Corneal neovascularization-pattern,causes and

management

Dr. pramod bhumarkarRSO 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.

During the early stages, this abnormal growth of blood vessels may produce no signs at all, or it may cause a variety of symptoms, including eye pain and excessive tearing, light sensitivity, redness, intolerance to contact lenses, and decreased vision

Pathophysiology• When compactness of corneal tissue is

lossened by either mechanically irritating the limbal sulcus or by creating corneal hypoxia, which leads to limbal inflammation, epithelial erosion, or hypertrophy, and, hence, angiogenic mediator release.

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

• Angiogenic factors released by local epithelial cells, keratocytes, and infiltrating leukocytes(eg macrophages, neutrophils)

• stimulate localized enzymatic degradation of the basement membrane of perilimbal vessels at the apex of a vascular loop. Vascular endothelial cells migrate and proliferate to form new blood vessels

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, lipids, cholesterol) in the normally transparent cornea.If the vessels extend to the point where such deposits occur in the visual axis, they can compromise vision.

•Corneal edema•Lipid keratopathy•Corneal opacity•Graft rejection In keratoplasty• Intrastromal /subepithelial bleeding• Blindness

Why need to treat neovascularisation

• Corneal neovascularisation (NV) represents the main risk factor for immune rejection after corneal transplantation.

• The healthy cornea devoid of blood vessels is said to be immune-privileged 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.

• The survival rates of corneal grafts placed onto vascularized recipient beds (high-risk keratoplasty) decrease significantly to below 50%.Additionally, even in the low risk setting, mild angiogenesis develops after keratoplasty and increases the risk for immune rejection.

• For this reason, aggressive treatment of neovascularization may be necessary prior to corneal transplant surgery to ensure a lower chance of graft rejection.

Prophylaxis Dietary Isoflavonoidsand Flavonoids

(Genistein, Fisetin and Luteolin) were dissolved in a microemulsion to increase bioavailability and applied topically in concentrations between0.5 and 1 ng ml.

Fisetinhad the strongest effect followed by Genistein and Luteolin. 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 \Tβ4

REFERENCE

Fotsis et al.Genistein,a dietary-derived inhibitor of in vitro angiogenesis. Journal of Refractive Surgery  Vol. 25   No. 9   September 2009

DEXPANTHENOL

• The topical use of dexpanthenol stable alcoholic analog of pantothenic acid

• Activation of fibroblast proliferation, which is of relevance in wound healing.

• Accelerated re-epithelization in wound healing

• Anti-inflammatory effect

TREATMENTMEDICAL

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

• Angiostatic steriod- It inhibits macrophages that release growth factor, prevent intercellular adhesion leading to leukocyte adhesion & transmigration.

• They can slow the progression of neovascularization ,but cannot stabilize or reverse the process

Vasculoendothelial growth factor inhibitor;

VEGF was expressed by epithelial cells, endothelial cells, vascular endothelial cells of limbal vessels and of newly formed vessels in the stroma, and weakly by keratocytes.

Drug which are under trial to inhibits VEGF

a Bevacizumab

b Pegaptanib sodium

c Ranibizumab; anti VEGF monoclonal antibodies

COX-2 inhibitor;Nepafenac;topical readily penetrates cornea &

metabolized to amfenac, a potent cox-1 & cox-2 inhibitor,antinflammatory action

Antioxidants :reactive oxygen species stimulate VEGF production. Vitamin-E inhibit reactive oxygen species& subsequent event also inhibit pericyte loss & play a role in decreasing microvascular change & angiogenesis

• 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

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).

• Drug: Bevacizumab Topical 10 mg/cc or subconjunctival 2.5 mg/0.1cc

• Destafeno et al* reported the use of a topical formulation of bevacizumab, a humanized monoclonal antibody to VEGF, in 2 patients with significant corneal NV.

• The Duke University Hospital assisted with the topical formulation of bevacizumab established by mixing the commercially available bevacizumab (Avastin 400 mg, 25mg/mL) with 0.5% (5 mg/mL) stock benzalkonium chloride (BAK) and sterile saline 0.9%. The final formulation yielded a concentration of bevacizumab 10 mg/mL (1.0%) in 0.01% BAK with a pH of 6.2. The solution was dispensed in 5 mL vials.

*Destafeno et al. Topical bevacizumab therapy for corneal neovascularization. Arch Ophthalmol.2007;125:834–36.

• 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 .

• corneal NV associated with contact lens wear. • 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.

• The use of subconjunctival bevacizumab in human studies has shown a positive effect on regression of corneal neovascularisation

• 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

Effect of topical amiloride• Potassium sparing diuretics, 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. 1999,21;491-7

o A clinical trial on human eyes was done in 2001 in freshly operated case of pterygium

o Topical amiloride (0.04)significantly prevented as well as regressed active neovascularization in qid dosage

o No effect on long standing cases of neovascularisationo Topical prepared by dissolving amiloride powder in

normal saline filling in tinted glass bottles which were autoclaved & finally stored in refrigerator

• SURGICAL

1 Noninvasive; LASER

2 Invasive;PERITOMYDIATHERMY

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. Br J ophthalmology. 1976;60(6);464-472

**Marsh et al,Bjophthalmology , treatment of lipid keratopathy with argon laser 1998 72.900-4

• Nirankari & Baer* treated patient of deep vascularization &reported good result with regard to reversal of active graft rejection

*NirankariVSBaer et al, CALP in penetrating keratoplasty 1986; 93 ,1304-1306

• 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, the procedure decreases the area of vascularisation, area of corneal opacity, and improves vision in a significant number of patients with lipid keratopathy

*Sharma A et al, Frequency doubled Nd :YAG (532 nm) laser photocoagulation

in corneal vascularisation : efficacy and time sequenced changes. Indian J Ophthalmol 2001;49;235

LASER PHOTOCOAGULATION

• Laser photocoagulation was done using frequency-doubled Nd: YAG (532 nm) laser and Abraham contact lens.

• Laser parameters used were 120-480 mw

of power, 50-150 mm spot size and 0.05 second pulse duration.

• The patients were followed up at one week, one month, two months and three months after the last laser treatment.

• The effect on laser-treated vessels was recorded as complete occlusion, partial occlusion, recanalisation and appearance of shunt vessels on slitlamp biomicroscopy

complications • Bleeding into lipid keratopathy,• corneal thinning• Iris atrophy• crystalline deposits on iris • peaking of pupil

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, parallel to and at same depth as the blood vessel(s) to be occluded.

• A unipolar diathermy unit was set to its lowest setting (0.5–1 mA). (Any unipolar diathermy unit with the capability of low power setting could be used.)

• In the coagulating mode, the diathermy probe was brought into contact with the corneal

needle, and contact was maintained until mild blanching of the corneal stroma occurred (usually a second or less).

• Each feeder vessel was treated individually.

• At each follow-up visit, patency and recanalization of vessels, visual acuity, intraocular pressure, and any other complications were noted.

• Patency of vessels was assessed using slit-lamp biomicroscope examination by observing the flow of red blood cells through corneal vessels.

• Side effects– Transient whitening of the cornea was

observed in the stroma , this occurred in all patients treated with FND and persisted for 24 to 48 hours, with complete resolution.

PERITOMY

• Performed under local anaesthesia. 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.

The underlying bloodvessels were destroyed thoroughly by heat cautery.

•Care was taken to avoid excessive cautery causing charring of sclera.

•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 patients were subsequently followed up once a week for 4 weeks and once a month thereafter. The average follow up period till now is 6 months.

THANKS YOU

REFERENCE• DeStafeno JJ, Kim T (2007) Topical bevacizumab therapy for

corneal neovascularization. Arch Ophthalmol 125:834–836• Erdurmus M, Totan Y (2007) Subconjunctival bevacizumab for

corneal neovascularization. Graefes Arch Clin Exp Ophthalmol 245:1577–1579

• Manzano RP, Peyman GA, Khan P, Carvounis PE, Kivilcim M, Ren M, Lake JC, Chévez-Barrios P (2007) Inhibition of experimental corneal neovascularisation by bevacizumab (Avastin). Br J Ophthalmol 91:804–807

• Barros LF, Belfort-Jr R (2007) The effects of the subconjunctival injection of bevacizumab (Avastin) on angiogenesis in the rat cornea. An Acad Bras Cienc 79:389–394

REFERENCE• Baer JC, Foster CS. Corneal laser photocoagulation of treatment of

neovascularisation. Ophthalmology 1992;9:173-79.      • Nirankari VS. Laser photocoagulation for corneal stromal vascularisation. Tr

Am Ophthalmol 1992;9 • Cherry PMH, Faulkner JD, Shaver RP, Wise JB, Witter SL. Argon laser

treatment of corneal neovascularisation. Ann Ophthalmol 1973;5:911-20.      

•    Reed JW, Fromer C, Klineworth GK. Induced corneal vascularisation remission with argon laser therapy. Arch Ophthalmol 1975;93:1017-19.      

• Goto S. Q switched Nd: YAG laser treatment for corneal neovascularisation. Jpn Ophthalmol 1992;36:291-300.

•   Sharma A, Samal A, Narang S, Gutpa A, Ram J, Gupta A. Frequency doubled Nd :YAG (532 nm) laser photocoagulation in corneal vascularisation : efficacy and time sequenced changes. Indian J Ophthalmol 2001;49:235