Neovascularization, Corneal, CL-related 

Updated: Aug 19, 2015
Author: Barry A Weissman, OD, PhD, FAAO; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

The normal cornea is transparent and maintains itself as an immune privileged site, in part because it is avascular. Ocular insult and ocular hypoxia due to infectious keratitis, immunological conditions, corneal trauma, alkali injury, and contact lens (CL) wear[1, 2, 3] can encourage new blood vessels to grow from the limbus and, hence, neovascularization (NV). NV is generally accompanied with an inflammatory response and always represents a state of disease.

With CL wear, superficial NV is more common than deep stromal vessels. It is speculated that deep stromal NV may reflect a more profound insult (hypoxia) compared to that which generates only superficial NV. Both superficial and deep stromal NV are reported with the use of hydrogel, hard (polymethyl methacrylate [PMMA]), rigid gas permeable CLs, and scleral lenses, especially with a history of aphakia, extended wear, poor compliance, low oxygen permeable CLs, long-term CL wear (many years), and poor follow-up care.[4] Deep stromal NV is serious, possibly leading to loss of optical transparency of the tissue through stromal hemorrhage, scarring, and lipid deposition.

Pathophysiology

NV is believed to result from an inflammatory or hypoxic disruption of an exquisitely balanced corneal immune system.[5, 6, 7] Hydrogel, hard, rigid gas-permeable CLs and scleral lenses stimulate NV 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.[8]

Epithelial trauma[9] and/or hypoxia[10] may stimulate production of angiogenic factors by local epithelial cells, keratocytes, and infiltrating leukocytes[11, 12] (eg, macrophages, neutrophils). Some of these factors (ie, acidic and basic fibroblast growth factors, interleukin 1 [IL-1], and vascular endothelial growth factor [VEGF]) have been identified and isolated from cornea and tears. Angiogenic factors[13] stimulate a 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.[14]

Epidemiology

Frequency

United States

Prevalence among CL wearers ranges from 0.1%-37%.[15, 16] Prevalence is lower in those who wear (rigid) gas permeable lenses than in soft CL wearers because the diameter of soft CLs are larger and cover the entire cornea, limbus, and surrounding perilimbal conjunctiva, decreasing oxygen from the atmosphere.[17, 18, 3] There is an increased risk for patients who have high myopia, dry eyes, or ocular surface disease (eg, idiopathic or associated with other diseases, such as acne rosacea, Sjögren syndrome, and immune dysfunction). There is also an increased risk in those who use extended wear hydrogel CLs and in those who use aphakic or therapeutic CLs.

Silicone hydrogel CLs with oxygen permeabilities approaching 100-200 Fatt Dk units have decreased the incidence of corneal NV among CL users.[16]

Mortality/Morbidity

This condition is not associated with mortality. Symptoms can range from asymptomatic and mild to severe with loss of vision. NV in the cornea's visual axis can threaten visual function directly or through secondary hemorrhage,[19] scarring, or lipid deposition.

Incidence of subsequent corneal graft rejection is estimated by one study to be 1.7 times higher in a setting of vascularized rather than nonvascularized host corneas. Risk and severity of a graft rejection is believed to depend on the depth and extent of NV; hence, deep stromal vessels incur more risk than superficial pannus, and the more quadrants involved, the higher the risk of rejection.[20]

Race

No ethnic predilection exists.

Sex

No gender predilection exists.

Age

NV can occur and progress at any age.

 

Presentation

History

Patients are almost always asymptomatic unless the central visual axis is involved.

Patients with CL-induced NV are often aphakic, report a history of sleeping or napping with their CLs on their eyes in an extended wear modality, or report many years of contact lens wear, especially with low oxygen permeability CLs.

Often, a history of poor compliance with proper CL wear (eg, wear extended intentionally or unintentionally through multiple sleep cycles) and care is present. Alternatively, the CLs may be "tight" (eg, restrict tear exchange) or may have low oxygen permeability (eg PMMA lenses or nonsilicone hydrogel CLs).

Physical

Slit lamp biomicroscopy

NV can be observed in the cornea via slit lamp biomicroscopy. It can be seen in direct illumination or in retroillumination as a continuum of the limbal peripheral vessel arcades. Measuring both the extent and the depth of the corneal NV is important to assist in monitoring this disease. NV can be categorized based on its source (ie, conjunctival, limbal, iris), location, depth, length, branching pattern, color, leakage, and nature of blood flow (ie, presence of corneal hemorrhages).[21, 22]

Limbal hyperemia is the earliest sign of corneal neovascularization.

Superficial vessels emerge in the anterior stroma and appear as single or multiple (pannus) tortuous vessels under low magnification.

Deeper stromal vessels emerge through the cornea as straight vessels that arborize, occasionally accompanied by nerve fibers. They are generally anterior ciliary vessels, appear dark red, and do not raise the epithelium.

Active engorged vessels, occasionally surrounded by lipid exudates and exceeding 1-2 mm in length from the limbus, should raise concern. Active vessels appear bright in color and may have accompanying surrounding corneal edema and leakage.

Lipid deposition appears as yellow-white opacities at the leading edge or surrounding the stromal vessels.

Careful gonioscopy in eyes with deep NV rules out an iris angle choroidal tumor.

NV also should be differentiated at clinical examination from a conjunctival carcinoma extending onto the corneal epithelium.

Ghost vessels have no active blood circulation, represent old corneal neovascularization, and are no longer active.

Measurement of corneal sensation

Measurement of corneal sensation can be helpful in differentiating CL-related NV from a herpes simplex virus (HSV) keratitis (typically reduced sensation with HSV).

Causes

All CLs (although less so with silicone CLs) can cause NV. This includes daily and extended-wear types of any hydrogel, hard (PMMA), and rigid gas permeable CLs (including orthokeratology CLs) and scleral lenses. NV primarily is related to corneal hypoxia from CL wear and/or chronic corneal desiccation associated with the edges or rigid lenses.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

For systemic medical reasons, it is important to obtain a thorough case history of CL wear and to exclude other potential causes of corneal NV, especially if NV is seen deep in the corneal stroma. Pay attention to causes of interstitial keratitis such as herpes keratitis, tuberculosis, measles, and syphilis.

Laboratory studies may include the following:

  • Herpes cultures if herpes is suspected and the diagnosis cannot be made on clinical examination
  • Tuberculosis (TB) skin test and/or chest radiography if TB is suspected
  • Rapid plasma reagin (RPR) and microhemagglutination- Treponema pallidum (MHA-TP) if syphilis is suspected
 

Treatment

Medical Care

The primary treatment of NV is eliminating the underlying cause. Ghost vessels remain even after NV is treated. Details are as follows:

  • For patients who wear CLs, NV can be minimized by decreasing CL wear time, discontinuing extended or all CL wear, refitting RGP CLs with improved edge designs and/or less tight (looser) fitting lenses, or refitting into higher oxygen permeable (Dk) CLs, such as high oxygen permeable (Dk) rigid gas permeable or soft silicone hydrogel lenses.
  • Since CL-induced NV is most common in patients who are highly nearsighted, have dry eyes, and use extended wear hydrogel CLs, these patients, depending on severity, should be refitted into daily wear, higher oxygen permeable silicone CLs [23] or daily wear rigid gas permeable CLs when NV is diagnosed.
  • For those patients with severe corneal NV, CL wear may be contraindicated.
  • Other coinciding injurious factors, such as acne rosacea, blepharitis, dry eye, and Staphylococcus hypersensitivity, should be addressed if present.

Topical corticosteroids can be used for active neovascularization. Discontinuation of CL wear is of essence during the recovery period for these patients. Corticosteroids can increase the risk of infection during CL wear, as well as glaucoma and cataracts.

More recently, topical and subconjunctival bevacizumab[24, 25, 26, 27] in combination with superficial keratectomy on ocular surface NV has shown promise as a new treatment option. Bevacizumab prevents the receptor binding of the soluble form of VEGF and, hence, prevents the process of the angiogenic pathway on superficial vessels. Bevacizumab alone is ineffective against existing blood vessels and is most effective in earlier than later stages of NV.[28]

Because angiogenesis is a multistep process, many treatments in animal models are being tested to inhibit the migration, proliferation, and differentiation of endothelial cells. Some authors have discussed treatment in animal models with angiostatic steroids, heparin,[29, 30] systemic amiloride, cyclosporine A,[31] thalidomide,[32] arachidonic acid inhibitors, flurbiprofen, curcumin,[33] and systemic suppression medications (cytotoxic agents).

Surgical Care

Severe corneal NV may result in central corneal scarring,[34] and permanent reduction in vision. In that case, and if medical management does not recover visual acuity, corneal transplantation may be indicated. Depending of the amount of neovascularization present (especially deep NV) such cornea grafts may be considered high risk.[35]

Investigators have treated corneal NV with photodynamic therapy[36, 37, 38] and argon laser obliteration of the vessel lumen. This can be achieved in the corneal part of the vessels (accessible to be lasered) but usually has a short-term effect, as the vessel lumen invariably reopens. Argon laser pannus obliteration is mainly a temporizing measure.

Hyperbaric oxygen treatment has been used with limited success. This treatment modality aims to suppress angiogenesis by supplying the corneal tissue with redundant oxygen supply.

Amniotic membrane transplantation regenerates the ocular surface and thereby prevents neovascularization.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Corticosteroids

Class Summary

Usually decrease inflammation that aggravates neovascularization.

Prednisolone ophthalmic (Omnipred, Pred Forte, Pred Mild)

Effective topical ophthalmic steroid use decreases the angiogenic effect during NV. The steroids decrease inflammation by reducing capillary permeability and cellular exudation, suppress lymphocytic proliferation, inhibit phospholipase A synthesis, and inhibit cell-mediated immune responses. Use of steroids is limited for short-term use only owing to the many side effects, including cataracts and glaucoma. Milder steroids such as loteprednol have lower risks of cataracts and glaucoma and are preferred over stronger steroids in these patients.

Loteprednol ophthalmic (Alrex, Lotemax)

Prevents inflammation by inhibiting capillary dilation, leukocyte formation, and edema. It is a mild corticosteroid with lower risks of developing cataracts and glaucoma and is preferred over stronger steroids in these patients.

Vascular Endothelial Growth Factor (VEGF) Inhibitors

Class Summary

Anti-VEGF antibodies bind and inactivate VEGF, which is an important mediator of angiogenesis that is upregulated during neovascularization. Anti-VEGF agents show promise in the treatment of severe corneal neovascularization though perhaps are excessive for contact lens–induced NV.

Bevacizumab (Avastin)

Monoclonal antibody that binds to and neutralizes vascular endothelial growth factor (VEGF). The binding of the monoclonal antibody to VEGF may inhibit the formation of new blood vessels, which may in turn reduce the growth of all tissues.

Ranibizumab (Lucentis)

Monoclonal antibody that binds to and neutralizes vascular endothelial growth factor A (VEGF-A). The binding of the monoclonal antibody to VEGF may inhibit the formation of new blood vessels, which may in turn reduce the growth of all tissues.

 

Follow-up

Further Outpatient Care

See the list below:

  • Monitor CL patients with corneal NV more frequently than nonpathological healthy CL wearers,[39] perhaps using clinical photography.

  • Provide CL evaluations at 3- to 4-month intervals in the absence of symptoms; the ophthalmic clinician can address promptly any growth of vessels by modifying or discontinuing CL use (or changes in CL fit and optics).

  • Reexamine patients using topical steroids more frequently, especially to monitor their intraocular pressure.

Further Inpatient Care

See the list below:

  • Patients are treated on an outpatient basis. In extreme circumstances, where compliance, secondary infection,or impending perforation exists, a brief hospital stay may be indicated.

Inpatient & Outpatient Medications

See the list below:

  • Monitor patients using topical steroids every few weeks to check the intraocular pressures and evaluate the corneal NV.

  • As the NV improves, the steroids can be tapered slowly and CL wear can be resumed on a limited basis after termination of the steroid use.

Deterrence/Prevention

See the list below:

  • Steps that can be taken to avoid corneal NV include avoiding overnight (extended) wear and CL fits that have poor edges or are too tight, while maximizing the oxygen permeability of CLs and the appropriate use of lubricating drops while the CLs are on the eyes.

Complications

See the list below:

  • New blood vessels are known to be leaky and occasionally deposit opaque material (eg, lipids, cholesterol) in the normally transparent cornea.[34] If the vessels extend to the point where such deposits occur in the visual axis, they can compromise vision.

    • These lipid deposits can resolve when the neovascularization disappears; however, this process can take weeks to months, and the lipid may never disappear.

    • Visual compromise due to deposits from corneal neovascularization occasionally requires corneal transplantation as treatment.

Prognosis

See the list below:

  • The prognosis for eyes with 1-2 mm of peripheral superficial corneal NV is very good. The prognosis for eyes with a significant degree (eg, 2-4 mm) of deep corneal NV is fairly good if treated appropriately. The prognosis for eyes with greater than 4 mm of deep stromal vessels, especially if there is significant lipid deposition, is guarded.

  • The success rate for corneal transplants in eyes with significant deep corneal NV is decreased because of the increased risk of graft rejection.

Patient Education

See the list below:

  • Because this is a silent disease, at least until the vessels compromise central vision, educate patients about the following:

    • Existence of CL-induced corneal NV

    • Course of corneal NV

    • Probable causes of corneal NV

    • Necessary treatment to minimize visual loss