Ophthalmology – Neovascular Glaucoma

Basics

Description

Neovascular glaucoma (NVG) is a severe secondary glaucoma caused by retinal ischemia–driven neovascularization of the iris and anterior chamber angle.

The disease progresses from:

• Iris neovascularization (rubeosis iridis)
• Angle neovascularization
• Formation of a fibrovascular membrane
• Contraction of this membrane
• Progressive peripheral anterior synechiae
• Secondary angle closure
• Markedly elevated intraocular pressure

NVG is often painful and potentially blinding.

Older synonyms include:

• Rubeotic glaucoma
• Hemorrhagic glaucoma
• Congestive glaucoma
• Thrombotic glaucoma

Major Causes

The most important causes are:

• Proliferative diabetic retinopathy
• Ischemic central retinal vein occlusion
• Ocular ischemic syndrome from carotid occlusive disease

Any condition causing sufficiently severe retinal ischemia may produce NVG.

Epidemiology

NVG is relatively uncommon but represents one of the most severe forms of secondary glaucoma.

It occurs predominantly in:

• Older adults
• Patients with diabetes
• Patients with retinal vascular disease
• Patients with severe systemic atherosclerotic disease

The risk is especially high in eyes with:

• Proliferative diabetic retinopathy
• Ischemic CRVO

Risk Factors

Major risk factors include:

• Severe retinal ischemia
• Proliferative diabetic retinopathy
• Ischemic CRVO
• Carotid occlusive disease
• Poorly controlled diabetes
• Hypertension
• Atherosclerosis

Historically, diabetic eyes undergoing extensive intraocular surgery were recognized as being at particularly high risk when severe untreated retinal ischemia was present.

Pathophysiology

The fundamental mechanism is:

Retinal ischemia → angiogenic factor release → anterior segment neovascularization → fibrovascular contraction → angle closure glaucoma

VEGF

Hypoxic retina produces angiogenic mediators, particularly:

Vascular endothelial growth factor (VEGF)

VEGF diffuses through the vitreous and aqueous humor and stimulates formation of abnormal vessels on the:

• Iris
• Pupillary margin
• Anterior chamber angle

Early Stage

Initially, new vessels appear:

• At the pupillary border
• On the anterior iris surface
• Within the anterior chamber angle

At this stage, the angle may still be anatomically open.

IOP may be:

• Normal
• Mildly elevated
• Significantly elevated

Early disease can sometimes be reversed if the underlying ischemic stimulus is treated promptly.

Fibrovascular Membrane Formation

Neovascular tissue is accompanied by fibrovascular proliferation.

This membrane grows across the:

• Iris
• Trabecular meshwork
• Anterior chamber angle

Contraction eventually pulls the peripheral iris anteriorly.

Late Stage

Progressive contraction leads to:

• Peripheral anterior synechiae
• Progressive angle closure
• Severe reduction of aqueous outflow
• Markedly elevated IOP

Once extensive synechial closure develops, regression of vessels alone does not reopen the angle.

Therefore, glaucoma treatment becomes much more difficult.

Etiology

Important causes of retinal ischemia associated with NVG include:

• Central retinal vein occlusion
• Proliferative diabetic retinopathy
• Ocular ischemic syndrome
• Central retinal artery occlusion
• Branch retinal vein occlusion
• Chronic retinal detachment
• Radiation retinopathy
• Sickle cell retinopathy
• Coats disease
• Eales disease
• Retinopathy of prematurity
• Severe chronic ocular inflammation
• Uveitis-glaucoma-hyphema syndrome
• Intraocular tumors
• Carotid-cavernous fistula
• Giant cell arteritis
• Takayasu arteritis
• Anterior segment ischemia
• Severe ocular trauma

Intraocular Tumors

Rarely, rubeosis may develop secondary to:

• Retinoblastoma in children
• Choroidal melanoma
• Other intraocular tumors

When the fundus cannot be visualized, an occult intraocular tumor must be considered before performing destructive glaucoma procedures.

Associated Systemic Conditions

Common systemic associations include:

• Diabetes mellitus
• Hypertension
• Hyperlipidemia
• Atherosclerotic cardiovascular disease
• Carotid artery disease

Clinical Stages

NVG can be considered in three broad stages.

Stage 1 – Rubeosis Iridis

Features:

• Fine iris neovascularization
• Usually begins at the pupillary margin
• Angle may remain open
• IOP may still be normal

This is the ideal stage for intervention.

Stage 2 – Open-Angle NVG

Features include:

• Neovascularization of the angle
• Fibrovascular membrane over the trabecular meshwork
• Increasing IOP
• Angle still partly open

This stage may still respond to rapid retinal ischemia treatment and IOP-lowering therapy.

Stage 3 – Synechial Angle Closure

Features include:

• Extensive peripheral anterior synechiae
• Closed angle
• Very high IOP
• Pain
• Corneal edema
• Marked visual loss

At this stage, glaucoma surgery is frequently required.

Diagnosis

History

Typical symptoms include:

• Painful red eye
• Ocular pressure sensation
• Headache
• Photophobia
• Decreased vision
• Halos around lights

Some patients may initially be asymptomatic when only iris neovascularization is present.

External and Anterior Segment Examination

Possible findings include:

• Conjunctival injection
• Ciliary flush
• Corneal edema
• Shallow or normal anterior chamber depending on stage
• Anterior chamber cells and flare
• Hyphema

Rubeosis Iridis

The earliest iris finding is often:

Fine abnormal vessels at the pupillary margin

These vessels:

• Are irregular
• Cross normal iris architecture
• Extend onto the anterior iris surface

They should not be confused with normal radial iris vessels.

Gonioscopy

Gonioscopy is essential.

Look for:

• Fine neovascular vessels crossing the scleral spur
• Neovascularization of the trabecular meshwork
• Peripheral anterior synechiae
• Extent of angle closure

Angle neovascularization can precede obvious iris neovascularization.

Hyphema

Fragile new vessels may bleed spontaneously, causing:

• Microhyphema
• Gross hyphema

Hyphema can further increase IOP.

Intraocular Pressure

IOP can be:

• Normal in very early rubeosis
• Moderately elevated in open-angle disease
• Extremely elevated after synechial angle closure

Posterior Segment Examination

A dilated retinal examination should identify the ischemic cause.

Central Retinal Vein Occlusion

Features suggesting CRVO include:

• Dilated tortuous retinal veins
• Widespread retinal hemorrhages
• Cotton-wool spots
• Disc edema
• Macular edema

Extensive ischemia greatly increases NVG risk.

Proliferative Diabetic Retinopathy

Look for:

• Neovascularization of the disc
• Neovascularization elsewhere
• Preretinal hemorrhage
• Vitreous hemorrhage
• Extensive capillary nonperfusion

Ocular Ischemic Syndrome

Possible findings include:

• Midperipheral dot-blot hemorrhages
• Narrow retinal arteries
• Dilated but often not markedly tortuous veins
• Delayed retinal arterial filling
• Iris neovascularization
• Ocular pain

Severe carotid stenosis should be investigated.

Central Retinal Artery Occlusion

Look for:

• Retinal whitening
• Cherry-red spot
• Attenuated retinal arteries

NVG is less common after CRAO than after ischemic CRVO but can occur when widespread ocular ischemia persists.

Diagnostic Testing

Fluorescein Angiography

Fluorescein angiography can identify:

• Areas of retinal capillary nonperfusion
• Retinal neovascularization
• Leakage
• Severity of ischemia

It can be particularly useful in:

• CRVO
• Diabetic retinopathy
• Ocular ischemic syndrome

OCT

OCT may be useful for evaluating:

• Macular edema
• Diabetic macular disease
• Retinal structural damage

It does not replace fluorescein angiography for assessing widespread retinal perfusion.

B-Scan Ultrasonography

B-scan is useful when the fundus cannot be seen because of:

• Dense cataract
• Vitreous hemorrhage
• Corneal opacity

It can help identify:

• Retinal detachment
• Intraocular tumor
• Other posterior segment abnormalities

Carotid Evaluation

When ocular ischemic syndrome or arterial occlusive disease is suspected, evaluation may include:

• Carotid duplex ultrasonography
• CT angiography
• MR angiography

Systemic vascular referral may be necessary.

Laboratory Evaluation

Laboratory testing depends on the underlying cause.

Possible tests include:

• Fasting glucose
• HbA1c
• Lipid profile
• Blood pressure assessment

In selected patients:

• ESR
• CRP
• Platelet count

may be appropriate when giant cell arteritis is suspected.

Younger patients with unusual retinal vascular occlusion may require targeted evaluation for:

• Hypercoagulable states
• Hyperviscosity disorders
• Systemic inflammatory disease

Follow-Up After CRVO

Eyes with CRVO require close surveillance for:

• Iris neovascularization
• Angle neovascularization
• Conversion to a more ischemic phenotype

The highest risk period is within the first several months.

Monthly anterior segment examination and gonioscopy during the early high-risk period is often appropriate, especially in ischemic or indeterminate CRVO.

Differential Diagnosis

Important differential diagnoses include:

• Uveitic glaucoma
• Fuchs uveitis syndrome
• Primary angle-closure glaucoma
• Posner-Schlossman syndrome
• Traumatic glaucoma
• Ghost-cell glaucoma
• Hemolytic glaucoma

The presence of iris or angle neovascularization strongly supports NVG.

Treatment Principles

Treatment has two simultaneous goals:

1. Eliminate the retinal ischemic stimulus
2. Lower intraocular pressure and control pain

Treating IOP alone without treating retinal ischemia usually fails.

Panretinal Photocoagulation

Panretinal photocoagulation (PRP) is the definitive treatment for retinal ischemia when sufficient retina can be visualized.

PRP reduces the ischemic retinal tissue producing VEGF.

It can cause regression of:

• Iris neovascularization
• Angle neovascularization

and helps reduce recurrent neovascularization.

Anti-VEGF Therapy

Intravitreal anti-VEGF treatment produces rapid regression of anterior segment neovascularization.

Common agents include:

• Bevacizumab
• Ranibizumab
• Aflibercept

Role of Anti-VEGF

Anti-VEGF therapy:

• Acts rapidly
• Reduces iris neovascularization
• Reduces angle neovascularization
• Reduces bleeding
• May facilitate subsequent glaucoma surgery

However:

Anti-VEGF therapy is temporary and does not replace PRP when retinal ischemia is present and treatable.

The ischemic retina continues to produce VEGF once the drug effect disappears.

PRP + Anti-VEGF

A common modern strategy is:

Anti-VEGF for rapid vessel regression + PRP for durable treatment of the ischemic drive

This combination is particularly valuable when there is:

• Florid rubeosis
• Hyphema
• Very active neovascularization

When PRP Cannot Initially Be Performed

PRP may be impossible because of:

• Dense vitreous hemorrhage
• Cataract
• Corneal edema
• Poor pupillary dilation

Options may include:

• Anti-VEGF as temporary control
• Pars plana vitrectomy
• Endolaser PRP during vitrectomy

depending on the underlying condition.

Medical IOP Treatment

Aqueous suppressants are preferred.

Useful medications include:

• Beta-blockers
• Alpha-2 agonists such as brimonidine
• Topical carbonic anhydrase inhibitors
• Oral acetazolamide when appropriate

Prostaglandin Analogs

Prostaglandin analogs may sometimes be used if additional IOP reduction is needed.

However, they may be less effective in severely inflamed or extensively closed angles and are generally not the central therapy.

Pilocarpine

Pilocarpine should generally be avoided.

Reasons include:

• Poor efficacy in a synechially closed angle
• Increased inflammation
• Potential worsening of ocular discomfort

Cycloplegics

Atropine or another cycloplegic may be useful to:

• Reduce ciliary spasm
• Improve pain
• Stabilize the blood-aqueous barrier

Topical Corticosteroids

Topical corticosteroids can help control:

• Anterior segment inflammation
• Pain
• Ciliary congestion

They do not treat the underlying retinal ischemia.

Hyperosmotic Therapy

For very high IOP in selected acute situations:

• Oral glycerol
• IV mannitol

may be considered, depending on systemic health.

These are short-term measures.

Glaucoma Surgery

If extensive angle closure has occurred and IOP remains uncontrolled, surgery is often necessary.

Glaucoma Drainage Device

A tube shunt is commonly favored in established NVG.

Examples include:

• Ahmed valve
• Baerveldt implant

Advantages include better performance than conventional filtration surgery in many eyes with:

• Active neovascularization
• Previous surgery
• Conjunctival scarring
• High risk of filtration failure

Trabeculectomy

Trabeculectomy with an antimetabolite such as mitomycin-C may be considered in carefully selected eyes.

Success is better when:

• Neovascular activity has been suppressed
• PRP has been completed
• The eye is relatively quiet

Failure rates are higher than in uncomplicated primary glaucoma because of aggressive scarring and inflammation.

Cyclodestructive Procedures

Transscleral cyclophotocoagulation can reduce aqueous production.

It is particularly useful in eyes with:

• Poor visual potential
• Severe pain
• Refractory IOP
• Poor candidacy for incisional surgery

Modern techniques include:

• Continuous-wave diode CPC
• Micropulse CPC in selected cases

Endocyclophotocoagulation

Endoscopic cyclophotocoagulation may be performed intraocularly in selected surgical situations but is less commonly used as primary therapy for severe NVG.

Painful Blind Eye

When visual potential is absent, management prioritizes comfort.

Options include:

• Cycloplegic drops
• Topical corticosteroids
• IOP-lowering therapy
• Cyclodestructive procedures

In a persistently painful blind eye despite treatment, definitive procedures such as:

• Enucleation
• Evisceration

may occasionally be considered.

Tumor-Associated NVG

If rubeosis is caused by an intraocular tumor, treatment is directed toward the tumor.

Possible treatments include:

• Radiation
• Tumor-directed therapy
• Enucleation in selected cases

Destructive glaucoma procedures should not be undertaken until an occult tumor has been excluded when the posterior segment cannot be visualized.

Systemic Disease Management

Control of systemic disease is essential.

This includes:

• Optimizing diabetes
• Treating hypertension
• Managing dyslipidemia
• Evaluating significant carotid disease
• Addressing systemic vascular risk

Referral

Patients with suspected NVG generally require urgent involvement of:

• Glaucoma specialist
• Retina specialist

Additional referral may include:

• Internal medicine
• Endocrinology
• Neurology
• Vascular surgery
• Stroke service

depending on the underlying cause.

Follow-Up

Follow-up is generally frequent until:

• Neovascularization regresses
• IOP stabilizes
• PRP is completed
• Underlying retinal disease is controlled

Monitoring includes:

• Visual acuity
• IOP
• Iris examination
• Gonioscopy
• Fundus examination
• Retinal imaging

Patient Education

Patients should understand that NVG is usually the consequence of severe retinal or ocular ischemia.

Important preventive measures include:

• Good diabetic control
• Blood pressure control
• Lipid management
• Smoking cessation
• Regular retinal examinations
• Timely treatment of proliferative diabetic retinopathy

Patients with retinal vascular occlusion require reliable follow-up even if the eye initially feels comfortable.

Prognosis

The prognosis is guarded.

Outcome depends on:

• Underlying retinal disease
• Severity of retinal ischemia
• Stage at diagnosis
• Amount of synechial angle closure
• Baseline visual function
• Response to PRP
• Ability to control IOP

Treatment during the early rubeotic stage offers a much better chance of avoiding severe glaucoma.

Complications

Potential complications include:

• Severe chronic ocular pain
• Hyphema
• Corneal edema
• Permanent optic nerve damage
• Complete visual loss
• Choroidal effusion
• Suprachoroidal hemorrhage
• Recurrent glaucoma after surgery
• Phthisis bulbi
• Loss of the eye

Ophthalmology Pearls

• Neovascular glaucoma = retinal ischemia → VEGF → rubeosis → fibrovascular membrane → peripheral anterior synechiae → angle closure.
• The three major causes are PDR, ischemic CRVO, and ocular ischemic syndrome.
• Rubeosis usually begins at the pupillary margin.
• Gonioscopy may reveal angle neovascularization before obvious iris vessels.
• Anti-VEGF causes rapid but temporary regression of neovascularization.
• PRP treats the underlying ischemic drive and is essential whenever feasible.
• Once extensive synechial closure has developed, vessel regression does not reopen the angle.
• Aqueous suppressants are preferred for IOP control; pilocarpine should generally be avoided.
• Established uncontrolled NVG frequently requires a glaucoma drainage device.
• A painful blind eye may eventually require cyclodestruction or definitive comfort surgery.
• After ischemic CRVO, careful surveillance during the first several months is crucial because anterior segment neovascularization can develop rapidly.