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ORIGINAL ARTICLE
Year : 2018  |  Volume : 10  |  Issue : 1  |  Page : 14-17

Effect of subconjunctival antivascular endothelial growth factor on corneal neovascularization after penetrating keratoplasty


Department of Ophthalmology, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, Uttarakhand, India

Date of Web Publication4-Sep-2018

Correspondence Address:
Renu Dhasmana
Department of Ophthalmology, Swami Rama Himalayan University, Dehradun - 248 140, Uttarakhand
India
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DOI: 10.4103/sjopthal.sjopthal_11_18

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  Abstract 


Purpose: To evaluate the effect of subconjunctival anti-VEGF on corneal neovascularisation post penetrating keratoplasty. Methods: A total of 31 eyes of 31 patients with corneal neovascularisation post penetrating keratoplasty were subjected to 2.5 mg/0.1 ml of subconjunctival bevacizumab in each quadrant of neovascularisation. We evaluated the regression of corneal neovascularisation after subconjunctival bevacizumab at 1 week, 4 weeks and 6 weeks and the incidence of complications and subjective complaints related to the treatment was also noted. Results: This was an experimental study, conducted from September 2015 to September 2016. A total of 31 patients with corneal neovascularisation post penetrating keratoplasty were included in the study, out of which 27(87.1%) were males and 4(12.9%) were females. 90.3% of patients had neovascularisation in all 4 quadrants, 6.5% had neovascularisation in 2 quadrants and only 3.2% had neovascularisation in only 1 quadrant. All patients who were subjected to subconjunctival bevcizumab, the regression of neovascularisation at 1 week, 4 weeks and 6 weeks was noted and there was a significant decrease in neovascularisation in central segments 1.97 ± 3.72 as compared to pre 5.13 ±7.12(p=0.001) and also in peripheral segments at 6 weeks 29.90 ± 15.73 as compared to pre bevacizumab 44.32 ± 17.97(p<0.001). Conclusion: The use of subconjunctival bevacizumab seems to be an effective and safe method in the treatment of corneal neovascularisation.

Keywords: Antivascular endothelial growth factor, bevacizumab, corneal neovascularization, penetrating keratoplasty, subconjunctival


How to cite this article:
Lochab D, Dhasmana R, Gupta N. Effect of subconjunctival antivascular endothelial growth factor on corneal neovascularization after penetrating keratoplasty. Sudanese J Ophthalmol 2018;10:14-7

How to cite this URL:
Lochab D, Dhasmana R, Gupta N. Effect of subconjunctival antivascular endothelial growth factor on corneal neovascularization after penetrating keratoplasty. Sudanese J Ophthalmol [serial online] 2018 [cited 2018 Sep 25];10:14-7. Available from: http://www.sjopthal.net/text.asp?2018/10/1/14/240540




  Introduction Top


The normal cornea is an avascular structure.[1] Due to some inflammatory diseases, the cornea gets invaded by pathologic blood and lymphatic vessels.[2] Corneal neovascularization (CNV) is due to the pathological ingrowth of vessels on the cornea from the limbal vascular plexus. This process is due to chronic reduction of oxygen in the cornea. Various other reasons for the formation of CNV in cornea include corneal infections, trauma, and immunological processes.[3] Penetrating keratoplasty (PK) is the procedure of choice to rehabilitate the patients with corneal blindness. CNV not only reduces visual acuity but also causes loss of the cornea's immune privilege which strongly contributes to a worse prognosis in PK and is a major risk factor for graft rejection and failure.

Current treatment protocols for treating CNV include medications, such as steroids or nonsteroidal anti-inflammatory agents, laser photocoagulation, fine-needle diathermy, photodynamic therapy or restoration of the ocular surface with the use of conjunctival, limbal, or amniotic membrane transplantation have demonstrated variable and largely limited clinical success. Side effects of topical and systemic corticosteroids such as cataract, glaucoma, and increased risk of infection are well known to clinicians who use these agents regularly in trying to arrest the progression of the disease. Other treatment modalities are often ineffective or vessel recanalization occurs requiring multiple treatment sessions which can lead to serious side effects. Furthermore, none of these treatments specifically target the molecular mediators of angiogenesis.[4]

At present, various vascular endothelial growth factor (VEGF) inhibitors such as pegaptanib sodium, ranibizumab, and bevacizumab are being used for the treatment of neovascularization (NV) and age-related macular degeneration (ARMD).[5] Bevacizumab (Avastin) inhibits the interaction between VEGF and its receptors; thus, blocking any VEGF activity and it is an antibody that acts against all isoforms of VEGF. Bevacizumab is currently approved for the treatment of colorectal carcinoma, non-small cell lung carcinoma, and renal carcinoma. It is widely used “off-label” for the treatment of choroidal NV secondary to ARMD.[6]

The proposed study was undertaken to evaluate the effect of subconjunctival anti-VEGF on CNV after PK.


  Materials and Methods Top


The proposed experimental study was conducted over 12 months at Swami Rama Himalayan University after obtaining approval from the Ethics Committee. All patients with vascularized cornea after PK were included in this study. Written informed consents were obtained from the patients before including them in the study. Pregnant females, patients with uncontrolled systemic hypertension, patients with previous history of myocardial infarction, patients with previous history of cerebral vascular accident, and patients who were not willing for follow-up and were not ready to give consent were excluded from the study.

Clinical assessment of the patients included detailed medical and surgical history with clinical ophthalmological examination according to the present format. Detailed clinical examination was performed. All patients after PK who presented with vascularized cornea were subjected to subconjunctival injection of bevacizumab. Topical anesthesia was given by proparacaine 0.5% eye drops; then, the eye was cleaned and draped under all aseptic precautions. 2.5 mg/0.1 mL of bevacizumab subconjunctival was given in each quadrant of NV with the help of a 30-G needle, and the subconjunctival injection was given 2 mm away from the limbus in the quadrant of neovascularization. Patients were followed after 1 week, 4 weeks, and 6 weeks.

  • The total area of NV was measured using a special pattern which comprised a 12-mm outer circle and 6-mm inner circle which was further divided into 72 outer triangles and 24 inner triangles. A reference point was marked at 12 o'clock and 6 o'clock on the digital photograph of the cornea, and this pattern was superimposed on the corneal photograph in Adobe Photoshop. The extent of CNV was expressed in the number of segments containing blood-filled vessels both in the peripheral and inner segments.[7]


Statistical analysis was performed using the SPSS statistical package (version 22.0; SPSS Inc., Chicago, IL, USA). Continuous variables, values over time within the groups were analyzed using repeated-measures analysis of variance followed by using Bonferroni's post hoc testing. Nominal or categorical data were analyzed and compared using the χ2 test. Fisher's exact test was used when fewer than five patients were expected. Values were given as mean (standard deviation [SD]), numbers, and percentages. P < 0.05 was considered statistically significant.


  Results Top


The proposed experimental study was conducted over 1 year. A total of 31 patients were included in this study, of which 27 (87.1%) were male and four (12.9%) were female. Age of patients varied from 10 to 90 years with a mean age of 54.77 ± 20.35 years (mean ± SD). The most common indication for penetrating keratoplasty was vascularized leukomas after herpetic keratitis (25%); other indications included perforated corneal ulcer (22.5%), infectious keratitis (20%), pseudophakic bullous keratopathy (13%), failed grafts (13%), and chemical burns (6.5%).

The mean NV in peripheral segments before subconjunctival bevacizumab was 44.32 ± 17.97. It was observed in our study that the mean NV postsubconjunctival bevacizumab decreased in peripheral segments at 1 week 40.65 ± 16.40, at 4 weeks 34.52 ± 15.22, and at 6 weeks 29.90 ± 15.73. There was a statistical decrease in NV, postinjection when compared to preinjection at 1 week (P = 0.006), at 4 weeks (P < 0.001), and at 6 weeks (P < 0.001) [Table 1].
Table 1: Neovascularization in peripheral corneal segments pre and postsubconjunctival bevacizumab

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The mean preinjection NV in central segments was 5.13 ± 7.12. The mean NV postsubconjunctival bevacizumab was found to be decreased in central segments at 1 week 4.10 ± 5.88, at 4 weeks 2.77 ± 4.76, and at 6 weeks 1.97 ± 3.72 as compared to premean of NV. There was a statistical decrease in NV, postinjection when compared to preinjection at 1 week (P = 0.001), at 4 weeks (P < 0.001), and at 6 weeks (P = 0.001) [Table 2].
Table 2: Neovascularization in central corneal segments pre- and post-subconjunctival bevacizumab

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The only complication noted was subconjunctival hemorrhage in three patients which was due to subconjunctival injection and not due to the drug. No other systemic and ocular complications were noticed after the injection.


  Discussion Top


Corneal transplant is the most successful organ transplant. However, it is only true for those corneal diseases which are considered to be low-risk diseases. The corneal graft success rate is over 90% in those eyes which are avascular and are devoid of any inflammatory process. However, where there is CNV or any inflammatory process, corneal graft survival rate drastically reduces to only 20%–40%, even with the use of systemic anti-inflammatory treatment.[8]

CNV is usually due to the presence of VEGF, and hence, its treatment with anti-VEGF antibodies seems to be an effective method. There has been seen a marked reduction in NV by their use. Bevacizumab has been used recently by ophthalmologists as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal NV in ARMD.[9] Many posterior segment specialists also have noticed impressive results in the settings of proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, and macular edema secondary to retinal vein occlusion.[10] When bevacizumab was injected in a dose of 1.25–2.5 mg in the vitreous cavity of rabbit eyes, no significant intraocular toxicity was noticed. Recently, several studies revealed the effects of topical or subconjunctival injection of bevacizumab in the inhibition of CNV.[11] The present study demonstrated similar results where subconjunctival injection of bevacizumab lead to regression of NV in post-PK eyes.

In this study, the dose of subconjunctival bevacizumab was taken as 2.5 mg/0.1 mL, and it showed to have significant results in the reduction of NV (P < 0.001). Similar results were seen in other studies, Hosseini et al. showed that the subconjunctival injection of bevacizumab (2.5 mg / 0.1 mL) had a significant effect on CNV (P < 0.009).[12] In another study, Papathanassiou et al. concluded that the subconjunctival administration of bevacizumab (3.75 mg / 0.15 mL) was found to inhibit NV significantly when administered early on the day 1, when CNV was induced in white rabbits, with less significant regression when administered later after 14 days of induced NV.[13]

The statistically significant decrease in NV was observed after injection of subconjunctival bevacizumab (P < 0.001) after 6 weeks in our study. In all the patients, there was either an improvement or stabilization of the CNV. Bahar et al. reported that the repeated subconjunctival bevacizumab administration (average 2.1 ± 0.8 injections of 2.5 mg / 0.1 mL) in 10 patients was tolerated well, and was associated with a partial regression of CNV during 3.5 ± 1.1 months of follow-up.[14]

The mean area of NV in the peripheral segment preinjection (44.32 ± 17.97) was found to be decreased after subconjunctival bevacizumab at 1 week (40.65 ± 16.40), 4 weeks (34.52 ± 15.22), and 6 weeks (29.90 ± 15.73). There was a statistically significant decrease in NV, postinjection when compared to preinjection at 1 week (P = 0.006), 4 weeks (P < 0.001), and 6 weeks (P < 0.001). Similar reports were seen by Krizova et al., where decrease in NV in peripheral segments was seen from pre (30.37 ± 23.40) to 4-week postsubconjunctival bevacizumab (25.65 ± 20.4) (P = 0.003).[7]

In the present study, there was also decrease in NV in peripheral segments when compared from 1-week postinjection to 4-week postinjection (P < 0.001) and 6-week postinjection (P < 0.001). The statistically significant decrement in NV was seen in peripheral segments at 6 weeks (P < 0.001) when compared to 4 weeks.

The mean NV postsubconjunctival bevacizumab was found to be decreased in central segments from 1 week (4.10 ± 5.88) to 4 weeks (2.77 ± 4.76) and 6 weeks (1.97 ± 3.72) as compared to a preinjection mean of NV (5.13 ± 7.12). There was a statistically significant decrease in NV, postinjection when compared to preinjection at 1 week (P = 0.001), at 4 weeks (P < 0.001), and at 6 weeks (P = 0.001). Similarly, Krizova et al. demonstrated decrease in central segments from pre (4.26 ± 5.9) to 4 weeks postsubconjunctival bevacizumab (3.42 ± 5.44) (P = 0.000).[7]

In the present study, there was also decrease in NV in central segments when compared from 1-week postinjection to 4-week postinjection (P = 0.001) and 6-week postinjection (P = 0.001). There was no statistically significant decrement in NV in central segments when compared between 4 weeks and 6 weeks (P = 0.012). Awadein treated three patients who had experienced CNV following keratoplasty using a single subconjunctival injection of 2.5 mg bevacizumab. Although there was an immediate regression of the new corneal vessels, more markedly in patients with smaller and/or fewer blood vessels, the antiangiogenic response was short-lived. Starting from the second week, the corneal vessels began to progress.[15] In contrast to the present study, where the regression of vessels at 4-week postsubconjunctival and 6-week postsubconjunctival bevacizumab was seen.

The only ocular complication seen in the present study was subconjunctival hemorrhage in 9.7% of patients which was due to subconjunctival injection and not due to the drug. No other ocular or systemic complications were noted in the present study. You et al. reported that pain at the subconjunctival injection site in nine eyes (31.0%), subconjunctival hemorrhages in eight eyes (27.6%), and ocular irritation in one eye (3.4%). There were no systemic complications, such as increased blood pressure or transient ischaemia, in their study.[16] Krizova et al. also reported tiny epithelial corneal defects in three patient's postsubconjunctival bevacizumab.[7] Erdurmus and Totan have reported dry eye in one patient after subconjunctival bevacizumab injection (2.5 mg/0.1 mL).[17]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kvanta A. Ocular angiogenesis: The role of growth factors. Acta Ophthalmol Scand 2006;84:282-8.  Back to cited text no. 1
    
2.
Proia AD, Chandler DB, Haynes WL, Smith CF, Suvarnamani C, Erkel FH, et al. Quantitation of corneal neovascularization using computerized image analysis. Lab Invest 1988;58:473-9.  Back to cited text no. 2
    
3.
Chang JH, Gabison EE, Kato T, Azar DT. Corneal neovascularization. Curr Opin Ophthalmol 2001;12:242-9.  Back to cited text no. 3
    
4.
Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.  Back to cited text no. 4
    
5.
Kim TI, Kim SW, Kim S, Kim T, Kim EK. Inhibition of experimental corneal neovascularization by using subconjunctival injection of bevacizumab (Avastin). Cornea 2008;27:349-52.  Back to cited text no. 5
    
6.
Spaide RF, Laud K, Fine HF, Klancnik JM Jr., Meyerle CB, Yannuzzi LA, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383-90.  Back to cited text no. 6
    
7.
Krizova D, Vokrojova M, Liehneova K, Studeny P. Treatment of corneal neovascularization using anti-VEGF bevacizumab. J Ophthalmol 2014;2014:178132.  Back to cited text no. 7
    
8.
Dekaris I. High-Risk Eyes: Can we increase corneal graft survival rate? J Clinic Experiment Ophthalmol 2012;S4:e001.  Back to cited text no. 8
    
9.
Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47.  Back to cited text no. 9
    
10.
Scott IU, Bressler NM, Bressler SB, Browning DJ, Chan CK, Danis RP, et al. Agreement between clinician and reading center gradings of diabetic retinopathy severity level at baseline in a phase 2 study of intravitreal bevacizumab for diabetic macular edema. Retina 2008;28:36-40.  Back to cited text no. 10
    
11.
Chen WL, Lin CT, Lin NT, Tu IH, Li JW, Chow LP, et al. Subconjunctival injection of bevacizumab (Avastin) on corneal neovascularization in different rabbit models of corneal angiogenesis. Invest Ophthalmol Vis Sci 2009;50:1659-65.  Back to cited text no. 11
    
12.
Hosseini H, Nejabat M, Mehryar M, Yazdchi T, Sedaghat A, Noori F, et al. Bevacizumab inhibits corneal neovascularization in an alkali burn induced model of corneal angiogenesis. Clin Exp Ophthalmol 2007;35:745-8.  Back to cited text no. 12
    
13.
Papathanassiou M, Theodossiadis PG, Liarakos VS, Rouvas A, Giamarellos-Bourboulis EJ, Vergados IA, et al. Inhibition of corneal neovascularization by subconjunctival bevacizumab in an animal model. Am J Ophthalmol 2008;145:424-31.  Back to cited text no. 13
    
14.
Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization. Cornea 2008;27:142-7.  Back to cited text no. 14
    
15.
Awadein A. Subconjunctival bevacizumab for vascularized rejected corneal grafts. J Cataract Refract Surg 2007;33:1991-3.  Back to cited text no. 15
    
16.
You IC, Kang IS, Lee SH, Yoon KC. Therapeutic effect of subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. Acta Ophthalmol 2009;87:653-8.  Back to cited text no. 16
    
17.
Erdurmus M, Totan Y. Subconjunctival bevacizumab for corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 2007;245:1577-9.  Back to cited text no. 17
    



 
 
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