macula-involving tractional retinal detachment (TRD) [32]. However, another study suggests that surgery should be performed 4 days after intravitreal bevacizumab as most TRD cases occur or progress ³5 days after the injection [33].

Recently, Parolini et al. [34] reported the rate of postoperative complications in 943 consecutive eyes operated on with 23-gauge transconjunctival pars plana vitrectomy. This report showed that 831 eyes (88%) did not have either significant intraor postoperative complications. Sclerotomy leakage requiring suture occurred in 37 eyes (3.9%). One choroidal detachment (0.1%) spontaneously resolved 1 week after surgery. At postoperative day 1, 31 eyes (3.3%) experienced transient hypotony. Forty-five eyes (4.8%) presented a subtle vitreous hemorrhage that resolved spontaneously. Two retinal detachments (0.2%) occurred, one at 1 month and one at 3 months. They concluded that 23-gauge complete vitrectomy and peripheral laser seem safe for a variety of vitreoretinal surgical procedures. The rate of postand intraoperative complications compares favorably with 25-gauge and with the standard 20-gauge vitrectomy [34].

Kim et al. [35] included 11 cases of vitreous hemorrhages, 10 cases of diabetic macular edema, and 1 case of tractional retinal detachment treated with 23-gauge transconjunctival sutureless vitrectomy (TSV). The median BCVA improved from 20/400 (LogMAR, 1.21+/−0.63) to 20/140 (LogMAR, 0.83+/−0.48) at 1 week (p=0.003), 20/100 (LogMAR, 0.85+/−0.65) at 1 month (p=0.002), and 20/100 (LogMAR, 0.73+/−0.6) at 3 months (p=0.001). Intraoperative suture placementwasnecessaryin7.5%,andtheauthorsreported no serious postoperative complications [35].

Current preliminary results have confirmed the safety and practicality of the 27-gauge instrument system for transconjunctival sutureless MIVS in selected cases. The favorable wound-sealing structures with few postoperative complications and acceptable operating time suggest the potential of the 27-gauge system for treating macular diseases, simple vitreous opacity or diabetic vitreous hemorrhage, and moderately severe diabetic retinopathy. Similar to the recent evolution of other small-gauge systems, further development and refinement of the 27-gauge instrument functionality and rigidity

are under way and are critical to the widespread use of this system for the full spectrum of vitreoretinal diseases in the future [36].

Pharmacotherapy

In recent years, further advances in pharmacotherapy have shown promise in the treatment of diabetic retinopathy. The three major classes of medications currently being studied are corticosteroids, VEGF antagonists, and miscellaneous agents.

Corticosteroids

Corticosteroids, a class of substances with antiinflammatory properties, have been demonstrated to inhibit the expression of the VEGF gene [37]. Corticosteroids are known to reduce vascular permeability, reduce blood-retinal barrier breakdown, downregulate the production of VEGF, and inhibit certain matrix metalloproteinases. Intravitreal triamcinolone (IVTA) has been studied experimentally in the prevention or treatment of choroidal neovascularization, retinal neovascularization, and proliferative vitreoretinopathy and for the treatment of refractory cystoid macular edema (CME) [38].

Triamcinolone Acetonide

Intravitreal triamcinolone has been used for the treatment of diffuse diabetic macular edema, which is characterized by diffuse leakage from extensive areas of posterior capillary bed, a scarcity of hard exudates, and a poor response to grid laser treatment [39]. Intravitreal injection of 1 or 4mgoftriamcinoloneacetonidemaybebeneficial as a treatment for diabetes macular edema with few complications [40].

Using a dosage of about 20 mg IVTA, the increase in VA was most marked during the first 3–6 months after injection and was evident for about 6–9 months [41]. Using a dosage of 4 mg, the duration of the effect (as measured by a reduction in macular thickness by OCT) was less than

6 months. These results lead to clinical trials comparing the efficacy of different IVTA doses, which confirmed that, in general, the duration of the effect increased with increasing dosage. Since the beneficial effects of IVTA are transient, with recurrence of macular edema, in a proportion of eyes, repeated injections may be necessary.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) has completed enrollment on a 3-year, randomized, prospective, multicenter clinical trial comparing two doses (1 and 4 mg) of preservative-free IVTA (Allergan, Irvine, CA, USA) with modified ETDRS photocoagulation for DME [42].Arecently published multicenter study, funded by the National Eye Institute and conducted through the DRCR.net, studied 840 eyes of 693 subjects with DME involving the fovea and with VA of 20/40 to 20/320. This 2-year study demonstrated that focal/grid photocoagulation is more effective and has fewer side effects than 1- or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with DME who have characteristics similar to the cohort in this clinical trial. The results of this study also support that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME [43].

The most important complication of IVTA is increased intraocular pressure (IOP) resulting in secondary open-angle glaucoma, which sometimes may be severe and intractable [44]. Elevation of IOP up to 24 mmHg may occur in about 4% of patients, usually within about 3 months. The second most important complication of IVTA is cataract formation, which may become visually significant in about half of eyes within 1 year [45]. The rates of injection-related endophthalmitis following IVTA have been reported to be in the range of 0.099– 0.87% per injection [46]. The incidence of pseudoendophthalmitis,duetomigrationoftriamcinolone acetonide crystals into the anterior chamber, is probably higher than that of infectious endophthalmitis. Other reported complications of IVTA (and of any intravitreal injection) include retinal detachment, lens trauma, and vitreous hemorrhage.

Peribulbar triamcinolone acetonide may have some limited efficacy for patients with DME although the bulk of the current literature appears to indicate that IVTA is more effective [47].

Fluocinolone Acetonide

In order to avoid the systemic toxicity of corticosteroids and immunomodulary therapy (IMT) or the repeated injections of local steroids necessary to control ocular inflammation, and to prevent development of cumulative damage resulting from recurrent episodes of inflammation, researchers have developed a number of local corticosteroid sustained-release devices that can be implanted directly into the vitreous of the eye, at the site of the inflammatory disease. Preliminary studies of such a device, the fluocinolone acetonide implant (Retisert, Bausch & Lomb, Rochester, NY, USA), have shown significant reductions in the number of inflammatory episodes and decreased reliance on systemic corticosteroids or other IMT [48].

Thefluocinoloneacetonideintravitrealimplant is US Food and Drug Administration (FDA)- approved for the treatment of chronic, noninfectious uveitis affecting the posterior segment [49] and is currently in clinical trials for the treatment of macular edema.

Extended-Release Dexamethasone

The extended-release dexamethasone implant (Ozurdex, Allergan, Irvine, CA, USA) is a biodegradable copolymer of PLGA (poly [lacticglycolic] acid) and is designed for intravitreal delivery of dexamethasone for approximately 35 days. It has shown favorable outcomes in the treatment of macular edema due to various etiologies, including diabetic retinopathy, retinal vein occlusions, pseudophakic CME, and uveitis, in a phase II study with randomized 306 patients 1:1:1 to Ozurdex 350 ug, Ozurdex 750 ug, or observation [50]. The primary efficacy endpoint was ≥2-line improvement in BCVA. Secondary endpoints included changes in retinal thickness by OCT measurement, change in contrast sensitivity, and improvement in angiographic leakage. Currently, Allergan completed the initial analysis of data from its phase III studies of Ozurdex® for macular edemaassociatedwithretinalveinocclusion(RVO) [51, 52]. Patients receiving either the 350 mg or the 700 mg dose of Ozurdex® demonstrated a statistically significant increase in vision based on a 3-line

or better improvement in visual acuity compared to a sham treatment. In addition, both doses of Ozurdex® were well tolerated in the studies. Less than 7% of patients receiving 700 or 350 mm of Ozurdex® experienced an elevation of intraocular pressure greater than 35 mmHg at any time during the 6-month study, and at 6 months, less than 1% of patients had an IOP above 25 mmHg. This new delivery system involves a single-use applicator that delivers the implant via pars plana injection and is performed in the office setting similar to an intravitreal injection. Ozurdex (dexamethasone intravitreal implant) has been approved by the FDA as first-line therapy for the treatment of macular edema following branch retinal vein occlusion or central retinal vein occlusion

Vascular Endothelial Growth

Factor Inhibitors

Vascular endothelial growth factor (VEGF) is thought to be a primary mediator of the vascular alterations in diabetic retinopathy. Vascular endothelial growth factor is produced in response to hypoxia from capillary loss and/or microaneurysm formation. It is a key mediator of angiogenesis and blood-retinal barrier breakdown in the ischemic retina. VEGF is upregulated in diabetic retinopathy and is present in increased levels in the aqueous and vitreous humor of patients with PDR [52, 53].At least five isoforms ofVEGF are known. At the moment of this writing, there are four main anti-VEGF agents in clinical use: (1) pegaptanib sodium (Macugen; OSI Eyetech Pharmaceuticals Inc., New York, NY; and Pfizer Inc., New York, NY, USA), (2) ranibizumab (Lucentis; Genentech Inc., South San Francisco, CA, USA), (3) bevacizumab (Avastin; Genentech, South San Francisco, CA, USA), and (4) Aflibercept, previously known as VEGF-Trap eye (Eylea®, Regeneron Pharmaceutics Inc., Tarrytown, NY).

Pegaptanib

Pegaptanib is a modified 28-base pegylated RNA aptamer that binds VEGF165 and the longer VEGF isoforms. It was the first FDA-approved ophthal-

mologic anti-VEGF agent for the treatment of choroidal neovascularization from age-related macular degeneration (AMD) [54]. A phase II clinical trial of pegaptanib in patients with DME followed up for 36 weeks resulted in better VA outcomes, reduced central retinal thickness, and reduced resort to additional photocoagulation therapy when compared with sham injections [55]. The retrospective analysis of a randomized clinical trial that aimed to study the effect of pegaptanib on diabetic macular edema suggested that pegaptanib might also induce neovascular regression [56].

Ranibizumab

Ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF. This quality makes it a powerful drug for VEGF inhibition. Intravitreal ranibizumab is FDA-approved for the treatment of exudative AMD. A pilot study in patients with CSME showed that therapy with this drug has the potential to maintain or improve VA and reduce retinal thickness [57]. The early experience in animal models with proliferative retinopathy and neovascular glaucoma shows that posterior and anterior neovascularizations are very sensitive to anti-VEGF therapy.

In a recent study, Nguyen et al. [58] compared the use of intravitreal ranibizumab (group 1, 42 patients) with focal/grid laser (group2, 42 patients) or a combination of both (group 3, 42 patients) in diabetic macular edema (DME). At month 6 of follow-up, they observed that the mean gain in BCVA was significantly greater in group 1 (+7.24 letters, p=0.01, analysis of variance) compared with group 2 (−0.43 letters), and group 3 (+3.80 letters) was not statistically different from groups 1 or 2. Excess foveal thickness was reduced by 50%, 33%, and 45% in groups 1, 2, and 3, respectively. These results indicated that during 6 months of follow-up, the application of intravitreal ranibizumab (0.5 mg) administered at baseline and months 1, 3, and 5 had a significantly better visual outcome than focal/grid laser treatment (at baseline and month 3 if needed) or a combination of 0.5 mg of ranibizumab and focal/grid laser at baseline and month 3 in patients with DME [58].

The outcome of two phase III clinical trials will increase our knowledge of the role of ranibizumab in the treatment of DME [59].

Bevacizumab

Bevacizumab is a full-length humanized monoclonal antibody against VEGF, which binds to all isoforms of human VEGF and its biologically active by-products. It is FDA-approved as an adjunctive systemic treatment for metastatic colorectal cancer. The angiogenic properties of bevacizumab, administered via intravenous infusion or intravitreal injection, have been studied in patients with choroidal neovascularization, macular edema, vitreous hemorrhage, and iris neovascularization [60, 61].

Vascular endothelial growth factor plays an important role in many diseases of the posterior pole that are characterized by macular edema and/or intraocular neovascularization. In most parts of the world, both pegaptanib sodium and ranibizumab are not readily available. Therefore, bevacizumab has been proposed as an alternative treatment option.

The Pan-American Collaborative Retina Study Group (PACORES) previously reported on their results on primary intravitreal bevacizumab at doses of 1.25–2.5 mg. Intravitreal bevacizumab seems to provide stability or improvement in VA, OCT, and FA in DME at 6 months [62] and appears to be safe and well tolerated during the first year [63]. In addition, PACORES recently

reported the 24-month anatomic and BCVA response after primary intravitreal bevacizumab (IVB) in patients with DME [20]. The results of this retrospective study demonstrated the efficacy of 1.25 or 2.5 mg of intravitreal bevacizumab as primary treatment for DME as 51.8% of eyes showed anatomical as well as functional improvement. In addition, these results suggest a reduced risk of VA loss in eyes with DME treated with intravitreal bevacizumab (97.1% of eyes). All eyes received an intravitreal injection at the initial visit; however, recurrences were retreated at the discretion of the treating physician. There were a total of 807 IVB injections performed. The mean number of IVB injections per eye was 5.8 (range 1–15 injections) at a mean interval of 12.2±10.4 weeks.

These results indicate that intravitreal bevacizumab injections may have a beneficial effect on macular thickness and VA for diffuse diabetic macular edema (DDME). Optical coherence tomography results were available for 139 eyes. At 1 month, the mean 1-mm CMT measurements decreased from 446.4 mm±154.4 mm to 333.75 mm±117 mm (p<0.001), and this overall improvement continued throughout the 24-month follow-up (Figs. 21.24 and 21.25). Therefore, in the future, this new treatment modality could replace or complement focal/grid laser photocoagulation. Furthermore, focal/grid laser photocoagulation could be used to consolidate the results obtained with one intravitreal bevacizumab injection and decrease the need for reinjections.

Fig. 21.24 (continued) bevacizumab at a dose of 2.5 mg in this eye. (b) OCT reveals decrease of macular edema and SRF at 1 month after bevacizumab injection. The retinal map analysis indicates a central foveal thickness of 421 mm. Visual acuity (VA) improved to 10/200. (c) Three months after the injection, the OCT scan shows improvement in foveal thickness (354 mm) and almost complete resolution of the SRF. VA improved to 20/200. (d) Four months after the first injection, his VA diminished to 20/400, and OCT scan demonstrated the reappearance of macular edema associated to increase of intraretinal cysts and SRF. Central foveal thickness increased to 861 mm. He received a second injection of intravitreal bevacizumab at a dose of 2.5 mg at this point. (e–g) OCT scans at 5, 6, and 9 months showed a progressive decrease in macular edema, intraretinal cysts, and SRF, which were confirmed with decreased of central foveal thickness (723, 436, and 397 mm, respectively). VA

also improved progressively (20/200, 20/160, and 20/125, respectively). (h) Twelve months after the first injection, OCT scan showed resolution of DME, with complete reabsorption of SRF and restoration of foveal anatomy. Central foveal thickness decreased to 200 mm, and visual acuity was 20/80. (i) OCT scans at 24 months showed a marked resolution of DME, with complete reabsorption of SRF and restoration of foveal anatomy. Central foveal thickness was 157 mm, and the visual acuity improved to 20/50 (Reprinted with permission from Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, Bonafonte S, Lujan S, DiazLlopis M, Restrepo N, Rodríguez FJ, Udaondo-Mirete P; Pan-American Collaborative Retina Study Group. Primary intravitrealbevacizumabfordiffusediabeticmacularedema the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 2009 Jun 20 [Epub ahead of print])

Fig. 21.24 Sequential optical coherence tomography (OCT) of a 32-year-old diabetic man with a 3-month history of loss of vision to counting fingers (CF) in his right eye that had developed diabetic macular edema (DME). (a) Ahorizontal OCT scan obtained through the fovea revealed

loss of the normal foveal contour, diffuse macular thickening, areas of low intraretinal reflectivity consistent with intraretinal cysts, and subretinal fluid (SRF). The retinal map analysis revealed a foveal thickness of 943 mm. The patient underwent an intravitreal injection of