Earlier detection and a wider array of treatment options allow a more proactive approach to prevention and treatment of CME.
Cystoid macular edema (CME) is commonly thought of in conjunction with cataract surgery, but it is also a symptom of a variety of disease processes that result in macular edema, including diabetic macular edema, central retinal vein occlusion, branch retinal vein occlusion, and uveitis. In some contexts CME is a finding, and in others a diagnosis. Because of its potential to permanently impair vision, CME is always a matter of concern regardless of setting.
CME following cataract surgery was first reported by Irvine in 1953. This was followed by an angiographic description of it by Gass and Norton in 1966, leading to the name Irvine-Gass syndrome for pseudophakic CME.1
Diagnosis and Incidence
Pseudophakic CME is termed “clinical” when vision drops below 20/40 without resolving within a few weeks. The “gold standard” for diagnosing CME is fluorescein angiography (Figure 1). Typical angiographic findings include late-developing staining with a cystoid-petaloid appearance. CME is sometimes seen on angiography of postoperative eyes with little or no loss of visual acuity, a finding termed “angiographic CME.”
While definitive, the use of fluorescein angiography is declining. As a practical matter, most CME is now detected by optical coherence tomography (OCT), which is fast, noninvasive, relatively easy, and does not require pupillary dilation.2 Using OCT, macular cysts and vacuoles are clearly visible, and retinal swelling can be measured (Figure 2). In time-domain OCT, a macular thickness between 200 and 250 microns indicates edema, while with spectral-domain OCT, macular thicknesses between 275 and 300 microns indicate swelling. Of course, the significance of the swelling depends upon the associated condition.3,4
It is difficult to estimate changes in incidence of CME, as both causal factors and the means of detection have changed. Today, improvements in cataract surgery have led to reduced capsule breakage and vitreous leakage, but other conditions that can produce macular edema, particularly diabetic retinopathy, are increasing. The ease of performing OCT also means that CME can be detected at an earlier, subclinical, stage; and treatment at that point may prevent clinically evident vision impairment.
Most CME from cataract surgery resolves spontaneously. However, because OCT enables early detection, and we now have additional treatment options, management by watchful waiting is being replaced with a more proactive approach. Early intervention is likely a significant factor in reducing the incidence of clinical CME.
The chief target of CME treatment are Müller cells, retinal glial cells that mediate the integrity of the blood-retina barrier and is activated by many pathogenic stimuli. In particular, cytokines released by activated inflammatory cells lead to blood-retina barrier breakdown and capillary leakage, as do inflammatory prostaglandins. Changes in the fluid transport by Müller cells can result in cyst formation from the accumulation of fluid in the outer plexiform layers and the inner nuclear layers of the retina. Swelling of Müller cells can contribute to CME even in the absence of vascular leakage or cyst formation. Since the job of the Müller cell is to support the survival of photoreceptors and neurons, impairment of Müller cell function can put neurons at risk.5
NSAIDs in CME
Topical nonsteroidal antiinflammatory drugs (NSAIDs), given before surgery or immediately afterwards, are the first line of defense against CME. NSAIDs inhibit the enzymes cyclooxygenase-1 and -2 (COX-1 and COX-2) that generate prostaglandins, and so work near the end of the inflammatory cascade. NSAIDs are approved for the treatment of pain and inflammation following cataract surgery, although many surgeons use them off-label to decrease the risk of CME formation after surgery. Topical NSAIDs are also used, again off-label, for longer periods to treat manifest macular edema.
In the 1990s a generic diclofenac formulation was recalled following reports of corneal melts, and corneal melt is still of concern with NSAID use today, especially when the drugs are used on a long-term basis. There have, however, been few reports of corneal melts with the newer NSAIDs, including nepafenac, bromfenac, and ketorolac.
To address the question of corneal melt incidence with these NSAIDs, I and a number of coworkers recently published a large single-center retrospective study of the incidence of corneal melts after administration of nepafenac, bromfenac, or ketorolac.6 Included patients were prescribed one of these drugs for at least 3 months. Over the course of the study, 1999-2009, no case of corneal melt (any persistent defect or thinning of the cornea, other than superficial punctate keratitis) was seen.
To check for missed findings, records of a random sample comprising anequal number of patients from each drug treatment group was examined in detail (n = 167 per group). The patients had been prescribed NSAIDs for full thickness macular hole (37.1%), macular cyst hole/pseudohole (19.2%), epiretinal membrane (30.5%), and CME (13.2%). The mean duration of use was 20.9 months for ketorolac, 21.7 months for bromfenac, and 36 months for nepafenac; most patients in each group were dosed QID.
Dry eye was a concomitant diagnosis for 34% of the patients, and 31% were diabetic. Although both these conditions have been implicated in corneal melts, they appeared to be without effect in this study. The three topical NSAIDs tested appear safe even at high doses over extended periods. A detailed review of the literature suggests corneal melt is actually a very rare postsurgical complication.6
Corticosteroids continue to be the mainstay treatment for CME. Corticosteroids act upstream of NSAIDs in the inflammatory cascade, by decreasing a host of inflammation mediators. As a result, they require several hours to take effect, but they have a longer duration of action. There are a number of choices within this class of drug, including new formulations that enable a more nuanced approach to management.
A new strong topical steroid, difluprednate, is an alternative to NSAIDs for the prevention of CME when given before or at the time of surgery. Administered topically, difluprednate can be an option for the treatment of existing CME before resorting to injectable or implantable steroid formulations.7
Among injectable formulations, there is dexamethasone, which is short-acting but very potent, and triamcinolone, which is longer acting but has a worrisome side-effect profile in regard to intraocular pressure (IOP) rise. For the longer-term treatment of CME, sustained-release options include Ozurdex® (Allergan), an intravitreal implant containing dexamethasone, and Retisert® (Bausch + Lomb), a pellet containing 0.59 mg of fluocinolone that is sewn into the eye. Iluvien® (Alimera Sciences), an intravitreal insert, has a lower dose of fluocinolone (0.2 mg or 0.5 mg); it was recently approved in Europe for diabetic macular edema, and may be available soon in the US.
Bevicizumab, an anti-vascular endothelial growth factor (VEGF) agent, is an off-label alternative to implanted or injectable steroids. Treatment with bevacizumab seeks to reduce edema by blocking capillary leakage. This approach appears to be effective in the short run, although it may not be better than injectable steroids over the course of a year or longer. But for several months, at least, there is good activity, and IOP rise is not a danger.8,9
Another alternative to steroids is Diamox® (acetazolamide), which can be used in macular edema due to non-surgical causes.10 A glaucoma medication, it changes the ionic flux of the retina and thus reduces swelling, but its unpleasant side effects—including finger tingling and metallic taste—make it a later choice.
Since vision loss in CME may be irreversible, it is important not to let chronic CME develop. In the future we can expect to see more interventional approaches to CME prevention and treatment as clinicians become familiar with the wider and more nuanced choice of drugs available. Physicians are becoming increasingly comfortable with ocular injections, and intraocular inserts have become easier to use. As a result, the risk-benefit ratio has shifted toward more aggressive treatment of macular edema, no matter what the cause.
THE BOTTOM LINE
The advent of OCT allows earlier and easier detection of CME, and the options for preventing and treating CME have expanded with new topical NSAIDs, strong topical steroids, and long-acting steroid inserts. As a result, a passive approach to the management of CME is no longer appropriate.
Michael A. Singer, MD, is a managing partner of Medical Center Ophthalmology Associates, and assistant clinical professor of ophthalmology at the University of Texas Health Science Center, San Antonio. He is a consultant for Allergan and Ista. Medical writer Zaid Smith, PhD, assisted in the preparation of this manuscript.
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