Corneal Clarity

A review of the three faces of the corneal epithelium

Understanding the good, bad and ugly can aid the clinician in preserving its integrity.

By Thomas John, MD

Thomas John, MD, a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. E-mail him at tjcornea@gmail.com.

The corneal epithelium is a fascinating cell layer that has multiple faces — good, bad and sometimes even ugly. Here, I will explore the corneal epithelium in its resting, healthy state, and then review its altered status in traumatic and diseased states. The corneal epithelium plays an important role in the final visual quality of our patients, especially following surgery. Hence, it is important to recognize the increasing importance of this layer of cells and focus on how to protect this cell layer.

THE GOOD

Anatomy of the corneal epithelium

The corneal epithelium is a self-renewing and regenerating layer that covers the front surface of the human cornea, which usually measures about 10.5 mm vertically and 11.5 mm horizontally. Central corneal thickness is about 500 μm (515-539) and peripheral thickness of approximately 650 μm (Table 1, page 23). Although the epithelium is only about 10% of the corneal thickness it has the ability to preserve or destroy vision.

Unlike skin, this surface layer of the corneal epithelium is a non-keratinized, stratified, squamous epithelium that allows clear vision through it. The epithelial basal cells produce the basal lamina and the epithelium attaches to this basement membrane. Thus, the basal lamina attaches the corneal epithelium to the underlying stroma. If the basal lamina is destroyed, the regeneration time is about six weeks. The corneal epithelial cells attach to one another via desmosomes and to the basal lamina via hemidesmosomes and other filaments. Stable attachment of this layer to the stroma plays important and essential roles in the ability of the eye to be comfortable and symptom free.

The surface epithelial cells have microvilli and microplicae that play a role in tear film adhesion and stabilization to the corneal surface. The epithelium consists of three types of cells: inner basal, middle wing and superficial squamous cells (Table 2, page 23). Only the basal cells have mitotic activity and contribute to new cell formation; these newly formed cells are progressively pushed toward the surface. In this process, they change from the basal cells to wing cells and finally into the surface cells that are then extruded from the surface as their cell attachments, the desmosomes, break or dissolve and are then shed into the tear film that bathes the corneal surface.

Stem cell matters

While the epithelium covers the corneal surface, the important stem cells are located at the limbus, within the limbal basal epithelial cells of palisades of Vogt, and extend in a bandwidth of about 0.5 to 1.0 mm. The maximal population density of the basal cells is located in the palisade region. These limbal, basal, epithelial cells demonstrate centripetal migration where, following cell division, the epithelial cells migrate toward the central cornea and outward, toward the corneal surface.

These stem cells are pluripotent and play an important role as a source of new corneal epithelium. When they are damaged, the conjunctival epithelium can invade the corneal space. The limbal epithelial stem cells maintain the corneal epithelium. Loss of these stem cells can have a catastrophic effect on both corneal transparency and vision.

Table 1. Relative thickness of corneal layers

Table 2. Corneal epithelial cell layers

No specific marker for limbal stem cells has yet been found. Some of the available limbal stem cell markers, namely, enolase¹ and p63², are expressed not only by basal cells at the limbus, but also by a majority of basal cells of various stratified squamous epithelium, making them not specific for the stem cells. Research for a specific limbal stem cell marker continues.³ The normal replacement of the entire epithelium takes about one week.

Barrier functions

The ability of the corneal epithelium to undergo continuous renewal is an essential and integral part of normal corneal function. This epithelial renewal also helps in its barrier function from preventing surface fluid entry into the cornea and preventing harmful microorganisms from entering and infecting the cornea.

Epithelial renewal centers on a pivotal balance between epithelial cell proliferation, differentiation and cell demise. The epithelial barrier function is essential for the maintenance of corneal homeostasis and is mediated via the tight junctions and adherens junctions.

The corneal epithelium also acts as a solid barrier against drug permeation. It is interesting to note that the cornea has a tri-lamellate layout comprised of a central hydrophilic, relatively rigid, corneal stroma sandwiched between the lipophilic surface epithelium and the inner endothelium. This makes drug penetration into the human eye a difficult process.

Two common pathways have been proposed for drug molecular transportation: paracellular and transcellular. Drug molecules often use the transcellular pathway to cross the corneal barrier where the lipid solubility of the unionized drug and dissociation are constant; that is, pKa of the drug is a significant parameter for drug molecular to enter through the cornea. The pH at the absorption site also plays a role.

Herpes simplex virus dendritic ulcer.

Keep in mind that only about 5% of the free drug applied onto the corneal epithelial surface actually enters through the cornea.

Additionally, the surface epithelium provides a smooth surface that absorbs oxygen and cell nutrients from the tears that bathe the corneal surface and then distributes these nutrients to corneal tissues. In the human body, the cornea is one of the most sensitive tissues due to its rich innervation with sensory nerves through the ophthalmic division of the trigeminal nerve. According to current research, the density of corneal pain receptors is 300 to 600 times greater than the skin, and 20 to 40 times greater than the dental pulp.⁴ Hence, corneal surface injury can be extremely painful.

THE BAD

Surface compromise

When this surface layer is compromised, for example, in a contact-lens-related abrasion, bacteria such as Pseudomonas aeruginosa can adhere to the disrupted edges of the epithelium and enter the corneal stroma. From there, it can rapidly progress into a corneal ulcer. If the clinician does not treat it optimally, the corneal ulcer can progress to corneal perforation and even endophthalmitis, possibly resulting in loss of the eye.

When the surface epithelium is injured secondary to a fingernail injury, a tree-branch abrasion or a paper-edge abrasion, it can progress to a recurrent erosion. The individual often awakes with significant pain, tearing, photophobia and, frequently, blurred vision. In addition to medical treatment, the patient may require a more definitive therapy such as corneal micropunctures for more permanent attachment of the loose epithelium to the underlying corneal stroma.

When a surface layer scratch results in an abrasion, the patient experiences pain due to the rich innervation of the cornea. This usually heals rapidly in the absence of any ocular surface issues and without permanent damage to the cornea.

Non-traumatic corneal compromises

In conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and vitamin A deficiency, however, the normal corneal epithelium is often transformed, resulting in surface keratinization. Depending on the severity and location, this may result in loss of translucency and even in blindness.

When it comes to herpes virus infection of the corneal epithelium, one must differentiate between herpes zoster and simplex (Figure), because the former often requires topical corticosteroid, a drug class contraindicated in the latter. Because it is essentially a clinical diagnosis, the clinician should be familiar between the two dendritic patterns. The clinical history and findings further assist in making the proper diagnosis.

Corneal dystrophies can involve the corneal epithelium, including map-dot-fingerprint dystrophy, Meesman’s, Reis-Bücklers, Lisch, lattice and Thiel-Behnke dystrophies. The findings are usually bilateral. Recognizing the clinical pattern, along with the patient’s history, assist in making the diagnosis. Of these, the Lisch epithelial dystrophy is unusual in that it does not cause spontaneous corneal erosions and it is the only one in this group of dystrophies that is an X-linked disorder.

THE UGLY

The ugly face of the cornea relates to persistent epithelial defect (PED) leading to corneal melt, perforation, endophthalmitis and possible loss of the eye.

It is important to note that diabetes mellitus has a deleterious effect on the human cornea. Diabetic keratopathy is a well-recognized clinical entity. These patients have an increased risk of manifesting superficial punctate keratitis (SPK), persistent epithelial defects, recurrent erosions and, on the posterior cornea, endothelial damage. Research indicates that these diabetic corneal complications are associated with abnormalities in corneal sensation, tear secretion and poor adhesion between the underlying basement membrane and the corneal epithelial cells.⁵

Truly this 50-μm corneal epithelial layer has many faces — in short, the good, bad, and the ugly. Proper homeostasis of the corneal epithelium is essential for preservation of corneal clarity that would allow the patient to see the world clearly. OM

References

1. Zieske JD, Bukusoglu G, Yankauckas MA, Wasson ME, Keutmann HT. Alphaenolase is restricted to basal cells of stratified squamous epithelium. Dev Biol. 1992;151:18-26.

2. Pellegrini G, Dellambra E, Golisano O, et al. P63 identifies keratinocyte stem cells. Proc Natl Acad Sci USA. 2001;98:315-316.

3. Samoila O, Soritau O, Calugaru M, Totu L, Susman S, Cristian C, Mihu CM: In vitro expansion and characterization of corneal stem cells isolated from an eye with malignant melanoma. Rom J Morphol Embryol. 2013;54:29-36.

4. Belmonte C, Gallar J: Corneal Nociceptors. Oxford University Press. p. 146, 1996.

5. Saini JS, Khandalavla B. Corneal epithelial fragility in diabetes mellitus. Can. J. Ophthalmol. 1995;30:142-146.