Pakistan Journal of Ophthalmology Vol. 31, No. 3, Jul – Sep, 2015 150 Original Article Role of Tetracycline in Corneal Neovascularization Arshad Ali Lodhi, Murtaza, Munawar Ahmed, Noman Ahmed, Ghulam Haider, Sameen Afzal Junejo, Mustafa Kamal Pak J Ophthalmol 2015, Vol. 31 No. 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . See end of article for authors affiliations …..……………………….. Correspondence to: Sameen Afzal Junejo Department of Ophthalmology. Liaquat University of Medical and Health Sciences/Jamshoro, Sindh Pakistan Email: sameenafzal1@gmail.com …..……………………….. Purpose: To find the efficacy of topical tetracycline in corneal neo- vascularization. Material and Methods: In this prospective observational clinical analysis, patients more than fifteen year’s age of either sex were enrolled. Anterior segment slit lamp examination was performed. Fluorescein 1% dye and rose bengal were used to stain cornea at the bed and margins simultaneously. The area of corneal vascularization was measured in mm using 0.5% fluorescein dye. The percentage of neovascularized corneal areas to the entire cornea was calculated. Result: Out of twenty eight patients twenty one completed follow up period of four months. Among 21 patients males were 10 (47.6%), and females 11 (52.38%) with unilateral and bilateral corneal neo-vascularization. 15 (71.42%) responded well and showed reduction in corneal new vessels from 7 mm pre- treatment to 2 mm (overall) post treatment at the end of fourth month. six patient showed poor or no response due to extended fibrosis. Conclusion: Topical tetracycline has remained quite instrumental in reducing superficial epithelial and sub-epithelial corneal new vessels. Key Words: Cornea; Neovascularization; Tetracycline; Therapeutic effect. cular neovascularization is the abnormal growth of blood vessels in the retina, choroid and cornea. They can lead to many complications like fibrosis, scarring and blindness. Common causes of corneal neovascularization are blepharitis, keratitis, corneal graft rejection, chemical injuries and improper or prolonged use of contact lenses.1 The main source of superficial corneal neovascularization arises from conjunctiva. The superficial vessels adopt the pattern of diffuse tree branches and are usually observed passing through the corneo-scleral junction invading anterior layers of cornea up to substantia propria. While deep corneal vessels are having straight course originate from deep scleral vessels and penetrate the deeper corneal layers including corneal stroma and beyond. Antibiotics, lasers and other treatment have limited approach. Steroids are used to combat with this problem but extended use can result in to unavoidable side effects and complications.1,2 Tetracycline is a second generation long acting non selective antibiotic.2,3 Topical application inhibits corneal lysis, treats corneal ulcers and encourages corneal epithelium healing.4,5 Apart from this, tetracycline has also been proved to be quite effective in inhibiting corneal new vessels by inhibiting matrix metalloproteinase (MMP) activity.6,7 Topically induced drugs have become more successful and better effective in the treatment of ocular surface disorders.8 Tetracycline or its derivative preparations (doxycycline, minocycline) accelerate corneal wound healing and promote reduction in corneal new vessels by inhibiting MMP activity.9, 10 The objective of this study was to document the O mailto:sameenafzal1@gmail.com ARSHAD ALI LODHI, et al 151 Vol. 31, No. 3, Jul – Sep, 2015 Pakistan Journal of Ophthalmology therapeutic effect of topical tetracycline on superficial corneal neovascularization. MATERIAL AND METHODS This prospective observational clinical analysis was performed at Liaquat University Eye hospital Hyderabad, Sindh of Liaquat University of Medical and Health Sciences / Jamshoro Pakistan from June 2011 to May, 2015. Inclusion criteria: The subjects of more than fifteen years of age from both genders with unilateral or bilateral superficial (epithelial and sub-epithelial bowman membrane) corneal vascularization associated with ocular surface disorders without any history of ocular surgery were included. All the enrolled cases were examined at outpatient department of the tertiary eye care center. Detailed history and verbal consent of the patients was obtained. Anterior segment was examined using slit lamp bio-microscope. Corneal staining was done with fluorescein 1% dye. Rose Bengal stains were used to stain devitalized cornea. The area of corneal vascularization was measured in mm by using 0.5% fluorescein under cobalt blue filter on slit lamp bio- microscope by the same ophthalmologist. The percentage of neovascularized corneal areas to the entire cornea was calculated. The primary treatment of different antibiotics and steroids was stopped. The secondary treatment was started with tetracycline (HCL-USP 5 mg) ophthalmic gel thrice a day. Tetracycline thus used during this study was arranged through a renowned pharmaceutical company. The area of corneal epithelial defect with new vessels was measured on 15th day, one month and every two months for four months. All the subjects were requested to complete the treatment follow up criteria of this study. Statistical Package of Social Science (SPSS) version 14 was used for statistical data analysis on corneal vascularization. RESULTS Out of 28, seven patients did not complete the 4 months follow up and will not be discussed in the results. In twenty one patients who completed follow up, male were 10 (47.6%), female 11 (52.38%) with unilateral and bilateral corneal neo-vascularization were registered for this study (Fig. 1-3). Most of the subjects belonged to rural areas. The characteristics of enrolled patients is mentioned in table 1. Seven (25.0%) subjects were lost to follow up. Out of remaining twenty one, there was significant reduction in corneal neo-vascularization in 15 (71.42%) patients. The student – t test was used to evaluate the data. The mean age of the patients was 39.38 years. The results of treatment were quite significant (2-tailed), with the P value 0.002. Standard deviation was 1.21253; confidence interval of the difference was ROLE OF TETRACYCLINE IN CORNEAL NEOVASCULARIZATION Pakistan Journal of Ophthalmology Vol. 31, No. 3, Jul – Sep, 2015 152 95%.The documented overall reduction in new vessels was from 7 mm to 2 mm after four months of treatment (Fig. 4 - 6). One (4.47%) lady recovered moderately and remaining five (23.81%) did not respond to the treatment due to extended fibrosis although the symptoms were relieved. DISCUSSION Corneal neovascularization (CNV) is a sight- threatening condition. Most often it develops secondary to inflammatory conditions and ocular surface disorders. Corneal trauma due to chemical burns causes severe corneal neovascularization.11 In this study two patients developed corneal neovascularization after alkali burn, which could not improve inspite of abrupt treatment with tetracycline and associated medications. Various sources promote neovascularization i.e. growth factors, prostaglandins and interleukins. The process of corneal new vessels formation consists of two steps. First is the vascular endothelial growth factor (VEGF) related to proliferation of vascular endothelium. Second step reformation of extracellular matrix followed by activation of cytokines. Corneal neovascularization due to alkali burns is related to inflammation. In response to a chemical burn the inflammatory cells release cytokines and MMPs. There is also a variety of compounds supposed to inhibit corneal new vessels. Such anti angiogenic factors are non-steroidal anti-inflammatory agents, steroids and immuno suppressives.12, 13 The treatment of choice in corneal neovasculari- zation is topical use of corticosteroids. But due to their disastrous side effects and complications now a days have got restricted application. 14 In our study steroids use was not documented in any registered subject. The efficacy of tetracycline depends upon its concentration, route of application, and patient’s acceptance. The recommended dosage of tetracycline is absolutely non-toxic to the corneal surface and adnexa. In our study tetracycline with the dosage of 5 mg was used topically three times a day. Its effect on cornea is biological oriented rather than antimicrobial. According to the recent global research, tetracycline also acts to suppress tumor growth, angiogenesis, resorption of bone.15, 16 Limitations to This Study In our area not much work has yet been done on this issue. We could not compare the results of our study with other national studies. There is no doubt a need for advanced study and research on the efficacy of tetracycline in different ocular diseases particularly corneal neovascularization. CONCLUSION Tetracycline has proved itself to be more promising in preventing and reducing superficial corneal neovascularization thus enhancing the inhibitory effects of angiogenesis. Author’s Affiliation Dr. Arshad Ali Lodhi Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Murtaza Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Munawar Ahmed Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Noman Ahmed Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Ghulam Haider Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Sameen Afzal Junejo Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Dr. Mustafa Kamal Department of Ophthalmology Liaquat University of Medical and Health Sciences/Jamshoro, Sindh/Pakistan Role of Authors Dr. Arshad Ali Lodhi Drafting, methodology, patient’s selection, and literature search. 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