and Neovascular Age Related Macular
Degeneration

Felix Y. Chau • Daniel F. Kiernan • Jennifer I. Lim

INTRODUCTION

Ocular steroids for the treatment of diabetic macular edema (DME) and neovascular age-related macular degeneration (NVAMD) have been utilized in an evolving treatment strategy over the course of many years. The unifying principle behind using steroids for treating these conditions is that steroids are capable of reducing the vascular permeability of capillary endothelial cells, suppressing vascular endothelial growth factor (VEGF) production, and reducing the inflammatory response that contributes to both DME and NVAMD. Over the last few years, studies have compared ocular steroid treatment for DME (sub Tenon’s or intravitreal) with focal laser and anti-VEGF agents for treating DME. Steroid therapy has also been compared with PDT and anti-VEGF agents for treating NVAMD. This chapter will review the underlying principles behind using steroids for DME and NVAMD, review current studies evaluating steroid use for treating DME and NVAMD, and offer expert opinion Jennifer Lim (JL) regarding the role of steroids for DME and NVAMD for the future (Box 16.1).

MOLECULAR MECHANISMS

Since Machemer and Peyman first suggested the use of the vitreous as a depot for drug delivery to the retina and conducted the first experiments using intravitreal steroids,^1–3 intravitreal and other means of delivering steroids to the retina have been employed with various scientific rationales. Inflammation, especially leukostasis within capillaries, is known to result in increased vascular permeability and subsequent fluid accumulation in the retina in both DME⁴ and NVAMD.⁵ Steroids can reduce retinal edema in both these conditions by reducing inflammation.

The exact anti-inflammatory mechanism of corticosteroids is still not fully understood. Corticosteroids may induce lipocortin synthesis, which subsequently inhibits phospholipase A2 in its production of arachadonic acid.⁶ The decreased production of arachadonic acid in turn results in reduced synthesis of its inflammatory cascade derivatives such as prostaglandins and leukotrienes.⁶ Steroids may thus reduce the chemical signals for inflammation.⁶

Steroids may also reduce leukocyte adhesion and extravasation that occur during inflammation by reducing the expression of immunoglobulin superfamily molecules during endothelial cell activation. Immunoglobulin superfamily molecules such as intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and major histocompatibility complex (MHC)-I and -II are expressed during vascular endothelial cell activation during the process of inflammation. These adhesion molecules help leukocytes adhere to the endothelial cell surface from the circulating blood stream and assist in their extravasation from the blood stream into the surrounding tissue. Triamcinolone acetonide has been found to reduce the cytokine-induced expression of ICAM1, MHC-I, and MHC-II antigen by choroidal endothelial cells as well as to reduce the permeability of choroidal endothelial cell monolayers in vitro.^7–9 By reducing choroidal endothelial cell adhesion molecule expression and permeability, triamcinolone acetonide may have a therapeutic role in treating these inflammation-related contributors to NVAMD.⁵ Similarly, by reducing retinal vascular endothelial cell expression of molecules such as ICAM-1 and CD-18 and by reducing leukocyte adhesion to retinal vascular endothelial cell walls, steroids may reduce the inflammation-related contributors to DME.^4,10–13

In addition to reducing inflammation and its associated increase in vascular permeability in DME and NVAMD, steroids may also reduce vascular permeability and retinal edema mediated in part by VEGF. VEGF has been found to increase vascular permeability through breakdown of the blood-retina barrier and is considered one of the mediators of edema in DME^14–16 and a major mediator of choroidal neovascularization (CNV) and edema in NVAMD.¹⁷ VEGF is thought to increase retinal vascular permeability in DME via several theories including (a) phosphorylation of the tight junctional protein occludin, which causes disruption of the tight junctional complex and (b) FAS-mediated endothelial cell apoptosis.^14–16,18 VEGF’s major role in the formation of CNV and its resulting fluid accumulation in the retina in NVAMD has resulted in anti-VEGF therapies becoming the current standard of care in treatment of NVAMD.¹⁹ As steroids have been found to inhibit the expression of VEGF and the VEGF gene,^20,21 steroids in principle should reduce the VEGF-mediated components of DME and NVAMD.

STEROID FORMULATIONS FOR DME AND NVAMD

Triamcinolone acetonide has been used clinically for the inhibition of neovascularization and reduction of retinal edema. Triamcinolone is a conventional steroid, with typical glucocorticoid and mineralocorticoid anti-inflammatory activity.⁶ In ophthalmic practice, it is available as an injectable suspension, usually either 4 or 20 mg. Although many commercial preparations exist, the most commonly used preparation is Kenalog-40 (triamcinolone acetonide, Bristol-Myers-Squibb, Peapack, NJ). Triamcinolone does not achieve significant systemic serum levels when injected intravitreally;²² however, differences in particle size (<1 to >20 mm) may contribute to variability in clearance times and durations of action following vitreous injection.²³ Although they are effective angiostatic agents, glucocorticoids are associated with significant ocular side effects, including the development of posterior subcapsular cataracts and ocular hypertension and iatrogenic glaucoma in sensitive patients.

Various rationales have led to the use of triamcinolone acetonide as an intravitreal injection for steroid treatment of the retina. Steroids given topically, systemically, or injected into the subconjunctival or sub-Tenon’s space often do not reach sufficiently high intraocular concentrations to achieve therapeutic levels or have serious systemic side effects when given long term.⁶ In contrast to soluble substances injected into the eye that leave the globe within hours to days, triamcinolone acetonide is normally in crystalline form of variable particle sizes that can be injected as a suspension. As solid crystals, triamcinolone is a more ideal steroid than soluble forms of steroid for achieving long-lasting concentrations of drug over time within the eye. Additionally, systemic concentrations of triamcinolone in the venous blood after intravitreal injection have been measured as insignificant compared to physiologic serum cortisol levels, suggesting intravitreal triamcinolone (IVTA) is ideally suited for treating the retina at high concentration with minimal systemic side effects.²⁴

Like triamcinolone, anecortave acetate has also been used for reducing retinal neovascularization and edema. Anecortave acetate (Retaane, Alcon Laboratories, Fort Worth, TX) is an artificially modified steroid that was specifically designed to eliminate the undesired side effects of glucocorticoids while enhancing angiostatic activity. It is synthesized by removing the 11b-hydroxyl group on the B ring of the steroid nucleus and by replacing it with a C9-11 double bond to form a unique pregnan cortisene compound. The altered structural configuration confers distinct angiostatic capabilities, inhibiting multiple steps in the neovascularization process, including initiation of the angiogenic cascade and elaboration of the angiogenic growth factors VEGF and insulin-like growth factor (IGF)-1 and their receptors.^25–28 Initial studies in chick embryos and mouse intraocular tumors demonstrated that anecortave effectively inhibited newly forming small vessels, whereas existing normal vessels were unaffected.^29–33

Dexamethasone has the highest relative strength of any other steroid used in ophthalmic practice.^6,34 A single dose of 0.18 mg/mL dexamethasone is equivalent to 1 mg/mL triamcinolone in terms of equal corticosteroid efficacy and is short acting, with faster clearance from the vitreous.³⁵ Intravitreal dexamethasone has been shown to suppress streptozotocin-induced leukostasis in diabetic rats³⁶ and VEGF-induced blood-retinal barrier breakdown in rabbits³⁷ via VEGF and ICAM-1 inhibition within the retinal vasculature. When administered as treatment pulses, it may be less likely to result in glaucoma or cataract progression than other sustained-delivery steroids.^38,39 Triple therapy using photodynamic therapy (PDT), intravitreal dexamethasone, and anti-VEGF agents is currently being assessed in patients with NVAMD for maintenance of visual acuity and reduction in the frequency of treatment of AMD patients.^38–41 Dexamethasone in a sustained release implant has also previously been used to treat macular edema secondary to diabetes, uveitis, and vein occlusions⁴² and recently gained FDA approval for treating macular edema from vein occlusions. It is currently being studied more carefully in treating DME.

Fluocinolone is another potent corticosteroid with high glucocorticoid receptor affinity. As an intravitreal implant that provides sustained release fluocinolone over about 2.5 years, the Retisert device has been U.S. FDA approved for the treatment of noninfectious posterior uveitis.⁴³ Cataracts and increased intraocular pressure are common side effects requiring surgical or medical management. In vitro studies using human retinal pigment epithelial (ARPE-19) cells have suggested fluocinolone inhibits VEGF expression via glucocorticoid receptors and inhibits tumor necrosis factor-alpha (TNF-alpha)–induced angiogenesis in chick chorioallantoic membrane.⁴⁴ These suggest a potential role along with anti-VEGF therapy for fluocinolone in treating NVAMD. Furthermore, the fluocinolone intravitreal implant was also found to help reduce DME and improve visual acuity in a 3-year study, although glaucoma-related complications and cataracts were again significant side effects.⁴⁵

STEROIDS AND DME: PRIOR STUDIES AND FUTURE DIRECTIONS

Triamcinolone Acetonide for DME

Potential benefits of steroids over focal and grid laser for DME include absence of damage to retinal tissue that would be caused by laser and broader treatment of the retina for more diffuse DME not easily treated by focal or grid laser. With these theoretical advantages, steroid treatment for DME has progressed from case reports in 2001 to randomized, controlled clinical trials comparing intravitreal steroids with placebo, focal/grid laser, and other controls as of 2009.^46–52

As shown in Table 16.1, many permutations of comparing IVTA at different doses against various control groups (placebo injection, observation, and later focal/grid laser) have suggested a trend of transient improvement of DME and visual acuity that gradually declines over a dose-dependent time. Early case studies of eyes with DME refractory to laser suggested the role of IVTA as alternative treatment. In 2001, Jonas et al.⁴⁶ performed one of the first intravitreal injections of triamcinolone acetonide (20 mg) in an eye with declining vision from DME refractory to grid laser treatment and found improvement in acuity from 0.10 to about 0.40 in 2 months. In 2002, Martidis et al.⁴⁷ treated 16 eyes with DME that failed to respond to at least two laser sessions with 4 mg of triamcinolone acetonide (Figs. 16.1, 2 to 16.3).⁴⁷ Vision improved by 2.4, 2.4, and 1.3 Snellen lines at the 1-, 3-, and 6-month follow-up intervals, respectively, with corresponding decreases in optical coherence tomography (OCT) central macular thicknesses of 55%, 57.5%, and 38%, respectively. Some cases did result in intraocular pressure increases above 21 mm Hg requiring topical treatment.⁴⁷

FIGURE 16.1. Nonproliferative diabetic retinopathy with chronic clinically significant macular edema. A: A color photograph after three laser sessions (6/30/98) showing multiple microaneurysms with hard exudate. Clinically, there was persistent thickening under the fovea with cystoid spaces. B: Fluorescein angiography corresponding to color photograph confirms diffuse macular leakage. Note the multiple laser scars surrounding the fovea. C: An OCT cross section corresponding to the color photograph shows persistent macular edema with development of large cystoid spaces. Visual acuity measures 20/50. Additional laser photocoagulation was performed.

FIGURE 16.2. Nonproliferative diabetic retinopathy with chronic clinically significant macular edema. A: An OCT cross section and macular map before IVTA. A total of five laser sessions had been performed previously. Note prominent cystoid spaces involving the fovea with diffuse macular edema. Visual acuity had declined progressively to 20/200. B: An OCT cross section 1 month after IVTA. Chronic macular thickening and cystoid spaces have resolved completely, and vision has returned to 20/60. C: An OCT cross section 3 months after IVTA. The macular edema remains controlled, and vision remains stable. (Reproduced from Martidis, et al. Ophthalmology. 2002;109:920, with permission.)

FIGURE 16.3. Proliferative diabetic retinopathy with chronic clinically significant macular edema. A: An OCT cross section before IVTA. Note the persistent macular thickening and cystoid macular edema despite two prior laser sessions. Visual acuity measures 20/80. B: An OCT cross section 1 month after IVTA shows resolution of macular edema with improvement of visual acuity to 20/50. C: An OCT cross section 3 months after IVTA shows sustained control of macular edema; visual acuity measures 20/60. (Reproduced from Martidis, et al. Ophthalmology. 2002;109:920, with permission.)

Further studies, many with control groups for comparison, clarified the potential role of triamcinolone for DME. In an inter-eye comparison in 2004, Jonas et al.⁵³ also found that steroid-treated eyes (20–25 mg triamcinolone) compared to observed eyes more often had two or more lines of Snellen visual acuity improvement (55% vs. 25%) or three or more lines of Snellen visual acuity improvement (35% vs. 10%). In the same year in a case series study, Jonas et al.⁵⁴ also estimated that 20 to 25 mg of triamcinolone produces a maximum visual improvement within 1 to 7 months with return to baseline vision in 8 to 9 months. In 2004, Sutter et al. performed in a randomized controlled trial comparing 4 mg IVTA in 34 eyes with placebo injection in 35 eyes. The steroid-treated eyes more often showed a gain of five letters or more (55% vs. 16%).⁵⁵ Also in 2004, Ciardella et al.⁵⁶ in a case series of 30 eyes found that 4 mg triamcinolone resulted in improved logMAR visual acuities; vision improved from a baseline of 0.17 ± 0.12 to 0.34 ± 0.18, 0.36 ± 0.16, and 0.31 ± 0.17 at 1, 3, and 6 months respectively with a reduction in hard exudates (Fig. 16.4).⁵⁶ The mean interval between first and second injections was 5.7 ± 2.7 months. The mean interval between second and third injections was 5.7 ± 3.3 months. Intraocular pressure rises above 21 mm Hg occurred in 40% of eyes. Correlating with other studies showed improved visual acuity, Ozkiris et al.⁵⁷ found in 2004 that 8 mg triamcinolone given to 40 eyes with DME resulted in significant improvements in pattern electroretinogram: with a mean follow-up of 6 months, both the mean visual acuity and mean p50 amplitude pERG improved. In 2005, Jonas et al.⁵⁸ determined that lower degrees of macular ischemia, higher preoperative visual acuity, and higher degrees of macular edema in diffuse DME correlated with improvement in visual acuity after treatment with IVTA. In 2005, Spandau et al.⁵⁰ in a prospective, randomized, double-masked interventional study of 27 eyes comparing doses of 2 mg (8 eyes), 5 mg (10 eyes), and 13 mg (9 eyes) of triamcinolone found more pronounced treatment effect and longer duration in the 13 mg group than the 5 and 2 mg groups. In 2007, Lam et al.⁵⁹ discovered in a randomized study of 111 eyes with DME comparing 4 mg triamcinolone (IVTA) combined with grid laser versus IVTA alone or grid laser alone that IVTA combined with grid laser was not better than IVTA alone, and that grid laser alone had the worst visual outcomes.

FIGURE 16.4. A 69-year-old diabetic man with reduced visual acuity in the right eye to the level of 0.1 secondary to diffuse diabetic macular edema. He had two previous laser treatments in the right eye. IVTA acetonide 4 mg in 0.1 mL was injected one time in the right eye. A: Clinical fundus photograph of the right eye at baseline demonstrated the presence of background diabetic retinopathy. There was diffuse macular edema, hard exudates, and intraretinal hemorrhages at the posterior pole. The white line represents the area scanned with the OCT. B: OCT cross section scan through the macula confirmed the presence of macular edema. There were intraretinal fluid-filled cystoid spaces and serous elevation of the neurosensory retina. The macular thickness in the fovea measured by OCT was 557 μm. C: False color topographic map of the macula demonstrated diffuse macular thickening. In the false color map, white corresponds to the area of maximal thickening and blue corresponds to the less thick areas. D: One month after IVTA, the visual acuity had improved to 0.2. The central macular thickness was decreased to 461 μm. OCT scan through the macula demonstrated slight resolution in the macular edema. E: False color topographic map of the macula demonstrated some reduction in retinal thickness especially in the inferonasal macula. F: Three months after IVTA, visual acuity had improved to 0.32. There was partial resolution of the serous neurosensory detachment in the macula by OCT. G: False color topographic map of the macula confirmed the partial resolution of the macular edema. There was still thickening temporally (white). H: Clinical photograph of the same eye 6 months after IVTA revealed resolution of the macular edema and reduction in the number of hard exudates at the posterior pole. Visual acuity had improved to 0.4. The white line represents the area scanned with the OCT. I: OCT scan through the fovea demonstrated almost total resolution of the serous neurosensory macular elevation. There was also disappearance of the intraretinal cystoid spaces. Central macular thickness was 173 μm. J: False color topographic map confirmed the presence of diffuse flattening of the macula. (Reproduced from Ciardella, et al. Br J Ophthalmol. 2004;88:1131, with permission)

In 2008, with many published independent studies looking at steroid treatment for macular edema, Grover et al.⁵¹ performed a meta-analysis of 632 eyes with DME from seven studies—four using IVTA and three using a fluocinolone acetonide implant (FAI) or dexamethasone drug delivery system (DDS).⁵¹ The study found visual improvement (improved mean difference in LogMAR visual acuity) with IVTA compared with controls at 3 months (-0.15 LogMAR, 7.5 letters), 6 months (-0.23 LogMAR, 11.5 letters), 9 months (-0.29 LogMAR, 14.5 letters), and 24 months (-0.11 LogMAR, 5.7 letters). The relative risk for improving one or more lines in visual acuity was 2.85 at 3 months, 1.25 at 6 months, and 2.17 at 24 months, all in favor of IVTA. Mean improvements in OCT retinal thickness were -131.97 μm at 3 months, -135 μm at 6 months, -133 μm at 9 months, and -59 μm at 24 months, all in favor of IVTA. Improved clinical outcomes of FAI and DDS trials were also reported. Elevated IOP and cataract progression occurred with IVTA but seemed manageable.⁵¹

In 2008, as a potentially definitive study comparing IVTA with focal/grid laser for DME, the Diabetic Retinopathy Clinical Research Network (DRCR.net) completed the 2-year follow-up for a multicenter, randomized, controlled clinical trial comparing 1 mg IVTA, 4 mg IVTA, and focal/grid laser.⁵² In this trial, 840 eyes with DME involving the fovea with visual acuities 20/40 to 20/320 were randomized to focal/grid laser (n = 330), 1 mg (n = 256), or 4 mg (n = 254) triamcinolone (IVTA). Retreatment was allowed for persistent or new edema at 4 months intervals. At 4 months, there was a greater positive treatment response on visual acuity in the 4 mg IVTA group compared with laser or 1 mg IVTA. However, at 1 year, little difference was found in visual acuity among the groups, and from 16 months to the 2 year primary outcome assessment, the laser group had superior visual acuities and better safety profiles (fewer eyes with intraocular pressure increases and cataracts) than either the 1 or 4 mg triamcinolone groups. OCT central subfield retinal thicknesses similarly showed greater initial treatment effect in the 4 mg group at 4 months, with later superior improvements for the laser treatment group at 2 years compared to both the 1 and 4 mg IVTA groups. The improvements in visual acuity by laser in this study were consistent with prior findings in the ETDRS in eyes with CSDME treated with focal/grid laser with similar entry criteria to the eyes enrolled in this study. In conclusion, the study stated that while IVTA likely is superior to the natural, untreated course of CSME over 2 years, the results suggest that focal/grid laser is more effective than IVTA in improving visual acuity and reducing OCT-measured retinal thickening in the long term.⁵²

Furthermore, the study also found that laser had fewer side effects than IVTA, especially regarding ocular hypertension, glaucoma, and the need for cataract surgery.⁵² In terms of ocular hypertension and glaucoma, more eyes in the 4 mg IVTA group (40%) than in the 1 mg IVTA group (20%) or laser group (10%) had one of the following at one or multiple visits from baseline: (a) increased intraocular pressure of 10 mm Hg or more above baseline, (b) intraocular pressure of 30 mm Hg or more, and (c) initiation of intraocular pressure-lowering medications (if not being treated at the study entry) or a diagnosis of glaucoma (p < 0.001 for all three pair-wise comparisons). Glaucoma surgery was only required in the 4 mg IVTA group (4 eyes: 2 filtering surgeries, 1 laser trabeculoplasty, 1 ciliary body destruction). For phakic eyes at baseline, cataract surgery was required before the 2-year outcome visit more often in eyes in the 4 mg IVTA group (51%) than in the 1 mg IVTA group (23%) or laser group (13%; p < 0.001 for all three pair-wise comparisons).⁵²

For the 3-year follow-up of this DRCR study, 306 eyes were available for further analysis (Fig. 16.5).⁶⁰ From 2 to 3 years, more eyes improved than worsened in all three treatment groups. The change in visual acuity letter score from baseline to 3 years was a gain of five letters in the laser group and no letters in each triamcinolone group. For the duration of the 3-year study, the probability of requiring cataract surgery was 31%, 46%, and 83% in the laser, 1 mg, and 4 mg triamcinolone groups, respectively. IOP rose by more than 10 mm Hg at any visit in 4%, 18%, and 33% of eyes in the laser, 1mg, and 4 mg triamcinolone groups, respectively. These findings were consistent with the 2-year results suggesting continued superior benefit in focal/grid laser–treated eyes compared to IVTA-treated eyes with less risk of visually significant cataract or elevated intraocular pressure. Indeed, most eyes in the 4 mg IVTA group required cataract surgery.⁶⁰

FIGURE 16.5. Mean visual acuity at each visit according to treatment group. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and IVTA for DME. (Reproduced from DRCR Network. Arch Ophthalmol. 2009;127:245, with permission.)

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