Photodynamic therapy with verteporfin for corneal neovascularization.

PURPOSE: To investigate the efficacy of photodynamic therapy (PDT) with verteporfin for the treatment of patients with corneal neovascularization.
MATERIALS AND METHODS: Retrospective interventional case series of 33 eyes of 32 patients with stable corneal neovascularization who were refractory to conventional treatment and were treated with single photodynamic therapy with verteporfin (6 mg/m(2)) at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia between January 1, 2007 and December 30, 2009. The mean age was 40.7 ± 19 years (range 16-76 years). The mean follow-up for all patients was 13.1 ± 5.5 months (range 6-24 months). The average amount of corneal neovascularization was 2.7 ± 1.9 (1-10). Corneal neovascularization was deep in 19 (57.6%) eyes and superficial in 14 (42.4%) eyes. Preoperative and postoperative visual acuity and intraocular pressure, and clinical outcome of the treatment were assessed. Statistical analysis was performed to investigate the association to potential risk factors, to assess the change in data and determine the risks for failure. A P-value less than 0.05 was statistically significant.
RESULTS: At the last follow-up visit, 22 (66.7%) eyes showed a decrease in corneal neovascularization and evidence of vascular thrombosis. Complete vascular occlusion was achieved in 14 (42.4%) eyes, partial occlusion was achieved in 8 (24.2%) eyes, and the vessels were patent in 11 (33.3%) eyes. The corneal neovascularization score and depth of the vessels were found to be significant risk factors for failure (P = 0.0001 and 0.046, respectively). However, the diagnoses or causes of corneal neovascularisation were not statistically significant. No significant systemic or ocular complications associated with photodynamic therapy were observed.
CONCLUSION: Photodynamic therapy with verteporfin was effective for the treatment of corneal neovascularization in the majority of the cases in this study.

INTRODUCTION

Corneal neovascularization occurs secondary to infectious, inflammatory, ischemic, or traumatic disorders of the cornea or limbal stem cell injury. The progression of this complication can lead to corneal scarring, lipid deposition, and inflammation, causing significant visual impairment and poor prognosis after subsequent penetrating keratoplasty.12

Available treatments for corneal neovascularization such as steroids or angiogenesis inhibitors, laser photocoagulation, fine needle diathermy, and surgery have clinical limitations and adverse effects.3–7 Agents that inhibit the action of vascular endothelial growth factor (VEGF), including bevacizumab, have recently been introduced for the treatment of chorioretinal neovascularization.8 The inhibitory effects of topical or subconjunctival bevacizumab on corneal neovascularization has been studied in animal models and in clinical cases.9–11

Photodynamic therapy (PDT) with a photosensitizer such as verteporfin can produce microvascular thrombosis with minimal damage to surrounding normal tissue. PDT with verteporfin has been used safely and effectively in corneal neovascularization and in many chorioretinal diseases.512–14 In the present study, we report the clinical outcomes of PDT with verteporfin for the treatment of patients with corneal neovascularization.

MATERIALS AND METHODS

Approval for this retrospective study was granted by the Institutional Review Board of the King Khaled Eye Specialist Hospital (KKESH) in Riyadh, Saudi Arabia. The medical records of all patients who underwent PDT with verteporfin for the treatment of corneal neovascularization at KKESH between January 1, 2007 and December 30, 2009 were reviewed. Inclusion criteria was a clinical diagnosis of stable superficial or deep (midstromal) corneal neovascularization that extended farther than 2 mm from the limbus and did not improve after treatment with topical 1% prednisolone acetate and/or topical 1% cyclosporine instilled four times per day for at least 3 months.

Patients were considered not to have clinically stable corneal neovascularization if they met any of the following criteria: (1) current or recent (≤3months) episode of corneal and ocular surface infection (bacterial, viral, or fungal); (2) uncontrolled corneal and ocular surface inflammation; (3) ocular surgery in the study eye, including cataract surgery, full-thickness or lamellar keratoplasty, ocular surface reconstruction, or limbal stem cell transplantation within 6months prior to study entry; (4) current or recent (≤3 months) use of contact lens; (5) current or recent (≤3 months) persistent corneal epithelial defects; and (6) active hepatitis or clinically significant liver disease, porphyria or other porphyrin sensitivity. Pregnant women were also excluded.

Data analyzed included age, sex, laterality, clinical diagnosis, number and the depth of corneal neovascularization, preoperative and postoperative visual acuity and intraocular pressure (IOP), and clinical outcome of the treatment. Thirty-two patients (33 eyes) were recruited for this study.

Lipid-formulated verteporfin (Visudyne; Novartis Ophthalmics AG, Hettingen, Switzerland) was prepared at a dose of 6 mg/m2 of body surface area and diluted with 5% dextrose in water to a volume of 30 ml. The solution was then administered intravenously over 10 minutes. Fifteen minutes after the beginning administration, a 689 nm nonthermal laser light (Opal Photoactivator; Coherent Inc., Santa Clara, CA) was delivered directly over a neovascular area with various spot sizes (3-5 mm) at a power intensity of 600 mW/cm2. A total light dose of 150 J/cm2 was delivered. When the neovascular area was larger than the intended spot size, consecutive overlapping laser spots were applied. When more than one corneal blood vessel was present, consecutive laser spots were applied. Patients were instructed to avoid exposure to direct sunlight and to wear protective sunglasses during outdoor activities for 3 days after treatment. Slit-lamp biomicroscopic examinations and corneal photographs were performed before and at 1 week, and every 2 months for at least 1 year after treatment.

The primary efficacy variables were the size and length as well as the number of corneal neovascularization. By comparing baseline corneal photographs with follow-up photographs, the efficacy of PDT in treatment of corneal neovascularization was evaluated.

Statistical analysis was conducted using SPSS version 19 (IBM Corp., Armonk, NY) Medcalc 11.6 (Medcalc Software, Mariakerke, Belgium) and Stats Direct 2.7.2. (Stats Direct Ltd., Cheshire, UK). Descriptive analysis were performed to evaluate the central tendency of both demographic and clinical indices, while inferential analysis was performed to investigate the association between potential risk factors and the outcome of interest. Student's t-test was performed on mean preoperative and postoperative IOP and corrected visual acuity. Visual acuity data were converted from Snellen to logarithm of the minimum angle of resolution (LogMAR) notation for analysis. Univariate analysis with Fisher's Exact test (due to small sample sizes in each category) was performed to detect risk factors for failure. A P-value less than 0.05 was considered statistically significant.

RESULTS

Thirty-three eyes of 32 patients with stable corneal neovascularization who were treated with single PDT with verteporfin were included in this study. The cohort comprised 20 (62.5%) males and 12 (37.5%) females. The mean overall age was 40.7 ± 19 years (range 16-76 years). The mean follow-up for all patients was 13.1 ± 5.5 months (range 6-24 months). The average amount of corneal neovascularization was 2.7 ± 1.9 (range 1-10). Deep neovascularization was present in 19 (57.6%) eyes and 14 (42.4%) eyes had superficial neovascularization. Causes of corneal neovascularization were penetrating keratoplasty (30.3%), herpetic keratitis (27.3%), bacterial keratitis (21.2%), lamellar keratoplasty (15.1%), and intrastromal corneal segments (6.1 %) [Table 1].

Table 1

Demographics, Pre-treatment and Post-treatment data

The mean corrected visual acuity was 0.74 ± 0.66 LogMAR (range 0.1-2 LogMAR) at presentation and 0.65 ± 0.50 LogMAR (range 0-2 LogMAR) at last follow-up visit. The increase in visual acuity was statistically significant (P < 0.01). The mean IOP was 15.7 ± 2.9 mmHg (range 10-22 mmHg) preoperatively, and 15.4 ± 2.6 mmHg (range 10-20 mmHg) postoperatively (P= 0.28).

From one week to one month after treatment, 24 (72.7%) had a notable decrease in corneal neovascularization and evidence of vascular thrombosis [Figures 1 and 2]. Complete vascular occlusion was noted in 14 (42.4%) eyes, partial occlusion was noted in 10 (30.3%) eyes, and the vessels were patent in 9 (27.3%) eyes. At the last follow-up visit, 22 (66.7%) eyes had a decrease in corneal neovascularization and evidence of vascular thrombosis. Complete vascular occlusion was achieved in 14 (42.4%) eyes, partial occlusion was achieved in 8 (24.2%) eyes, and the vessels were patent in 11 (33.3%) eyes. Two eyes showed revascularization after temporary occlusion.

Figure 1

Penetrating keratoplasty in the left eye complicated by corneal neovascularization. (a) The baseline photograph shows superficial and deep corneal neovascularization. (b) 3 months after photodynamic therapy with verteporfin and suture removal. Note the complete resolution of corneal neovascularization

Figure 2

A 70-year-old man with a history of herpetic keratitis in the right eye complicated by corneal neovascularization. (a) The baseline photograph shows deep corneal neovascularization with lipid exudation involving the visual axis. (b) 6 months after photodynamic therapy therapy with verteporfin. Note the significant reduction in the area of neovascularization and blood vessel caliber

Risk factors for the outcomes were investigated. Eyes with a score of 2 or less for corneal neovascularization were statistically significantly better in responding to PDT with verteporfin than eyes with a score of 3 or more (P< 0.0001). The response to PDT with verteporfin was statistically significantly lower in eyes with deep corneal neovascularization than eyes with superficial corneal neovascularization (P<0.046). However, the diagnoses or causes of corneal neovascularization were not statistically significant risk factors [Table 2].

Table 2

Risk factors for success or failure after photodynamic therapy with verteporfin for corneal neovascularization

During the follow-up period, endothelial rejection did not occur after PDT in any patients with corneal allograft. No other significant systemic or ocular complications associated with PDT with verteporfin were observed.

DISCUSSION

Verteporfin binds to endogenous low-density lipoproteins in the serum, forming a complex that can then bind to low-density lipoprotein receptors on vascular endothelial cells.5 After its cellular uptake, applied laser energy produces cytotoxic oxygen-free radicals, which cause damage to endothelial cells and induce thrombus formation. The optimal time to begin laser treatment after administration of verteporfin was 15 minutes, similar to that used to treat choroidal neovascularization. However, the maximum effective laser energy necessary to induce long-term regression was 150 J/cm2, which is three times higher than that used to treat choroidal neovascularization.

PDT with verteporfin has been used for the treatment of corneal neovascularization in patients and in animal models.51214 In human studies, Brooks and associates12 and Fossarello and associates15 reported the beneficial effects of photodynamic therapy with verteporfin in one and two patients, respectively. Yoon et al.,5 conducted 1-year follow-up study on verteporfin PDT monotherapy in 18 patients and reported that 77.8% of cases showed a decrease in neovascularization and 50.0% showed complete vascular occlusion. A recent study of combined PDT with verteporfin and subconjunctival injection of bevacizumab for corneal neovascularization in 12 eyes reported complete occlusion in 66.7% of the cases and partial occlusion in 25.0% of the cases at last follow-up.6

Triple therapy (combination of PDT with verteporfin and subconjunctival bevacizumab and triamcinolone acetonide) may offer a promising result in the treatment of corneal neovascularization as reported recently.16

In the present study, we investigated the efficacy of PDT with verteporfin in 33 eyes of 32 patients with clinically stable corneal neovascularization. The outcomes of the present study are similar to previous reports. For example, a study of 18 eyes reported 77.8% had decreased corneal neovascularization, and 9 eyes (50.0%) showed complete vascular occlusion after PDT with verteporfin.5 Our outcomes are similar with 66.7% of eyes that had a decrease in corneal neovascularization and evidence of vascular thrombosis and complete vascular occlusion was achieved in 42.4% eyes.

Treatment was more effective in eyes with lower score of corneal neovascularization which concurs with Yoon et al.'s5 observations. Eyes with high score or extensive corneal neovascularization may require several repeat treatments prior to achieving adequate results.

Additionally, the response to PDT with verteporfin was statistically significantly lower in eyes with deep corneal neovascularization. Likely, the maximum effective laser energy necessary to induce long-term regression for deep corneal neovascularization needs to be higher than that used to treat superficial corneal neovascularization.

Advantages of PDT for corneal neovascularization are that treatment is relatively selective for corneal neovascular vessels with little damage to surrounding tissue and multiple treatments are possible for recurrent or resistant lesions. The limitations of our study include the lack of a comparative control group and the sample size as well as the retrospective nature of the study. In addition, the outcomes of repeat treatments were not evaluated. Future randomized studies are warranted.

In conclusion, our results indicate that photodynamic therapy with verteporfin seems to be an effective treatment for corneal neovascularization in the majority of the cases. Eyes with lower amounts of neovascularization and superficial neovascularization respond better to PDT.