PEER REVIEWED

Steroid Response After Intravitreal Steroid Implants for Retinal Disease

Retinal physicians should consider the optic nerve.

EDWARD B. MOSS, MD, FRCSC • YVONNE M. BUYS, MD, FRCSC

Intravitreal corticosteroids are effective for treating macular edema secondary to venous occlusive disease (retinal vein occlusions), uveitis, diabetes (diabetic macular edema), and choroidal neovascularization,^1-8 but the effect on intraocular pressure remains an important potential complication.

Before using intravitreal corticosteroids to treat a patient with retinal disease, the clinician must consider the likelihood of an IOP rise, the potential impact on the particular patient, and how best to mitigate the damage of this complication.

This article is intended to review some of the background knowledge and to recommend an approach to minimize the risk of vision loss due to glaucoma.

INTRAVITREAL CORTICOSTEROID IMPLANTS

Conventional intravitreal steroid injections (triamcinolone acetonide, dexamethasone) have a short half-life, mediated by the rate of elimination from the vitreous. Therefore, multiple injections may be needed to maintain the therapeutic effect.

In cases of chronic macular edema, this greater number of injections increases the risk of injection-related complications, such as endophthalmitis, retinal tears and detachments, vitreous hemorrhage, and subconjunctival hemorrhage.^8,9 Intravitreal corticosteroid implants were designed to reduce these risks.⁷

Three Devices

Figure 1 illustrates the three FDA-approved devices for delivering sustained-release intravitreal steroids.¹⁰ The Retisert fluocinolone acetonide (FA) implant (Bausch + Lomb, Rochester, NY) is a nonbiodegradable sustained-release implant that is sutured to the sclera at the pars plana, where it releases FA for approximately 30 months.⁷ The 0.59-mg dose was FDA-approved in 2005 for the treatment of noninfectious posterior uveitis.

Figure 1. Sustained-release intravitreal steroid implants. (top) Retisert, fluocinolone acetonide (Bausch + Lomb, Rochester, NY). (center) Iluvien (with grain for size comparison), fluocinolone acetonide (Alimera Sciences, Alpharetta, GA). (bottom) Ozurdex with applicator, dexamethasone (Allergan, Irvine, CA).

Iluvien (Alimera Sciences, Alpharetta, GA) is a nonbiodegradable intravitreal FA implant injected via a 25-gauge needle through the pars plana. In the eye, it releases 0.2 µg/day of FA for at least three years. It was approved by the FDA on September 26 for the treatment of chronic DME.¹¹

Ozurdex (Allergan, Irvine, CA), a biodegradable implant made of dexamethasone embedded in a degradable polymer is administered through a 23-gauge needle at the pars plana. It releases dexamethasone into the vitreous⁶ for up to six months, as revealed in a study of primate eyes.¹²

The FDA approved the 0.7-mg dose of Ozurdex for macular edema following RVO in 2009 and to treat noninfectious intermediate and posterior uveitis in 2010. Recent randomized controlled trials (RCTs) for dexamethasone in DME report favorable comparisons to sham treatment¹³ and to intravitreal bevacizumab.¹⁴

The FA and dexamethasone implants have demonstrated comparable efficacy for macular edema. Lower cost, easier administration, and lower complication rates —– especially secondary cataract and glaucoma¹⁵ —– have led to wider adoption of the dexamethasone implant.

Expanded indications will likely increase the role of this treatment. As examples, recent studies have investigated the dexamethasone implant for vasoproliferative retinal tumors,¹⁶ macular edema in retinitis pigmentosa,¹⁷ and macular edema caused by radiation retinopathy.¹⁸

OCULAR HYPERTENSION SECONDARY TO INTRAVITREAL STEROIDS

Ocular hypertension (OHT) following intravitreal steroids can occur in two phases: immediately following the injection; or weeks to months later. The immediate rise in IOP is secondary to the volume of the intravitreal injection delivered into the fixed space of the globe.

More than one-third of eyes receiving 0.05 mL of anti-VEGF intravitreally experience an immediate pressure rise of >50 mm Hg, which undergoes a rapid, spontaneous decline in most cases.¹⁹ One study demonstrated this concept well, reporting that 0.1 mL of intravitreal triamcinolone acetonide (IVTA; Kenalog, Bristol-Myers Squibb, New York, NY) caused a greater immediate pressure increase when the injection procedure did not cause vitreous reflux.²⁰

The second phase, occurring weeks to months later, is commonly referred to as a “steroid response,” which in general occurs in 18% to 36% of the population and in 46% to 92% of people with primary open-angle glaucoma (POAG).²¹ Early studies of the steroid response^22-24 identified an increase in resistance to outflow (identified as a reduction in outflow facility on tonographic measurements), attributed to alterations of the trabecular meshwork.

Current theories credit the increased resistance to various biomolecular effects induced by steroids: greater extracellular matrix deposition in the meshwork; inhibition of meshwork cell phagocytotic and lysosomal functions; alteration of meshwork cytoskeletal structures; and/or an increase in the meshwork expression of cell-to-cell adhesion molecules.¹⁰

The route of drug delivery, dose, steroid type, and patient-dependent risk factors all affect the likelihood and severity of steroid response. Most episodes of steroid-induced OHT from intravitreal corticosteroids are limited in duration and amenable to medical management.

However, approximately 1% of patients may require surgery for uncontrolled IOP after treatment with 4 mg of intravitreal triamcinolone acetonide,²⁵ and up to 45% required surgery to lower pressure after intravitreal FA implantation.²⁶

RISK STRATIFICATION FOR OHT FOLLOWING INTRAVITREAL DEXAMETHASONE IMPLANT

To properly inform patients about the potential for OHT and to provide appropriate monitoring, the clinician must best estimate how patient- and treatment-specific variables affect the likelihood of OHT. Here, we present data from a recent meta-analysis¹⁰ that included many current and important studies of dexamethasone implant safety.

For some risk factors, the reader will notice that information is cited from studies of other forms of intravitreal steroids, because it may be necessary to extrapolate a similar relationship for the dexamethasone implant, when specific data are insufficient.

For that reason, we begin by presenting data on the overall risk related to the dexamethasone implant, compared to other forms of intravitreal steroid.

TREATMENT-RELATED RISK

In a meta-analysis by Kiddee et al, OHT developed in 11% (95% CI 6.4-7.9) and 15% (95% CI 9.2-24.3) of individuals following 0.35- and 0.7-mg intravitreal dexamethasone implants, respectively.¹⁰ OHT was defined as an IOP increase ≥10 mm Hg from baseline or an IOP ≥25 mm Hg. For comparison, OHT (by a similar definition) was identified in 32% (95% CI 28.2-36.3) following treatment with 4 mg of IVTA and in 66% (95% CI 50.2-78.8) and 79% (95% CI 72.2-84.5) following 0.59-mg and 2.1-mg scleral-sutured FA implants, respectively.¹⁰

PATIENT-RELATED RISK FACTORS

A majority of studies investigating the impact of age on OHT after 4 mg of IVTA found younger age (cutoff 45-55 years old) increased the likelihood and magnitude of steroid-induced OHT.¹⁰

Underlying Ocular Disease

Eyes receiving IVTA showed the greatest prevalence of OHT (42.7%; 95% CI 28.4-58.3) in patients with uveitis (as compared to AMD, RVO, DME, or CNV); however, this difference was not statistically significant in the meta-analysis. After 0.35- or 0.7-mg dexamethasone implants for DME, 15.7% (95% CI 10.0-23.8) and 14.9% (95% CI 10.2-21.3) of eyes developed OHT.¹⁰

In a six-month trial, Lowder et al reported OHT in 8.7% and 7.1% of eyes with noninfectious uveitis receiving a single 0.35-mg or 0.7-mg dose, respectively, compared to 4.2% who developed OHT with sham treatment.²⁷

The GENEVA study group showed that 3.9% and 4% of eyes with RVO developed OHT following a single 0.35-mg or 0.7-mg Ozurdex, respectively. At 12 months, however, patients requiring a second treatment received 0.7 mg, and 33% of those receiving 0.7 mg/0.7 mg exhibited elevated IOP.⁶

Higher Baseline IOP

Several studies of IVTA have reported that eyes with baseline IOP ≥15 mm Hg are at greater risk for poststeroid OHT.^25,28

History of Glaucoma

There may be an increased risk of OHT following intravitreal steroids in both patients with a history of glaucoma and patients with family histories of glaucoma.^25,29

History of OHT After Intravitreal Steroids

A history of IOP elevation after previous IVTA injection is a risk factor for OHT. A 5.5 times greater risk for OHT was reported for patients receiving subsequent IVTA after a prior treatment-induced IOP elevation. ²⁹

OHT TIME COURSE

For Ozurdex in eyes with RVO, the GENEVA group observed elevated IOP most commonly at the visit 60 days post-treatment. This elevation resolved in the majority by six months.⁶ In a randomized, controlled trial reporting three-year results of Ozurdex for DME, mean IOP following retreatment every six months (as indicated, mean 4.1 or 4.4 injections over three years for 0.35 and 0.7 mg, respectively) peaked between months 2 and 3 and decayed to near baseline by month 6, following a similar pattern after each injection.¹³

MANAGING COMPLICATIONS AND RECOMMENDED IOP SURVEILLANCE

IOP elevation after intravitreal steroid treatment consists of two components: an immediate-onset elevation due to the mechanical effects of additional volume in the eye; and a late elevation caused by the steroid-induced reduction in aqueous outflow rates.

We echo the recommendations by Kiddee et al¹⁰ for monitoring and treating OHT. For any patient receiving intravitreal steroid therapy, a baseline assessment must be completed to assess and document the presence and severity of underlying glaucoma. Risk factors (Table) should be identified and recorded.

For eyes with glaucomatous optic neuropathy, IOP should be assessed immediately after and 30 minutes after implantation, with a low threshold to treat using paracentesis or IOP-lowering medications. The pressure should be checked again at two weeks following Ozurdex implantation and then every two weeks for the first month and finally monthly for six months.

IOP >21 mm Hg or greater than the target pressure in eyes with glaucoma and IOP >28 mm Hg in eyes without pre-existing glaucoma, should prompt the initiation of hypotensive therapy. This must be followed by close monitoring of IOP, optic disc changes, and visual fields. IOP of 22-28 mm Hg without preexisting glaucoma should be monitored at least monthly.

Six to 16 percent of eyes with DME and 26% of eyes with RVO receiving a 0.7-mg implant required topical therapy at six months. This rate increased to 36% at 12 months. While medical therapy is sufficient to treat the majority of steroid responses to dexamethasone implantation, 0.6% of eyes with RVO treated by the GENEVA group required a procedure to lower IOP during the initial six-month analysis, including laser trabeculoplasty, glaucoma drainage device insertion, deep sclerectomy, and cycloablative therapy.³⁰

Trabeculectomy, other filtering procedures, and vitrectomy to remove the residual implant have also been described to manage OHT following intravitreal corticosteroids. For patients with glaucoma or otherwise at greater risk, comanagement with a glaucoma specialist prior to initiating therapy represents a prudent option.

SUMMARY

While intravitreal corticosteroids play an important role in managing a variety of posterior-segment diseases, they are associated with various complications, including OHT and secondary glaucoma. Patients must be informed of these potential risks, and protocols for diagnosing and managing complications should be established.

Kiddee et al presented the aforementioned surveillance steps in the form of an algorithm for monitoring IOP after intravitreal steroid injection or implantation. The algorithm is reproduced here (in Figure 2, page 23, and the Table, page 22). The use of such a treatment protocol is essential to minimizing irreversible vision loss that can result from an undetected and uncontrolled steroid response. RP

Figure 2. Algorithm for intraocular pressure monitoring following intravitreal steroid injection/implantation.
CREDIT: ELSEVIER

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