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Neovascularization corneal regression in patients treated with photodynamic therapy with verteporfin

How to cite this article: Díaz-Dávalos CD, Carrasco-Quiroz A, Rivera-Díez D. [Neovascularization corneal regression in patients treated with photodynamic therapy with verteporfin]. Rev Med Inst Mex Seguro Soc. 2016;54(2):164-9.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26960043


ORIGINAL CONTRIBUTIONS


Received: December 4th 2014

Accepted: January 26th 2015


Neovascularization corneal regression in patients treated with photodynamic therapy with verteporfin


César David Díaz-Dávalos,a Arturo Carrasco-Quiroz,a Dirce Rivera-Díeza


aDivisión de Oftalmología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México


Comunicación con: César David Díaz-Dávalos

Telephone: (55) 5627 6900, extensión 21706

Email: maxdiaz_7@hotmail.com


Background: Corneal neovascularization is a vision-threatening condition usually associated with inflammatory or infectious disorders of the ocular surface. One current treatment is photodynamic therapy, which uses a photosensitizer to occlude the vessel, is successfully produced microvascular thrombosis with minimal damage to surrounding normal tissue. The aim of this article is to quantitatively determine the percentage of regression of corneal neovascularization experienced by patients treated with photodynamic therapy with verteporfin.

Methods: A before and after treatment; experimental, analytical, prospective and longitudinal.

Results: Of the 25 new vessels analyzed, 8 glasses (32 %) had total occlusion one month after, 15 vessels (60 %) had a partial occlusion in the range of 15.3 to 85.1 %, and 2 vessels (8 %) worsening in corneal vascularization. The mean area of corneal neovascularization decreased significantly a 70 % from 0.147 ± 0.118 mm2 to 0.045 ± 0.046 mm2 (p < 0.0005) after photodynamic therapy. No side efects were reported.

Conclusions: Photodynamic therapy with verteporfin is a safe and effective method of reducing corneal neovascularization and can be used to inhibit angiogenesis in the cornea.

Keywords: Corneal diseases; Corneal transplantation; Corneal neovascularization; Phototherapy

Corneal clarity and avascularity are important for proper optical performance of the cornea.1 Recent research has focused on understanding the mechanisms responsible for the maintenance of corneal vascularity in homeostatic conditions and in response to a corneal wound.1,2

Corneal neovascularization is defined as the formation of new vascular structures in areas that were previously avascular. It has been shown that there is a balance between angiogenic factors such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and some angiogenic molecules, such as angiostatin, endostatin, or pigment epithelium-derived factor (PEDF) in the cornea. Various inflammatory, infectious, degenerative, and traumatic disorders are associated with corneal neovascularization, in which the balance leans towards angiogenesis.1,3

Corneal neovascularization after corneal transplantation is one of the main risk factors for failure secondary to corneal graft rejection, so it is important to seek methods that reduce neovascularization, which improves survival of the transplanted graft.4-12

Current treatments for corneal neovascularization include drugs such as steroids or angiogenesis inhibitors; argon laser photocoagulation and surgery have clinical limitations and significant side effects.12-16

The use of photodynamic therapy (PDT) with verteporfin for the treatment of corneal neovascularization was studied in humans in cases series where the occlusion of new vessels has been observed clinically, with a good safety profile.17-26

The main objective of this study was to quantitatively measure the degree of regression of corneal neovascularization after PDT with verteporfin, because so far this has only been measured qualitatively.

Methods

A study was conducted before and after treatment; it was experimental, longitudinal, analytical, and prospective.

Patients older than 18 years were studied who had at least one quadrant of corneal neovascularization, who underwent corneal PDT for the first time between October 2013 and May 2014 in the Servicio de Oftalmología of the Hospital de Especialidades del Centro Médico Nacional Siglo XXI.

Clinical photographs were taken with an 8-megapixel camera with 4.0x zoom and a slit lamp adapter to for corneas with corneal neovascularization before and after treatment with PDT (1 month). Photographs were analyzed using the program ImageJ version 1.47, by measuring the area (in mm2) of corneal neovascularization in the periods pre and post-PDT. Data were analyzed using the non-parametric Wilcoxon signed ranks test for related samples.

Results

In total 25 vessels were analyzed that were given PDT with verteporfin (Visudyne), with the spot size of 4 mm, applying 2 to 3 laser irradiations. Of the patients studied, 80% were female and 20% male. The average age was 46.8 years with a range of 26-78 years. As for comorbidities, 3 patients had diabetes mellitus.

The most common diagnosis was vascularized leukoma secondary to herpetic keratitis (n = 3, 60%), followed by corneal rejection (n = 2, 40%). Of the 5 eyes treated, patient A (Figure 1) had PDT done to 4 corneal neovascularizations (2 superficial and 2 deep); patient B 2 corneal neovascularizations (2 deep); patient C (Figure 2) 9 corneal neovascularizations (4 superficial, 5 deep); patient D 8 corneal neovascularizations (1 superficial, 7 deep), and patient E 2 corneal neovascularization (2 deep). In total 25 corneal neovascularizations were treated, 7 of which were superficial (28%) and 18 deep (72%) (Table I). 


Figure 1 Patient A, vessel 2. A) Clinical photograph of cornea prior to PDT. B) Analysis of selected vessel pre-PDT; area 0.136 mm2, perimeter 10.714 mm. C) Clinical photograph of cornea one month after PDT. D) Analysis of selected vessel post-PDT; area 0.079 mm2, perimeter 4.125 mm.


Figure 2 Patient C, vessel 4. A) Clinical photograph of cornea prior to PDT. B) Analysis of selected vessel pre-PDT; area 0.117 mm2, perimeter 7.324 mm. C) Clinical photograph of cornea one month after PDT. D) Analysis of selected vessel post-PDT showing total occlusion of the vessel indicated.


Table I Corneal vascularization treated with photodynamic therapy in Hospital de Especialidades CMNSXXI from October 2013 - May 2014
P Sex Age

(years)

Laterality Diagnosis Previous condition Number of vessel Vascular depth Irradiations

(n)

Area mm2

Pre-PDT

Area mm2

Post-PDT

Result

% occlusion

A F 35 Right Rejection CT due to KC 1 SS 3 0.276 0. 041 85.1
2 SS 3 0.136 0.079 41.9
3 DS 3 0.197 0.083 57.8
4 DS 3 0.288 0.193 32.9
B F 78 Right VL HK 5 DS 3 0.112 0.071 36.6
6 DS 3 0.023 0.059 Ni
C F 43 Left Rejection CT due to ET 7 DS 2 0.085 0.042 50.5
8 SS 2 0.123 0 100
9 SS 2 0.171 0 100
10 DS 2 0.117 0 100
11 SS 2 0.109 0 100
12 DS 2 0.071 0.031 56.3
13 DS 2 0.058 0.03 100
14 SS 2 0.437 0 100
15 DS 2 0.493 0 100
D F 52 Right VL HK 16 DS 3 0.158 0.086 45.5
17 DS 3 0.17 0.048 71.7
18 DS 3 0.065 0.055 15.3
19 DS 3 0.087 0.032 63.2
20 SS 3 0.039 0.046 Ni
21 DS 3 0.051 0.023 54.9
22 DS 3 0.024 0 100
23 DS 3 0.054 0.022 59.2
E M 26 Right VL HK 24 DS 3 0.203 0.136 33
25 DS 3 0.128 0.062 51.5
Average
SD
Median
Range
p		 0.117
0.118
0.147
0.023-0.493 		0. 041
0.046
0.045
0-0.193 < 0.0005
P = patient, F = female; M = male; mm = millimeter; mm2 = square millimeter; PDT = photodynamic therapy; CT = corneal transplantation; KC = keratoconus; HK = herpetic keratitis; ET = eye trauma VL = vascularized leukoma; SS = superficial stroma; DS = deep stroma; Ni = No improvement

The post-PDT area was measured in mm2 1 month after the first application of photodynamic therapy. 

The pre-PDT and post-PDT areas were measured in mm2 with the program IMAGEJ version 1.47. Previous clinical photographing of anterior segment with 8-megapixel iSight camera and slit lamp adapter.

p < 0.05 is statistically significant. Analysis Wilcoxon signed ranks test for related samples. SPSS version 22


Of the 25 new vessels analyzed, 8 vessels (32%) had total occlusion of 100% at one month; 15 vessels (60%) had partial occlusion in the range of 15.3 to 85.1%, and 2 vessels (8%) had worse corneal vascularization. The mean area of ​​the pre-PDT corneas was 0.147 ± 0.118 mm2, median 0.117mm2 with a range of 0.023 to 0.493 mm2. The mean area of ​​the post-PDT corneas was 0.0.45 ± 0.046 mm2, median 0.041 mm2 with a range of 0.0 to 0.193 mm2. The percentage of neovascular regression between pre-PDT and post-PDT patients was 69.38% on average. When doing the Wilcoxon signed ranks test for related samples, a significant difference was found between the group pre- and post-PDT with a p < 0.0005 (Table I).

As for the adverse effects of all patients treated, only one had ocular burning and photophobia after PDT (patient A).

Discussion

Corneal neovascularization is one of the risk factors for major corneal rejection in transplant patients, so selective vascular occlusion with progressive PDT using verteporfin can help decrease the rate of graft rejection. The literature has a series of isolated cases of patients with corneal neovascularization in whom they (qualitatively) observed vessel occlusion, improvement of corneal edema, and other symptomologies with a good safety profile.

Qualitatively, Abdullah et al.10 studied 33 eyes that were given PDT, finding that 22 of them (66.7%) had a decrease in corneal neovascularization and evidence of vascular thrombosis. Complete vascular occlusion was achieved in 14 eyes (42.4%), partial occlusion was achieved in 8 eyes (24.2%), and no vascular occlusion in 11 eyes (33.3%). Similarly, another study by Verdiguel et al.24 clinically (qualitatively) determined decreased corneal neovascularization with PDT. 

Only one experimental quantitative study is reported in rabbits by Kyung et al.,7 which reports a reduction in the average percentage area of corneal neovascularization at 3 days, one week, and 2 weeks from PDT with 90.3% ± 3.5%, 71.6% ± 6.2% and 43.6% ± 15%, respectively. This compares with our study, in which, of the 25 new vessels analyzed, 8 (32%) had total occlusion of 100% at one month, 15 vessels (60%) had partial occlusion in the range of 15.3 to 85.1%, and two vessels (8%) had worse corneal vascularization. Other quantitative studies are not reported in the literature.

PDT is selective for neovascularization of the cornea, and causes little or no damage to surrounding tissue. In humans, the adverse reactions most commonly associated with verteporfin include: blurred vision, reactions at the injection site (rash and pain), and photosensitivity.24,25 Verdiguel et al.24 reported a higher frequency of adverse effects; their study found stromal bleeding in 10 patients (20%), blurred vision in 7 (14%), tears in 5 (10%), mild eye pain in 5 (10%), burning in 4 (8% ), foreign body sensation in 3 (6%), and photophobia in 1 (2%); 27 patients (54%) had no adverse effects.

The response to PDT with verteporfin was less successful in eyes with deep neovascularization than in eyes with superficial neovascularization.10 These results contrast with what was identified in our study, which found no difference in the success rate, having presented one case without improvement for deep neovascularization and one with surface neovascularization.

The failures obtained in the post-PDT corneas are multifactorial in origin, some of the reasons may be: the application technique, the need for power variation of the laser wave according to the depth of neovascularization, or needing new PDT application.

Conclusions

Our results indicate that verteporfin PDT may be effective for the treatment of corneal neovascularization. For the first time it was demonstrated quantitatively, not only clinically or qualitatively, that the total area of ​​corneal neovascularization decreased by up to 100% (69.3% on average) between pre- and post-PDT patients using vascular closure at one month from application.

This is a safe procedure, as in this study and other reports in the literature,7-10,24-26 no significant side effects were found that limit its application.

Limitations of this study include small sample size and short follow-up period (1 month). Longer follow-up with these patients is recommended.

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Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.

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