Mechanics of NSAIDs to treat CME

Nonsteroidal anti-inflammatory drugs have been shown to prevent cystoid macular edema and should be used in all cataract surgeries. Cystoid macular edema is the most frequent cause of visual decline following uncomplicated cataract surgery and is more common than endophthalmitis because it occurs in one in eight, or approximately 12%, of patients.¹

Causes of CME

Although cystoid macular edema (CME) is associated with visual acuity of 20/40 or worse, patients with 20/25 vision can have subtle CME. High patient expectations have influenced ophthalmologists to examine these patients more closely. Optical coherence tomography (OCT) is useful in detecting subtle CME because it measures subtle postoperative retinal thickening and monitors patients’ responses to therapy.² Inflammation, aging, glaucoma or systemic vasculopathy result in the release of prostaglandins, causing a breakdown of the blood aqueous and retinal barriers and the onset of CME (Figure 1).³ Breakdown of the blood-aqueous barrier activates components, leading to chemotaxis, which attracts inflammatory cells to the inflamed tissue and causes increased vascular permeability. Increased prostaglandins result in surgical miosis, CME and postoperative pain due to increased tissue levels of prostaglandins. Inflammatory sequelae can be inhibited by reducing the biosynthesis of prostaglandins. ⁴

Mechanics of NSAIDs

NSAIDs are effective in preventing CME and in improving visual acuity.⁵ Corticosteroids alone do not effectively prevent or treat CME.¹ In the mechanism of action of combined NSAID and corticosteroid therapy, corticosteroids inhibit the conversion of phospholipids to arachidonic acids, inhibit platelet-activating factor, reduce the amount of cytokines and neurogenic inflammation and block the activity of cytokines. NSAIDs inhibit cyclooxygenase and reduce the production of prostaglandins.⁶

The ideal NSAID is a uniform inhibitor of cyclooxygenase and the target tissues in the eye and should affect all ocular barriers. Because the pathway is similar, it should inhibit the prostaglandins from the ciliary body as well as from retinal prostaglandin synthesis. The ideal NSAID would also penetrate the target intraocular tissues, both in the aqueous and posterior segment, and reduce the presence of CME. The ideal NSAID would have analgesic properties and be safe and comfortable.

Patients undergoing cataract surgery who are at high risk for CME should receive NSAIDs preoperatively for 1 week and postoperatively for 4 weeks to several months. Patients who are at low risk or who are not at risk for CME should have preoperative NSAIDs for 1 to 2 days, followed by postoperative NSAIDs for 4 weeks.

Patients who have failed conventional topical therapy may be treated with a posterior subtenon injection of 20 mg of triamcinolone in combination with a topical NSAID administered four times a day for 6 weeks. Dosage is reduced by one drop a day for the next 3 weeks, with a total of 12 weeks of treatment. Patients who are not responsive to periocular steroid treatment may be treated with intraocular triamcinolone. IOP should be monitored in these patients because secondary glaucoma is a complication of steroid use. Phakic patients treated for CME with steroids are at risk for cataract formation. All CME patients are at risk for permanent visual loss, making prophylaxis paramount. Historically, most retinal specialists have used a steroid injection alone because previously available NSAIDs did not achieve effective penetration or target tissue concentrations. However, ophthalmologists are beginning to use NSAIDs more often because drugs with more effective penetration are available.

Study shows nepafenac to improve CME

My colleagues and I performed a study in which nepafenac was shown to reduce retinal thickening.¹ My colleagues and I examined 11 patients, all of whom responded to corticosteroids with increased IOP. The figure shows results for two of the 11 patients. Eight patients had had cataract surgery and three patients had macular pucker and associated CME. Because these patients responded to corticosteroids, they were treated with nepafenac alone, which was administered four times each day for 6 weeks, and then reduced over an additional 6 weeks of therapy. No patients experienced further visual loss, and eight of 11 patients gained at least two lines or 10 ETDRS letters. Three patients were stable or had fewer than 10 letters or two lines of improvement. OCT showed that 10 patients had a corresponding mean reduction of approximately 122 µm in retinal thickness with a range of 55 µm to 276 µm. However, no correlation between the amount of reduction of retinal thickness and visual acuity occurred.

Reference

Warren, KA. NSAIDs for the treatment of CME in steroids responders. Retina. In press.

Figure 1a

Post-Cataract Surgery OCT Images

Figure 1a: Post-Cataract Surgery OCT Images
The first OCT image was taken before nepafenac was administered. Visual acuity was 20/70 and retinal thickness was 584 µm. The second OCT image was taken after nepafenac was administered four times a day for 1 month. Visual acuity was 20/50 with no IOP elevations and retinal thickness was 361 µm.

Figure 1b

Figure 1b: Post-Cataract Surgery Images
The first OCT image was taken before nepafenac was administered, 1 month postoperative. Visual acuity was 20/50 and retinal thickness was 342 µm. The second OCT image was taken after nepafenac was administered four times a day for 3 weeks. Visual acuity improved to 20/30 3 weeks after initiation of nepafenac therapy. Two and one-half months postoperative, visual acuity improved to 20/25 and retinal thickness was 193 µm.

Images: Warren, KA

NSAIDs studies promising

Michael A. Kapin, PhD, conducted a study in which nepafenac ophthalmic suspension 0.1% was shown to inhibit prostaglandin synthesis compared to diclofenac ophthalmic sodium 0.1% and ketorolac tromethamine solution 0.5%.⁷Dr. Kapin induced inflammation in rabbits by administering concanavalin-A, a potent mitogen. He then administered five drops of nepafenac, diclofenac and ketorolac to prevent the development of induced retinal edema each day beginning 1 day prior to the injection of the mitogen and continuing for 3 days post-injection. Nepafenac inhibited prostaglandin synthesis, concomitant with significant suppression of blood retinal barrier breakdown. Neither diclofenac nor ketorolac inhibited accumulation of these markers of inflammation. These animal data provide scientific support of the efficacy and mechanism of action of nepafenac as well as a platform for translation into meaningful clinical application.

Seenu M. Hariprasad, MD, conducted a study in which nepafenac was shown to reduce macular thickening and improve visual acuity. The study included a 42-year-old man with chronic CME secondary to pars planitis. Topical steroid and NSAID therapy was ineffective. The patient had 20/80 vision and 20/100 vision and a retinal thickness of 681 µm. He was treated with 4 mg of intravitreal triamcinolone, which was effective. Although his vision recovered to 20/25, his IOP was raised to approximately 56 mm Hg, which required topical treatment. Because the right eye was chronically inflamed with CME, Hariprasad treated this patient with nepafenac. After 3 months, his vision was 20/20 with retinal thickness of 164 µm and a normal contour of the foveal pit. This patient experienced no rise in IOP and had significant visual improvement. Thus, an NSAID alone can be used to successfully treat patients with CME.

David S. Rho, MD,⁸ conducted a study in which diclofenac and ketorolac 0.5% were shown to be equally effective in treating CME in patients after routine phacoemulsification cataract extraction. In addition, both NSAIDs were shown to improve visual acuity.

Prophylaxis for prevention

CME remains the most common cause of visual loss following uncomplicated cataract surgery. NSAIDs demonstrate efficacy in delivering this concentration and preventing and treating CME. Despite the available treatments, vision loss is common in patients with CME. It is imperative to use prophylaxis before and after surgery to prevent CME and preserve quality of vision.

References

McColgin AZ, Raizman MB. Efficacy of topical diclofenac in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999;40:289.

Heier JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic treatment may avert vision loss. Ophthalmology Management. October 2004;63-72.

Miyake K, Masuda K, Shirato S, et al. Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: A multicentered prospective trial. Jpn J Ophthalmol. 2000;44:58-67.

Srinivasan BD, Worgul BV, Iwamoto T, Eakins KE. The reepithelization of rabbit cornea following partial and complete epithelial denudation. Exp Eye Res. 1977;25:343-451.

Samiy N, Foster CS. The role of nonsteroidal anti-inflammatory drugs in ocular inflammation. Int Ophthalmol Clin. 1996;36:195-206.

Jampol LM. Pharmacologic therapy of aphakic cystoid macular edema. A review. Ophthalmology. 1982;89:891-897.

Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the rabbit is inhibited by topical nepafenac. Inflammation. 2003;27:281-291.

Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac versus ketorolac. J Cataract Refract Surg. 2003;29:2378-2384.