Macular edema is a common problem in patients with uveitis, often sabotaging good vision. Optical coherence tomography (OCT) studies disclose that macular edema is far more common in these patients than previously thought, even in patients with anterior non-granulomatous uveitis.1-3 It precludes good vision even after the uveitis is apparently in remission, for reasons that include retinal pigment epithelial (RPE) dysfunction, vitreomacular traction, and epiretinal membrane (ERM) formation; however, in some cases subclinical inflammation with cytokines effects on the RPE cause macular edema. Figure 1 shows cystoid macular edema (CME) formation on fluorescein angiography (FA) and OCT. It is important to use both FA and OCT for imaging in the long-term care of patients with history of uveitis because these patients often have subclinical vision with edema that does not show on an OCT, but that is evident on FA.
The MERSI Approach for Treating Uveitis Associated Macular Edema
It is crucial that the phraseology “patients with a history of uveitis” is emphasized when discussing management of macular edema because efforts to treat edema in uncontrolled uveitis are futile. Thus, the approach that I use at the Massachusetts Eye Research and Surgery Institution (MERSI) for treating patients with macular edema associated with uveitis is to first and foremost ensure that uveitis is under control. However, we continue to see many patients who are referred to our institution for uveitic macular edema who, despite having active uveitis, have received multiple injections with either corticosteroids and/or antivascular endothelial growth factor agents. This approach is misguided and doomed to fail.
As earlier stated, we take baseline FAs and OCTs and repeat this imaging frequently to document the progress of treatment. When we begin treatment, we have traditionally used a stepwise approach.
Step 1. We typically will first inject triamcinolone acetonide regionally using a lower lid septum approach. The Nozik technique of posterior sub-Tenons injections are less patient friendly, in my opinion, and have proved no more effective in the cases that we have followed.
Step 2. Topical nonsteroidal anti-inflammatory drug (NSAID) therapy (off-label use) can also be useful with the selection of an NSAID that shows evidence of penetration to the back of the retina and the choroid, such as bromfenac.4
Step 3. Additionally, the concomitant use of a systemic NSAID, preferably a COX-2 specific inhibitor, such as celecoxib, has an effect in discouraging a relapse of macular edema.
Step 4. For recalcitrant macular edema, systemic acetazolomide at 250 to 500 mg twice daily can be effective. Although there have been reports on the use of higher doses, the additional therapeutic benefit is insufficient in my experience.
Step 5. The next step that we take for patients in the presence of persistent edema after obtaining the proper patient consent regarding the complications of endophthalmitis, glaucoma, cataract, and retinal detachment, is to employ an intravitreal injection of preservative-free triamcinolone acetonide.
Step 6. We may use choose an intravitreal anti-VEGF agent (off-label use), such as ranibizumab (Lucentis, Genentech) or bevacizumab (Avastin, Genentech), after obtaining patient consent regarding the risk of endophthalmitis with intravitreal injections.
Step 7. We may also choose to use a combination of both steroid and anti-VEGF injections, as this has proved effective in some patients, when single agent injections have failed.
Step 8. The next step is to inject 20 mg intramuscular octreotide once a month (off-label use). There are octreotide receptors on the retinal RPE, ligation of which help improve RPE pump function.
Step 9. Vitrectomy with ILM peeling is appropriate in instances where OCT scanning discloses vitreomacular traction.
Step 10. For patients who either refuse frequent injections of steroid of anti-VEGF, or for whom relapse occurs shortly after an injection, we will inject the dexamethasone intravitreal implant.
Case #1
Figure 2 shows the baseline reports for a patient with macular edema and a history of uveitis. The uveitis was put into remission with systemic immunomodulatory therapy with no use of corticosteroids. Intraocular evaluation showed no evidence of active inflammation; however, macular edema was causing visual acuity loss to 20/60 in the left eye.
The choices for treatment include (1) a topical NSAID; (2) a regional corticosteroid injection; (3) a systemic NSAID; and (4) an intravitreal anti-VEGF agent. We chose to employ a regional trans-septal steroid injection along with topical bromfenac twice daily and systemic celecoxib 200 mg twice daily. Although in the past we did not use a multimodal strategy, we found we were already using all of these approaches in a stepwise fashion, so decided to simply start with all three from the beginning.
Over the course of 1 year and long-term maintenance with celecoxib, the visual acuity improved to 20/20 and there have been no relapses of macular edema (Figure 3).
Case #2
Figure 4 shows the FA and OCT scans of a patient who had significant macular edema in the right eye and visual acuity of 20/80.
The patient had been treated previously in a similar manner as Case #1, with a three-pronged approach with regional corticosteroid injection, topical NSAID, and a systemic NSAID, and the macular edema persisted.
The choices for treatment at this point included (1) acetazolamide; (2) intravitreal triamcinolone; and (3) intravitreal bevacizumab. We chose to use intravitreal bevacizumab, because the patient is phakic (steroid has increased risk of cataract). The patient responded to the intravitreal bevacizumab with resolution of the edema, (Figure 5) improvement of the visual acuity to 20/20. We maintained treatment with the topical and systemic NSAID and the patient has had no relapse of macular edema over the course of 2 years.
Case #3
Figure 6 are the FAs and OCTs from a patient in whom uveitis was in remission and who was on systemic immunomuodulatory therapy. The left eye had a retinal thickness greater than 600 μm even after we applied topical and systemic NSAIDs, 2 regional injections of triamcinolone, intravitreal triamcinolone, intravitreal bevacizumab, and systemic acetazolomide.
At this point, our options included (1) a vitrectomy with an ILM peel; (2) more intravitreal injections; and (3) dexamethasone intravitreal implant. We chose to inject the dexamethasone intravitreal implant for this patient and postinjection the patient achieved 20/20 vision and a reduction of macular edema (Figure 7).
Discussion
We have more treatment options for noninfectious posterior uveitis than ever before with off-label use of corticosteroids and anti-VEGF agents, but the dexamethasone intravitreal implant was specifically designed to address intraocular inflammation and macular edema. The purpose of the Huron trial (A Double- Masked, Sham-Controlled, Randomized Study of Dexamethasone Intravitreal Implant for the Treatment of Uveitis)5 was to evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant for the treatment of noninfectious intermediate or posterior uveitis.
The primary outcome measure in this trial was the proportion of patients with a vitreous haze score of 0 at week 8. Additional outcome measures were vitreous haze through week 26, best corrected visual acuity (BCVA), adverse events, intraocular pressure (IOP), and biomicroscopy/ ophthalmoscopy.
The results of the trial showed that a single dexamethasone intravitreal implant was significantly more effective than sham at eliminating vitreous haze. At the primary timepoint of week 8, approximately 4 times more eyes treated with the dexamethasone implant 0.7 mg had complete resolution of vitreous haze compared to sham. Treatment with the dexamethasone intravitreal implant also led to a significant improvement in BCVA by week 3 that persisted through week 26.
In regard to safety, IOP increases were relatively low in the treatment groups. Fewer than 10% of eyes that received the 0.7-mg dexamethasone implant had IOPs greater than or equal to 25 mm Hg at any scheduled visit, and at week 26, the percentage was 0. Seventeen percent of eye with the 0.7-mg dexamethasone implant and 9% of sham eyes were on IOP-lowering medications at week 26. There was no statistically significant difference in rate of cataract surgery between treatment groups and sham, but it is important to note that follow-up was only 6 months for this study.
In summary, the 0.7-mg dexamethasone intravitreal implant appears to be safe and effective for the treatment of noninfectious intermediate and posterior uveitis and its availability will help physicians deal with the under-recognized problem of uveitic macular edema.
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