eMedicine Specialties > Ophthalmology > Cornea

Neovascularization, Corneal, CL-related

Barry A Weissman, OD, PhD, FAAO, Chief of Contact Lens Service, Professor, Department of Ophthalmology, Jules Stein Eye Institute, University of California at Los Angeles
Karen K Yeung, OD, FAAO, Director of Optometry, Arthur Ashe Student Health and Wellness Center, University of California at Los Angeles

Updated: Apr 10, 2009

Introduction

Background

The normal cornea is transparent and maintains itself as an immune privileged site, in part because it is avascular. Ocular insult, including infectious keratitis, immunological conditions, corneal trauma, alkali injury, and contact lens wear (CL),^1,2 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]), and rigid gas permeable CLs, especially with a history of aphakia, extended wear, poor compliance, and poor follow-up care.³ 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.^4,5,6 Hydrogel, hard, and rigid gas permeable CLs 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.⁷

Epithelial trauma⁸ and/or hypoxia⁹ may stimulate production of angiogenic factors by local epithelial cells, keratocytes, and infiltrating leukocytes^10,11 (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 factors¹² 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.¹³

Frequency

United States

Prevalence among CL wearers is 1-30%; prevalence is lower in those who wear gas permeable lenses than in soft CL wearers.¹⁴ 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.

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,¹⁵ 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 upon 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.¹⁶

Race

No ethnic predilection exists.

Sex

No gender predilection exists.

Age

NV can occur and progress at any age.

Clinical

History

• Patients are almost always asymptomatic unless the central visual axis is involved.
• Patients with CL-induced NV are often aphakic or report a history of sleeping or napping with their CLs on their eyes in an extended wear modality.
• Often, a history of poor compliance with proper CL wear and care is present. The CLs may be tight.

Physical

• 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.
  • 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.
  • Active engorged vessels, occasionally surrounded by lipid exudates and exceeding 1-2 millimeters in length from the limbus, should raise concern.
  • 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.
• 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, including extended-wear hydrogel, daily-wear hydrogel, hard, and rigid gas permeable CLs, can cause corneal NV. NV primarily is related to corneal hypoxia from CL wear and chronic corneal desiccation associated with the edges or rigid lenses.

Differential Diagnoses

Other Problems to Be Considered

Trauma and other diseases that cause interstitial keratitis (eg, ocular herpes simplex and zoster virus infections, measles, tuberculosis, syphilitic keratitis, onchocerciasis)

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.
  • Herpes cultures if herpes is suspected and the diagnosis cannot be made on clinical examination
  • Tuberculosis (TB) skin test 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.
  • For patients who wear CLs, NV can be minimized by decreasing CL wear time, discontinuing 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 CLs¹⁷ 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.
• More recently, topical and subconjunctival bevacizumab¹⁸ 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. 
• 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,^19,20 systemic amiloride, cyclosporine A,²¹ thalidomide,²² arachidonic acid inhibitors, flurbiprofen, curcumin,²³ and systemic suppression medications (cytotoxic agents).

Surgical Care

• Severe corneal NV may result in central corneal scarring,²⁴ 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.²⁵
• Investigators have treated corneal NV with photodynamic therapy^26,27 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.

Medication

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

Corticosteroids

Usually decrease inflammation that aggravates neovascularization.

Prednisolone (Inflamase Forte, Pred Forte, Lotemax)

Effective topical ophthalmic steroid that can decrease inflammation by reducing capillary permeability and cellular exudation, suppressing lymphocytic proliferation, inhibiting phospholipase A synthesis, and inhibiting cell-mediated immune responses.

Dosing

Adult

1 gtt 0.125% qid

Pediatric

<2 years: Not established
>2 years: Administer as in adults

Interactions

Combination with NSAIDs may slow or delay wound healing

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypertension; known to cause cataracts, glaucoma, corneal thinning, optic nerve damage, loss of vision, and secondary ocular infection

Follow-up

Further Inpatient Care

• 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.

Further Outpatient Care

• Monitor CL patients with corneal NV more frequently than nonpathological healthy CL wearers.²⁸
• 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 on topical steroids more frequently, especially to monitor their intraocular pressure.

Inpatient & Outpatient Medications

• 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.

Deterrence/Prevention

• 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

• New blood vessels are known to be leaky and occasionally deposit opaque material (eg, lipids, cholesterol) in the normally transparent cornea.²⁴ 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

• 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

• 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

Miscellaneous

Medicolegal Pitfalls

• Missing the diagnosis of HSV infection and initiating treatment with topical corticosteroids may have disastrous consequences.
• Not treating eyes with significant corneal NV, but still with good vision, risks visual loss.

References

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2. Dixon JM, Lawaczec E. Corneal vascularization due to contact lenses. Arch Ophthalmol. 1963;69:106-9.

3. Chan WK, Weissman BA. Corneal pannus associated with contact lens wear. Am J Ophthalmol. May 1996;121(5):540-6. [Medline].

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6. Ashton N, Cook C. Mechanisms of corneal neovascularization. Brit J Ophthal. 1953;37:193-209.

7. Madigan MC, Penfold PL, Holden BA, Billson FA. Ultrastructural features of contact lens-induced deep corneal neovascularization and associated stromal leukocytes. Cornea. Apr 1990;9(2):144-51. [Medline].

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18. Qian CX, Bahar I, Levinger E, Rootman D. Combined use of superficial keratectomy and subconjunctival bevacizumab injection for corneal neovascularization. Cornea. Oct 2008;27(9):1090-2. [Medline].

19. Benelli U, Bocci G, Danesi R, Lepri A, Bernardini N, Bianchi F. The heparan sulfate suleparoide inhibits rat corneal angiogenesis and in vitro neovascularization. Exp Eye Res. Aug 1998;67(2):133-42. [Medline].

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Keywords

cornea, contact lens, neovascularization, corneal trauma

Contributor Information and Disclosures

Author

Barry A Weissman, OD, PhD, FAAO, Chief of Contact Lens Service, Professor, Department of Ophthalmology, Jules Stein Eye Institute, University of California at Los Angeles
Barry A Weissman, OD, PhD, FAAO is a member of the following medical societies: American Academy of Optometry, American Optometric Association, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Karen K Yeung, OD, FAAO, Director of Optometry, Arthur Ashe Student Health and Wellness Center, University of California at Los Angeles
Karen K Yeung, OD, FAAO is a member of the following medical societies: American Academy of Optometry
Disclosure: Nothing to disclose.

Medical Editor

Andrew W Lawton, MD, Medical Director of Neuro-Ophthalmology Service, Section of Ophthalmology, Baptist Eye Center, Baptist Health Medical Center
Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Institute
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other; Vistakon Honoraria Speaking and teaching

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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