CAUSES ANDMANAGEMENT OF

NEOVASCULARIZATIONPREPARED BY

MUHAMAD HAZIMIN BIN ISHAK5034

MUHAMMAD AMINUDDIN BIN KHALID5037

MUHAMMAD ARIF IMRAN BIN ZAINAL RASHID5038

MUHAMMAD BASHEER BIN YAHYA5039

MUHAMMAD FIKRI BIN ISMAIL5041

MUHAMMAD HASIF BIN KAMARUDIN5043

MUHAMMAD IKRAAM BIN ABDUL LATIF5046

SUPERVISED BY: DR. AHMED ABDULLAH

CONTENT

CONTENT PAGEPREFACE 3

INTRODUCTION 4

1.0: PROLIFERATIVE DIABETIC RETINOPATHY

5

2.0: RETINOPATHY OF PREMATURITY

8

3.0: AGE-RELATED MACULAR DEGENERATION

12

4.0: SICKLE CELL 142

RETINOPATHY5.0: CENTRAL RETINAL VEINOCCLUSION

17

6.0: OCULAR INFLAMMATIONS& NEOVASCULARISATION

19

REFERENCES 20

PREFACE

In the name of Allah the Most Gracious and the Most Merciful,

praise be to Allah for that we have finished our task for a

group assignment entitled “Causes and Management of

Neovascularization”. Special regards to our beloved and

passionate supervisor, Dr. Ahmed Abdullah for his guide in the

making of this project. Not to forget, all the staff members

of Ophthalmology Department, Kasr Al Ainy Medical School for

their generous help and support for us upon finishing this

project. We are very lucky to have them alongside us all

through this journey. Last but not least, we love

ophthalmology!

3

INTRODUCTION

1. What is neovascularization?

Neovascularization is a pathologic process consisting of the

proliferation of blood vessels in abnormal tissues or in

abnormal positions. Neovascularization within the eye

contributes to visual loss in several ocular diseases.

4

2. What are among the causes known for this phenomenon?

The most common of which are proliferative diabetic

retinopathy, neovascular age-related macular degeneration, and

retinopathy of prematurity. Together, these three diseases

afflict persons in all stages of life from birth through late

adulthood and account for most instances of legal blindness.

Retinopathy of prematurity, proliferative diabetic

retinopathy, and neovascular age-related macular degeneration

are but three of the ocular diseases which can produce visual

loss secondary to neovascularization. Others include sickle

cell retinopathy, retinal vein occlusion, and certain

inflammatory diseases of the eye. These, however, account for

a much smaller proportion of visual loss caused by ocular

neovascularization.

1.0: PROLIFERATIVE DIABETIC RETINOPATHY

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1. Proliferative diabetic retinopathy affects insulin-dependent

diabetes mostly.

2. There is major ischemia process during the phase of non

proliferative and the severe non proliferative characterized

by the soft exudates, and maybe due to microaneurysm and

hemorrhages.

3. Fluorescein angiogram is used to detect the ischemic parts

of the retina.

4. The ischemic retina secretes a vasostimulating substance

that results in budding of the new vessels.

5. Neovascularization may occur at the optic disc (NVD). This

is dangerous that it may cause Primary Optic Nerve atrophy.

6. Neovascularization can also occur along the vessels of

retina termed new vessels elsewhere (NVE).

7. These new vessels are unhealthy and liable to leak and

hemorrhage occurs. This will further cause ischemia to the

retina as bleeding causes scar in the retinal tissue.

6

Fig. 1.0: Fundus exam showing non-proliferative diabetic retinopathy

Fig. 1.1: Fundus exam showing the neovascularization process in the

proliferative diabetic retinopathy.

MANAGEMENT

Follow up diabetic patients and regular fundus examinations

every year.

When there is leaking of vessels, focal laser

photocoagulation is indicated.

If the new vessels are developed (NVD or NVE or even

rubeosis iridis), pan retinal laser photocoagulation is

indicated.

7

o This procedure is indicated to kill the new budding

endothelial cells in the formation of the

neovascularization.

Vitrectomy.

Anti-Vascular Endothelial Growth Factor (Anti-VEGF)

o When there is a lack of nutrient in the Retinal Pigment

Epithelium, the VEGF plays its role by forming a new

budding blood vessels in order to restore the oxygen and

nutrients level of the cell

o However, the budding blood vessels are weak and liable to

rupture causing haemorrhages.

o This is dangerous as the hemorrhages can cause retinal

scars and subsequently, the patient will lose his vision.

o Thus, Anti-VEGF is used to prevent the formation of

neovascularization in the cases like:

1. Age-related macular edema

2. Proliferative diabetic retinopathy (PDR)

3. Central retinal vein occlusion (CRVO).

8

Fig. 1.3: Fundus exam showing the Pan Retinal Photocoagulation

2.0: RETINOPATHY OF PREMATURITY (ROP)

1. Doctors do not know for certain what causes ROP. But it is

known that by the 4th month of pregnancy, the unborn child's

retina has begun to develop vascularization. Such formation

of blood vessels appears to be very sensitive to the amount

of oxygen supplied, either naturally or artificially.

2. Blood vessels in the eye normally finish developing in the

last few weeks before birth. Premature infants, however,

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leave the protective uterus before blood vessels of the eye

have had a chance to fully develop. The less developed the

retina at birth the worse ROP is likely to be. ROP occurs in

two opposite phases:

Phase I consists of delayed retinal vascular growth and

vessel loss after premature birth resulting in hypoxia.

Phase II consists of hypoxia-induced vascular

proliferation.

3. Both oxygen-regulated and non-oxygen-regulated factors

contribute to normal vascular development and retinal

neovascularization. Vascular endothelial growth factor

(VEGF) is an important oxygen-regulated factor. A critical

non-oxygen-regulated growth factor is insulin like growth

factor-I (IGF-I).

4. In premature infants, the absence of IGF-1 (normally

provided by the placenta and the amniotic fluid) inhibits

blood vessel growth. As the eye matures, it becomes oxygen

starved, sending signals to increase VEGF. As the infant’s

organs and systems then continue to mature, IGF-1 levels

rise again, suddenly allowing the VEGF signal to produce

blood vessels. This neovascular proliferation of phase II of

ROP can cause blindness.

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Fig. 2.0: Schematic representation of IGF-I and VEGF control of blood vessel

development in ROP

5. Some risk factors have been identified that may have an

effect on ROP development include:

Low birth weight (less than 1250g).

Low gestational age (before 30 weeks of gestation).

Use of supplemental oxygen after birth.

Vitamin E deficiency.

Various types of infections (especially concurrent).

Race (Caucasians are more at risk than African-

Americans).

Anemia.

Respiratory complications & cardiac defects.

MANAGEMENT

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The norma l growth of the bl ood vessels i s directed to relativel y low-oxyge n

ar eas of the retina, but the vessels remain in

th e plane of the retin a and do no t grow i nto

th e vitreous h umor.

If excess ox ygen is g iven,

normal bloo d ves sels

d egrade and cease to de velop.

Wh en the excess oxygen

envi ronmen t is r emoved , the b lood vessel s rapidl y begin

formin g again and grow into

the vitreous humor of the eye from the

retina

The main goal of treatment is to prevent progression of

fibrovascular proliferation and to avoid retinal detachment.

In this case, timing is critical to any intervention that will

be done.

Replacement of IGF-1 early on might promote normal blood

vessel growth; whereas late supplementation with IGF-1 in the

neovascular phase of ROP could exacerbate the disease.

Similarly, inhibition of either VEGF or IGF-1 early after

birth can prevent normal blood vessel growth and precipitate

the disease; whereas inhibition at the second neovascular

phase might prevent destructive neovascularization.

At any rate, screening at-risk preterm infants at proper

times and intervals is very important.

Although oxygen therapy has been blamed for ROP

progression in the past, maximizing the oxygen saturation

(to 95%) may induce regression in pretreshold disease.

Cryotherapy (regional retinal destruction using a probe

to freeze the desired areas) was the original mode of

treatment (since the 1970s).

While laser surgery (e.g. xenon, argon, diode) is as

effective as cryotherapy, does not require general

anesthesia, and has a lower complication rate.

12

Fig. 2.1: showing fresh laser-coagulation burns in the avascular periphery of a Stage 3

ROP

Scleral buckling surgery and/or vitrectomy are usually

performed for severe ROP (stages 4 and 5) that progresses

to retinal detachment.

Fig. 2.2: The silicone band (scleral buckle, blue) is placed around the eye. This

brings the wall of the eye into contact with the detached retina, allowing the retina to

re-attach.

Recently, intravitreal injection of bevacizumab (Avastin)

has been reported as a supportive measure in aggressive 13

posterior retinopathy of prematurity. This therapy

appears to have lower risk of very high myopia than laser

therapy (according to a 2011 clinical trial)

Fig 2.3: Some of the different preparations of Avastin®, a drug that starves cancer

cells.

3.0: AGE-RELATED MACULAR DEGENERATION (AMD)

1. Age-related macular degeneration (AMD) affects an estimated

14 million people worldwide, and is the leading cause of

severe, irreversible vision loss in individuals over the age

of 50 years in Western societies.

2. It is characterized by the aged patients having vision loss

associated with drusen and atrophy of the RPE.

14

3. Choroidal neovascularization (CNV), the hallmark of 'wet',

'exudative' or 'neovascular' AMD, is responsible for

approximately 90% of cases of severe vision loss due to AMD.

4. Vascular endothelial growth factor (VEGF) has been shown to

play a key role in the regulation of CNV and vascular

permeability.

Fig 3.0: Pathological illustration of AMD

Fig 3.1: Fundus examination of AMD

MANAGEMENT

15

The standard treatment has been elapsing very quickly; from

laser photocoagulation in the early 1990s to Photodynamic

Therapy (PDT) in 1999, where a dye in injected intravenous

and the lesion is exposed to a laser of a certain wavelength

to produce a chemical reaction and coagulate the new

vessels.

Ranibizumab , the current gold standard in the US for the

treatment of neovascular AMD, exerts its effect through

binding and inhibition of all isoforms of VEGF. Randomized

controlled clinical trials have established ranibizumab as

the first US FDA-approved therapy for neovascular AMD to

result in improvement in visual acuity. Despite impressive

outcomes, treatment with ranibizumab requires sustained

treatment regimens and frequent intravitreal injections. In

this review, we discuss promising emerging therapies for

neovascular AMD that aim to improve outcomes, safety and

treatment burden through novel mechanisms of action.

Currently in phase III clinical trials, VEGF Trap is a

receptor decoy that targets VEGF with higher affinity than

ranibizumab and other currently available anti-VEGF agents.

Another promising therapeutic strategy is the blockade of

VEGF effects by inhibition of the tyrosine kinase cascade

downstream from the VEGF receptor; such therapies currently

in development include vatalanib, TG100801, pazopanib,

AG013958 and AL39324.

Small interfering RNA technology-based therapies have been

designed to downregulate the production of VEGF

16

(bevasiranib) or VEGF receptors (AGN211745) by degradation

of specific messenger RNA.

Other potential therapies include pigment epithelium-derived

factor-based therapies, nicotinic acetylcholine receptor

antagonists, integrin antagonists and sirolimus.

4.0: SICKLE CELL RETINOPATHY

1. According to the presence or absence of neovascularization

in the eye.

2. Proliferation of new blood vessels on the retina is the key

biological event that sets the stage for progression to

vitreous hemorrhage and retinal detachment.

NON PROLIFERATIVE SICKLE-CELL RETINOPATHY

1. Non-neovascular or "non-proliferative" ocular manifestations

of sickle hemoglobinopathies include :

conjunctival vascular occlusions which transform smooth

vessels into comma-shaped fragments

iris atrophy

17

retinal "salmon patch" hemorrhages

retinal pigmentary changes

2. These clinical findings are readily apparent on dilated

ophthalmoscopy and all occur due to local vaso-occlusive

events but rarely have visual consequences.

PROLIFERATIVE SICKLE-CELL RETINOPATHY

1. Patients with sickle-cell hemoglobinopathy can develop

peripheral neovascularization when vascular occlusions

induce retinal ischemia.

2. The hemoglobin protein in patients with sickle-cell anemia

is altered by a single amino acid substitution of valine for

glutamine, causing polymerization of the deoxygenated

hemoglobin and sickling of the erythrocyte.

3. It is currently believed that the rigid, elongated, and

sickle-shaped erythrocyte causes mechanical microvascular

occlusions, resulting in retinal ischemia. Furthermore, the

sickled erythrocytes irritate the endothelial cells,

stimulating a cascade of inflammatory events leading to

vascular stasis and prearteriolar capillary occlusion.

4. The initiating event in the pathogenesis of proliferative

disease is thought to be peripheral retinal arteriolar

occlusions.

5. Local ischemia from repeated episodes of arteriolar closure

is presumed to trigger angiogenesis through the production

of endogenous vascular growth factors, such as vascular

endothelial growth factor (VEGF) and basic fibroblast growth

factor (bFGF)

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6. Goldberg has defined five stages of proliferative

retinopathy.

Stage I: peripheral arteriolar occlusion is

present.

Stage II: vascular remodelling occurs at the boundary

between perfused and non-perfused peripheral retina with

the formation of arteriovenous anastomoses.

Stage III: actual pre-retinal neovascularization

occurs. The neovascularization is classically described

as sea-fan neovascularization, but this is not

pathognomonic for sickle-cell hemoglobinopathy and can

occur in other retinopathies.

Stage IV: is defined by the presence of vitreous

hemorrhage.

Stage V: is defined by the presence of retinal

detachment.

MANAGEMENT

Treatment is reserved for eyes which have progressed to

proliferative retinopathy and are thus at risk for severe

visual loss from bleeding and retinal detachment. Given the

high rate of spontaneous regression and/or lack of

progression of neovascularization in some eyes, the

indications for treatment of retinal neovascularization are

not always clear.

19

Therapeutic intervention is usually recommended in cases of

bilateral proliferative disease, spontaneous hemorrhage,

large elevated neovascular fronds, rapid growth of

neovascularization, or cases in which the fellow eye has

already been lost to proliferative retinopathy.

The goal is early treatment aimed at inducing regression of

neovascular tissue before progression to bleeding and

retinal detachment. Proliferative sickle cell retinopathy

often spontaneously regresses due to auto-infarction of the

neovascular fronds.

Techniques such as diathermy, cryotherapy and laser

photocoagulation (least side effect) have all been used to

cause involution of neovascular lesions.

Cryotherapy is used to treat the peripheral ischemic retina

when laser treatment is not possible due to poor

visualization of the peripheral retina because of media

opacity.

Specific methods of laser application include direct

coagulation of feeder vessels, local scatter

photocoagulation with and without focal ablation of the

neovascular frond, and 360 degree peripheral scatter

delivery.

Feeder vessel photocoagulation has also been successful in

treating PSR by closing sea-fan vessels that persists

following scatter laser treatment.

Scatter laser photocoagulation of the ischemic retina and

tissue surrounding the sea-fan can cause regression of the

20

neovascular lesions and prevention of late-stage disease

complications by reducing angiogenic factors.

If retinal detachment and/or non-clearing vitreous

hemorrhage is present, surgical intervention is usually

required. Surgical techniques include vitrectomy with or

without the placement of a scleral buckle. Surgery carries a

significant risk of intraoperative and postoperative

complications, including severe ocular ischemia, recurrent

hemorrhage and elevated eye pressure.

Fig 4.0: In this picture, the left side is more peripheral and more anterior; the right is

more posterior. On the left side, the peripheral retina is completely non-perfused. The right

side shows a partially perfused retina. The brighter areas are the junction where the

neovascularization is leaking.

5.0: CENTRAL RETINAL VEIN OCCLUSION

21

1. It is the second most common retinal vascular disease after

diabetic retinopathy.

2. There are two distinct types, which are perfused or non-

ischemic and non-perfused or ischemic which are determined

according to the amount of retinal capillary ischemia seen

by the ophthalmologist on fluorescein angiography.

3. In ischemic retina, there are increased levels of the

products of hypoxia regulated genes, including vascular

endothelial growth factor (VEGF).

4. Such a distinction is relevant to the clinician, since two

thirds of patients with the ischemic type develop the

dreaded complications of macular edema, macular ischemia,

and neovascularization that lead to blindness.

5. There are some risk factors leading to occlusion:

Age

Hypertension

Hyperlipidaemia. (A total cholesterol > 6.5 mmol/l is

present in 35% of patients)

Diabetes mellitus

Oral contraceptive pill (The risk may be exacerbated by

thrombophilia)

Raised intraocular pressure

Smoking

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Fig. 5.0: Central retinal vein occlusion showing dilation and tortuosity as well as

intraretinal hemorrhages in all four quadrants.

MANAGEMENT

No known effective medical treatment is available for either

the prevention of or the treatment of central retinal vein

occlusion (CRVO). Identifying and treating any systemic

medical problems to reduce further complications is

important. Because the exact pathogenesis of the CRVO is not

known, various medical modalities of treatment have been

advocated by multiple authors with varying success in

preventing complications and in preserving vision.

Advocated treatments are as follows:

o Anti-inflammatory agents.

o Isovolemic hemodilution.

o Systemic anticoagulation with warfarin, heparin, and

alteplase.

o Fibrinolytic agents.

o Systemic corticosteroids.

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o Local anticoagulation with intravitreal injection of

alteplase.

o Intravitreal injection of ranibizumab.

o Intravitreal injection of bevacizumab.

Laser photocoagulation is the known treatment of choice in

the treatment of various complications associated with

retinal vascular diseases.

Chorioretinal venous anastomosis is performed by creating an

anastomosis to bypass the site of venous occlusion in the

optic disc (high risk of complications).

Radial optic neurotomy (RON) is a new surgical technique in

which a microvitreoretinal blade is used during pars plana

vitrectomy to relax the scleral ring around the optic nerve.

The central retinal artery and vein passes through the

narrow openings of the cribriform plate in the optic disc.

Vitrectomy is a technique in which the vitreous is

surgically removed along with removal of the posterior

hyaloid.

6.0: OCULAR INFLAMMATIONS & NEOVASCULARIZATION

A. INTERSTITIAL KERATITIS

Interstitial keratitis (IK) is a broad, descriptive term that

has become synonymous with syphilitic disease. Although

24

syphilis remains the leading cause of interstitial keratitis,

various bacterial, viral, parasitic, and autoimmune causes of

interstitial keratitis are known.

STAGES & SIGNS:

Progressive stage (2 weeks):

Infiltration and vascularization of cornea and it is triggered

by inflammation or surgery.

Florid stage:

Extensive infiltration and neovascularization occurs. Variable

corneal stromal neovascularization is depending on the

severity of the inflammation. Usually the neovascularization

occurs at the corneal limbus. It commonly occurs at the deep

stromal layer but it may be seen ath the superficial layer.

Stromal inflammation overlying the vessel often causes the

salmon-coloured patch due to pinkish color imparted by the

stromal vessels. Intrastromal haemorrhage may occur.

Regressive stage:

Scarring of the corneal stromal and collagen remodeling occur.

The superficial vessel resorb, snd the deeper vessel may

constrict , resulting in ghost vessels.

25

Fig. 6.0: Interstitial keratitis manifests with varying degrees of corneal opacification

and neovascularization. Neovascularization can cause orange-red areas (salmon patches).

TREATMENTS:

Topical and systemic corticosteroid.

IV Penincilin in cases of syphilis.

Keratoplasty in cases of corneal opacities.

B. UVEITIS

Uveitic neovascularization affects both uveal and retinal

tissues. It more commonly involves the retina––either through

neovascularization of the disk (NVD) or neovascularization

elsewhere (NVE)––and the choroid (choroidal

neovascularization, CNV).

Both NVD and NVE can be detected by fundoscopy and

angiography.

The new vessels tend to grow on the retinal surface. Later

these vessels will penetrate the internal limiting membrane

26

and posterior vitreous hyaloid face, and proliferate into the

vitreous. They are fragile and tend to bleed, resulting in

vitreous hemorrhage.

Retinal Neovascularization

1. Retinal neovascularization often occurs in uveal

inflammations that are associated with occlusive retinal

vasculitis, such as Behçet’s & Eales’ diseases.

2. Eales’ disease is notable for its presentation of retinal

periphlebitis, ischemia, and neovascularization. In

contrast, Behçet’s disease presents with intraocular

inflammation consisting of retinal vasculitis, oral and

mucosal ulcerations, and skin lesions.

3. Although retinal neovascularization rarely occurs in pars

planitis, both NVE and NVD leading to vitreous hemorrhage

have been reported.

4. Other uveitides reported to develop NVD and NVE include

systemic lupus erythematosus, sarcoidosis, birdshot

retinochoroidopathy and retinal vasculitis.

5. Infectious uveitis such as AIDS and others can also be

associated with retinal neovascularization.

27

Fig 6.1: Retinal vasculitis with hemorrhages and cotton wool spots.

Choroidal Neovascularization (CNV)

1. CNV includes choroidal and subchoroidal neovascularization.

CNV occurs in both infectious and noninfectious choroiditis.

2. Usually CNV presents with subretinal or intraretinal

hemorrhage, pigment epithelial detachment and a grayish-

green subretinal membrane. It is often associated with

chorioretinal scar.

3. CNV is an important feature of ocular histoplasmosis, which

manifests as the classic triad of discrete atrophic

choroidal scars in the macula or midperiphery (histo spots),

peripapillary atrophy, and choroidal neovascularization.

4. CNV has also been associated with serpiginous choroidopathy.

5. CNV is associated with a poor prognosis in Vogt-Koyanagi-

Harada syndrome (VKH).

6. Several infections are known to be complicated by CNV,

including toxoplasmosis and Candida choroidoretinitis.

28

Fig. 6.2: Retinal photograph of ocular histoplasmosis, with the clinical triad of

multiple white, atrophic choroidal scars, peripapillary pigment changes (dark spots around

optic disc of the eye)

Iris and Ciliary Neovascularization

1. Neovascularization in the iris and ciliary body is a rare

and ominous complication of chronic iridocyclitis.

2. An Iris neovascularization, or rubeosis irides, is new

vessel growth on the surface of the iris, which can result

in hyphema and/or rubeotic glaucoma.

29

Fig. 6.1: Fluorescein angiogram of the iris in case of chronic anterior uveitis.

MANAGEMENT

Currently available treatments for uveitic

neovascularization include immunotherapy, photocoagulation,

photodynamic therapy (PDT), and surgical excision of the CNV

neovascular membrane.

In uveitic neovascularization, there is always an

inflammatory component. Therefore, antiinflammatory and/or

immunosuppressive therapies should be prescribed.

Corticosteroids are antiinflammatory and antiangiogenic.

Local (including periocular) injections and vitreal

implants, as well as systemic corticosteroids, have been

reported to treat NVD effectively in sarcoidosis, multiple

sclerosis, juvenile rheumatoid arthritis, cyclitis, and

idiopathic uveitis.

Although corticosteroids alone may be less favorable for

CNV, additional immunosuppressive agents such as 30

cyclosporine and azathioprine have been used successfully to

regress neovascularization in sympathetic ophthalmia,

multifocal choroiditis, ocular histoplasmosis syndrome,

serpiginous choroiditis, and endogenous posterior uveits.

With the recent advance in understanding of angiogenesis,

antiangiogenic factors such as anti-VEGF agents are being

introduced as treatments for neovascularization, including

ocular neovascularization.

Laser photocoagulation and PDT for uveitic

neovascularization have been reported in a few small case

series. PDT appeared to stabilize or improve vision in a few

patients with subfoveal CNV secondary to multifocal

choroiditis and panuveitis.

The surgical mechanical excision of CNV associated with

ocular histoplasmosis and multifocal choroiditis produces

less damage to the photoreceptor cells than laser

photocoagulation. However, this surgical procedure is rather

difficult and requires skillful surgeons. Surgical

complications are frequent.

REFERENCES

- Ophthalmology Department, Cairo University. General

Ophthalmology for Undergraduate (6th edition) 2012-13.

31

- A.M. Joussen, T.W. Gardner, B. Kirchhof, S.J. Ryan

(Eds.). Retinal Vascular Disease; Springer-Verlag Berlin

Heidelberg New York 2007.

- Shaker A. Mousa. Angiogenesis Inhibitors and Stimulators

Potential Therapeutic Implications; Landes Bioscience &

Eurekah.com 2000.

- Chi-Chao Chan (MD) and Robert B. Nussenblatt (MD). Ocular

Inflammation and Neovascularization, Ophthalmology:

Ocular Angiogenesis: Diseases, Mechanisms, and

Therapeutics.

- Leila Laatikainen. Vascular Changes in the Iris in

Chronic Anterior Uveitis, British Journal of

Ophthalmology 1979.

- http://www.ncbi.nlm.nih.gov/pubmed/18484796

- http://www.stlukeseye.com/conditions/cnvm.html

- http://www.lucentis.com/hcp/amd/about-ranibizumab-

amd.html

- http://www.retinalphysician.com/articleviewer.aspx?

articleID=102207

- http://sickle.bwh.harvard.edu/eye.html

- http://www.medscape.com/ophthalmology

- http://www.eyecalcs.com/DWAN/pages/v4/v4c042.html

- http://shop.onjoph.com/catalog/index.php

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