Corneal neovascularizationpattern,causes and managementDr. pramod bhumarkar RSO Ophthalmology G.M.H, S.S.M.C REWA Cornea is a immunologically privileged organ because of its non vascular nature Avascularity helps in maintaining corneal transparency Essential for good visual acuity VASCULOGENESIS & ANGIOGENESIS New blood vessel formation occurs by two mechanism; 1.Vasculogenesis: by differentiation of angioblasts & endothelial cell 2.Angiogenesis: from preexisting microvasculature there is balance between endogenous stimulators & inhibitors any imbalance result in vascularisation WHY NEOVASCULARIZATION OCCUR Corneal neovascularisation is the condition in which excessive in- growth of blood vessels takes place, from the limbal vascular plexus into the cornea. It is caused due to less intake of oxygen from the air Inflammatory & hypoxic disruption of balanced corneal immune system In response the body attempts to provide necessary nutrients and oxygen to the deprived corneal tissues by the creation of new blood vessels. . including eye pain and excessive tearing. and decreased vision . intolerance to contact lenses. During the early stages. or it may cause a variety of symptoms. redness. this abnormal growth of blood vessels may produce no signs at all. light sensitivity. EPITHELIAL EROSION. hence.Pathophysiology When compactness of corneal tissue is lossened by either mechanically irritating the limbal sulcus or by creating corneal hypoxia. . OR HYPERTROPHY. and. angiogenic mediator release. which leads to LIMBAL INFLAMMATION. ANGIOGENESIS STIMULATOR Vascular endothelial growth factor Fibroblast growth factor Insulin like growth factor Integrins Platelets derived growth factor Transforming growth factor Tumor necrosis factor Matrix metalloproteinase . Common causes of Angiogenesis Disease leading to inflammation herpetic keratitis Disease leading to Hypoxia contact lenses Disease with inherited Aniridia acquired chemical cautery . Causes of Corneal Neovascularisation. The causes of corneal neovascularisation includes: Any trauma to eyes Wear and tear in contact lenses Immunological disease Burn to eye due to some chemical . Vascular endothelial cells migrate and proliferate to form new blood vessels . neutrophils) stimulate localized enzymatic degradation of the basement membrane of perilimbal vessels at the apex of a vascular loop. and infiltrating leukocytes(eg macrophages. Angiogenic factors released by local epithelial cells. keratocytes. Types Superficial deep pannus superficial deep pannus . SUPERFICIAL Vessels arrange in arborizing pattern& below epithelial layer & can be traced with conjuctival vessel trachoma phytenular conjuntivitis superficial corneal ulcer rosacea keratitis . DEEP Derived by anterior cilliary artery & lie in corneal stroma usually straight & not anastomosing continuity can not be traced beyond limbus Interstitial keratitis deciform keratitis deep corneal ulcer chemical burn sclerosing keratitis graft rejection . Pannus extensive superficial vascularisation with cellular infiltration 1 progressive 2 regressive . ADVANTAGES OF NEOVASCULARISATION Transport humoral & cellular elements of immunological defense & raw material Repair & regeneration Carry antibiotic & drugs to sites of infection Eliminates toxic substance . Disadvantages of neovascularisation Persist after healing process is completed Interfere with corneal transparency Lymphatic establishment which disrupt immune privilege Sensitization to other antigen Graft rejection & failure in keratoplasty . Complications New blood vessels are known to be leaky and occasionally deposit opaque material (eg.If the vessels extend to the point where such deposits occur in the visual axis. lipids. they can compromise vision. cholesterol) in the normally transparent cornea. Corneal edema Lipid keratopathy Corneal opacity Graft rejection In keratoplasty Intrastromal /subepithelial bleeding Blindness . even in the low risk setting.Why need to treat neovascularisation Corneal neovascularisation (NV) represents the main risk factor for immune rejection after corneal transplantation. The survival rates of corneal grafts placed onto vascularized recipient beds (high-risk keratoplasty) decrease significantly to below 50%. aggressive treatment of neovascularization may be necessary prior to corneal transplant surgery to ensure a lower chance of graft rejection.Additionally. . The healthy cornea devoid of blood vessels is said to be immuneprivileged and when corneal grafts are placed into an avascular recipient corneal bed (low-risk keratoplasty) the two-year survival approaches 90% under treatment with a topical corticosteroid. mild angiogenesis develops after keratoplasty and increases the risk for immune rejection. For this reason. 25 No. Riboflavin-UVA Ribonuclease Inhibitor Regulates Neovascularization by Human Angiogenin Human angiogenin (ANG) is a homologue of bovine pancreatic ribonuclease (RNase A) that induces neovascularization RGN-259 is a sterile eye drop formulation of thymosin beta 4 \T 4 REFERENCE Fotsis et al.a dietary-derived inhibitor of in vitro angiogenesis.Genistein.5 and 1 ng ml. Fisetin and Luteolin) were dissolved in a microemulsion to increase bioavailability and applied topically in concentrations between0. Fisetinhad the strongest effect followed by Genistein and Luteolin. 9 September 2009 . Journal of Refractive Surgery Vol.Prophylaxis Dietary Isoflavonoidsand Flavonoids (Genistein. which is of relevance in wound healing. Accelerated re-epithelization in wound healing Anti-inflammatory effect .DEXPANTHENOL The topical use of dexpanthenol stable ALCOHOLIC ANALOG OF PANTOTHENIC ACID Activation of fibroblast proliferation. TREATMENT MEDICAL Treat the cause first Other mode of treatment are Lubricating NSAIDS Topical corticosteriod Antiangiogenic agent . ANTIANGIOGENIC AGENT Angiostatic steriods Vascular endothelial growth factor inhibitor Protein kinase c inhibitor Matrix metalloprotinase inhibitor Cox-2 inhibitor Antioxidants Thalidomide Dietary derived inhibitor Ion channel blockers . It inhibits macrophages that release growth factor. prevent intercellular adhesion leading to leukocyte adhesion & transmigration. Angiostatic steriod.but cannot stabilize or reverse the process . They can slow the progression of neovascularization . Drug which are under trial to inhibits VEGF a Bevacizumab b Pegaptanib sodium c Ranibizumab. VEGF was expressed by epithelial cells. anti VEGF monoclonal antibodies . endothelial cells. and weakly by keratocytes.Vasculoendothelial growth factor inhibitor. vascular endothelial cells of limbal vessels and of newly formed vessels in the stroma. Vitamin-E inhibit reactive oxygen species& subsequent event also inhibit pericyte loss & play a role in decreasing microvascular change & angiogenesis .topical readily penetrates cornea & metabolized to amfenac. a potent cox-1 & cox-2 inhibitor. Nepafenac.antinflammatory action Antioxidants :reactive oxygen species stimulate VEGF production.COX-2 inhibitor. Dietary derived inhibitor ± genistein a synthetic isoflavonoid compound inhibitor of endothelial cell production & angiogenesis ION CHANNEL BLOCKER: Amiloride inhibits capillary morphogenesis completely & block endothelial cell proliferation . 5 mg/0. Drug: Bevacizumab Topical 10 mg/cc or subconjunctival 2.1cc .Topical/Subconjunctival Injection of Bevacizumab (Avastin) for the Treatment of Corneal Neovascularization Bevacizumab (trade name Avastin. Genentech/Roche) is a humanized monoclonal antibody that recognises and blocks vascular endothelial growth factor (VEGF). in 2 patients with significant corneal NV. *Destafeno et al.2007.125:834±36. a humanized monoclonal antibody to VEGF. . 25mg/mL) with 0.01% BAK with a pH of 6. The Duke University Hospital assisted with the topical formulation of bevacizumab established by mixing the commercially available bevacizumab (Avastin 400 mg. Destafeno et al* reported the use of a topical formulation of bevacizumab. The final formulation yielded a concentration of bevacizumab 10 mg/mL (1. The solution was dispensed in 5 mL vials.2.0%) in 0.5% (5 mg/mL) stock benzalkonium chloride (BAK) and sterile saline 0. Topical bevacizumab therapy for corneal neovascularization. Arch Ophthalmol.9%. corneal NV associated with contact lens wear. The use of subconjunctival bevacizumab in human studies has shown a positive effect on regression of corneal neovascularisation . Topical anti-VEGF therapy could play an important role in improving graft survival in patients who have preexisting corneal NV or NV develops after penetrating keratoplasty . The reduction or elimination of corneal NV could therefore allow for corneal transplantation or refractive surgery in those patients who were previously considered high risk and had contraindications to surgery. But because of its cost & lack of availablity in our institution we are not using The cost of preparation for this topical solution was about $500/5ml vial . 21. 1999. competitive inhibitor of urokinase plasminogen activator (uPA) uPA is serine protease degrade basement membrane & permits endothelial invasion Amiloride inhibit the conversion of plasminogen to plasmin& prevent degradation Avery et al* studied effect of systemic amiloride in rabbit eyes & observed 55% regression Sood et al** reported topical use accelerate healing & delay neovascularisation in mechanically produced ulcer in rabbits *Avery et al arch ophthalmology 1990.108.1474-6 **Sood et-al methods find exp clin pharmacol.491-7 .Effect of topical amiloride Potassium sparing diuretics. 04)significantly prevented as well as regressed active neovascularization in qid dosage o No effect on long standing cases of neovascularisation o Topical prepared by dissolving amiloride powder in normal saline filling in tinted glass bottles which were autoclaved & finally stored in refrigerator .o o A clinical trial on human eyes was done in 2001 in freshly operated case of pterygium Topical amiloride (0. PERITOMY DIATHERMY . LASER 2 Invasive. SURGICAL 1 Noninvasive. LASER PHOTOCOAGULATION Used to treat vascularization in lipid keratopathy & graft rejection Cherry & garner* first reported the use of argon laser in human Marsh & coworkers **treated lipid keratopathy patient with minimum followup period of 9 month *Cherry PMH et al. Argon laser treatment of corneal neovascularisation.60(6).Bjophthalmology .900-4 . treatment of lipid keratopathy with argon laser 1998 72. 1976.464-472 **Marsh et al. Br J ophthalmology. 1304-1306 . 93 . CALP in penetrating keratoplasty 1986. Nirankari & Baer* treated patient of deep vascularization &reported good result with regard to reversal of active graft rejection *NirankariVSBaer et al. Frequency doubled Nd :YAG (532 nm) laser photocoagulation in corneal vascularisation : efficacy and time sequenced changes. area of corneal opacity.235 . A sharma* demonstrates that corneal laser photocoagulation is a safe and effective method of decreasing the area of corneal vascularisation in quiescent eyes with vascularised corneal opacities.49. and improves vision in a significant number of patients with lipid keratopathy *Sharma A et al. Indian J Ophthalmol 2001. the procedure decreases the area of vascularisation. LASER PHOTOCOAGULATION Laser photocoagulation was done using frequency-doubled Nd: YAG (532 nm) laser and Abraham contact lens. .05 second pulse duration. Laser parameters used were 120-480 mw of power. 50-150 mm spot size and 0. one month. recanalisation and appearance of shunt vessels on slitlamp biomicroscopy . The effect on laser-treated vessels was recorded as complete occlusion. partial occlusion. The patients were followed up at one week. two months and three months after the last laser treatment. complications Bleeding into lipid keratopathy. corneal thinning Iris atrophy crystalline deposits on iris peaking of pupil . parallel to and at same depth as the blood vessel(s) to be occluded. .DIATHERMY single-armed needle attached to a 10±0 monofilament black nylon suture was used with a microsurgical needle holder The needle was inserted close to the limbus. the diathermy probe was brought into contact with the corneal needle.5±1 mA). and contact was maintained until mild blanching of the corneal stroma occurred (usually a second or less). (Any unipolar diathermy unit with the capability of low power setting could be used. . A unipolar diathermy unit was set to its lowest setting (0. Each feeder vessel was treated individually.) In the coagulating mode. Patency of vessels was assessed using slit-lamp biomicroscope examination by observing the flow of red blood cells through corneal vessels. intraocular pressure. and any other complications were noted. . patency and recanalization of vessels. visual acuity. At each follow-up visit. this occurred in all patients treated with FND and persisted for 24 to 48 hours. Side effects ± Transient whitening of the cornea was observed in the stroma . with complete resolution. . Xylocaine 4% was used as surface anaesthesia and Xylocaine 2% was infiltrated subconjunctivally in the selected area. . A 3 mm broad strip of conjunctiva extending on either side 1 mm beyond the extent of the ulcer was removed from the limbus.PERITOMY Performed under local anaesthesia. The underlying bloodvessels were destroyed thoroughly by heat cautery. Care was taken to avoid excessive cautery causing charring of sclera. The patients were subsequently followed up once a week for 4 weeks and once a month thereafter. An antibiotic eye drop was applied and the eye was patched for 3-4 days. . The antibiotic eye drop was continued for further 10 days. The average follow up period till now is 6 months. THANKS YOU . Graefes Arch Clin Exp Ophthalmol 245:1577±1579 Manzano RP. An Acad Bras Cienc 79:389±394 . Kim T (2007) Topical bevacizumab therapy for corneal neovascularization. Khan P. Br J Ophthalmol 91:804±807 Barros LF. Peyman GA. Kivilcim M. Lake JC. Ren M. Arch Ophthalmol 125:834±836 Erdurmus M. Totan Y (2007) Subconjunctival bevacizumab for corneal neovascularization. Carvounis PE. Belfort-Jr R (2007) The effects of the subconjunctival injection of bevacizumab (Avastin) on angiogenesis in the rat cornea.REFERENCE DeStafeno JJ. Chévez-Barrios P (2007) Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). 5:91120.REFERENCE Baer JC. Faulkner JD. Wise JB. Goto S. Fromer C.93:1017-19.36:291-300. Gupta A. Ram J. Narang S.9 Cherry PMH. Nirankari VS. Samal A. Induced corneal vascularisation remission with argon laser therapy. Shaver RP. Klineworth GK. Q switched Nd: YAG laser treatment for corneal neovascularisation. Frequency doubled Nd :YAG (532 nm) laser photocoagulation in corneal vascularisation : efficacy and time sequenced changes. Jpn Ophthalmol 1992. Indian J Ophthalmol 2001. Ophthalmology 1992. Reed JW. Argon laser treatment of corneal neovascularisation. Corneal laser photocoagulation of treatment of neovascularisation. Arch Ophthalmol 1975. Tr Am Ophthalmol 1992. Witter SL. Ann Ophthalmol 1973.49:235 . Foster CS. Laser photocoagulation for corneal stromal vascularisation. Sharma A.9:173-79. Gutpa A.