c
 


  
 
 
 



  



   
c !"
‡ Cornea is a immunologically privileged
organ because of its non vascular nature
‡ Avascularity helps in maintaining corneal
transparency
‡ Essential for good visual acuity
 ïASCULOGENESIS &
ANGIOGENESIS
New blood vessel formation occurs by two
mechanism;
1.ï
 : by differentiation of
angioblasts & endothelial cell
2." : from preexisting
microvasculature there is balance between
endogenous stimulators & inhibitors any
imbalance result in vascularisation
 
NEOïASCULARIZATION 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.
± 2uring 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
È    
‡ hen compactness of corneal tissue is
lossened by either mechanically irritating
the limbal sulcus or by creating corneal
hypoxia, which leads to ð
ð
ð

 
 
ð ð

   
  and,
hence,   

.
ANGIOGENESIS STIMULATOR
‡ ïascular 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
‡ 2isease leading to #  
herpetic keratitis
‡ 2isease leading to  $
contact lenses
‡ 2isease with 
 
Aniridia
 %


chemical cautery
c
 #c
& 

  '

The causes of corneal neovascularisation

includes:

± Any trauma to eyes

± ear 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. ïascular
endothelial cells migrate and proliferate to
form new blood vessels
Types
Superficial
deep
pannus
superficial

deep pannus
 SUPERFICIAL
± ïessels arrange in arborizing pattern&
below epithelial layer & can be traced with
conjuctival vessel
‡ trachoma
‡ phytenular conjuntivitis
‡ superficial corneal ulcer
‡ rosacea keratitis
 2EEP
± 2erived 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
 "ï"&(" )
& ï"c*+","(,&

‡ Transport humoral & cellular elements of

immunological defense & raw material
‡ Repair & regeneration
‡ Carry antibiotic & drugs to sites of infection
‡ Eliminates toxic substance
 2isadvantages 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
c    
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
 hy need to treat
neovascularisation
‡ Corneal neovascularisation (Nï) 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
±  
, #   )  
(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.
±  #*ï"
±  
 ,

 & 

   

"  uman angiogenin (ANG) is a homologue of
bovine pancreatic ribonuclease (RNase A) that induces
neovascularization
± &-./ is a sterile eye drop formulation of thymosin beta 4 \Tȕ4
 )  &c
Fotsis et al.Genistein,a dietary-derived inhibitor of in vitro
angiogenesis. ß
  
 
     
    
 2EXPANT ENOL
‡ The topical use of dexpanthenol stable
ðð  ð 

   
‡ Activation of fibroblast proliferation, which
is of relevance in wound healing.
‡ " 
 
    0


‡ " #
##
 TREATMENT
 ,c"+
(
   
#

 
  #
  


‡ Lubricating
‡ NSAI2S
‡ Topical corticosteriod
‡ Antiangiogenic agent
 ANTIANGIOGENIC AGENT
‡ Angiostatic steriods
‡ ïascular endothelial growth factor inhibitor
‡ Protein kinase c inhibitor
‡ Matrix metalloprotinase inhibitor
‡ Cox-2 inhibitor
‡ Antioxidants
‡ Thalidomide
‡ 2ietary 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
ïasculoendothelial growth factor
inhibitor;
ïEGF 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.
2rug which are under trial to inhibits ïEGF
a Bevacizumab
b Pegaptanib sodium
c Ranibizumab; anti ïEGF monoclonal antibodies
 c1-
;
± Nepafenac;topical readily penetrates cornea
& metabolized to amfenac, a potent cox-1 &
cox-2 inhibitor,antinflammatory action

± "  $  :reactive oxygen species

stimulate ïEGF production. ïitamin-E inhibit
reactive oxygen species& subsequent event
also inhibit pericyte loss & play a role in
decreasing microvascular change &
angiogenesis
‡  



± genistein a synthetic isoflavonoid compound
inhibitor of endothelial cell production &
angiogenesis
‡ ,&c"&& +2+c3 :
‡ Amiloride inhibits capillary morphogenesis
completely & block endothelial cell
proliferation
 (  4
 5
  ,5   #
2 
 6" 7#
 (
  
#c
& 

  
‡ Bevacizumab (trade name Avastin,
Genentech/Roche) is a humanized monoclonal
antibody that recognises and blocks vascular
endothelial growth factor (ïEGF).
‡ 2rug: Bevacizumab Topical 10 mg/cc or
subconjunctival 2.5 mg/0.1cc
‡  #  8 reported the use of a topical formulation of
bevacizumab, a humanized monoclonal antibody to ïEGF, in 2
patients with significant corneal Nï.
‡ The 2uke University ospital 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 p of 6.2. The solution was dispensed
in 5 mL vials.

*2estafeno et al. Topical bevacizumab therapy for corneal

neovascularization. Arch Ophthalmol.2007;125:834±36.
‡ Topical anti-ïEGF therapy could play an important role in
improving graft survival in patients who have preexisting
corneal Nï or Nï develops after penetrating keratoplasty .
‡ corneal Nï associated with contact lens wear.
‡ The reduction or elimination of corneal Nï 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
‘ A clinical trial on human eyes was done in 2001 in
freshly operated case of pterygium
‘
Topical amiloride (0.04)significantly prevented as well as
regressed active neovascularization in qid dosage
‘ No effect on long standing cases of neovascularisation
‘ 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;
PERITOM

2IAT ERM

LASER P OTOCOAGULATION
‡ Used to treat vascularization in lipid keratopathy
& graft rejection
‡ c

9

8first reported the use of argon laser in
human
‡ 
9 0

88treated lipid keratopathy patient
with minimum followup period of 9 month

*Cherry PM 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
‡ &

 92
8treated patient of deep
vascularization &reported good result with
regard to reversal of active graft rejection

*NirankariïSBaer 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

8
" et al, Frequency doubled Nd :
AG (532 nm) laser photocoagulation

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

‡ Laser photocoagulation was done using

frequency-doubled Nd:
AG (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
    
‡ Bleeding into lipid keratopathy,
‡ corneal thinning
‡ Iris atrophy
‡ crystalline deposits on iris
‡ peaking of pupil
 2IAT ERM

‡ 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 FN2 and persisted for 24
to 48 hours, with complete resolution.
 PERITOM

‡ 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.


 REFERENCE
‡ 2eStafeno JJ, Kim T (2007) Topical bevacizumab therapy for
corneal neovascularization. Arch Ophthalmol 125:834±836
‡ Erdurmus M, Totan
(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 ïS. Laser photocoagulation for corneal stromal vascularisation. Tr
Am Ophthalmol 1992;9
‡ Cherry PM , Faulkner J2, Shaver RP, ise JB, itter SL. Argon laser
treatment of corneal neovascularisation. Ann Ophthalmol 1973;5:911-
20.
‡ Reed J, Fromer C, Klineworth GK. Induced corneal vascularisation
remission with argon laser therapy. Arch Ophthalmol 1975;93:1017-19.

‡ Goto S. Q switched Nd:
AG 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 :
AG (532 nm) laser photocoagulation in corneal
vascularisation : efficacy and time sequenced changes. Indian J Ophthalmol
2001;49:235