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ORIGINAL ARTICLE
Year : 2015  |  Volume : 28  |  Issue : 4  |  Page : 908-913

Evaluation of the role of antivascular endothelial growth factor in the management of pterygium


Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menofia Governorate, Egypt

Date of Submission11-Dec-2014
Date of Acceptance12-Apr-2015
Date of Web Publication12-Jan-2016

Correspondence Address:
Mohamed H Tarawa
31111 Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.173615

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  Abstract 

Background
Pterygium is a common condition. Many theories have been proposed for its pathogenesis, but excessive sun exposure is the most accepted. Studies show that immunostaining of vascular endothelial growth factor is more intensive in pterygial than in normal conjunctival sections.
Objectives
The aim of the study was to conduct a trial evaluating the role of antivascular endothelial growth factor in the management of pterygium.
Materials and methods
Fifty eyes with primary pterygium were included in a nonrandomized trial to evaluate the effect of subconjunctival bevacizumab before excision using the bare sclera technique. None of the eyes had any history of previous ocular disease or surgery. Eyes were examined at presentation, 3 weeks after injection, and 3 and 6 months postoperatively. Examinations included best-corrected visual acuity (BCVA), slit-lamp, and fundus examinations. Pterygium was assessed with regard to site, vascularity, horizontal length, and recurrence after 3 and 6 months. Recurrence was defined as any fibrovascular growth over the cornea 1 mm beyond the limbus.
Results
There were statistically significant results regarding age, sex, and occupation; 72% were male; the average age was 43.00 ± 13.47 years; 80% worked outdoors. The pterygia resolved with a postoperative recurrence rate of 36% after 6 months.
After injection, there was no statistically significant difference regarding improvement in visual acuity. There was significant improvement in ocular irritation, inflammation (82.14%), and horizontal length. Preinjection length average was 2.99 ± 1.08 mm and postinjection length average was 1.78 ± 0.99 mm. Vascularity improved in all cases by one grade after injection. Before injection, 14 cases (28%) were grade I, 22 cases (44%) were grade II, and 14 cases (28%) were grade III. Three weeks after injection, 36 cases (72%) were grade I and 14 cases (28%) were grade II.
Conclusion
Subconjunctival bevacizumab is well tolerated without local or systemic side effects. The main effect was reduction of inflammation and vascularity of the pterygium with no effect on recurrence.

Keywords: antivascular endothelial growth factor, bevacizumab, pterygium


How to cite this article:
ElSayed SH, Badawi NM, AlHagaa AA, Tarawa MH. Evaluation of the role of antivascular endothelial growth factor in the management of pterygium. Menoufia Med J 2015;28:908-13

How to cite this URL:
ElSayed SH, Badawi NM, AlHagaa AA, Tarawa MH. Evaluation of the role of antivascular endothelial growth factor in the management of pterygium. Menoufia Med J [serial online] 2015 [cited 2020 Feb 17];28:908-13. Available from: http://www.mmj.eg.net/text.asp?2015/28/4/908/173615


  Introduction Top


A pterygium is an elevated, superficial, external ocular lesion that is formed over the perilimbal conjunctiva and extends onto the corneal surface [1] . It is a common disorder of the ocular surface, with a prevalence of 2% in temperate areas and up to 20% in tropical regions [2] .

The pathogenesis behind its formation is not fully understood. Various studies have implicated environmental factors, such as ultraviolet light, chronic irritation, and inflammation. Recent studies have also provided evidence implicating genetic components, antiapoptotic mechanisms, cytokines, growth factors, extracellular matrix remodeling, immunological mechanisms, and viral infections in the pathogenesis of the disease [3] .

Immunohistochemistry studies show that immunostaining of vascular endothelial growth factor (VEGF) is more intensive in pterygial sections than in normal conjunctival sections. Decreased angiogenic inhibitors, together with increased stimulators, have been hypothesized as playing roles in the formation and progression of pterygia [4] .

Surgical excision of pterygium is generally essential when the visual axis is threatened and/or the pterygium causes severe irritation or cosmetic problems [5] .

The primary aim is to excise the pterygium and prevent its recurrence. As bare sclera excision is associated with a high recurrence rate, pterygium excision is often combined with conjunctival autograft, mitomycin C, β-irradiation, or other adjunctive therapies to reduce recurrence rates [6] .

Anti-VEGF treatment has shown great promise in other ocular neovascular diseases and potentially has a significant role in inhibiting fibroblastic and neovascular proliferation, which promotes pterygium growth and recurrence [7] .


  Materials and methods Top


This study included 50 eyes presented to the outpatient clinic of the ophthalmology department in Menoufia university hospital from January 2013 to January 2014.

Patients with primary nasal pteryium were included in the study.

Exclusion criteria

Patients with recurrent pterygium, with other ocular pathology such as ocular cicatrizing condition, or patients who had undergone previous ocular surgery were excluded from the study.

The privacy of participants and confidentiality of the data were ensured by covering the other parts of the face as possible. Informed consent was obtained from all participants in the study.

All patients were evaluated as follows:

  1. Complete history taking, including:
    1. Demographic data on age and sex.
    2. Sun exposure.
    3. Occupation.
    4. Ocular symptoms (redness, irritation, foreign body sensation, etc.).
    5. Diseases: history of any ocular pathology.
    6. Surgery: history of any previous ocular surgery.
  2. Complete ophthalmological examination was performed, focusing mainly on the following:
    1. Best-corrected visual acuity (BCVA): BCVA (before surgery) and BCVA (after surgery) using Landolt broken C chart.
      1. Slit-lamp biomicroscopy of the anterior segment.
      2. Fundus examination.
      3. Intraocular pressure (IOP) (to exclude cases of glaucoma).


Pterygium examination

  1. Site of pterygium.
  2. Extension on the corneal head.
  3. Vascularity, using vascular grading, as follows:
    1. Episcleral vessels are easily seen under the pterygium.
    2. Episcleral vessels are moderately seen under the pterygium.
    3. Episcleral vessels are hard to be seen under the pterygium.


Technique for injection of avastin in the pterygium

All patients were categorized under a single group for the study. All injections were administered under topical anesthesia using benoxinate hydrochloride 0.4% (Benox).

A speculum was inserted and the conjunctival bag was sterilized with povidone iodine 5% (Betadine). The pterygium body was grabbed using nontoothed forceps and bevacizumab (1.25 mg in 0.05 ml) was injected subconjunctively.

The speculum was then removed and the patient was discharged with postoperative medications (combined antibiotic and steroid drops four times daily, plus artificial tear substitute four times daily).

The patient was scheduled for surgical excision after 3 weeks.

Surgical technique of pterygium excision

All operations were performed in the operating room by the same surgeon following the bare sclera technique under local anaesthesia. After the eyes had been prepared and draped, topical anesthesia using benoxinate hydrochloride 0.4% (Benox) was applied.

A speculum was inserted and the conjunctival bag was sterilized:

  1. A subconunctival injection of lignocaine was injected under the pterygium body.
  2. A blunt dissection was performed under the neck of the pterygium to separate it from the underlying sclera.
  3. A full-thickness vertical incision was made at the junction between the head and the body of the pterygium.
  4. The head of the pterygium was dissected from the cornea using the keratome.
  5. The body was then dissected from the overlying conjunctiva. The body was then incised as far as possible taking care not to injure the medial rectus muscle.
  6. A few cautery burns were applied to stop bleeding points, when needed.
  7. Subconjunctival injection of steroids and antibiotics was done at the end of the operation.
  8. The eyes were patched for 1 day.
  9. The patient was discharged with topical antibiotic drops and combined antibiotic and steroid ointment at bedtime, systemic analgesic, systemic antibiotic, and artificial tear substitute drops and gel for 3 weeks.
  10. The patients were instructed to attend follow-up visits 1, 3, and 6 months after surgery.


Follow-up visits

During these visits, the following criteria were evaluated:

  1. Patient satisfaction.
  2. State of the eye (injection, photophobia, irritation, foreign body sensation, and subconjunctival hemorrhage).
  3. BCVA.
  4. Recurrence, which was defined as invasion of the cornea by a fibrovascular growth more than 1 mm from the limbus.


Statistical analysis

This phase took 12 months (January 2013 to January 2014).

Statistical analysis of the data was performed, including coding, entering, sorting, and statistical manipulation. The collected data were organized and tabulated using statistical package for social studies, version 21 (IBM Inc., Chicago, Illinois, USA). For quantitative variables, the mean and SD were calculated. For categorical variables, the number and percentage were calculated. For analytical statistics the paired t-test and the Wilcoxon signed ranks test were used. P values less than 0.05 were considered significant.


  Results Top


Fifty eyes of 50 patients were included. Thirty-six patients (72%) were male and 14 (28%) were female ([Table 1]). The main complaint of the patients in the study group was ocular irritation (28 cases, 56%), which was relieved after injection of avastin in 23 cases (82.14%). Cosmetic problem was the main complaint in 22 cases (44%), which improved in 15 cases (68.18%) to the patients' satisfaction (Graph 1).
Table 1 Sex and occupation distribution within the study group


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Vascular grading was applied in all cases within the study group before injection and 3 weeks after injection of avastin. Before injection, 14 cases (28%) were graded as grade I, 22 cases (44%) were grade II, and 14 cases (28%) were grade III. Three weeks after injection of avastin, 36 cases (72%) were grade I and 14 cases (28%) were grade II ([Table 3] and Graph 2).



The extent of growth of the head of the pterygium over the cornea was assessed using the beam of the slit-lamp before administration of a single injection of avastin. The average length was 2.99 ± 1.08 mm, ranging from 1.5 to 5 mm. The length of the head of the pterygium was then assessed 3 weeks after injection. The average length was 1.78 ± 0.99 mm, ranging from 0.5 to 3.8 mm ([Table 2] and [Table 4] and Graph 3).
Table 2 The effect of a single injection of bevacizumab on the horizontal length of the head of the pterygium


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Table 3 Shows the statistical analysis of the effect of anti-VEGF on the degree of vascularization of pterygium


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Table 4 Statistical analysis of the effect of anti-VEGF on the horizontal length of the head of the pterygium over the cornea


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Best-corrected visual acuity was recorded at the time of presentation, 3 weeks after injection, and 6 months after excision of the pterygium.

Best-corrected visual acuity at the time of presentation was as follows.

Two cases (4%) were 6/12, 12 cases (24%) were 6/18, six cases (12%) were 6/24, six cases (12%) were 6/36, 12 cases (24%) were 6/60, six cases (12%) were 2/60, two cases (4%) were 3/60, and four cases (8%) were 5/60.

The best-corrected visual acuity remained the same 3 weeks after a single injection of bevacizumab.

Best-corrected visual acuity 6 months after surgical excision using the bare sclera technique was as follows.

A total of 22 cases (44%) were 6/9, 15 cases (30%) were 6/12, seven cases (14%) were 6/18, two cases (4%) were 6/24, and four cases (8%) were 6/36.

Most cases gained an additional one to two lines on the Landolt broken C chart after surgical excision, which was preceded by injection of avastin 3 weeks earlier.

The most common postoperative complaints were irritation, mild pain, and hyperemia. Symptoms usually improved within a few weeks of treatment.

One case showed postoperative granuloma and was admitted later outside the study for surgical excision after it persisted following a 3-month course of topical steroids. At the follow-up visit at 3 months, 14 cases showed recurrence of pterygium growth over the cornea. At the follow-up visit at 6 months, another four cases showed recurrence. After 6 months of follow-up, 18 cases showed recurrence ([Table 5]).
Table 5 Recurrent cases within the study group


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  Discussion Top


Simple excision of the pterygium has a very high rate of recurrence (about 30-50%). Adjunctive forms of treatment, including radiation, antimetabolites, antifibrotics, antiangiogenic therapy, and conjunctival and limbal grafts, are used to decrease recurrence after excision [8] .

In our study, we used bevacizumab as a subconjunctival injection 3 weeks before surgical bare scleral excision. On following up the patients for 6 months, we found recurrence in 18 cases (36%).

This is consistent with the findings by Shenasi and colleagues, who excised the pterygia using the bare sclera technique; in their study, 33 patients received 1.25 mg of subconjunctival bevacizumab and another 33 subjects as the control group had distilled water administered intraoperatively. The control group experienced a higher recurrence rate (defined as any fibrovascular growth crossing the limbus and extending over the cornea) as compared with the bevacizumab group; however, this difference was not statistically significant [9] .

We used the bare sclera technique because of decreased surgical intervention, more rapid healing time, less discomfort, and decreased cost (we focused on assessing mainly the effect of bevacizumab on the recurrence rate, regardless of the surgical technique used). Moreover, our results are in accordance with those of Leippi [10] ; however, they used bevacizumab as eye drops (25 mg/ml) as an adjunct after excision of recurrent pterygia. We preferred subconjunctival injection over eye drops as it negates the ability of the tear film to dilute the medication, increasing the exposure time to the subconjunctival tissue. It is imperative that the concentration and dose of bevacizumab be carefully monitored because errors may lead to side effects and we wanted to exclude the personal errors made by patients while taking the drops at home. In contrast to previous studies, Wu et al. [11] reported the case of one patient with impending recurrent pterygium who was treated with topical bevacizumab eye drops (25 mg/ml) and did not develop any recurrent pterygium.

In our study, there was no statistically significant difference as regards improvement in visual acuity after injection of bevacizuman.

This is consistent with the results of Shahin [12] , who found no statistical difference as regards visual acuity following bevacizumab injection.

This randomized comparative clinical trial was conducted on 40 eyes of 38 patients. Three days before simple bare scleral excision of the pterygia, 20 patients (case group) received 2.5 mg/0.1 ml bevacizumab and the 20 other patients (control group) did not receive any medications. The main outcome measures were recurrence of pterygia and complications during the first 6 postoperative months.

There were no statistically significant differences regarding age, sex, or operated eye between the two groups. The pterygia resolved in 14 (70%) of 20 eyes in each group, with a recurrence rate of 30% during a follow-up period of 6 months. There were no statistically significant differences regarding improvement in visual acuity, corneal epithelial healing, conjunctival erythema, subconjunctival hemorrhage, lacrimation, or photophobia between the case and control groups.

As regards the effect of bevacizumab on vascularity, it is believed that early anti-VEGF therapy can prevent limbal conjunctival neovascularization by blocking access to the nutrients necessary for fibroblast proliferation and fibrous tissue growth [8] . In our study, we observed that there was a reduction in vascularization on the day of the surgery. Our study is different from all previous studies, as we operated 3 weeks after injection of bevacizumab to derive the benefit of working in a less vascular field requiring less manipulation; this can be reflected positively on the postoperative complications later on. Kim et al. [13] concluded that topical application of bevacizumab is effective in reducing corneal neovessels within the first month, which is similar to what was observed in our study. Moreover, the results of the study by Mansour [14] are in agreement with ours; however, he reported the case of only one patient and injected the inflamed residual pterygial bed subconjunctivally with bevacizumab 10 days after surgery. Therefore, treatment of primary pterygium with subconjunctival bevacizumab results in a short-term decrease in vascularization and irritation.

In contrast, Bahar [15] did not demonstrate any significant clinical regression of neovessels after bevacizumab injection.

As regards postoperative complications, most postoperative complications were related to the pterygium surgery itself, such as subconjunctival hemorrhage, photophobia, and conjunctival injection. All of these complications occurred in the short postoperative period but without delayed epithelial healing. One case showed postoperative granuloma and was scheduled for excision later outside the study [16] . Use of bevacizumab made the operative field less vascular and the subconjunctival hemorrhage was less remarkable. Other complications such as scleral melting were not encountered.


  Conclusion Top


A single preoperative administration of bevacizumab for treatment of pterygium is well tolerated. It significantly reduces inflammation, vascularity, and the horizontal length of the pterygium. It has no effect on the visual acuity, rate of recurrence of the pterygium, or on early postoperative complications. It only helps to reduce bleeding during surgery.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Coroneo MT, Di Girolamo N, Wakefield D. The pathogenesis of pterygia. Curr Opin Ophthalmol 1999; 0 :282-288.  Back to cited text no. 1
    
2.
Papadia M, Barabino S, Valente C, Rolando M. Anatomical and immunological changes of the cornea in patients with pterygium. Curr Eye Res 2008; 33 :429-434.  Back to cited text no. 2
    
3.
Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004; 23 :195-228.  Back to cited text no. 3
    
4.
Jin J, Guan M, Sima J, Gao G, Zhang M, Liu Z, et al. Decreased pigment epithelium-derived factor and increased vascular endothelial growth factor levels in pterygia. Cornea 2003; 22 :473-477.  Back to cited text no. 4
    
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Bazzazi N, Ramezani A, Rabiee MA. A comparative study of conjunctival autograft and minimally invasive pterygium surgery in primary pterygia. Pak J Biol Sci 2010; 13 :409-412.  Back to cited text no. 5
    
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8.
Razeghinejad MR, Hosseini H, Ahmadi F, Rahat F, Eghbal H. Preliminary results of subconjunctival bevacizumab in primary pterygium excision. Ophthalmic Res 2010; 43 :134-138.  Back to cited text no. 8
    
9.
Shenasi A, Mousavi F, Shoa-Ahari S, Rahimi-Ardabili B, Fouladi RF. Subconjunctival bevacizumab immediately after excision of primary pterygium: the first clinical trial. Cornea 2011; 30 :1219-1222.  Back to cited text no. 9
    
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Leippi S, Grehn F, Geerling G. Antiangiogenic therapy for pterygium recurrence. Ophthalmologe 2009; 106 :413-419.  Back to cited text no. 10
    
11.
Wu PC, Kuo HK, Tai MH, Shin SJ Topical bevacizumab eyedrops for limbal-conjunctival neovascularization in impending recurrent pterygium. Cornea 2009; 28 :103-104.  Back to cited text no. 11
    
12.
Shahin M. Efficacy of subconjunctival bevacizumab adjunctive therapy before primary pterygium surgery. The Annual American Society for Cataract and Refractive Surgery (ASCRS) and ASOA Symposium and Congress. Ascrs, 2014  Back to cited text no. 12
    
13.
Kim SW, Ha BJ, Kim EK, Tchah H, Kim TI. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology 2008; 115 :e33-e38.  Back to cited text no. 13
    
14.
Mansour AM. Treatment of inflamed pterygia or residual pterygial bed. Br J Ophthalmol 2009; 93 :864-865.  Back to cited text no. 14
    
15.
Bahar I, Kaiserman I, McAllum P, Rootman D, Slomovic A. Subconjunctival bevacizumab injection for corneal neovascularization in recurrent pterygium. Curr Eye Res 2008; 33 :23-28.  Back to cited text no. 15
    
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Detorakis ET, Spandidos DA. Pathogenetic mechanisms and treatment options for ophthalmic pterygium: trends and perspectives (Review). Int J Mol Med 2009; 23 :439-447  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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