Since the introduction of intravitreal triamcinolone for the treatment of uveitic cystoid macular edema (6), it has become clear that steroids have a direct effect on the retinal vascular endothelium, decreasing leakage and restoring the blood retinal barrier. This discovery has led to the widespread use of intravitreal steroids for macular edema due to multiple causes, including diabetic retinopathy and retinal vein occlusions. Recent reports from the Intravitreal Steroid Injection Studies-Diabetic Macular Edema (7) (ISIS-DME) have shown that intravitreal injections of triamcinolone (Kenalog) result in significant visual improvement (three or more lines) in 38% of patients. Subgroup analysis revealed that 62% of patients with cystoid macular edema improved at least three lines of vision, whereas only 9% of those with noncystoid macular edema had a similar response. The macular edema recurred in approximately 50% of patients 6 months after the injection. Complications noted were steroid glaucoma in approximately a third of patients. Intravitreal steroids have other important complications in addition to steroid glaucoma. Posterior subcapsular cataract formation is a well-recognized complication of steroids and should be considered whenever injections are to be performed in phakic individuals. The authors do not use steroids in the management of diabetic macular edema because of the untenable steroid glaucoma and cataract rates.

The widespread use of intravitreal injections of steroids has been followed by various drug delivery systems that promise to prolong the release of steroids with slowrelease devices implanted in the vitreous. Currently, there are two types of drug delivery steroid implants in clinical trials: biodegradable implants (e.g., Osurdex dexamethasonepolyacticglycolic acid) and nonbiodegradable (e.g., Retisert fluocinolone implant). Both types of implants have potential advantages and disadvantages. Biodegradable implants have the advantage of requiring one implantation (that can be performed in the office with a 22-gauge injection applicator) but may have nonlinear release kinetics, whereas nonbiodegradable implants, although having linear release kinetics, require more complex surgical implantation and subsequent removal unless the implant is left in place. The Retisert clinical
trials reported a 90% incidence of steroid glaucoma and a 34% incidence of glaucoma filtering procedures. The risk/benefit and cost/benefit analyses of these implants in comparison with repeated intravitreal injections of triamcinolone suggest that the implants are too costly, in addition to causing an unacceptably high rate of steroid glaucoma and cataracts.

Because of steroid glaucoma and steroid-induced cataracts, the authors do not use intravitreal steroids for diabetic macular edema and use a combination of anti-VEGF therapy (Avastin), PASCAL laser, and topical nonsteroidal agents (Nepafenac, Alcon).

Macular edema is caused by vascular endothelial growth factor (VEGF) (8, 9, 10), the same agent that causes retinal neovascularization in diabetes and choroidal neovascularization in age-related macular degeneration. VEGF downregulates the tight junctions of the endothelium of the retinal vessels, causing breakdown of the blood-retinal barrier, and therefore leakage of fluid and macromolecules into the retinal intercellular space. Ischemia leading to VEGF production may be a factor in certain macular edema cases. For this reason, patients with macular edema not responding to direct focal treatment of leaking microaneurysms, or areas of leakage on fluorescein angiography, may respond to treating areas of ischemia. Heavy grid photocoagulation probably has little effect in reducing neovascularization but significantly reduces central visual fields and therefore reading speeds and often causes patients with excellent Snellen acuity to complain that they “cannot see.”

The introduction of anti-VEGF therapy has led to a new mode of therapy for macular edema secondary to NPDR as well as for venous occlusive disorders. Bevacizumab (Avastin) is an anti-VEGF antibody currently approved by the FDA for systemic therapy of cancer. Intravitreal Avastin is widely used for the treatment of choroidal neovascularization in age-related macular degeneration. Avastin is also being used for macular edema secondary to Branch Retinal Vein Occlusion (BRVOs) (11) and Central Retinal Vein Occlusion (CRVOs) as well as for retinal neovascularization in proliferative diabetic retinopathy (PDR). The initial published results as well as the authors’ results demonstrate that anti-VEGF therapy combined with laser should become standard therapy in the management of diabetic macular edema and PDR.

The recent advances in pharmacotherapy and surgical therapy for diabetic macular edema, added to the well-known and time-proven approaches with laser photocoagulation, provide the clinician multiple therapeutic possibilities. Although there are no trials that clearly indicate which combination and sequence of therapies should be employed, the authors present their current perspective of management of diabetic macular edema, with the understanding that this protocol may change in the near future as clinical research is presented. Combination therapy is an appealing concept but is appropriate in some instances and not in others. Combination chemotherapy in oncology is utilized because the agents have narrow windows between effective and toxic drug levels as well as to provide multiple barriers to the evolution of cancer cells. Combination therapy for infectious disease is utilized in severe infections when the infectious agent has not been identified and delayed treatment would produce bad outcomes. Combination therapy for infectious disease creates multiple barriers for evolution of the infectious agent but unfortunately leads to higher incidence of resistance. Focal and/or PRP laser plus anti-VEGF therapy is very effective in diabetic retinopathy and can be broadly defined as combination therapy. Topical nonsteroidal (Nepafenac) therapy in combination with laser and anti-VEGF compounds is effective for diabetic macular edema because of multiple mechanisms, VEGF, and inflammation.

Early experimental work incorrectly concluded that vitreous hemorrhage caused neovascularization via organization of the blood clot. Vitreous hemorrhage is a result of neovascularization rather than the cause. Although long-standing vitreous hemorrhage can deposit iron on many intraocular structures, there is usually no retinal damage from a vitreous hemorrhage. Retinal detachment, macular damage, ischemia, and optic nerve function will determine the ultimate visual outcome when long-standing vitreous hemorrhages are removed, not the hemorrhage per se.

If the other eye has good vision, a unilateral hemorrhage can be followed indefinitely with ultrasound, unless retinal detachment, anterior vitreous cortex (AVC) neovascularization, or iris neovascularization occurs. An eye without prior PRP is at greater risk for the development of neovascular complications and must be watched more closely. B-scan ultrasonography should be repeated at each visit, preferably at 1-month intervals until the blood clears or surgery is performed. Ultrasonic evidence of posterior pole detachment requires immediate vitrectomy. The usual question of duration of a vitreous hemorrhage plays a less important role in the surgical decision-making process than other factors. If it does not appear that near-term clearing will occur, bilateral hemorrhage requires surgery on the eye with the best visual prognosis. Vitreous hemorrhage in a patient with only one eye as well as the better eye of bilateral cases should be operated on to improve visual function. Those patients with shortened lifespan and multisystem disease need immediate visual rehabilitation for emotional and social reasons. Subposterior vitreous detachment and preretinal hemorrhages clear more rapidly than does hemorrhage in the vitreous cortex. For this reason, patients with bilateral or only-eye sub-PVD or preretinal hemorrhage can be followed up for as long as the patient’s emotional and social needs permit. If one eye has macular ischemia and the other, better, eye develops a vitreous hemorrhage, vitrectomy may be indicated to improve the patient’s overall visual function.

TRD can be diagnosed by ophthalmoscopic or ultrasonic examination. If the macula is detached, vitreous surgery should be performed within 3 weeks, unless there are medical contraindications. If there is active neovascularization, it is better to perform PRP before vitrectomy if possible. Because of extensive exudation and fibrous proliferation, panretinal cryopexy should not be utilized. If vitrectomy indications are present, endo-PRP can be combined with vitrectomy. If vitrectomy is postponed until PRP-induced or spontaneous involution of neovascularization occurs, the incidence of postoperative NVG and AVCFVP is dramatically reduced.

Recent studies demonstrate that intravitreal anti-VEGF therapy with bevacizumab can precipitate TRDs in patients with severe neovascularization (18). These patients should be followed closely after anti-VEGF therapy and the surgeon should be ready to proceed to vitrectomy if progression to TRD is evidenced.

Because of the relatively high rate of biologic complications and medical risk factors, vitrectomy is not indicated in extramacular TRD. This is true even if progression toward the macula or a similar condition in the other eye seems to “threaten” the macula. It is safer to operate on actual, rather than predicted, visual loss. The rate of progression of extramacular TRD to include the macula is about 15% per year (19,19a,20). After several years, progression to MTRD stabilizes at a cumulative rate of about 30%, and there are many patients with 5 to 10 years duration extramacular TRDs surrounding the macula with good vision that never required surgery.

Cataract surgery can result in anterior movement of the vitreous with progression of extramacular TRD to macular involvement. Once again, vitreous surgery should only be performed if the macula actually becomes elevated (21).

The frequency of cardiovascular and renal disease in the diabetic patient requires careful preoperative evaluation by the primary care physician or internist and utilization of cardiologists, endocrinologists, and other consultants as needed. The anesthesiologist should review the preoperative medical evaluation. Diabetic vitrectomies can be performed in the ambulatory surgery center setting if systemic disease is stable, an anesthesiologist is available and the patients systemic specialists (nephrologists, cardiologists) give adequate consent for surgery. Patients that are not controlled systemically and require vitrectomy surgery that cannot be delayed should be operated in a hospital outpatient setting. It is essential to have MD anesthesia function in an immediate availability and supervisory role if CRNA anesthesia is utilized. Proximity to the hospital ensures availability of cardiologists, endocrinologists, pulmonary specialists, and intensive care facilities as well as providing higher facility fees than free-standing ambulatory surgery centers, thereby facilitating access to best technology. An intravenous line, EKG, pulse oximetry, blood pressure monitoring, and oxygen mask with suction hose to prevent hypercapnia must be utilized in all cases. The anesthesiologist or nurse anesthetist should make liberal use of intraoperative serum glucose monitoring. Operating times are always less than 1 hour and usually about 30 minutes, which is compatible with local anesthesia and the associated reduction in nausea, vomiting, and medical complications of general anesthesia. Minimal, if any, sedation is used after the block, which is performed with a 27-gauge, 1.25-inch needle at the outer “corner” of the orbit.