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HomemipatientCorneal Graft Neovascularisation

Corneal Graft Neovascularisation

Delving into a patient’s complex eye health history and a lot of thinking outside the box can bring a happy resolution for previously unsolvable vision issues.

In walks my patient. Quietly confident, affable, mid 50s, with the demeanour and insight of the really sharp medical specialist that he turns out to be. He needs to see as clearly as possible to look after his patients and perform specialised microscopy work. Plus work and leisure means lots of time spent on digital devices. It only takes a few sentences to establish that he is incredibly knowledgeable, not just about his eyes, but generally about all things medical, and the severity of his keratoconus.

Ever since moving to Sydney a few years ago, he had been dissatisfied with the vision and comfort experienced from his contact lenses. He also described developing corneal neovascularisation in his left host cornea immediately after his full thickness corneal keratoplasty in New Zealand in 1986. This was the result of a near miss with corneal graft rejection at that time.

Minimising Rejection, Inflammation and Infection

In comparison with other tissues in the body, the eye has a unique blood barrier, and limited lymphatic drainage into the general circulation, and so, very cleverly, has some level of immune privilege. This means there is generally a lack of immune response to corneal allograft transplants, i.e., transplantation of human corneal tissue in the eye compared to transplantation of other organs in the body.1 Despite this, the incidence of corneal graft rejection a year after transplantation is approximately 10 per cent.1,2 Even when successful, a future corneal transplant rejection can eventually occur over a prolonged period of time.1,2,3

there is generally a lack of immune response to corneal allograft transplants

When prescribing contact lenses in keratoconus or in any situation of corneal compromise, we know that the compromised, fragile cornea has increased susceptibility to abrasion, adverse inflammatory events and infections.4 Additionally, we are aware there is twice the risk of inducing corneal scarring in keratoconus patients who wear contact lenses vs. those who do not.5

Corneal scarring and keratoconus are the primary reasons for corneal grafts,5 and, as we know, repeated corneal graft surgery results in higher rates of graft rejection and a shorter graft lifespan.3 Yet, the contact lens is essential to restore the patient to functional vision, and the visual improvement is profound.

Why Does Corneal Neovascularisation Happen?

It is well established that corneal neovascularisation is a significant risk factor for corneal graft failure, by triggering an irreversible immunological rejection. One of the best references for this is the Australian Corneal Graft Registry (ACGR),6 which show that the degree of neovascularisation is proportional to the risk of failure, based on number of quadrants involved.

The leading reason for corneal neovascularisation is usually herpetic keratitis.6 Ophthalmologists and optometrists and contact lens prescribers need to be mindful that herpetic keratitis by its very nature is proinflammatory, and whilst contact lenses can be carefully utilised to restore eyesight that would otherwise not be possible to attain, the contact lens itself is also pro-inflammatory.

Human leukocyte antigens (HLA) are glycoproteins that function as cell surface antigens and allow us to recognise what is part of our genetic material defined by ‘self’ vs. genetic material that is ‘non-self’. After a corneal transplant occurs, it takes up to 14 days for this recognition of donor tissue, and, if this is activated, a steadily escalating inflammatory cascade occurs that requires fairly moderate to strong topical corticosteroid therapy to circumvent and retain the graft tissue.

In terms of known high risk factors for corneal graft failure, Williams et al. showed that key predictors were an indication for graft other than keratoconus or corneal dystrophy; a failed previous graft in the other eye; aphakia; the presence of inflammation at the time of graft; an anterior chamber or iris-clip intraocular lens; a graft size outside the range of 7 to 7.9 mm diameter; and, relevant to this case, corneal vascularisation occurring in the postoperative period.6

This image depicts a corneal graft rejection with corneal oedema, stromal haze, and the Khodadoust line delineating corneal rejection (highlighted by arrow). The Khodadoust line highlights a corneal graft rejection line of white blood cells on the endothelium. This line typically begins in one area where the corneal rejection starts and eventually travels across the corneal endothelium. As the inferior cornea displays much more stromal haze and corneal oedema, in this example, it can be seen that the corneal rejection began inferonasally and is migrating across to the superior corneal tissue.
If a thin optic section is used, if the line of white blood cells appears to be on the level of the corneal endothelium, it assists in confirming it is a Khodadoust line. Photos courtesy of webeye.ophth.uiowa.edu/eyeforum/atlas/pages/khodadoust-line.htm

Physiologically, induced corneal hypoxia causes cells to release inflammatory cytokines such as Vascular Endothelial Growth Factor (VEGF), which can induce new vascular growth.7 Keratocytes, as we know, are the normally dormant stromal cells that go into ‘repair mode’ when triggered by a stimulus. It is thought that keratoconus accelerates the programmed death of keratocytes. This keratocyte apoptosis may occur following an injury, minor external trauma (e.g. eye rubbing, poorly fitting contact lenses or ocular allergies) and this releases cytokines from the epithelium to transmit a message for keratocyte apoptosis.8 It is theorised that perhaps keratoconus, traditionally thought of as a non-inflammatory condition,9 perhaps isn’t all that non-inflammatory after all, and stimulates a low-grade inflammatory response.10

This is supported by corneal neovascularisation seen associated with keratoconus, and also because keratoconus is often seen in conjunction with inflammatory conditions such as ocular allergy signs and symptoms, especially allergic conjunctivitis, vernal keratoconjunctivitis and contact lens-related giant papillary conjunctivitis.

Treatments for corneal neovascularisation include a range of treatment options including topical steroid, topical or subconjunctival bevacizumab (Avastin), and cautery. There seems to be a lack of strong high-level evidence that any of them change the long-term outcome of corneal grafting, and each treatment option carries their own not insignificant risks. In the opinion of some subspecialty corneal ophthalmologists, the latter two, Avastin or cautery, would be given most consideration prior to any graft being undertaken on an eye with extensive focal or diffuse neovascularisation, to lower the subsequent risk of rejection. Yet, in the case of patients with neovascularisation from long-term contact lens wear, this often shows as mild diffuse peripheral neovascularisation. In the opinion of some corneal ophthalmologists, the contact lens wearing patients with this type of neovascularisation might be best on a carefully administered and observed course of topical steroids, rather than the other options.

Is There a Happy Ending?

So, back to my patient in the chair, forearmed with that background information, how did things turn out for him? You’ll need to read the next column of ‘mipatient’ to find out. There is an interesting twist in the tale of his journey.

To explain the cryptic twist, as the wonderfully talented artist Michelangelo once said, with reference to the masterpieces he created, “If people knew how hard I worked to achieve my mastery, it wouldn’t seem so wonderful after all”.

Margaret Lam is an optometrist with practices in greater Sydney and Sydney CBD. Margaret practises full scope optometry, but with a passionate interest in contact lenses, retail aspects of optometry and successful patient communication. She has extensive experience in specialty contact lens fitting in corneal ectasia, keratoconus and orthokeratology, and is a past recipient of the Neville Fulthorpe Award for Clinical Excellence.

Margaret writes ‘mipatient’ on alternate months wth Jessica Chi.

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2. Williams K, Coster, D. The immunobiology of corneal transplantation. Transplantation. 2007 Oct 15;84(7):
3. Bersudsky V,Blum-Hareuveni T, Rehany U,Rumelt S. The profile of repeated corneal transplantation. Ophthalmology. 2001 Mar;108(3):461-9.
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5. Barr JT, Wilson BS, Gordon MO, et al. Estimation of the incidence and factors predictive of corneal scarring in the Collaborative Longitudinal Evaluation Of Keratoconus (CLEK) Study. Cornea 2006 Jan;25(1):16-25.
6. Keryn A. Williams, KA, Roder D, Esterman A, Muehlberg SM, Coster DJ. Factors Predictive of Corneal Graft Survival: Report from the Australian Corneal GraftRegistry, Ophthalmology 99,3, March 1992, 403-414.
7. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may

mediate hypoxia induced angiogenesis. Nature 1992;359:843-845.
8. Kim WJ, Rabinowitz YS, Meisler DM, Wilson SE. Keratocyte apoptosis associated with keratoconus. Exp Eye Res 1999 Nov;69(5):475-81.
9. Rachmer JH, Feder RS, Belin MW. Keratoconus and related non-inflammatory corneal thinning disorders. Surv. Ophthalmol 1984; 28: 293–322.
10. Yeung KK, and Weissman BA. 32nd Annual Contact Lens Report: An Updated Perspective on Keratoconus. Rev Optom Apr 2004.