Treating Cystoid Macular Edema With an Ocular NSAID
First in a series exploring the viability of NSAIDs in the treatment of CME and DME
BY SEENU M. HARIPRASAD, MD
Ocular inflammation, a frequent occurrence after cataract surgery, can lead to numerous serious complications, including cystoid macular edema (CME). Although the incidence of CME following cataract surgery varies widely in the literature, it has been recognized as a postoperative complication for more than 50 years, and it is the most common cause of decreased vision following cataract surgery.1, 2
CYSTOID MACULAR EDEMA
CME is the cystic accumulation of fluid in the central retina due to the breakdown of the blood-retinal barrier. Acute CME is defined as edema of less than 4 months' duration and can be classified as angiographic or clinical. Angiographic CME is macular edema evidenced by fluorescein angiography, but patients typically have no associated vision loss. The incidence of angiographic CME following uncomplicated cataract surgeries is approximately 20% to 30%.3-6
|Cystoid macular edema is apparent on both the fundus photograph and the fluorescein angiogram of an 80-year-old patient who underwent a complicated cataract extraction and IOL implantation 2 years prior to my examination.|
Clinical CME that causes vision loss is much less frequent, being reported in 2% to 12% of uncomplicated cataract surgeries.3,7,8 Fortunately, vision loss from acute, clinical CME typically is reversible. However, it remains a genuine concern because patients' expectations have risen alongside recent surgical advances that have restored vision more rapidly. Failure to meet unrealistic expectations is correlated with patient dissatisfaction.9
Chronic CME, defined as persisting for 4 months or more, produces a significant risk of permanent vision loss.
One study10 reported that only 29% of eyes with chronic CME regained visual acuity better than 20/40. Thus, it is crucial that patients with chronic macular edema be treated immediately and followed closely to ensure optimal visual outcomes.
Figure 1. The patient's initial visual acuity was 20/300-1. The patient was started on treatment with nepafenac tid and prednisolone acetate qid.
ORIGINS OF CME
Although the pathogenesis of CME is unclear, it widely accepted that this condition is associated with ocular inflammation.7 Thus, anti-inflammatory therapies, such as corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are used commonly as prophylaxis and/or treatment of CME.11,12
Figure 2. At the follow-up visit, the patient's visual acuity had improved to 20/80+2. The patient was instructed to continue using nepafenac but not prednisolone.
There are no FDA-approved NSAIDs indicated for CME, but NSAIDs often are used to treat and protect against the development of this condition.
Numerous studies have determined that NSAIDs are effective in the treatment of pseudophakic CME, including ketorolac tromethamine 0.5% (Acular),13,14 diclofenac sodium 0.1% (Voltaren),15 and bromfenac 0.09% (Xibrom).16 Moreover, additional studies have indicated the ability of these NSAIDs to prevent the development of postsurgical CME.17, 18
Figure 3. The second follow-up visit showed continued improvement in the patient's vision. His visual acuity had improved to 20/60+1. The patient continues to use nepafenac tid.
USING NEPAFENAC TO TREAT CME
Nepafenac 0.1% (Nevanac) is the only ocular NSAID with a prodrug structure, in which intraocular hydrolases convert it to the more active metabolite amfenac.19 These hydrolases are present in ocular tissues, such as the cornea and iris/ciliary body, and they are at their highest concentrations in the retina/choroid. As a result, the more active form of the drug, amfenac, is effectively targeted to the inflamed macula of patients with CME. The properties of nepafenac suggest that it may be especially effective in treating posterior segment inflammation, including CME. The following case illustrates the efficacy of nepafenac used to treat a patient with chronic CME.
An 80-year-old man had undergone complicated cataract extraction and IOL implantation in the anterior chamber of his left eye 2 years previously at an outside facility. He had missed all postoperative follow-up visits. During his initial examination with me, the patient's visual acuity in the left eye was 20/300-1. I confirmed CME with optical coherence tomography (OCT), which revealed a retinal thickness of 699 μm (Figure 1). I treated the patient with nepafenac three times a day and prednisolone acetate 1% (Pred Forte) four times a day.
During an examination 2 months later, the patient's visual acuity already had improved to 20/80+2 and his retinal thickness had decreased to 479 μm (Figure 2). I continued treating the patient with nepafenac, but the steroid was discontinued at that time so I could determine if the positive treatment outcomes were due to prednisolone or nepafenac.
Two months later, having used nepafenac alone, the patient's visual acuity had improved to 20/60+1 and OCT revealed a retinal thickness of 413 μm (Figure 3). The patient continues to use nepafenac.
CME is a common risk for patients who have undergone cataract surgery, and it is a risk that leads to frustration for patients and surgeons. Although the efficacy of nepafenac for anterior segment inflammation has been reported,20, 21 its clinical usefulness in the treatment of CME and posterior segment inflammation has not been prospectively investigated. Preclinical evidence, however, suggests that nepafenac may be uniquely suited for this indication.
First, nepafenac exhibits enhanced corneal permeability relative to diclofenac, allowing for greater intraocular drug accumulation.22 As mentioned previously, the rate of hydrolysis of nepafenac to the more active amfenac is much greater in the retina/choroid (approximately 20 times) than in the iris/ciliary body.19, 22 Finally, the administration of nepafenac also produces sustained inhibition of prostaglandin synthesis (a marker of inflammation) relative to diclofenac (6 hours vs. 20 minutes).19
The increased absorption, targeted activation and greater duration of action of nepafenac may lead to improved efficacy in the posterior segment over other NSAIDs lacking these properties. In fact, support for this hypothesis can be found in a study of concanavalin A-induced retinal edema in rabbits, where nepafenac demonstrated superior inhibition of retinal inflammation compared to either diclofenac or ketorolac.23
The case presented here suggests that nepafenac has activity in treating chronic CME, both in combination with a steroid and as monotherapy. Although this patient presumably had developed CME 2 years previously following cataract surgery, he had never been treated for the condition. Therefore, the improvement observed after only several months of treatment with nepafenac and prednisolone acetate is striking. A reduction in retinal thickness of over 200 μm and an improvement of five Snellen lines was achieved without the use of an intravitreal injection of triamcinolone acetonide (Kenalog) or bevacizumab (Avastin).
This case supports existing preclinical evidence that suggests nepafenac is a promising drug for the treatment of posterior segment inflammation, including CME. Further investigation is warranted in a randomized, controlled clinical trial to determine if certain patients with recalcitrant or chronic CME would benefit from topical new-generation NSAID therapy before being considered for an intravitreal injection of a steroid or an anti-VEGF agent. RP
Seenu M. Hariprasad, MD, is assistant professor and director of clinical research and chief of vitreoretinal service at the University of Chicago, Pritzker School of Medicine, Department of Ophthalmology and Visual Science in Chicago.