Cystoid macular edema (CME) remains one of the most important causes of postoperative vision loss after cataract surgery¹ and can result in visual impairment in up to 14% of eyes.² Annual total ophthalmic claims can go up to 41% higher in Medicare patients with CME.³ This article offers a review of the latest evidence on preventing and treating it.

CME: A LITTLE BACKGROUND

What it is

First described in 1953 by S. Rodman Irvine, MD, and J. Donald M. Gass, MD,⁴ CME is precipitated by the release of prostaglandins and other inflammatory mediators after cataract surgery, resulting in an increase in perifoveal capillary permeability, blood-retinal barrier disruption and subsequent fluid accumulation and cystoid changes in the retina.⁵ CME begins with inner nuclear layer (INL) cystic changes and progresses to involve combined INL and outer plexiform layer (OPL) with subsequent subretinal fluid accumulation.

The INL is the most frequently involved layer, and isolated INL cystoid changes can be present within the first 3 postoperative months with no visual significance,⁶ even in the fellow, phakic eye.^7,8

CME has been classified as clinical (observed in slit lamp examination in patients with measurable decline in distance corrected visual acuity), angiographic (leakage detected on fluorescein angiography) and as presence of intraretinal fluid with or without subretinal fluid on OCT.⁹

CME risk and rates

Due to the diverse classification and the different studied patient populations with different risk factors, the reported CME incidence rate varies substantially between studies.^1,3,9-18 After modern small-incision cataract surgery in healthy individuals, CME has been reported as high as 19% using fluorescein angiography criteria, but as low as 0.82% using visual acuity and OCT findings.^1,9,10 Comparatively, certain groups are at higher risk of developing CME (Table), particularly uveitis patients,^1,11 diabetic patients with or without retinopathy,^3,12 eyes with capsule rupture during surgery with or without vitreous loss, patients with pseudoexfoliation,¹³ who frequently require pupillary expansion devices intraoperatively,¹⁴ patients with pre-existing epiretinal membrane,¹⁵ history of retinal vein occlusion, especially those who experienced macular edema after occlusion¹⁶ and retinal detachment repair.¹

Interestingly, postoperative use of topical prostaglandin analogues and beta blockers for management of glaucoma has also been associated with an increased risk of CME. Therefore, IOP management with these agents should be pondered with this increased risk.

Considering that the etiology of CME stems from increased levels of intraocular prostaglandins, it may be assumed that femtosecond laser-assisted cataract surgery, known to increase the level of prostaglandins in the anterior chamber,²⁰ poses a higher risk for postoperative CME. The literature in this regard is still inconclusive, with conflicting results in various peer-reviewed publications. Some studies show a decrease in the rate of postoperative CME,²¹ while others show no significant difference between FLACS and manual cataract surgery²² or an increased risk for CME when femtosecond laser is part of the surgical procedure.^23,24

Nevertheless, it is worth considering this potential outcome, especially in patients at higher-risk for CME.

CME PROPHYLAXIS

Less CME, but increasingly crucial to treat

CME after uncomplicated cataract surgery in low-risk patients tends to resolve spontaneously,^5,25,26 and no evidence suggests that perioperative anti-inflammatory treatment affects incidence or long-term visual outcomes. Additionally, advances in cataract surgery, such as more efficient phacodynamics and reduced time of surgery, and the insertion of a posterior chamber IOL have dramatically reduced the risk of postoperative CME.

However, perioperative control of inflammation may hasten the speed of visual recovery in the first several weeks postoperatively, and this becomes relevant in the days of refractive cataract surgery. Since the early stages of cataract surgery, the mainstay of perioperative anti-inflammatory treatment has been topical steroids, with no difference in the preventive efficacy of prednisolone vs. dexamethasone.²⁷

The role of NSAIDs

In the 1980s, NSAIDs began to be considered as an adjuvant — or even replacement — of postoperative treatment with topical steroids for routine cataract surgical cases. Initial studies evaluated indomethacin or ketorolac in addition to corticosteroid treatment^25,26,28 and showed a significant reduction of angiographic leakage in the initial postoperative period (as early as 10 weeks),²⁶ but no significant difference in angiographic findings or visual acuity beyond 3 months.

Later publications also showed less postoperative angiographic CME in eyes treated with diclofenac (18.8%) vs. eyes treated with betamethasone (58%) at 5 weeks but no significant differences in visual acuity between groups at 8 weeks.²⁹ Even studies comparing 1 to 3 days preoperative treatment with ketorolac to only postoperative treatment have shown significantly better visual outcomes at 2 weeks compared with control eyes, but this difference did not persist by 3 months.³⁰

There is a lack of level I evidence supporting long-term benefits of NSAID therapy in preventing vision loss attributed to CME.³¹ This is likely due to the selective blockage of cyclooxygenase enzyme by NSAIDS, which inhibits the synthesis of pro-inflammatory prostaglandins,^5,32 compared to the inhibition of prostaglandins and leukotrienes by corticosteroids. Corticosteroids also downregulate other inflammation-mediated processes, providing broader anti-inflammatory properties compared to NSAIDs.

It therefore remains to be determined if a synergistic effect occurs when both anti-inflammatory drugs are combined, or if dual treatment is simply redundant.

Hence, topical NSAIDs, though approved by the FDA for “treatment of pain and inflammation associated with cataract surgery,” are yet to be approved for the prevention or treatment of CME or for treatment durations longer than 14 days.³¹ NSAIDs are currently used off-label by many ophthalmic surgeons in the United States as prophylaxis and treatment of CME, especially in high-risk patients.

More recently, newer NSAID formulations with better intraocular penetrations, such as bromfenac and nepafenac, have been compared to topical steroids alone and to other NSAIDs.^33-35 Nepafenac has been equivalent to diclofenac³³ and ketorolac³⁴ with no significant differences in final visual acuity at 4 weeks. Bromfenac 0.09% alone has shown CME development in as low as 0.44% of cases, compared to the combination of prednisolone 1% and generic (2.2%) or name-brand ketorolac 0.45% (0.9%),¹⁰ as well as to dexamethasone alone.³⁵

The potential prophylactic benefit of perioperative treatment with topical NSAIDs appears to exist in high-risk patients. Patients with pseudoexfoliation syndrome¹⁹ and diabetes,³⁶ who are treated with topical bromfenac 0.09% or nepafenac 1% combined with a topical steroid, experience lower rates of postoperative CME. Preoperative treatment in diabetic patients, however, may not offer added benefits compared to postoperative treatment only.³⁷

Steroids and delivery methods

Newer approaches for perioperative prophylaxis of intraocular inflammation include:

• Preoperative oral corticosteroids in high-risk patients¹¹
• Intracameral dexamethasone drug deposits^38-41
• Intracameral administration of triamcinolone acetonide^42,43
• Transzonular intravitreal administration of compound antibiotic and anti-inflammatory drugs (caution is advised given the risk of iatrogenic zonular instability)
• Fluocinolone acetonide intravitreal implant⁴⁴
• Perioperative subconjunctival triamcinolone.^45,46

Interestingly, none of these steroid delivery methods have yet been found to increase the risk of postoperative IOP spike compared to topical steroids.^40,47,48 New drug delivery methods are also being studied, such as intracanalicular dexamethasone deposits⁴⁹ and using the IOL as a drug delivery device.^50-52

CME TREATMENT

Our options

Though no strong evidence from randomized controlled trials shows superior outcomes compared to observation in uncomplicated eyes, the combination of topical NSAID and topical steroid for at least 6 weeks has been the main off-label approach for treatment of visually significant CME. However, other treatment modalities have been proposed and shown results that are promising but still comparable to topical treatments in the majority of cases: intravitreal dexamethasone implants,⁵³ especially in diabetic patients⁵⁴ and patients with vitrectomized eyes,⁵⁵ intravitreal anti-VEGF drugs,^56,57 sub-tenon’s corticosteroids⁵⁸ and oral acetazolamide,⁵⁹ which shows beneficial in patients with known steroid-induced elevation in IOP.

Because CME is also known to resolve spontaneously, we need further large population randomized controlled studies with longer follow up to assess the true benefit of all these therapeutic approaches.

Summary

CME arises from changes in the INL and OPL of the retina resulting from the increase in the level of intraocular inflammation after even uncomplicated cataract surgery. In certain groups, the incidence is much higher and can lead to significant vision loss. We have limited evidence on best strategies for prophylaxis, but the most effective approach to date appears to be treating prophylactically only those at higher risk for developing CME after cataract surgery.

There is a weak association between angiographic and OCT evidence of CME and visual acuity and strong evidence suggesting that CME after cataract surgery in low-risk patients resolves spontaneously. Therefore, subclinical CME diagnosed by OCT or angiography in low-risk cases may be observed and only treated should it become visually significant.

Conversely, in high-risk patients (who are more prone to recalcitrant edema and decline in vision), medical treatment can be initially considered followed by intravitreal anti-inflammatory, or anti-VEGF injections if there is no response. OM

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About the Author

Claudia Perez-Straziota, MD, is a Cornea specialist at The Cole Eye Institute at The Cleveland Clinic in Cleveland, Ohio. She specializes in advanced endothelial keratoplasty techniques, complicated cataract extraction / premium intraocular lenses, and keratoconus diagnosis and management.

Originally from Caracas, Venezuela, she completed Medical School at the Universidad Central de Venezuela and then moved to the United States to complete her Ophthalmology Residency and Fellowship in Cornea, External Disease and Refractive Surgery at Emory University in Atlanta, Georgia.

Dr. Perez Straziota is a member of the Young Eye Surgeons Committee in the American Society of Cataract and Refractive Surgery and a reviewer for multiple national and international peer reviewed journals. She also has numerous peer reviewed publications and book chapters, as well as more than 20 presentations in National and International Ophthalmology conferences. She has been awarded best Paper multiple times at the ASCRS annual meetings and featured as a promising young physician in the Millennial Eye organization.