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Purpose To review the current therapeutic options for the management of diabetic retinopathy (DR) and diabetic macular edema (DME) and examine the evidence for integration of laser and pharmacotherapy. Methods A review of the PubMed database was performed using the search terms diabetic retinopathy, diabetic macular edema, neovascularization, laser photocoagulation, intravitreal injection, vascular endothelial growth factor (VEGF), vitrectomy, pars plana vitreous surgery, antiangiogenic therapy. With additional cross-referencing, this yielded 835 publications of which 301 were selected based on content and relevance. Results Many recent studies have evaluated the pharmacological, laser and surgical therapeutic strategies for the treatment and prevention of DR and DME. Several newer diagnostic systems such as optical coherence tomography (OCT), microperimetry, and multifocal electroretinography (mfERG) are also assisting in further refinements in the staging and classification of DR and DME. Pharmacological therapies for both DR and DME include both systemic and ocular agents. Systemic agents that promote intensive glycemic control, control of dyslipidemia and antagonists of the renin-angiotensin system demonstrate beneficial effects for both DR and DME. Ocular therapies include anti-VEGF agents, corticosteroids and nonsteroidal anti-inflammatory drugs. Laser therapy, both as panretinal and focal or grid applications continue to be employed in management of DR and DME. Refinements in laser devices have yielded more tissue-sparing (subthreshold) modes in which many of the benefits of conventional continuous wave (CW) lasers can be obtained without the adverse side effects. Recent attempts to lessen the burden of anti-VEGF injections by integrating laser therapy have met with mixed results. Increasingly, vitreoretinal surgical techniques are employed for less advanced stages of DR and DME. The development and use of smaller gauge instrumentation and advanced anesthesia agents have been associated with a trend toward earlier surgical intervention for diabetic retinopathy. Several novel drug delivery strategies are currently being examined with the goal of decreasing the therapeutic burden of monthly intravitreal injections. These fall into one of the five categories: non-biodegradable polymeric drug delivery systems, biodegradable polymeric drug delivery systems, nanoparticle-based drug delivery systems, ocular injection devices and with sustained release refillable devices. At present, there remains no one single strategy for the management of the particular stages of DR and DME as there are many options that have not been rigorously tested through large, randomized, controlled clinical trials. Conclusion Pharmacotherapy, both ocular and systemic, will be the primary mode of intervention in the management of DR and DME in many cases when cost and treatment burden are less constrained. Conventional laser therapy has become a secondary intervention in these instances, but remains a first-line option when cost and treatment burden are more constrained. Results with subthreshold laser appear promising but will require more rigorous study to establish its role as adjunctive therapy. Evidence to support an optimal integration of the various treatment options is lacking. Central to the widespread adoption of any therapeutic regimen for DR and DME is substantiation of safety, efficacy, and cost-effectiveness by a body of sound clinical trials.

BACKGROUND AND OBJECTIVE To determine the prophylactic and therapeutic value of a single subthreshold 810-nanometer laser treatment in patients with high risk drusen as a manifestation of dry age-related macular degeneration in both eyes. PATIENTS AND METHODS The Prophylactic Treatment of Age-related Macular Degeneration study enrolled 1,278 eyes of 639 participants who were 50 years or older with at least 5 drusen 63 µm or more in diameter in each eye. Treatment consisted of the placement of an annular grid of 48 extrafoveal, subthreshold 810-nm diode laser applications centered at but sparing the foveola in one eye of each participant, with the fellow eye serving as a control. Development of choroidal neovascularization and change in best-corrected visual acuity were compared between treated and untreated eyes. RESULTS Subthreshold laser treatment did not decrease the incidence of choroidal neovascularization in treated versus untreated eyes. A modest visual acuity benefit in treated eyes was found at 24 months (1.5 letter difference; P = .04) and in the treated eyes of participants with a baseline visual acuity between 20/32 and 20/63 (4.0 letter difference; P = .0034). However, this treatment effect was not sustained at 3 years. CONCLUSION A single subthreshold 810-nanometer laser treatment to eyes of participants with bilateral high risk drusen is not an effective prophylactic strategy against choroidal neovascularization. [Ophthalmic Surg Lasers Imaging 2009;40:530-538.] AUTHORS From the UPMC Eye Center (TRF, PMB), University of Pittsburgh, Pittsburgh, Pennsylvania; the Shiley Eye Center (WRF), University of California–San Diego, La Jolla, California; and the W. K. Kellogg Eye Center (DCM), University of Michigan, Ann Arbor, Michigan. Accepted for publication December 19, 2008. Supported by Iridex Corporation, Mountain View, California, and the sources listed under the individual center descriptions found at the end of the article; the Eye and Ear Foundation of Pittsburgh, Pittsburgh, Pennsylvania; Research to Prevent Blindness, Inc., New York, New York; and unrestricted funds from several participating centers. Presented in part at the annual meeting of the American Academy of Ophthalmology, October 15-18, 2005, Chicago, Illinois, and the annual meeting of the Association for Research in Vision and Ophthalmology, April 30-May 4, 2006, Ft. Lauderdale, Florida. The authors thank photographic readers Cheryl Hiner, Columbia, MD, Rosemary J. Brothers, Madison, WI, and Linda Huang, MD, and Maria Palaiou, MS, Pittsburgh, PA; the Data and Safety Monitoring Committee voting members Donald J. D’Amico, MD, Mark W. Johnson, MD, J. Richard Landis, PhD, and nonvoting ex-officio member, Dr. Musch; and Giorgio Dorin for his contribution to the manuscript. The authors have no financial or proprietary interest in the materials presented herein. Address correspondence to Thomas R. Friberg, MS, MD, UPMC Eye Center, 203 Lothrop Street, Suite 824, Pittsburgh, PA 15213. doi: 10.3928/15428877-20091030-01

The fundus abnormalities seen in diabetic retinopathy can conceptually be split into three categories – those findings resulting from leaking microvasculature (hemorrhages, lipid exudates, retinal edema); those findings resulting from structural damage to the microvasculature wall (microaneurysms); and those findings resulting from ischemia with a subsequent overproduction of vascular growth factors (cottonwool patches, intraretinal microvascular abnormalities [IRMA], preretinal neovascularization, fibrous proliferation, and vitreous hemorrhage). The severity of each of these findings can be classified and quantified based on the degree of retina involvement, e.g., the number of microaneurysms and hemorrhages in each quadrant or photographic field, the area of retina affected by neovascular tissue or IRMA, the area of macula involved with retinal thickening. Classification schemes are a means to categorize the varying degrees of such findings to facilitate communication.As with all specialized languages, the value of these languages depends upon who is speaking to whom. The ultimate goal of classification schemes is to provide a system to improve patient care. This may be achieved initially by precise communication among researchers to define categories by which the natural history and subsequent response to intervention(s) can be identified. Once these research goals have been achieved these classification schemes should be understandable and reproducible by practicing clinicians. If not, then modification of these classification schemes is desirable to allow clinicians to communicate among themselves and with their patients the expected results of therapies demonstrated to be beneficial in clinical trials. One should realize that the goals of communication between researchers may be different from the goals of communication between clinicians and may likewise be different from the goals of communication between clinician and patient. Evolution of classification schemes is desirable dependent upon who is communicating with whom.

In previous chapters, the emphasis has been on a detailed understanding of a particular aspect of diabetic retinopathy. In this chapter the approach will be more topical and practical and the principles presented previously will be exemplified in characteristic situations. Actual cases will be presented with discussions regarding management. These cases were circulated among the co-authors and comments on management independently solicited and then compiled. The discussants for the cases used the comments as a springboard to review the literature and provide a synthesis that reflects both the diverse clinical judgments of the reviewers and the published evidence pertinent to the case.

If one follows the assumption that management of patients with diabetic retinopathy begins with an appropriate history and clinical examination then the purpose of ancillary diagnostic testing should be to add value to evaluation of the patient. Examples of such value may be to provide patient education to gain compliance with treatment recommendations (blood sugar control); to decide when additional intervention is beneficial either at baseline (detection of diabetic macular edema) or follow-up (response of diabetic macular edema to therapy); and to help establish prognosis such that appropriate follow-up schedules can be mutually agreed upon. In a research setting, there are additional purposes for ancillary testing but the emphasis in this chapter is on clinical care of patients with diabetic retinopathy.

To determine whether verteporfin photodynamic therapy (PDT) can safely reduce the risk of vision loss in patients with subfoveal occult with no classic choroidal neovascularization (CNV) due to age-related macular degeneration.Eligible patients wereor =50 years of age with lesion sizeor =6 disc areas and best-corrected vision 20/40-20/200. A total of 364 patients with occult with no classic CNV were randomly assigned 2 : 1 to verteporfin PDT (n = 244) or placebo (n = 120). The primary outcome measures were loss ofor =15 andor =30 letters of visual acuity (VA) from baseline at 12 and 24 months.This study was registered with ClinicalTrials.gov on 20 July 2005. ClinicalTrials.gov identifier: NCT00121407.A total of 37% and 47% of verteporfin-treated patients versus 45% and 53% of placebo recipients lostor =15 letters of VA at month 12 and month 24, respectively; 16% and 23% of verteporfin-treated patients versus 17% and 25% of placebo recipients lostor =30 letters at month 12 and month 24, respectively. These differences were not statistically significant. Four (1.6%) verteporfin-treated patients and one placebo patient (who received verteporfin in error) experienced an acute severe VA decrease; all five patients recovered some degree of vision. No unexpected ocular or systemic adverse events were identified.Verteporfin PDT in the treatment of occult with no classic CNV was safe and well-tolerated. The differences between the two groups in the primary efficacy variables were not significant. Baseline characteristics and patient selection methods may have contributed to the small treatment effect.

A 42-year-old woman had severe, bilateral visual loss and the initial symptom of systemic lupus erythematosus. Fundus photographs and fluorescein angiograms demonstrated an inflammatory process and severe ischemia. Vision in the less severely affected eye markedly improved after systemic and retrobulbar administrations of corticosteroids.