Changes of Inflammatory Factors After Intravitreal Triamcinolone Acetonide for Macular Edema with Central Retinal Vein Occlusion

Introduction

Various inflammatory factors have been reported to contribute to macular edema associated with central retinal vein occlusion (CRVO).^1–3 The SCORE study ⁴ showed that intravitreal injection of triamcinolone acetonide (IVTA) could improve visual acuity and macular edema in patients with CRVO. However, little is known about the influence of IVTA on inflammatory factors in CRVO patients with macular edema. Therefore, we measured vitreous levels of vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule 1 (sICAM-1), and pigment epithelium-derived factor (PEDF) before and after IVTA in 2 CRVO patients with macular edema.

Case Reports

Two eyes of 2 CRVO patients (1 woman aged 69 years and 1 man aged 71 years) with macular edema received IVTA under local anesthesia at the Department of Ophthalmology of Tokyo Women's Medical University (Table 1). Written informed consent was obtained from both patients. The dosage of triamcinolone acetonide was 4.0 mg in 0.1 mL, which was injected via the pars plana at 3–4 mm posterior to the limbus with a sterile technique. Prophylactic topical antibiotics were applied for 1 week afterward. On fluorescein angiography, both patients had nonischemic CRVO. They had not undergone previous surgery or retinal photocoagulation. Central macular thickness (CMT) was measured by optical coherence tomography (Stratus model 3000; Carl Zeiss, Dublin, CA). The indications for IVTA were a CMT>300 μm and best-corrected visual acuity worse than 20/40.

Samples of undiluted aqueous humor (100 μL) were obtained at the initial and repeat IVTA procedures, placed into sterile tubes, and rapidly frozen at −80°C. VEGF and sICAM-1 were measured by enzyme-linked immunosorbent assay (ELISA; VEGF: R&D Systems, Minneapolis, MN; sICAM-1: Bender Med Systems, Burlingame, CA).^1,2 PEDF was measured with a human PEDF sandwich ELISA kit (Chemicon International, Temecula, CA). ⁵ This study was conducted according to the Declaration of Helsinki and institutional review board approval was obtained.

Both patients had unilateral CRVO and the duration of their symptoms was 3 and 5 months. The baseline foveal thickness was 842 μm in case 1 and 632 μm in case 2. After the first injection, macular edema (CMT: 291 μm at 3 weeks and 177 μm at 1 month after IVTA, respectively) improved in both patients. However, macular edema recurred (CMT: 793 μm at 5 months and 546 μm at 3 months after IVTA, respectively), so IVTA was repeated after 6 and 4 months, respectively. VEGF levels in aqueous humor samples obtained during initial intravitreal therapy (441 and 191 pg/mL, respectively) were higher than at reinjection (381 and 147 pg/mL, respectively) in both patients. The initial sICAM-1 levels (7.4 and 6.4 ng/mL, respectively) were also higher than at reinjection (5.9 and 5.3 ng/mL, respectively). Conversely, the initial PEDF levels (15.3 and 12.2 ng/mL, respectively) were lower than at reinjection (24.5 and 16.4 ng/mL, respectively) in both patients.

Discussion

We performed IVTA for macular edema in 2 patients with CRVO because the SCORE study ⁴ recently showed that triamcinolone acetonide could improve visual acuity and macular edema due to CRVO. We found that the VEGF and sICAM-1 levels in aqueous humor samples obtained during initial therapy were higher than at reinjection in both patients, suggesting that triamcinolone acetonide modulates vascular permeability by downregulating VEGF and ICAM-1 expression. ⁶ Conversely, the initial PEDF level was lower than that at reinjection in both patients. Tombran-Tink et al. reported that corticosteroids increase PEDF protein and RNA levels in retinal cells and endothelial cells. ⁷ Thus, triamcinolone acetonide may not only downregulate expression of VEGF and ICAM-1, but also upregulate PEDF expression.

Park et al. ⁸ reported that the mean aqueous humor levels of VEGF and PEDF were significantly decreased in responders to intravitreal bevacizumab among patients with macular edema secondary to branch retinal vein occlusion (BRVO). On the other hand, we found that the aqueous humor level of VEGF was decreased by IVTA, while the PEDF level was increased. Based on our findings, the reduction of VEGF is smaller with IVTA than bevacizumab, while PEDF is more strongly induced by IVTA than by bevacizumab. Park et al.^8,9 reported that aqueous humor levels of VEGF remained high in nonresponders to IVTA or bevacizumab because the nonresponders had ischemic occlusion, suggesting that overexpression of VEGF may persist due to ischemia. Our patients had nonischemic occlusion, so VEGF expression would probably decline after IVTA. Taken together, IVTA may be an option for nonischemic CRVO patients with low PEDF and/or moderate VEGF and sICAM-1 levels, although the CRUISE trial clearly showed improvement of visual acuity with ranibizumab. ¹⁰ However, we only have 2 case reports and the pathophysiology of CRVO differs from that of BRVO. Accordingly, a randomized prospective clinical trial of anti-VEGF therapy versus triamcinolone acetonide would be required to demonstrate its efficacy for macular edema associated with BRVO or CRVO.

In conclusion, aqueous humor levels of VEGF and sICAM-1 decreased after IVTA in 2 CRVO patients, while the PEDF level increased. IVTA could be a treatment option for patients with a low PEDF level and/or moderate VEGF and sICAM-1 levels.