Chang and Sarraf approved treatment modalities are currently in clinical use and/or are under investigation for the treatment of various aspects of DR. Corticosteroids Periocular and intraocular triamcinolone acetonide (TA) have been used for the treatment of macular edema, including DME. This effect may be most pronounced in cases of cystoid macular edema (CME) or diffuse macular edema recalcitrant to laser therapy (Jonas et al 2001). A small randomized prospective clinical trial showed a beneﬁcial effect of intravitreal TA (Jonas et al 2006). 40 eyes with diffuse DME were randomized to receive a single 20 mg intravitreal TA or sham injection. At 3 and 6 months, 81% and 87% of the eyes in the TA group had greater than a 2 line improvement in visual acuity versus less than 30% in the control group. A beneﬁt was also seen in a randomized, controlled prospective trial of intravitreal TA for refractory DME with two-year follow-up (Gillies et al 2006). 69 eyes were randomized to receive sham or intravitreal TA injections (4 mg), repeated up to ﬁve times. Participants in both groups were eligible to receive focal photocoagulation if deemed necessary. At the end of the study, TA-treated eyes had a decreased mean retinal thickness and improved visual outcome, with a 5 line improvement in 56% or eyes, versus 26% in the placebo group. A prospective trial comparing intravitreal TA to macular grid photocoagulation for the treatment of CME showed that TA was more effective than focal laser in this setting (Avita- bile et al 2005). 48 patients with DME were randomized to receive photocoagulation, 4 mg TA, or both. The TA group had improved visual acuity and decreased retinal thickness when compared to the photocoagulation group. The group receiving both TA and photocoagulation was similar to TA alone. The Diabetic Retinopathy Clinical Research (DRCR) study group is currently evaluating TA versus photocoagula- tion for the treatment of DME. Triamcinolone has also been used as an adjunctive treatment to FML or PRP, to potentiate the effect of focal or panretinal photocoagulation or to minimize the develop- ment or progression of macular edema (Kaderli et al 2005; Bandello et al 2006; Zein et al 2006; Choi et al 2007; Iida 2007; Lam et al 2007). Despite the clear beneﬁts of steroid therapy these must be judged against signiﬁcant side effects which include local problems such as redness, discomfort and ﬂoaters in the ﬁrst week after the injection and a high incidence of increased intraocular pressure and cataract. Blinding complications such as endophthalmitis, vitreous 428 hemorrhage, or retinal vascular occlusion are fortunately very rare (Jonas et al 2006). To circumvent the need for repeated injections, a number of sustained release devices are under investigation. A dexamethasone drug delivery system (Posurdex DDS, Dexamethasone Posterior Segment Drug Delivery System, Allergan) consists of a biodegradable copolymer of lactic acid and glycolic acid which releases dexamethasone for up to 6 months into the vitreous cavity. In a randomized control trial of the DDS for the treatment of persistent macular edema involving 315 patients with macular edema, 152 of whom had DME, use of a 700 implant μg was associated with a higher rate of 10 and 15-letter improvement in visual acuity, decreased ﬂuorescein leakage, and decreased retinal thickness (Kuppermann et al 2007). While there was an increased rate of IOP elevation in the treatment group, no eyes required glaucoma surgery or laser. Other steroid delivery devices are being investigated for the treatment of ocular inﬂammation, but may eventually ﬁnd use in the management of DME. Retisert (Control Delivery Systems and Bausch and Lomb) is an implantable nonbiode- gradable intraocular device that delivers ﬂuocinolone aceton- ide and is FDA approved for the treatment of noninfectious posterior uveitis (Jaffe et al 2006). Importantly, during the 34-week trial, over 50% of patients required antihypertensive eyedrops and almost 6% required glaucoma ﬁltering surgery and nearly 20% experienced signiﬁcant cataract progression, 10% requiring cataract surgery. Thus, while such delivery devices may circumvent the need for repeated injections, they are still subject to signiﬁcant side effects. The exact mechanisms by which steroids affects vascular permeability are not known. Downregulation of inﬂammatory mediators and angiogenic cytokines has been demonstrated in various in vitro models (Antonetti et al 1998, 2002; Nauck et al 1998). However, a decrease in macular edema, as determined by OCT, was observed as soon as one hour after intravitreal injection of TA, arguing that nongenomic effects, such as direct restoration of the blood-retina bar- rier or modulation of membrane channels, contribute to its salutary effects (Felinski and Antonetti 2005; Miyamoto et al 2006). Vascular endothelial growth factor (VEGF) VEGF has a central role in vascular permeability and angiogenesis in neovascular age-related macular degenera- tion. VEGF has also been implicated in DR as an important angiogenic growth factor produced by areas of ischemic Clinical Ophthalmology 2008:2(2)