Corneal Neovascularisation

Hypoxia-Induced

• Contact lens wear: The most common cause in developed countries; extended-wear, overnight, or high-water-content lenses with low oxygen transmissibility (Dk/t) are highest risk; even modern silicone hydrogel lenses can induce CNV with chronic overwear
• Corneal oedema: Chronic oedema from any cause creates a hypoxic microenvironment that promotes angiogenesis
• Eyelid closure: Prolonged ptosis or patching may reduce corneal oxygen supply

Inflammatory and Infectious

• Herpes simplex keratitis (HSK): Recurrent stromal keratitis is a major cause of deep stromal CNV
• Herpes zoster ophthalmicus (HZO): Chronic stromal inflammation and neurotrophic sequelae promote vascularisation
• Interstitial keratitis: Syphilitic interstitial keratitis classically produces deep stromal "salmon-patch" vessels; also seen in tuberculosis and Cogan's syndrome
• Bacterial keratitis: Suppurative infections trigger significant inflammatory angiogenesis
• Acanthamoeba keratitis: Severe inflammatory response associated with progressive neovascularisation
• Vernal and atopic keratoconjunctivitis: Chronic superior pannus formation
• Trachoma: A leading global cause; chronic Chlamydia trachomatis infection causes superior pannus (Herbert's pits at the superior limbus)
• Phlyctenular keratoconjunctivitis: Immune response to bacterial antigens (Staphylococcus, TB) causes a characteristic vessel track from limbus to phlycten
• Peripheral ulcerative keratitis (PUK): Associated with systemic vasculitides

Structural and Degenerative

• Limbal stem cell deficiency (LSCD): Loss of the limbal epithelial barrier allows conjunctival epithelium and vessels to encroach onto the corneal surface; causes fibrovascular pannus
• Chemical and thermal burns: Alkali burns particularly devastating due to liquefactive necrosis; cause extensive limbal ischaemia and LSCD
• Pterygium: Fibrovascular proliferation from the bulbar conjunctiva advancing over the limbus onto the cornea
• Corneal graft failure: Failed or rejected grafts undergo inflammatory neovascularisation
• Stevens-Johnson syndrome / mucous membrane pemphigoid: Severe ocular surface disease with LSCD and secondary CNV

Maintenance of Corneal Avascularity

The normal cornea maintains avascularity through a dynamic balance between pro-angiogenic stimulators and constitutively expressed anti-angiogenic inhibitors:

• Anti-angiogenic factors (constitutively expressed): Thrombospondin-1 and -2, angiostatin, endostatin, pigment epithelium-derived factor (PEDF), soluble VEGFR-1 (sFlt-1), and a low-oxygen-tension microenvironment relative to the highly vascular limbus
• Pro-angiogenic factors (normally suppressed): VEGF-A, VEGF-C (lymphangiogenic), basic FGF (bFGF), interleukins (IL-1β, IL-8), matrix metalloproteinases (MMP-2, MMP-9), and HIF-1α

Mechanism of Neovascularisation

1. Initiating stimulus: Hypoxia (contact lens wear), inflammation (keratitis, uveitis), or injury (chemical burn, trauma) disrupts the angiogenic balance
2. HIF-1α upregulation: Hypoxia-inducible factor-1α is stabilised under low-oxygen conditions → transcriptional activation of VEGF-A and other angiogenic genes
3. VEGF-A release: The master regulator of angiogenesis; binds VEGFR-2 on endothelial cells of the limbal capillaries → endothelial cell proliferation, migration, and tube formation
4. MMP activation: Matrix metalloproteinases degrade the basement membrane and extracellular matrix of the corneal stroma, creating a pathway for sprouting vessels
5. Vessel sprouting and ingrowth: New vessels (and lymphatic vessels via VEGF-C/VEGFR-3 signalling) sprout from limbal capillaries and advance centripetally into the corneal stroma
6. Lipid deposition: Newly formed, leaky vessels allow plasma lipoproteins to extravasate into the stroma; macrophages ingest lipid → lipid keratopathy (yellow-white deposits along vessel tracks)
7. Ghost vessels: When the inciting stimulus resolves, vessels may regress leaving empty, non-perfused basement membrane channels (ghost vessels); these can reactivate if the stimulus recurs

1. By Depth

• Superficial (pannus): Vessels grow between the epithelium and Bowman's layer; associated with chronic hypoxia (CL wear), trachoma, vernal keratoconjunctivitis, and superior limbic keratoconjunctivitis; appears as a thin vascularised membrane advancing from the limbus
• Deep stromal: Vessels grow within the corneal stroma; associated with HSV/VZV stromal keratitis, interstitial keratitis (syphilis, tuberculosis), and chemical burns; carries a higher risk of lipid keratopathy and permanent scarring

2. By Quadrant Extent (Grading)

3. By Vessel Activity

• Active (perfused) vessels: Red, clearly visible, actively growing toward the visual axis; leaky on fluorescein angiography; require intervention
• Ghost (non-perfused) vessels: Regressed, translucent, empty basement membrane channels; not actively growing; may reactivate with recurrent stimulus; carry a residual risk of lipid keratopathy

4. Lymphangiogenesis

• Lymphatic vessels frequently co-migrate with blood vessels into the cornea; identified by LYVE-1 and podoplanin markers; corneal lymphangiogenesis is an independent risk factor for corneal graft rejection by facilitating immune cell trafficking

Contact Lens–Related

• Extended or overnight wear: Highest risk; eyelid closure during sleep already reduces corneal oxygenation; contact lenses compound this significantly
• Low-Dk/t materials: PMMA and older hydrogel lenses with low oxygen transmissibility; risk is lower but not absent with high-Dk silicone hydrogels
• Ill-fitting lenses: Tight lens fit causes limbal compression and local hypoxia
• Long cumulative wearing time: Even daily wear over many years can produce peripheral CNV

Ocular Surface and Corneal Factors

• Prior keratitis: Viral (HSK, HZK), bacterial, fungal, or parasitic keratitis leaves a pro-angiogenic stromal environment
• Limbal stem cell deficiency: Loss of limbal barrier function allows conjunctival vessel ingrowth; caused by chemical burns, Stevens-Johnson syndrome, mucous membrane pemphigoid, aniridia, or contact lens abuse
• Ocular surface inflammation: Chronic atopic, vernal, or cicatricial conjunctivitis
• Previous ocular surgery: Penetrating keratoplasty, particularly in vascularised host beds
• Corneal trauma or chemical burns: Alkali burns cause more extensive CNV than acid burns due to deeper penetration

Systemic Factors

• Systemic inflammatory diseases: Rosacea, rheumatoid arthritis, systemic vasculitides (Wegener's granulomatosis, SLE)
• Infectious systemic disease: Syphilis, tuberculosis, HIV
• Immunosuppression: Reduced ability to control corneal infections increases risk of inflammatory CNV

Primary Corneal Signs

• Active blood vessels: Bright red, perfused, tortuous vessels arising from the limbus and extending centripetally into the normally avascular cornea; may be superficial (sub-epithelial) or deep stromal
• Ghost vessels: Empty, translucent, non-perfused basement membrane channels visible on retroillumination; appear greyish or white; do not leak on fluorescein angiography
• Superficial pannus: A fibrovascular membrane overlying the corneal surface, typically superior; associated with chronic hypoxia or trachoma
• Stromal haze and scarring: Opacification along vessel tracks and in areas of prior inflammation
• Lipid keratopathy: Yellow-white crystalline or creamy deposits adjacent to or along vessel tracks; caused by lipoprotein extravasation from leaky vessels; may be dense enough to cause significant visual impairment
• Corneal oedema: Stromal oedema from concurrent endothelial dysfunction or active inflammation

Associated Ocular Signs (by Cause)

• CL-related: Peripheral superior or circumferential pannus; minimal scarring in early disease; lens deposits; reduced tear break-up time
• HSV/HZV stromal disease: Corneal hypoesthesia; KPs; stromal scarring; sectoral iris atrophy (VZV)
• Chemical burn: Extensive peripheral neovascularisation; conjunctivalisation of corneal surface; LSCD signs (loss of limbal pallisades of Vogt)
• Interstitial keratitis (syphilitic): Deep stromal vessel tracks ("salmon-pink" appearance in active disease); ghost vessels in healed disease
• Trachoma: Superior pannus; follicular conjunctival scarring; Herbert's pits at the superior limbus

Visual Symptoms

• Blurred or reduced vision: Occurs when vessels or associated lipid deposits, scarring, or oedema encroach on the visual axis; may be insidious in onset
• Glare and halos: From corneal irregular astigmatism, scarring, or lipid deposits near the pupillary zone
• Photophobia: Particularly with associated active keratitis or uveitis

Ocular Surface Symptoms

• Redness: Circumcorneal or diffuse conjunctival injection; may be minimal with chronic low-grade CNV
• Foreign body sensation: From associated ocular surface disease or corneal epithelial irregularity
• Tearing: Reflex lacrimation from corneal irritation
• Asymptomatic: Peripheral CNV — especially CL-related grade 1–2 — may be entirely asymptomatic and detected only on routine slit-lamp examination

Visual Complications

• Lipid keratopathy: Dense yellow-white lipid infiltrates along vessel tracks; may cause significant visual loss if involving the visual axis; one of the most common vision-threatening complications
• Corneal scarring and opacification: Progressive with each episode of active inflammation; permanent reduction in corneal transparency
• Irregular astigmatism: Distortion of corneal curvature from fibrovascular membrane formation and stromal remodelling
• Amblyopia: In children with significant corneal opacity obstructing the visual axis

Surgical Complications

• Corneal graft rejection: The most clinically significant complication of CNV in the context of keratoplasty; pre-existing corneal vascularisation is the leading risk factor for immune-mediated graft rejection; even ghost vessels confer elevated risk by facilitating immune cell trafficking via co-migrated lymphatic vessels
• Graft failure: Repeated rejection episodes lead to endothelial decompensation and graft failure
• Reduced contact lens tolerance: Progressive CNV forces cessation of contact lens wear

Other Complications

• Spontaneous corneal haemorrhage: Rare; from fragile, newly formed vessels
• Recurrent epithelial erosions: From disruption of the epithelial basement membrane by fibrovascular pannus
• Secondary infection: Compromised corneal barrier increases susceptibility to microbial keratitis

Systemic Diseases Associated with CNV

• Ocular rosacea: Chronic meibomian gland dysfunction, lid margin telangiectasia, and corneal pannus; corneal neovascularisation (typically inferior) is a feature of rosacea keratitis; systemic rosacea treatment (doxycycline) may reduce ocular manifestations
• Rheumatoid arthritis (RA): Peripheral ulcerative keratitis (PUK) with associated neovascularisation is the most severe corneal manifestation of RA; requires systemic immunosuppression; CNV may be a marker of inadequate disease control
• Systemic vasculitides: Granulomatosis with polyangiitis (formerly Wegener's), systemic lupus erythematosus, and polyarteritis nodosa can cause PUK and secondary CNV; corneal findings may be the presenting feature of undiagnosed systemic vasculitis
• Syphilis (Treponema pallidum): Interstitial keratitis is a classic manifestation of congenital and acquired syphilis; deep stromal vessels producing a "salmon-pink" cornea in the active phase; ghost vessels persist in healed disease; requires systemic penicillin
• Tuberculosis: Phlyctenular keratoconjunctivitis and interstitial keratitis associated with TB hypersensitivity; CNV along phlycten track; systemic anti-TB therapy required
• Sarcoidosis: Granulomatous anterior uveitis with secondary corneal involvement; band keratopathy and occasional CNV
• HIV/AIDS: Increased susceptibility to infectious keratitis (HSV, HZV, Acanthamoeba, microsporidial) with secondary CNV; CNV in a young patient warrants HIV screening if no other cause is identified
• Mucous membrane pemphigoid / Stevens-Johnson syndrome: Severe cicatrising ocular surface disease with LSCD; secondary corneal conjunctivalisation and CNV; requires systemic immunosuppression

Clinical Assessment

• History: Contact lens wear type, duration, and modality; prior ocular infections or surgery; chemical exposure; systemic diseases and medications; family history
• Slit-lamp biomicroscopy: The gold standard; assess vessel depth (superficial vs. stromal), number of quadrants involved, distance from limbus, activity (perfused vs. ghost), associated lipid deposits, pannus, and corneal scarring
• Corneal sensation testing: Reduced sensation with HSV/HZV-related CNV; Cochet-Bonnet aesthesiometer or cotton-wool wisp
• Visual acuity: Document BCVA; formal refraction to assess contribution of irregular astigmatism

Imaging and Ancillary Tests

• Corneal photography: Documents the extent and progression of CNV; grading systems (quadrant, clock-hours, area measurement) allow longitudinal monitoring
• Fluorescein angiography (FA): Distinguishes active (leaking) from ghost (non-perfused) vessels; maps the entire vascular network including sub-clinical vessels not visible on slit-lamp; the gold standard for vessel activity assessment
• Anterior segment OCT (AS-OCT): Determines depth of vessels (superficial vs. stromal vs. deep stromal); quantifies stromal oedema and corneal thickness; monitors treatment response
• In vivo confocal microscopy (IVCM): Allows visualisation of stromal vessels, inflammatory cells, keratocytes, and nerve fibres at the cellular level; useful in assessing CNV associated with LSCD or post-infection scarring
• Corneal topography / tomography: Assesses associated irregular astigmatism from fibrovascular pannus; useful pre-operatively

Systemic Investigation (Selected Cases)

• Syphilis serology (RPR/VDRL + TPHA/FTA-ABS) for bilateral deep stromal CNV
• ANCA, ANA, RF, complement for suspected vasculitis-associated PUK
• Tuberculin skin test (Mantoux) or IGRA for phlyctenular CNV in endemic populations
• HIV serology in young patients with unexplained or severe CNV

1. Treat the Underlying Cause

• Contact lens–related CNV: Reduce daily wear time; switch to higher Dk/t silicone hydrogel lenses; change from extended to daily wear modality; switch to daily disposable lenses; consider lens cessation if grade ≥2 or progression toward visual axis
• Infectious keratitis: Appropriate antimicrobial therapy (antiviral for HSV/HZV, antibacterial, antifungal, antiparasitic); anti-VEGF therapy as adjunct once active infection is controlled
• Inflammatory disease: Treat the underlying systemic condition (systemic immunosuppression for RA, vasculitis; systemic antibiotics for syphilis/TB); topical steroids for immune-mediated stromal keratitis
• LSCD: Address the root cause; limbal stem cell transplantation (LSCT) for significant LSCD-related CNV

2. Anti-VEGF Therapy

• Subconjunctival bevacizumab (1.25–2.5 mg/0.05 mL): Injected adjacent to the leading edge of neovascularisation; repeated at 4–6 week intervals as required; most effective for active vessels; performed by ophthalmologist
• Topical bevacizumab (1% solution, off-label): Applied 3–4 times daily; may reduce vessel calibre and length; less effective for deep stromal vessels; can be prescribed as a compounded formulation
• Ranibizumab and other VEGF inhibitors: Used off-label; limited comparative data versus bevacizumab for CNV
• Best results when combined with elimination of the inciting stimulus (e.g., lens cessation + anti-VEGF)

3. Topical Corticosteroids

• Prednisolone acetate 1% or fluorometholone 0.1% for inflammation-driven CNV (immune stromal keratitis, uveitis-associated)
• Reduce pro-angiogenic cytokine release (IL-1, IL-8) and VEGF expression
• Monitor IOP with prolonged use; use lowest effective dose and taper
• Do not use as monotherapy without antiviral cover in herpetic disease

4. Fine-Needle Diathermy (FND)

• Electrocauterisation of corneal vessels using a fine needle under topical anaesthesia; performed at the slit-lamp
• Most effective for superficial, well-defined vessels; can be combined with anti-VEGF therapy
• May produce transient corneal haze; risk of scarring with deep vessels
• Used primarily for ghost vessel occlusion prior to corneal transplantation to reduce rejection risk

5. Laser Treatment

• Photodynamic therapy (PDT): Verteporfin-activated laser selectively destroys active neovascular vessels; used for deep stromal CNV; more targeted than diathermy
• Argon laser photocoagulation: Occludes feeder vessels; less commonly used due to risk of corneal scarring

6. Surgical Management

• Limbal stem cell transplantation (LSCT): Conjunctival limbal autograft (CLAU), cultivated limbal epithelial transplantation (CLET), or allograft for LSCD-related CNV
• Amniotic membrane transplantation: Reduces inflammation and promotes re-epithelialisation; useful adjunct in acute chemical burns and LSCD
• Penetrating or lamellar keratoplasty: For vision-threatening corneal scarring; pre-operative vessel occlusion with diathermy or anti-VEGF reduces rejection risk

Management Summary Table

Prognosis by Disease Type

• CL-related CNV (grade 1–2): Good; vessels typically regress or stabilise with lens modification or cessation; ghost vessels may persist permanently but do not threaten vision in peripheral location
• Inflammation-driven CNV (HSV/HZV stromal): Variable; depends on frequency of recurrence and adequacy of treatment; each inflammatory episode risks adding vessel extent and scarring
• CNV involving the visual axis: Guarded; associated lipid keratopathy and scarring may permanently reduce visual acuity; corneal transplantation may be required
• LSCD-related CNV: Poor without definitive surgical intervention (LSCT); progressive conjunctivalisation of the corneal surface leads to persistent vascularisation and scarring
• Post-keratoplasty CNV: Significantly worsens graft survival; up to 4-fold increase in rejection risk with pre-existing stromal vascularisation; long-term topical steroid prophylaxis and surveillance essential

Prognostic Factors