Corneal Ulcers - A Logical Approach to a Potential Catastrophe
World Small Animal Veterinary Association World Congress Proceedings, 2015
D. Williams, MA, VetMD, PhD, CertVOphthal, CertWEL, FRCVS
Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

Corneal ulceration is a condition that always requires urgent attention as it can present as, or progress to, painful blinding ocular disease. We will discuss a rational approach to any corneal ulcer a little later, but first we need to understand the basic biology - the anatomy and physiology - of the cornea.

The Cornea - Some Basic Science to Start With

It is, to my mind, quite remarkable that the cornea is a solid structure exposed continually to the ravages of the outside world on the one hand and the pressure of the aqueous humour on the other and yet maintaining perfect transparency and regular structure which allows it to be a major refractive agency in the eye and a flawless transmitter of visual images. This perfect structure consists of an epithelium, stroma and endothelium all of which act together to maintain the transparency and protection characteristic of the cornea.

The corneal epithelium is a stratified squamous structure with a stem cell population at the limbus continually producing new basal cells which migrate to the central cornea and then become wing cells, rising up the stratified layers of cells and becoming more squamous, losing cell organelles until they are eventually desquamated as the lids rub them off the corneal surface. This mechanism of epithelial rejuvenation, termed the X, Y, X hypothesis by Richard Thoft where X stands for epithelial cell formation at the limbus, Y the move to the central cornea and Z the desquamation from the ocular surface, explains how the normal healthy cornea heals epithelial erosions rapidly. It is only where age slows epithelial cell generation or more commonly where a defect in attachment between the basal cells and the underlying basement membrane occurs, that superficial corneal epithelial erosions fail to heal. These basal epithelial cells attach to the basement membrane with hemidesmosomes, rather to my mind like spot welds. They link to each other with tight junctions which prevent water movement through the epithelial layer. It is only where an epithelial erosion occurs that we see water movement from the tears into the underlying stroma, with the uptake of the highly polar molecule fluorescein with characteristic dye uptake in an ulcer.

The stroma, unlike the epithelium is highly hydrophilic, this because it is composed of collagen fibrils which are held apart by water molecules attracted to the negatively charged proteoglycans which are attached to defined sites on the collagen fibrils. In this way only just enough water is held in the cornea, keeping it transparent. The endothelium of the cornea acts continually to pump excess water across and into the aqueous humour, thus preventing corneal oedema and the associated translucency of the cornea seen when there is endothelial damage or dysfunction. The key reason for corneal transparency, and the reason why it is lost in corneal oedema, is that the collagen fibrils are exactly the same diameter and held at exactly the same distance apart, both of these measurements being around 22–25 nm. As the wavelength of visible light is around 20 times this measurement light passes unimpeded through the cornea. Excess water in the stroma leads to a variation in intrafibrillar distance with the classic ground-glass appearance of the cornea where endothelial function is lost through trauma, endothelial dystrophy, degeneration or pressure damage in glaucoma.

More than that, we now recognise that there are high levels of various crystallin molecules in the cornea which may well be responsible for maintaining transparency even where there are cells such as epithelial cells and keratocytes with organelles which one might think would reduce transparency. In rather the same way that enzymes and heat shock proteins can crystallise in the lens, similar proteins at high concentrations in the cornea can render the structure transparent.

The endothelium has a thick basement membrane, Descemet's membrane, which we see in the critical situation of a deep corneal ulcer which has progressed as far as Descemet's membrane which bulges from the corneal surface, showing its elastic properties. As with all epithelial basement membranes Descemet's membrane is composed of collagen type IV and the glycoprotein laminin and has collagen type VII filaments anchoring the overlying cells.

The endothelium is derived from the neural crest and its cells are generally considered to be post-mitotic and unable to regenerate once damaged. This may not be the case in all companion animal species and in rabbits and maybe even young cats and dogs there may be some endothelial mitotic activity. The endothelium forms a single cell layer crucially having tight junctions between each of the hexagonal cells. This allows the cells to control movement of water and solutes with leakage of these solutes and nutrients from the aqueous humour into the corneal stroma while at the same time pumping water out into the aqueous humour. This dual function is known as the pump-leak hypothesis and is an energy-driven process requiring ATP consumption by the sodium/potassium ATPase pump and carbonic anhydrase (CA). Bicarbonate ions produced by CA action are translocated across the cell membrane and water follows. Well that is the theory, although the fact that carbonic anhydrase inhibitors such as dorzolamide used as anti-glaucoma drugs do not result in corneal oedema might question the role of CA in corneal transparency. In fact one can see an increase in corneal thickness in patients taking dorzolamide and there may be differences in the effect of these CA inhibitors on corneal endothelial and ciliary body epithelial CA activity, though the question still rather hangs unanswered in midair, or mid-aqueous maybe one should say!

Dealing with the Corneal Ulcer

There are three key questions to ask of any ulcer. First what is the cause? Second how deep is the ulcer and third is the ulcer healing? Regarding aetiology we can have exogenous trauma - the history often gives a good clue here although often trauma is a default diagnosis where we do not have clear evidence. Next we have what I call endogenous trauma, a factor in the eye which predisposes to ulceration. This can be distichiasis, ectopic cilia, trichiasis or a basement membrane dystrophy of which we will talk more later. KCS and corneal oedema are two other conditions which may well lead to ulceration. Finally infection may range from feline herpes virus in cats to Pseudomonas in melting ulcers across the species.

Regarding depth we can have superficial/epithelial erosions - often these are traumatic but a non-healing superficial erosion often involves a basement membrane defect. Mid-depth stromal ulcers may involve persistent corneal exposure, KCS or a persistent irritative focus like facial fold hair. A deep stromal/ulcer or a bulging descemetocele where the ulceration has reached Descemet's membrane are true emergencies.

Concerning healing, a superficial ulcer should heal in 5 days or so as the natural flow of cells from the stem cell population in the limbus to the central cornea restores epithelial integrity. As noted before a superficial non-healing ulcer may involve basement membrane dystrophy where not healing is related to nonadherence of the epithelial cells to the underling stroma. Deeper ulcers take longer but should epithelialise to a facet quickly. Thus one should always note signs of healing in a normal eye with a corneal ulcer, specifically epithelialisation and vascularisation.

What to Do Once You've Answered Those Questions...

For superficial traumatic healing ulcers what is required may just be a few days for healing but to protect from infection it is generally considered that one should give topical antibiotic drops. In a superficial non-healing ulcer the key is to debride dead epithelium under local anaesthetic, and then to perform grid keratotomy or diamond burr debridement to encourage/facilitate healing. One might also consider protecting the ocular surface with a contact lens or third eyelid flap and this would be particularly worthwhile in amid-stromal healing ulcer. A deep ulcer or descemetocele generally requires surgery using a pedicle conjunctival flap or corneoconjunctival transposition to prevent perforation.

Basement Membrane Dystrophy

This condition, causing persistent, recurrent superficial epithelial erosion is also known as the indolent ulcer or Boxer ulcer. It occurs in other breeds, particularly the Cardigan Corgi but is most often seen in the Boxer. A reduction in the hemidesmosome number seems to be associated with the poor epithelial adhesion. Protection of the healing ulcer with a contact lens or third eyelid flap once dead non-adherent epithelium has been removed is important to facilitate healing. A grid keratotomy or diamond burr debridement is easy to perform under local anaesthetic and probably disrupts abnormal basement membrane and maybe also creates an inflammatory cell bed onto which the migrating epithelial cells can readily adhere. Recurrence is, however, still possible or even likely and owners should be warned that they are likely to get to know the vet's waiting room pretty well!

The Melting Ulcer

In any ulcer (in reality any cornea diseased or healthy) there is a balance between collagenases breaking down the stroma and collagen production by stromal fibroblasts. Where a bacterial population like invading Pseudomonas species synthesises its own collagenases, or a profound neutrophil infiltration overloads the stroma with endogenous matrix metalloproteinases, this balance can be tipped to produce stromal melting. The cornea turns white and fluid and will soon perforate. Treatment must include antibiotic to reduce bacterial infection - gentamicin or polymyxin/bacitracin or better still a fluoroquinolone together with anti-collagenase treatment - autologous serum (contains protease inhibitors like alpha-2-macroglobulin), EDTA (binds calcium required as an enzyme cofactor), acetylcysteine (binds zinc similarly needed as a cofactor).

A New Way Forward

Having said all of that a recently developed cross-linked hyaluronan polymer gel Remend®, distributed by Bayer has been shown to promote the healing of stromal ulcers though forming a scaffold across the ocular surface and is recommended for use in any stromal ulcers. It does not work on its own in basement membrane dystrophy erosions but can improve ulcer healing after debridement. Similarly, it should not be used in the deepest ulcers liable to rupture and in descemetoceles but otherwise should be first line treatment to heal any stromal defect.


Speaker Information
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David Williams, MA, VetMD, PhD, CertVOphthal, CertWEL, FRCVS
Department of Veterinary Medicine
University of Cambridge
Cambridge, UK

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