Intravitreal Steroid Injections for Macular Edema: Way of the Future?
SOPHIE J. BAKRI, MD, PETER K. KAISER, MD

In the past few years, intravitreal steroids have played an increasing role in the treatment of macular edema. Are intravitreal steroids a passing fad or the way of the future? As with any new treatment modality, we have to ask what evidence do we have to support its use, and are we improving the disease course and visual acuity of our patients.

HISTORY OF INTRAVITREAL STEROIDS USE IN RETINAL DISEASE

Machemer first popularized the use of intravitreal steroids in 1979 in an effort to halt cellular proliferation after retinal detachment surgery.¹ Graham, McCuen, Tano, and others have studied its use in both animal models and humans.^2-4 Several steroids have been evaluated; however, triamcinolone acetonide is the steroid of choice because of its long half-life and lack of toxicity, and it is generally well tolerated.^3,5 In addition, a considerable body of literature describes the long-term efficacy of triamcinolone administration in various ocular diseases, including uveitis, macular edema secondary to ocular trauma or retinal vascular disease, proliferative diabetic retinopathy, intraocular proliferation such as proliferative vitreoretinopathy, and choroidal neovascularization from age-related macular degeneration.^6-12

USE OF STEROIDS FOR THE TREATMENT OF MACULAR EDEMA -- THE CURRENT TREND

Corticosteroids have antiangiogenic, antifibrotic, and antipermeability properties. The principal effects of steroids are stabilization of the blood-retinal barrier (BRB), resorption of exudation, and down-regulation of inflammatory stimuli. Experimentally, corticosteroids have been shown to reduce inflammatory mediators, including interleukin-5, interleukin-6, and interleukin-8; prostaglandins; interferon gamma; and tumor necrosis factor alpha.^13-15 They also decrease levels of vascular endothelial growth factor (VEGF), a potent permeability factor, and improve BRB function.^16-18 Several known mechanisms of action of corticosteroids explain the stabilization of the BRB, including stabilization of cell and lysosomal membranes, reduction of the release or synthesis of prostaglandins, inhibition of cellular proliferation, blockage of macrophage recruitment in response to macrophage migration inhibitory factor, inhibition of phagocytosis by mature macrophages, and decreased polymorphonuclear infiltration into injured tissues.^19-22 Triamcinolone acetonide in particular has been shown to have an antiangiogenic effect. Studies have shown it inhibits bFGF-induced migration and tube formation in choroidal microvascular endothelial cells and down-regulates metalloproteinase 2 (MMP2), decreases permeability, down-regulates intercellular adhesion molecule-1 (ICAM-1) expression in vitro, and decreases MHC-II antigen expression.^23-25

Penfold and associates found that triamcinolone acetonide significantly decreased MHC-II expression consistent with immunocytochemical observations, which revealed condensed microglial morphology.²⁵ The modulation of subretinal edema and microglial morphology correlated with in vitro observations, suggesting that the down-regulation of inflammatory markers and endothelial cell permeability are significant features of the mode of action of triamcinolone acetonide. In another study, they investigated the capacity of triamcinolone to modulate the expression of adhesion molecules and permeability using a human epithelial cell line (ECV304) as a model of the outer BRB. They found that triamcinolone modulated transepithelial resistance of Ter and ICAM-1 expression in vitro, suggesting that reestablishment of the BRB and down-regulation of inflammatory markers are the principal effects of intravitreal triamcinolone in vivo. The results indicate that triamcinolone has the potential to influence cellular permeability, including the barrier function of the retinal pigment epithelium.

Why Deliver The Steroid By Intravitreal Injection?

Topical steroids have not been shown to penetrate the posterior segment. Posterior sub-Tenon's steroids have been shown to be useful in the treatment of macular edema, but they take longer to diffuse into the posterior segment, and placement over the macula may be variable. In addition, there is considerable systemic absorption with a sub-Tenon's injection, which may pose a problem in diabetic patients. The best way to circumvent the blood-ocular barrier is by direct intravitreal injection. Intravitreal triamcinolone has been shown to deliver high initial concentrations to the target tissue and provide effective levels for at least 3 months²⁶.

PRECLINICAL EVALUATION OF THE SAFETY OF INTRAVITREAL TRIAMCINOLONE

A single, pure intravitreal triamcinolone injection is well tolerated in rabbit eyes. In one study, electroretinographic data showed no significant differences between treated and control eyes and both light and electron microscopy were normal in both groups.³ Hida and associates investigated the vehicles of 6 commercially available depot corticosteroids in rabbit eyes, and found no effect on the retina and lens with the vehicle in Kenalog (commercially available triamcinolone acetonide) at levels 2 times higher than in the marketed drug.⁵ However, preservatives present in the vehicle for Kenalog, including benzyl alcohol, were shown to have toxic effects on the retina in other steroid preparations. The use of preservative-free triamcinolone for macular edema has also been reported.²⁷ This formulation has a shelf life of 45 days and can be obtained from a compounding pharmacy. Other pharmaceutical companies are evaluating the production of a purified, preservative-free, single-use triamcinolone acetonide formulation. These products are being tested in the current clinical trials evaluating intraocular steroids for macular edema sponsored by the National Eye Institute.

EFFICACY OF INTRAVITREAL TRIAMCINOLONE FOR MACULAR EDEMA

Several small case series have described the use of intravitreal triamcinolone acetonide for the treatment of macular edema associated with diabetic retinopathy, uveitis, and retinal vein occlusions.

Diabetic Macular Edema

Martidis and colleagues first reported in a retrospective review the use of intravitreal steroids in diabetic macular edema (DME).²⁸ They injected 4 mg of intravitreal triamcinolone into 16 eyes with clinically significant macular edema (CSME) that failed to respond to at least 2 previous sessions of laser photocoagulation. With all patients completing 1- and 3-month follow-up and 50% completing 6 or more months, the mean improvement in visual acuity was 2.4, 2.4, and 1.3 Snellen lines at the 1-, 3-, and 6-month follow-up intervals, respectively. The central macular thickness measured by optical coherence tomography (OCT) decreased by 55%, 57.5%, and 38%, respectively, over these same intervals from a baseline mean thickness of 540 microns. Reinjection was performed in 3 of 8 eyes after 6 months because of recurrence of macular edema.

Another interventional case series followed that included 26 eyes of 20 patients who received a higher dose of intravitreal triamcinolone acetonide (25 mg) by repeatedly filtering and concentrating the stock steroid preparation for treatment of diffuse diabetic macular edema.²⁹ The study group was compared with a control group of 16 patients who underwent macular grid laser coagulation. In the study group, visual acuity improved significantly (P <0.001), from 20/166 (0.12) at baseline to 20/105 (0.19) over a mean of 6.64 months follow-up. Seventeen (81%) of 21 eyes with a follow-up period of more than 1 month had improved visual acuity. In contrast, the visual acuity of the control group did not significantly change.

In the prospective pilot study of the ISIS trial, 30 patients received either 2 mg or 4 mg of intravitreal triamcinolone for CSME for at least 3 months following maximal laser. At 3-month followup, 33% of patients had a >= 3 ETDRS line increase in vision and 21% had a similar increase at 6-month follow-up.³⁰ Visual improvement and resolution of macular edema was more effective in the 4-mg group.

In the only small, prospective, randomized study, Massin and associates evaluated 12 patients with bilateral DME unresponsive to laser photocoagulation where one eye was randomized to receive 4 mg of intravitreal triamcinolone and the other eye observed.³¹ Seven of the 12 patients had a follow-up of 6 months; the remaining 5 were followed up for at least 3 months. The baseline central macular thickness on OCT was 510 microns in injected eyes and 474 microns in control eyes. Four weeks after injection, retinal thickness significantly improved (P <0.001) to 207 microns in injected eyes and remained stable in control eyes (506 microns). Retinal thickness remained normal in the injected eyes after 12 weeks (207 microns) and significantly (P = 0.005) different from the control eyes (469 microns). The difference between the central macular thickness of injected and control eyes was no longer significant at 24 weeks because of the recurrence of macular edema in 5 of 12 (42%) injected eyes. Despite the excellent OCT results, at no time was the difference between the visual acuity scores measured on the ETDRS chart for injected and control eyes significant.

Pseudophakic Cystoid Macular Edema

Several small case series have described the use of intravitreal steroids in pseudophakic cystoid macular edema (CME). A retrospective case series showed a beneficial effect of 4-mg intravitreal triamcinolone on visual acuity and angiographic leakage in 8 eyes of 8 patients with recalcitrant pseudophakic cystoid macular edema of a mean duration of 20 months.³² Another study of 3 patients found an increase in vision and a decrease in macular thickness on OCT 1 month after intravitreal triamcinolone injection for pseudophakic CME.³³ However, the macular edema recurred in all cases and even recurred in the 2 eyes that had a repeat injection. In another prospective study of 5 patients, visual acuity improved after intravitreal triamcinolone injection from 20/77 (0.26) to a mean maximal visual acuity of 20/33 (0.60) after a followup period of 6.6 months.³⁴

Macular Edema Due to Vein Occlusions

Several reports document the use of 4-mg intravitreal triamcinolone for macular edema due to central and branch retinal vein occlusions (BRVO). Greenberg and Ip did the first case reports of a beneficial effect in central retinal vein occlusions (CRVO).^{35, 36} Park and associates injected 10 eyes with macular edema due to CRVO and reported a statistically significant increase in visual acuity from 58 letters at baseline to 78 letters at a mean followup of 4.8 months and a statistically significant improvement in macular thickness on OCT.³⁷ However, 40% of eyes had an intraocular pressure rise requiring aqueous suppressants, and 1 eye required a trabeculectomy.

Several case reports also show macular edema due to BRVO responding to intravitreal triamcinolone.³⁸ Jonas compared a group of 10 consecutive eyes that received 20 mg to 25 mg of intravitreal triamcinolone acetonide with a control group of 18 eyes who did not over a mean followup of 8.7 months. In the study group, the mean visual acuity increased significantly (P=0.02) from 20/74 (0.27) preoperatively to a mean postoperative visual acuity of 20/44 (0.45). Visual acuity measurements determined 1 month after the injection were significantly (P=0.027) higher than baseline values. In the ischemic subgroup, visual acuity did not change significantly, while in the nonischemic subgroup visual acuity increased significantly. In the control group, visual acuity did not vary significantly (P=0.27). The gain in visual acuity was significantly higher in the study group than the control group at 1 (P=0.016) and 2 months (P=0.012) after injection.

Macular Edema Due To Uveitis

Antcliff reported the use of 4-mg intravitreal triamcinolone in 6 patients with chronic CME resistant to treatment with systemic steroids, orbital floor steroids, and cyclosporine A.³⁹ There was complete anatomic resolution of CME in 5 of the 6 cases within 1 week after injection; however, cystoid spaces began to return between 6 weeks and 3 months after injection.

Macular Edema Due To Other Causes

Scott and associates described 2 patients with idiopathic CME who experienced an improvement in vision and resolution of macular edema on OCT.⁴⁰ The macular edema recurred and responded again to intravitreal triamcinolone. Macular edema due to radiation retinopathy and retinitis pigmentosa has also been reported to respond favorably to intravitreal triamcinolone.^41,42

WHAT IS THE RIGHT DOSE?

The appropriate dose of intravitreal triamcinolone is still not known. Several different doses of triamcinolone have been reported ranging from 2mg to 25 mg. In the United States, 4 mg (in 0.1 cc) is the most common dose; however, no formal studies have evaluated either this or lower doses. In Germany the literature reports results using 20 mg to 25 mg, which is obtained by repeatedly filtering and concentrating the triamcinolone preparation. Studies comparing the efficacy, complications, and duration of different doses of triamcinolone in different diseases are needed before we can best establish the optimum dose for intravitreal injection. The Intravitreal Steroid Injection Study (ISIS) is a dose-escalation study looking at 2-mg vs 4-mg doses of triamcinolone acetonide for the treatment of macular edema associated with diabetes as well as other disorders. Preliminary data reported at the Vail Vitrectomy Society showed the 4-mg dose to be more effective than the 2-mg dose.³⁰ The Diabetic Retinopathy Clinical Research network is conducting a prospective, randomized trial comparing laser treatment with intravitreal injection of 1-mg and 4-mg doses of a new formulation of triamcinolone acetonide for diabetic macular edema. In addition, the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) Study is evaluating 2-mg and 4-mg purified triamcinolone acetonide vs standard of care for the treatment of macular edema due to vascular occlusions. These large randomized studies may shed some light on the appropriate dose necessary to treat retinal diseases.

SAFETY OF INTRAVITREAL TRIAMCINOLONE

Many possible complications of intravitreal steroid injections can occur, including endophthalmitis, retinal detachment, retinal tears, vitreous hemorrhage, increased intraocular pressure, and cataract formation. The most common adverse effect of intravitreal triamcinolone has been increases in intraocular pressure.^43-45 Bakri found that within 12 weeks after a 4 mg intravitreal triamcinolone injection, 49% of 43 eyes demonstrated a pressure rise of 5 mmHg or greater, and 28% had a pressure rise of 10 mmHg or greater. The mean time for an IOP rise of 5 mmHg or greater to occur was 4.1 weeks, and the mean time to reach maximum IOP was 6.6 weeks. The difference between the mean pre-injection IOP (15.12, n=43) and the maximum post-injection IOP (20.74, n=43) was statistically significant (P<0.0001). All eyes in this study responded to topical ocular hypotensive medications within 6 months.⁴⁵ Jonas found that after intravitreal injection of a higher dose of 25 mg of triamcinolone acetonide, an intraocular pressure elevation developed in about 50% of eyes, starting 1 to 2 months after the injection.⁴⁴ In the vast majority, IOP was normalized by topical medications and returned to normal values without further medication about 6 months after the injection. Wingate reviewed 113 patients at a single timepoint (3 months) after a 4-mg intravitreal triamcinolone injection and found that 32% had a rise of 5 mmHg or greater, and 11% had a pressure rise of 10 mmHg or greater.⁴³ In most of these series, IOP was controlled with topical medications; however, there have been reports of eyes with uncontrolled intraocular pressure elevations requiring trabeculectomy or even vitrectomy to remove the triamcinolone.^{37, 46} In another study of 143 eyes receiving 4-mg intravitreal triamcinolone for diabetic macular edema due to diabetes and vein occlusions, 50% of patients had a rise in IOP with a peak incidence 7 weeks after injection.⁴⁷

Infectious Endophthalmitis ­ The Most Feared Complication

Acute bacterial endophthalmitis has been reported following intravitreal triamcinolone acetonide injection. Moshfeghi and associates published a retrospective, multicenter review of 922 intravitreal triamcinolone acetonide injections in which acute bacterial postoperative endophthalmitis in the first month following injection was reported in 0.87% of patients (95% confidence interval of 0.38%-1.70%).⁴⁸ Potential predisposing risk factors in these 8 patients included noninsulin dependent diabetes mellitus (n=5), injection from a multiuse Kenalog bottle (n=2), filtering blebs (n=1), and blepharitis (n=1). The median time to presentation was 7.5 days (range, 1-15 days). Mycobacterium chelonae endophthalmitis has also been reported after intravitreal steroid injections with the eye eventually requiring enucleation.⁴⁹

Pseudoendophthalmitis ­ A Confusing Entity

Acute sterile inflammatory vitritis, or pseudoendophthalmitis, has also been reported following intravitreal triamcinolone injection.^{50 - 52} The incidence has been reported to range from 0.87-5%.⁴⁷ Clues to differentiating inflammatory vitritis from true endophthalmitis include earlier onset, better visual acuity at presentation, lack of growth on culture or organisms on gram stain, and better final visual acuity, all associated with inflammatory vitritis . Another diagnostic possibility to consider when evaluating a patient with evidence of hypopyon and anterior chamber/vitreous reaction is the presence of triamcinolone acetonide particles in the anterior chamber, which produces a pseudohypopyon from the crystals and resulting inflammation.⁵³

SUMMARY

Evidence supporting the effectiveness of intravitreal triamcinolone acetonide in treating macular edema in retinal diseases has come from small interventional case series. We have seen a dramatic response on OCT with cases demonstrating resolution of increased retinal thickening with large cystoid spaces and return of normal retinal contours after intravitreal triamcinolone injections. However, we commonly see less impressive visual results. Whether this is due to permanent photoreceptor damage at the time of injection in these refractory cases or a lack of efficacy still needs to be determined.

In our practice, we treat patients with intravitreal triamcinolone that have had long-standing macular edema unresponsive to conventional treatments such as focal or grid laser or posterior sub-Tenon's triamcinolone injection. Without results from a randomized clinical trial, we believe that patients should fail conventional treatments before this experimental procedure is employed, and caution should be exercised when using it as a primary therapy. Even though the macular anatomy is often restored after intravitreal triamcinolone, the visual acuity remains stable. Moreover, the macular edema often recurs, necessitating further intervention. This relapse certainly poses a clinical dilemma, especially in those patients whose retinal anatomy improves after the first injection but have no change in vision. With the increasing emphasis today on visual rather than anatomic outcome, it is difficult to justify repeat intravitreal triamcinolone in these situations. However, left untreated, cystic degeneration of the outer retinal layers as well as lamellar holes may occur, and visual improvement is even less likely.

Randomized clinical trials are needed to address the many unanswered questions surrounding the use of intravitreal triamcinolone. Would treating with intravitreal triamcinolone at an earlier stage of the disease be more beneficial from a vision standpoint? When does macular edema recur and what should be the frequency of retreatment? How many retreatments can be administered? Are visual outcomes better than with conventional treatments? What is the optimum dose of triamcinolone? What is the true incidence of ocular adverse event? Several multicenter, randomized clinical trials sponsored by the National Eye Institute are currently enrolling patients to evaluate the effectiveness of 2-mg and 4-mg intravitreal triamcinolone on macular edema due to diabetic retinopathy and retinal vein occlusions. Perhaps these trials will provide the answers we need to better treat our patients with macular edema.

From the Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio.

Address correspondence to: Peter K. Kaiser, MD, Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk i3, Cleveland, OH 44195. Telephone: (216) 444-6702. Fax: (216) 445-2226. E-mail: kaiserp@ccf.org.

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