therapy
Therapy of Central Serous Chorioretinopathy and Diabetic Macular Edema Using NSAIDS
JUAN ORELLANA, MD, MS, FACS

Topical diclofenac (Voltaren, Novartis), ketorolac (Acular and Acular LS, Allergan), nepafenac (Nevanac, Alcon), and bromfenac (Xibrom, ISTA Pharmaceuticals) all belong to the group of medications called non-steroidal antiinflammatory drugs (NSAIDs). As an antiinflammatory class, they function by inhibiting the enzyme cyclooxygenase (COX), which blocks the synthesis of prostaglandins. A reduction in prostaglandin formation results in decreased inflammation. Inflammation functions to make the blood-retinal barrier more permeable. It appears that the principle pathway involved in pain and inflammation is the COX-2 pathway, where the NSAIDs seem to play a significant role.

The current uses for topical NSAIDs have been limited to the prevention of intraoperative miosis during phacoemulsification,^1,2 relief of postoperative pain, inflammation and photophobia,³ therapy for ocular atrophy,⁴ and the reduction of postcataract cystoid macular edema (CME).³ Many cataract surgeons have used NSAIDs, such as diclofenac, preoperatively to block the formation of CME.⁵ For patients who develop persistent postoperative CME, NSAIDs have been dispensed to reduce the postoperative edema and improve the patient's vision. Little attention, however, has been paid to an NSAID's ability to penetrate into the eye and treat other causes of macular edema that may have an inflammatory component.

Figure 1 (top). Eye afflicted with central serous retinopathy before treatment. Figure 2 (middle). Eye afflicted with central serous retinopathy during treatment with bromfenac. Figure 3 (bottom). Eye afflicted with central serousretinopathy after successful treatment.

CENTRAL SEROUS CHORIORETINOPATHY
Case History/Presentation

A 53-year-old male was sent for treatment of central serous chorioretinopathy (CSR). He had noted a central blurriness of vision in the OD beginning 6 months earlier. He saw an optometrist at that time and his records documented a best-corrected visual acuity (BCVA) of 20/40-2 OD and 20/20 OS. He noted a gradual diminution of his acuity as his emotional stress levels had increased due to his work and financial situation. In our office, his BCVA was 20/400 OD and 20/20 OS. His ocular coherence tomography (OCT) documented a foveal avascular zone (FAZ) thickness of 546 μm while the juxtafoveal thicknesses ranged from 317 μm to 648 μm (Figure 1). The angiogram demonstrated a smokestack lesion with extensive leakage.

Treatment

He began treatment with bromfenac bid. After 1 month of therapy, his BCVA was 20/40 OD with an FAZ thickness of 350 μm on OCT (Figure 2). After
an additional month of bromfenac therapy, his acuity improved to 20/25, where it has remained. The outlines of his original CSR cavity demonstrate a mottling of the retinal pigment epithelium (RPE), but no fluid is present (Figure 3).

DIABETIC MACULAR EDEMA
Case History/Presentation

A 65-year-old diabetic female presented with bilateral blurred vision of 6 months' duration. Her hemoglobin A1c varied between 7.1% and 7.4% over the prior year. She had been taking oral hypoglycemic agents since being diagnosed 11 years ago. Clinical evaluation revealed a BCVA of 20/200 OD and 20/100 OS. Her lenses demonstrated mild nuclear sclerosis. The fundu-scopic evaluation revealed extensive posterior pole edema accompanied by scattered hemorrhages and lipid deposition. Numerous microaneurysms could be seen in both eyes.

Treatment

After a discussion detailing the risks, benefits, and alternative therapies available, she opted to try topical NSAID therapy. Her OCT and angiogram demonstrated extensive leakage in both eyes. The foveal avascular zone (FAZ) measured 450 μm in the right eye and 405 μm in the left. She was placed on bilateral ketorolac (Acular LS) qid. After 2 weeks of therapy, she noted a definite improvement but confessed that she omitted doses on a frequent basis. The OCT tended to show an improvement but the differences were minor. Her acuity was 20/100 OD and 20/80 OS. At this time, it was decided to substitute bromfenac for ketorolac. The rationale was that bromfenac was administered bid as opposed to qid for ketorolac. She returned 2 weeks later and her acuity was 20/70 OU. She was enthusiastic about the results and opted for continued therapy with bromfenac. After 6 weeks of bromfenac therapy, her acuity was 20/30 OU. The angiogram demonstrated persistent mild staining but the FAZ was clearly visible. The macular thickness by OCT was 290 μm in the OD and 275 μm in the OS. She has continued bromfenac therapy bid for 4 months without any evidence of corneal toxicity.

DISCUSSION
Central Serous Chorioretinopathy

Central serous chorioretinopathy is usually a self-limiting disease comprised of a serous neurosensory detachment associated with males of Type A personality. The angiogram may demonstrate a localized area of RPE leakage or a diffuse mottling of the RPE with a large hyperfluorescent cavity. Elevated levels of epinephrine may alter choroidal circulation and permit an accumulation of fluid that ultimately leaks through the RPE. Physiologically, prostaglandins cause vasodilation and increase the permeability of the blood-retinal barrier. This disruption of the RPE may cause inflammation and further decompensation of the RPE, resulting in a protracted disease course and extensive neurosensory detachment. This increased permeability is manifested as weakening of the tight junctions between capillary endothelial cells and slowing down of the active retinal fluid-pumping mechanism of the pigment epithelium.

Indocyanine green (ICG) studies point to a choroidal circulation that demonstrates a hyperpermeability coexisting with areas of hypofluorescence indicating a diffuse dysfunction of the choroidal circulation.⁶ This buildup of choroidal fluid ultimately leads to the RPE leakage seen on fluorescein angiography. Recent studies have demonstrated that bromfenac remains in an effective concentration in the aqueous humor for 12 hours and persists in both the choroidal and retinal tissues.⁷ This may explain why an NSAID, such as bromfenac, reverses the vascular hyperpermeability and permits fluid resorption. In a small percentage of patients, resolution of the CSR extends beyond the usual 8 weeks. Some of these patients fail to recover a visual acuity of better than 20/40. Therapeutic intervention may help resorb their fluid quickly and avoid dyschromatopsia and metamorphopsia.

Diabetic Macular Edema

In a similar fashion, the endothelial tight junctions in the retinal capillaries erode and permit fluid to leak into the retina in diabetic patients. Retinal capillary pericyte necrosis, an early change in diabetic retinopathy, may also contribute to inflammation, as well as an alteration of capillary structure regulation and function. Continued stress on these endothelial cells induces a more widespread loss of cell-to-cell integrity and a greater outpouring of fluid. Topical NSAID therapy crosses into the retinal tissue and bathes these cells to a degree that the tight junctions are reformed and the cells resume a more normal function.⁷ Continued treatment serves to strengthen these endothelial cells and possibly remove the inflammatory agent that prompted the original loss of the tight junctions.

CONCLUSION

It is interesting to see that in the case of diabetic macular edema (DME), both ketorolac and bromfenac were successful. One study has demonstrated that ketorolac qid is as effective as bromfenac bid in the treatment of pseudophakic CME.⁸ Bromfenac at a bid dosage was preferred by the patient since it allowed her to comply with the prescribed regimen. It is well known that patient compliance with a bid regimen is better than that with a qid regimen. Treatment with NSAIDs can certainly be a first line of therapy for patients with diabetic macular edema. Topical medical treatment is better than risking foveal damage from laser and causing a field defect from too intense therapy. Photodynamic therapy may be another useful modality in treating CSR patients.⁶ In my experience, patients appreciate the alternative of NSAID therapy and adhere to its regimen when bromfenac is used.

My experience with NSAIDs and retinal disorders such as CME, CSR, and leakage from confluent retinal drusen or macular edema from vascular occlusions or diabetes mellitus has been extremely encouraging. The finding that bromfenac can be found throughout the eye suggests adequate penetration that may explain the efficacy seen in treating several retinal disorders. To some extent, ocular inflammation may be a contributing cause of the macular edema we see in both CSR and diabetic maculopathy. While using NSAIDs will not make a focal laser treatment obsolete in either CSR or diabetic maculopathy, it is an excellent alternative to laser treatment.

REFERENCES

1. Ohara K, Obuto A, Miyamoto T, Miyakubo H, Nezu N. Prevention of miosis during cataract surgery by topical bromfenac sodium. Jpn J Clin Ophthalmol. 2004;58: 1325-1328.

2. Data on file. ISTA Pharmaceuticals Xibrom US Phase 111 Trials.

3. Seward MS, Cooke DL, Grillone LR, Sacks RM, Bromfenac Study Group. Topical Xibrom™ 0.09% significantly reduced ocular pain following cataract surgery. Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology; April 30,2006; Fort Lauderdale, Fla.

4. Miyake K, Masuda K, Shirato S, Oshika T, Eguchi K, Hoshi H, Majima Y, Kimura W, Hayashi F. 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.

5. Schalnus R. Topical nonsteroidal anti-inflammatory therapy in ophthalmology. Ophthalmologica. 2003;217:89-98.

6. Yannuzzi LA, Slakter JS, Gross NE, et al. Indocyanine green angiography-guided photocoagulation of central serous chorioretinopathy: a pilot study. Retina. 2003;23:288-298.

7. McNamara T, Baklayan GA, Deshmukh HM, Patterson HM, Gow JA. Concentrations of radioactivity in ocular tissues following a single topical ocular dose of 14C-bromfenac ophthalmic solution (Xibrom™). Poster presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 4, 2006; Fort Lauderdale, Fla.

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

Juan Orellana, MD, MS, FACS, is founder of Orellana Retina Associates, PLLC, in Raleigh, NC. He is also a clinical associate professor at the University of North Carolina-Chapel Hill. Dr. Orellana has received research grants from and is a speaker for ISTA Pharmaceuticals.