor-A (VEGF-A),

these drugs decrease vascular permeability and proliferation.241,244,245 The most commonly used drug

in this class is bevacizumab, which blocks all isoforms of VEGF-A.246 The aqueous half-life of 1.5 mg intravitreally injected bevacizumab (IVB) is 9.82 days in the non-vitrectomized human eye and is similar to that of ranibizumab.247 In general, impressive results of bevacizumab have been reported in treating macular edema, retinal neovas-

cularization, neovascular glaucoma, and other complications of PDR.241,248–250 IVB prior to PRP

decreases the risk of post-laser foveal thickening

and loss of acuity through its inhibition of the vasopermeability effect of VEGF.251,252 In vitrecto-

mized eyes the effect of IVB on improving diabetic macular edema is diminished.253 In the short term,

IVB induces regression of NV in active, progressive PDR.242,254–259 However, due to limited duration of

effect, they may be best used adjunctively with other

modalities, such as laser and/or vitrectomy.257,260,261 In eyes with PDR and dense vitreous

hemorrhage, IVB may stabilize NV until sponta-

neous clearing of hemorrhage allows for PRP.262,263 Some investigators have found that the

preoperative injection of bevacizumab improves the

ease of vitrectomy, especially in eyes with traction retinal detachment.246,264 With regression of NV,

membranes may be dissected from the retina more readily and intraoperative bleeding is reduced.265 However, the optimal timing of the preoperative injection is uncertain. Injections less than 7 days

prior to vitrectomy may allow for regression of NV and permit surgical intervention before adherent fibrous membranes develop.266 Bevacizumab is

also used adjunctively with laser/surgery for the management of neovascular glaucoma.250,267,268

The rapid resolution of iris neovascularization may halt the progression of angle synechiae while retinal ablative therapy takes effect and may improve the outcome of glaucoma surgery by

decreasing risk of intraoperative or postoperative hemorrhage.242,248,267,269 IVB may also help prevent

bleb failure.270 Resolution of vitreomacular traction has been reported in a diabetic patient after ranizumab injection.271 However, adverse effects of anti-VEGF injections for PDR include newonset traction retinal detachment (approximate

2–5% incidence) occurring at a mean of 13 days following injection (range, 3–31 days).212,254,255,272,273

Notable progression of pre-existing TRD may occur in approximately 18% of cases.274 These complications may occur because of the unop-

posed action of connective tissue growth factors in PDR.24,85,86 Similar rapid progression of fibro-

vascular traction with retinal detachment may occur following panretinal photocoagulation.120 There is also concern that pan-VEGF inhibition may induce neurosensory apoptosis in ischemic conditions, such as PDR.275 Of interest, however, is the finding of short-term improvement in peripheral retinal perfusion after a single IVB injection in a small series.276 Currently, the use of IVB is

widespread and further studies will help define the optimal role of anti-VEGF therapy.6,210

Hyaluronidase: Purified, preservative-free, ovine hyaluronidase has been shown to speed the clearance of vitreous hemorrhage to allow earlier treat-

ment with PRP compared with sham injection in a randomized, controlled trial.277–279 Its use may be

limited by relative slow onset of action and doserelated iritis.277 Nonetheless, this treatment option may be of special use for patients in whom the systemic risks of vitrectomy surgery and anesthesia are unacceptably high.

Pharmacologic vitreolysis: Pharmacologic vitreolysis offers improved ease of separation of vitreous from the retina.280 Eyes with PDR and posterior vitreous detachment (PVD) follow a more favorable course than those without PVD.38 Reports of small series described improved ease of surgery (no