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.
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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.
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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.
Retinal Physician, Issue: November 2006