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Chapter 56 – Corneal Epithelium

Chapter 56 – Corneal Epithelium










• The anterior-most cellular layer of the cornea.



• Together with the tear film, it is the major refractive surface of the eye.

• Tight junctions provide barrier function.

• Limbal basal epithelium contains the reservoir of stem cells.

• Corneal epithelial dystrophies: map-dot-fingerprint, Meesmann.



• Recurrent erosions and persistent epithelial defects.

• Epithelial neoplasia and dysplasia.





A healthy corneal epithelium is necessary to provide a proper anterior refractive surface and to protect the eye against infection and structural damage to the deeper components of the eye.


Embryologically, the corneal epithelium is derived from surface ectoderm at approximately 5–6 weeks of gestation. It is composed of nonkeratinized, nonsecretory, stratified squamous epithelium ( Fig. 56-1 ), which is 4–6 cell layers thick (40–50?µm). The epithelium is covered with a tear film of 7?µm thickness, which is optically important in smoothing out microirregularities of the anterior epithelial surface. Without this film, degradation of visual images would result. The tear–air interface, together with the underlying cornea, provides roughly two thirds of the total refractive power of the eye. The mucinous portion of tears, which forms the undercoat of the tear film and is produced by the conjunctival goblet cells, interacts closely with the corneal epithelial cell glycocalyx to allow hydrophilic spreading of the tear film with each eyelid blink. Recent studies have shown that part of this mucinous layer may be secreted by the corneal epithelial cells.[1] [2] Loss of the glycocalyx from injury or disease results in loss of stability of the tear film. The tear film also helps protect the corneal surface from microbial invasion, as well as from chemical, toxic, or foreign body damage. Thus the ocular surface tear film and the corneal epithelium share an intimate mutual relationship, both anatomically and physiologically.

Corneal epithelial cells undergo orderly involution, apoptosis (programmed cell death), and desquamation. Complete turnover of corneal epithelial cells occurs in about 7–10 days,[3] with the deeper cells eventually replacing the desquamating superficial cells in an orderly, apically directed fashion. The most superficial cells of the corneal epithelium form an average of two to three layers of flat, polygonal cells. Extensive apical microvilli and microplicae characterize the cell membranes of the superficial cells, which in turn are covered by a fine, closely apposed, charged glycocalyceal layer. The apical membrane projections increase the surface area of contact and adherence between the tear film’s mucinous undercoat and the cell membrane. Laterally adjacent superficial cells are joined by barrier tight-junctional complexes, which restrict entry of tears into the intercellular spaces. Thus a healthy epithelial surface repels dyes such as fluorescein and rose bengal. This is consistent with the high resistance (12–16?kOcm2 ) and low ionic conductance of the apical tight junctions.[4] Superficial cells contain relatively sparse intracytoplasmic organelles.

Beneath the superficial cell layer are the suprabasal or wing cells, so named for their cross-sectional alar shapes. This layer is about 2–3 cells deep and consists of cells that are less flat than the overlying superficial cells, but possess similar tight, lateral, intercellular junctions. Beneath the wing cells are the basal cells, which comprise the deepest cellular layer of the corneal epithelium. The basal cell layer is composed of a single-cell layer of columnar epithelium approximately 20?µm tall. Besides the stem cells and transient amplifying cells (vide infra in the “Epithelial Regeneration” section), basal cells are the only corneal epithelial cells capable of mitosis.[5] [6] Thus they possess relatively large numbers of intracytoplasmic organelles, mitochondria, filaments (intermediate filaments, microfilaments [e.g., actin], and microtubules), and glycogen granules. Basal cells, which are the source of both wing and superficial cells, possess lateral intercellular junctions characterized by gap junctions and zonulae adherens. The basal cells are attached to the underlying basement membrane by an extensive basal hemidesmosomal system. This attachment is of pivotal importance in preventing the detachment of the multilayer epithelial sheet from the cornea. Abnormalities in this bonding system may result clinically in either recurrent corneal erosion syndromes or in persistent, nonhealing epithelial defects.

The basement membrane is composed of an extracellular matrix material secreted by the basal cells. Following destruction of the basement membrane, about 6 weeks is required for it to reconstitute and heal. The epithelial bond to the underlying, newly laid basement membrane tends to be unstable and weak during this period. The epithelium also adheres relatively poorly to bare stroma or Bowman’s layer. Under ordinary conditions, type IV collagen and laminin are the major components of the basement membrane; however, fibronectin production increases to high levels during acute epithelial injury. The basement membrane, approximately 0.05?µm in thickness, adheres to the underlying Bowman’s membrane through a poorly understood mechanism that involves anchoring fibrils and plaques.[7]

The central cornea is normally devoid of antigen processing and presenting cells. Under certain conditions (e.g., corneal graft rejection, herpesvirus infection, or injury), immunologically active dendritic macrophages (Langerhans’ cells) migrate rapidly from the limbal periphery. These cells are derived from the bone marrow and express major histocompatibility complex class II molecules that, upon interacting with CD4-positive T-lymphocytes, release immunomodulatory cytokines.





Figure 56-1 Cross-sectional view of the corneal epithelial cell layer.



Figure 56-2 Whorl-like deposition keratopathy in corneal epithelium seen in Fabry’s disease.

Epithelial Regeneration

Epithelial stem cells—undifferentiated pluripotent cells that serve as an important source of new corneal epithelium—have been localized to the limbal basal epithelium. As the cells migrate to the central cornea, they differentiate into transient amplifying cells (cells capable of multiple, but limited cellular division) and basal cells. The corneal epithelial cell layer mass appears to be the complex resultant of three phenomena. According to the “X, Y, Z hypothesis,” X is the proliferation of basal epithelial cells, Y is the centripetal mass movement of peripheral epithelial cells, and Z is the cell loss resulting from



Figure 56-3 Light micrograph that shows the leading edge of migrating rat corneal epithelium as it tapers to a layer of one-cell thickness. As the epithelial defect is rapidly covered by migrating cells, it is initially coated with a thin, rarefied cell population prior to onset of mitotic activity (hematoxylin & eosin).

death and desquamation.[8] These three phenomena probably are not totally independent of each other, but rather are controlled by a complex interactive feedback mechanism that maintains the status quo, vis-à-vis cell density, cell distribution and polarity, and cell layer thickness. These cytodynamics are likely to be responsible for the striking verticillate (vortex or whorl-like) biochemical deposition patterns seen in Fabry’s disease ( Fig. 56-2 ) and drug deposition keratopathies (e.g., from chloroquine and amiodarone). Newly formed limbal cells are thought to migrate toward the central cornea in such an arcuate, whorl-like pattern.







Figure 56-4 Double-fluorescent labeling at the leading edge of a migrating corneal epithelial cell in tissue culture. This is for, A, actin and, B, vinculin. Vinculin-rich adhesion foci are abundant in cell membrane protrusions and at the front edge of the cell. Actin fibers terminate into these foci and are oriented in the direction of cell migration.


Within minutes after a small corneal epithelial injury, cells at the edge of the abrasion begin to cover the defect as rapidly as possible by a combination of cell migration and cell spreading. A longer delay of up to 4–5 hours is seen in larger defects. This lag phase is necessary for the preparatory cellular changes of an anatomical, physiological, and biochemical nature to occur before rapid cell movement. Various cell membrane extensions, such as lamellipodia, filopodia, and ruffles, develop at the leading edge of the wound. Anchoring hemidesmosomes disappear from the basal cells. This early nonmitotic wound coverage phase is remarkable for its speed; the cells have been measured to migrate at a rate of 60–80?µm/h ( Fig. 56-3 ).[9] The migrating sheet of epithelial cells is attached most firmly to the underlying substrate at the leading margin.[10] The relatively firmer adhesion at the leading margin suggests that the epithelial sheet movement may have “front-wheel drive,” with the less well-anchored cells behind the leading margin being pulled forward, possibly by intracellular contractile mechanisms that involve actin.[11] Vinculin, a 130?kD cytoplasmic protein found specifically in focal adhesion plaques on the cytoplasmic side of the cell membrane, may be involved in the linkage of intracytoplasmic actin stress fibers to the cell membrane at these focal junctions. Vinculin links actin fibers to the cell membrane protein, talin, which in turn is linked to integrin, a major cell-to-substrate adhesion protein.[12] These adhesion protein complexes are most numerous at the leading edge of the migrating cells, which enables the cells to adhere to the basement membrane in the absence of hemidesmosomes. The contraction of actin fibers ostensibly pulls the soma (cell body) forward in the direction of the leading edge ( Fig. 56-4 ). Fibronectin, a ubiquitous extracellular matrix protein present in plasma and in fresh wounds, is thought to be a key element in the mediation of cell-to-substrate adhesion and cell migration. Present on the extracellular side of adhesion plaques, it is thought to mediate the linkage between the vinculin–talin–integrin complex and the substrate during epithelial migration after a wound has occurred ( Fig. 56-5 ). Laminin, a less ubiquitous extracellular matrix protein, is thought to serve a similar function.

At 24–30 hours after medium-sized epithelial injuries, mitosis or cell proliferation begins and restores the rarefied epithelial cell population. After large epithelial injuries, significant increases in cellular division occur as late as 96 hours.[13] Only the basal cells, transient amplifying cells, and the limbal stem cells partake in this reconstitutive mitosis.[5] [6]



Figure 56-5 Transmembrane interactions. The transmembrane interactions between the intracellular (intracytoplasmic) actin-containing contractile fibers, the focal intramembranous adhesion protein complexes, and the extracellular substrate of fibronectin during epithelial migration in wound healing are shown. After wound healing, more permanent and firmly rooted hemidesmosomal attachments become established.

In laboratory and clinical trials, various agents known to influence epithelial migration, mitosis, apoptosis, adhesion, and differentiation have been studied as possible therapeutic agents to enhance corneal epithelial healing. These include growth factors, fibronectin, and retinoids (see Soong[14] for review). Although primarily mitogenic agents, growth factors also stimulate production of extracellular matrix components to enhance cell-to-substrate adhesion. Whether growth factors enhance cellular migration and spread remains in dispute. Topical fibronectin eyedrops effectively accelerate corneal epithelial healing in persistent epithelial defects associated with several conditions; these include herpes simplex keratitis, cataract surgery, and trophic keratitis.[15] On the other hand, fibronectin eyedrops show no significant efficacy in the treatment of epithelial defects that follow corneal alkali injury or that occur in dry eye conditions.[16] Furthermore, exogenous fibronectin by itself did not enhance epithelial wound closure rates in an in vitro



study of scraped corneal epithelial wounds, nor did it enhance the concomitant effects of growth factor.[17] The lack of efficacy of exogenously applied fibronectin in these studies may be caused by the presence of endogenously produced fibronectin at the wound site, in response to the injury.[17] Topical tretinoin (all-trans-retinoic acid), a vitamin A analog, promotes differentiation of epithelial cells and enhances corneal epithelial wound closure rates in rabbits.[18] [19] It may also indirectly promote the healing of corneal epithelium by maintaining the proper anatomy, differentiation, and function of the conjunctival and stem cells. [18]

Several extrinsic factors are involved in the control of directed cell movements during cell migration. These include contact inhibition, chemotaxis, haptotaxis (cell migration guided by signals within the extracellular matrix substrate), and contact guidance. Corneal epithelial cells also have been shown to generate electrical fields during wound healing (injury currents). Interestingly, the movement of the cells appears to be influenced by these biological, self-generated fields. Such fields may serve to guide and stimulate the migration of epithelial cells into the area of the defect (galvanotropism and galvanotaxis).[20] It is attractive to hypothesize that these biologically generated electrical fields may constitute an alternative form of nonhumoral intercellular communication.[20]

Persistent Epithelial Defects

Various pathological conditions may delay or prevent the normal corneal epithelial healing process. These include the following:

• Damage to the cellular substrate (caused by herpetic or other infectious disease, diabetes mellitus, chemical burns, or basement membrane injuries and/or dystrophies)

• Ocular surface inflammation or atopic disease (with release of deleterious polymorphonuclear leukocyte and mast cell products)

• Medicamentosa associated with topical ophthalmical drugs (or their vehicles or preservatives)

• Dry eyes

• Neurotrophic and exposure keratopathies

• Conjunctival disease (e.g., pemphigoid, radiation keratoconjunctivitis, and Stevens-Johnson syndrome)

• Extensive damage to the limbal stem cells (e.g., chemical burns and limbal ischemia)

• Eyelid abnormalities (e.g., entropion, ectropion, lagophthalmos, and trichiasis)

The epithelial healing problems of postinfectious (metaherpetic) ulceration, seen after acute herpetic keratitis, are believed to be caused by damage to the basement membrane from antiviral drug toxicity or from overzealous iatrogenic scraping of the corneal surface using either mechanical or chemical means.[21] In neurotrophic corneas it is possible that interruption of corneal innervation results in depletion of substance P, a neurogenic chemical known to regulate corneal physiological functions. Diabetic corneas may manifest abnormally thickened and easily delaminated basement membranes ( Fig. 56-6 ), perhaps akin to basement membrane abnormalities elsewhere, as in the renal glomeruli. [22] Persistent epithelial defects associated with topical anesthetic abuse may be caused by a combination of pharmacological interruption of corneal nerve function and damage to the epithelial cells and substrate.[23] [24] Limbal stem cell deficiency is an increasingly recognized cause of nonhealing epithelial defects.

Treatment is directed toward the underlying condition in a stepwise fashion. Unless absolutely needed, all topical medications should be discontinued with the use of only preservative-free lubricants. Punctal occlusion should be performed in the presence of dry eyes with treatment of concomitant ocular surface inflammation as needed. Autologous serum eyedrops, bandage soft contact lenses, and amniotic membrane transplantation



Figure 56-6 Recurrent erosion in a diabetic cornea. Note the abnormally thick basement membrane (asterisk) and the intralamellar split within (arrow) (hematoxylin & eosin).

can be used. Ultimately, tarsorrhaphy appears to remain the best means of healing persistent epithelial defects.


Although most corneal epithelial defects heal quickly and permanently, some may be characterized by recurrent breakdowns of the epithelium as late as several years after the initial episode. The majority of corneas that have recurrent epithelial erosions often show abnormalities in the underlying basement membrane microstructure. Microscopic derangement in the epithelial basement membrane either may occur as sequelae of trauma or may be a result of dystrophy or disease. Recurrent corneal erosions are a relatively common problem. The majority of cases occur after corneal trauma, frequently following superficial epithelial abrasions from fingernails, paper, or mascara brushes. Although less commonly encountered, chemical and thermal burns also may lead to recurrent epithelial breakdown.

Post-Traumatic Erosions Without Primary Basement Membrane Abnormalities

Posttraumatic, nondystrophic, recurrent corneal erosion is clinically the most common form of repetitive corneal epithelial breakdown. After corneal surface injury, basement membrane thickening, discontinuities, and duplications are typically seen for 8–12 weeks; the overlying epithelium is vulnerable to detachment during this period. [25] [26] [27] These changes occasionally may persist for a prolonged period, in which case the cornea is susceptible to repetitive breakdown even years after the original injury. Slit-lamp findings similar to those in epithelial basement membrane dystrophy may be seen in some patients, whereas in others the cornea may clinically look disarmingly normal between erosive episodes.

Erosions Associated with Corneal Dystrophy

Epithelial basement membrane dystrophy (Cogan’s microcystic dystrophy; map–dot–fingerprint dystrophy) is frequently seen in general ophthalmic practice and is the most common form of anterior corneal dystrophy. Intraepithelial lesions that resemble geographic map-like gray patches, dots or microcysts, and fingerprint or whorl-like patterns ( Figs. 56-7 and 56-8 ) characterize this dystrophy. No known systemic associations occur. Slit-lamp examination under direct illumination may not be sufficient to elicit the often subtle and small intraepithelial lesions. Retroillumination through a dilated pupil in a dark examining room best highlights fingerprint lines and microcystic dots. Rapid







Figure 56-7 Epithelial basement membrane dystrophy. A, Slit-lamp view of fingerprint lines and microcysts under direct illumination (left) and retroillumination (right). B, Map lesion under direct illumination.

tear-film breakup resulting from subtle surface contour irregularities also occurs over these lesions, especially the maplike patches.

Clinicopathologically, epithelial basement membrane dystrophy is associated with three basic elemental findings[28] :

• Thickening of the basement membrane with fingerlike or lamellar extensions into the overlying epithelial layer

• Intraepithelial microcysts formed by trapped, degenerating epithelial cells

• Fibrillar material between the basement membrane and the underlying Bowman’s layer (as viewed by electron microscopy)

This dystrophy of the epithelial basement membrane is associated with recurrent corneal erosions in up to 10% of cases. From a converse perspective, 50% of individuals with recurrent corneal erosions may show clinical findings compatible with this disorder.[29] Most cases of epithelial basement membrane dystrophy are bilateral and remain asymptomatic. Although they probably are autosomal dominant in inheritance,[28] many show no apparent familial pattern. Other studies have observed similar corneal findings incidentally during routine examination in a large proportion of the general population.[30] Irregular astigmatism from these superficial lesions sometimes can lead to decreased visual acuity. Irregular astigmatism may be readily diagnosed by keratometry, keratoscopy, or computed topography.

Painful, recurrent corneal erosions are more common after the third decade of life and usually are self limited, with spontaneous resolution after several years. Permanent deficits in visual acuity are extremely rare. The recurrent erosions may occur either in association with a history of previous trauma or spontaneously without any obvious antecedent precipitating incidents. Histopathologically, erosions result from poor epithelial adhesion to the abnormal basement membrane or from lamellar splitting and/or shearing of the abnormally fragile membrane. Large, single sheets of loose epithelium may often be peeled off the cornea during therapeutic debridement. Recurrent erosions may occur in other anterior corneal dystrophies, such as Reis-Bücklers’ and Meesmann’s dystrophies.

Meesmann’s epithelial dystrophy is an autosomal dominant, inherited, bilateral disorder usually seen as early as the first year of life as multiple tiny intraepithelial vesicles ( Fig. 56-9, A-B ).[28] No systemic associations occur. The patient remains asymptomatic until middle age, at which time the diffusely distributed intraepithelial vesicles break through the anterior epithelial surface and cause punctal staining ( Fig. 56-9, C ), intermittent irritation, and irregular astigmatism.

Histopathologically, the epithelial layer is thickened and contains intraepithelial cysts mostly in its anterior aspect ( Fig. 56-10 ). These correspond to vesicles seen clinically and may



Figure 56-8 Cogan’s microcystic dystrophy. The dot pattern is caused by cysts that contain desquamating surface epithelial cells. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St Louis, Mosby; 2002.)

stain with fluorescein and rose bengal stains. The basement membrane may show multilaminar thickening with occasional projections into the overlying epithelial layer. These basement membrane changes may be responsible for disordered epithelial adhesion to the substrate. Ultrastructurally, an intracytoplasmic fibrillogranular “peculiar substance” is seen consistently in Meesmann’s dystrophy.[28]

Anterior involvement in lattice, macular, and granular stromal dystrophies may be associated with epithelial erosions. Recurrent epithelial breakdown in Fuchs’ dystrophy is due to an edematous process, rather than to abnormalities in the substrate.

Erosions Associated with Diabetes Mellitus

Recurrent corneal erosions are not uncommon in severe diabetics and may further compromise vision already made tenuous by concomitant retinopathy. These erosions usually are posttraumatic following apparently mild injuries; however, epithelial breakdown may also occur after ophthalmic surgery, such as cataract extraction and vitrectomy procedures. In some instances the surgeon may elect to scrape off the epithelium intraoperatively to improve visualization of the intraocular structures. As mentioned earlier, a thickened and fragile basement membrane ( Fig. 56-6 ), reduced penetration of the basal anchoring fibrils into Bowman’s layer, and effete duplication of anchoring fibrils in diabetic corneas have been described.[31] Unlike the case with nondiabetic erosions, these diabetic corneas not only are prone to recurrent erosions, but also tend to have persistent nonhealing









Figure 56-9 Meesmann’s epithelial dystrophy with intraepithelial vesicles. A, Direct illumination. B, Retroillumination. C, Punctate staining of Meesmann’s corneal epithelium with fluorescein.

epithelial defects. This may be caused by additional factors such as neurotrophic disease and limbal vasculopathy.

Clinical Symptoms and Signs of Recurrent Erosion

Typically, the onset of corneal erosion is upon awakening in the morning, although it may occur at any time. This propensity may be caused by relative anoxia, hypercapnia, or edema of the corneal epithelium when the eyelids are closed during sleep. Also, the sudden opening of the eyelids upon awakening may easily rub off the vulnerable epithelium. The patient frequently experiences pain, blurring, photophobia, foreign-body sensation, blepharospasm, and tearing. The symptoms may vary among individuals and with the extent of the surface breakdown. Depending on the severity, the erosion may spontaneously resolve within minutes to weeks, or alternatively may be



Figure 56-10 Meesmann’s dystrophy. In this thin, plastic-embedded section, numerous tiny cysts of uniform size and one surface pit are present within the epithelium. One cyst to the right of center resembles a cell. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St Louis, Mosby; 2002.)

subject to multiple brief, repetitive breakdown episodes before finally subsiding.

Slit-lamp examination may show a frank epithelial defect, often with an entire loose sheet of epithelium hanging tenuously from the corneal surface. Filamentary keratitis, intraepithelial microcysts, fingerprint lines, bullae, epithelial irregularity, subepithelial haze, and epithelial edema may also be present. Between erosive episodes, the basement membrane changes may be difficult to see on direct illumination; however, retroillumination against the background of a dilated pupil may bring out subtle epithelial and subepithelial lesions ( Fig. 56-7, A ).

Treatment of Recurrent Corneal Erosion

For mild erosions, the use of ocular surface lubricants (artificial tears and/or ointments) or pressure patches may be enough to improve patient comfort and perhaps reduce the deleterious frictional effects of each eyelid blink. The efficacy of pressure patching a corneal abrasion is currently debatable. Hypertonic sodium chloride eyedrops and ointments may have an additional yet poorly understood (and disputed) beneficial effect. Typically, hypertonic eyedrops are used 3–4 times during waking hours, and the ointment form is used at bedtime for at least 3 months. Although the ointment form has superior lubrication effects and pharmacologic contact time, it does significantly compromise visual acuity. Antimicrobial prophylaxis and cycloplegics are given at the discretion of the physician. For beneficial long-term behavior modification, patients should learn to open their eyes slowly, cautiously, and with deliberation when awakening from sleep.

In cases of more extensive erosion accompanied by large, loose sheets of epithelium and devitalized cells, scraping and debridement of the affected area with a cellulose spear (Weck-cel) or a smooth-edged, nonincisional instrument, such as the Kimura spatula, may help provide a smoother and more hospitable epithelial substrate. Sharp instruments or chemicals should not be used, since they may cause excessive damage to the substrate. Surrounding areas also should be checked for the presence of loosely adherent epithelial sheets by gently probing suspicious-looking regions with a cellulose spear or a cotton-tipped applicator. Lifting with fine surgical forceps may facilitate removal of these poorly adherent epithelial sheets.

Extended-wear bandage soft contact lenses may provide comfort and support the healing process, with minimal compromise of vision. They have the additional benefit of protecting and isolating the fragile, healing epithelium from the windshield-wiper effects of blinking eyelids. These lenses should remain on the cornea for at least 6–8 weeks to allow the basement membrane







Figure 56-11 Carcinoma in situ of the conjunctiva, limbus, and cornea. A, Slit-lamp appearance. B, The dysplastic conjunctival and corneal epithelia stained with rose bengal.

and hemidesmosomes time to reorganize. The patient should be warned of the slight risk of microbial infection associated with the use of extended-wear lenses. The authors remove the bandage lens once at 4 weeks and insert either a new lens or reinsert the original one after sterilization; concomitant antibiotic prophylaxis generally is not used. In the acute phase of erosion marked by inflammation, bandage lenses should be checked within 24 hours after insertion for any evidence of the tight-lens syndrome. If the lens is tolerated poorly, it either should be replaced with a smaller diameter, flatter lens or should be removed and not replaced. Cautious and judicious use of topical corticosteroids and cycloplegics may reduce inflammation and enhance patient comfort. Hypertonic sodium chloride preparations should not be used in conjunction with these high water content lenses. An alternative for short-term relief and epithelial support is a collagen shield.

If the erosions are severe or frequent, anterior stromal micropuncture or superficial keratectomy are the therapeutic options. Superficial stromal micropuncture for recurrent corneal erosions, first described by McLean et al.,[32] is highly efficacious in the stabilization of susceptible epithelium and very effective in the provision of a long-term cure for erosions. The mechanism of action is unclear, but epithelial plugs remain in the puncture sites as anchors for months after therapy. [33] The action is analogous to tacking down a loose carpet with nails. The procedure is performed at the slit lamp, using a 25- or 27-gauge sterile hypodermic needle. Some clinicians prefer to use a larger (20-gauge) needle, which covers more area and perhaps reduces the likelihood of corneal perforation; however, these larger needles cause more scarring because of the sheer size of the micropuncture wound they create. The needle may be attached to a 1?cm3 tuberculin syringe for surgeon comfort and ease of application. A 60–90° bend is made in the direction of the bevel, being careful not to blunt the tip in the process. The bend enhances the surgeon’s ergonomic comfort and provides a mechanical stop to reduce the chance of corneal perforation. Since only the superficial stroma needs be punctured, there is little reason to push excessively hard with the needle into the cornea. Multiple punctures are applied to include the surrounding normal cornea and to ensure that the erosion does not spread centrifugally. Some clinicians do treat the central visual axis lightly in severe cases and apparently encounter little or no significant visual sequelae, but others prefer to leave at least a 3.0?mm clear central optical zone. If necessary, the anterior stromal micropuncture procedure may be repeated later, with either extension of the treatment beyond the original zone or additional filling in of the area previously treated. The use of argon or YAG laser, surface cauterization, or diathermy to perform this procedure does not offer any advantages over the needle technique and may cause more scarring and corneal topographic changes than does the micropuncture technique.

Superficial keratectomy is an effective treatment for recurrent corneal erosions. It removes the diseased basement membrane down to the Bowman’s layer and superficial stroma. A scarifier blade or blunt lamellar dissection blade may be used to peel and dissect off gently the abnormal superficial tissue. Sharp blades may cause excessive damage to the stroma and should be avoided. The fine-grade diamond polishing drill (Ugo-Fisch) is a very simple and effective instrument with which to remove superficial corneal tissue. Compared with dissectional methods, the polishing procedure is less technically demanding and creates a very smooth corneal surface.[34] Alternatively, excimer laser phototherapeutic keratectomy may be used to achieve the same ends. Induced hyperopia with excimer laser keratectomy for recurrent corneal erosions is usually minimal because of the superficial nature of the treatment.


Dysplastic disturbances of squamous cells constitute the most common true neoplastic processes of the corneal epithelium. Owing to the intimate anatomical, functional, and cytological relationships between corneal and conjunctival epithelia, such tumors appear to be inseparable from those that affect the conjunctiva. The majority of dysplastic corneal epithelial lesions, consequently, have a portion of the lesion in direct contiguity with the highly mitotic stem cells at the limbus ( Fig. 56-11 ). Dysplastic cells manifest increased nuclear:cytoplasmic ratio, atypical size and shape, and disturbed polarity and maturation. Most such lesions occur in the exposed interpalpebral regions in fair-skinned, older men, which suggests the causal role of actinic transformation. Dysplastic corneal epithelium appears translucent or gelatinous, in contrast to clear, normal epithelium. Occasionally, keratinization from squamous metaplasia may impart a whitish, leukoplakic appearance to the lesion. Another useful way to distinguish dysplastic epithelium from normal epithelium is to apply fluorescein or rose bengal stain ( Fig. 56-11 ). Normal epithelium does not stain, whereas dysplastic epithelium shows diffuse, punctate staining.

Squamous dysplasia and carcinoma in situ are histopathologically distinguished by the degree of anaplastic involvement (loss of differentiation, increased mitotic figures, and dysmaturation). In squamous dysplasia, atypical cells replace only a portion of the corneal epithelium, whereas in carcinoma in situ these cells occupy the entire epithelial layer from basement









Figure 56-12 Corneal and limbal conjunctival squamous cell carcinoma in situ. A, Clinical appearances. B, Close-up view of the corneal epithelial lesion with fimbriated edges. C, Histopathology of the limbal conjunctiva showing dysplasia of the entire epithelial layer (hematoxylin & eosin).

membrane to the superficial cells. In both cases the basement membrane is intact. The practicality of this distinction is questionable, and some now prefer to use the term “intraepithelial neoplasia” to encompass both entities ( Fig. 56-12 ).

Squamous dysplasia and carcinoma in situ are treated by scraping off the affected corneal epithelium, preferably with a blunt instrument such as a Kimura or Paton spatula, which reduces damage to the basement membrane. Occasionally, an adherent fibrovascular pannus may be present and must be dissected from Bowman’s layer using sharp dissection. Some surgeons recommend additional chemical devitalization of the limbus with absolute alcohol. Contiguous limbal and conjunctival lesions are excised down to bare sclera, and additional lateral margins (1–2?mm) of apparently normal conjunctiva are removed. The limbus, peripheral cornea, base, and conjunctiva are treated with a cryoprobe in a rapid double- or triple-freeze fashion. Extensive, prolonged, or deep treatment is not recommended, however, because of the superficiality and ready accessibility of these lesions. In these noninvasive lesions, it is unnecessary to risk deep structural freeze damage to the cornea, trabecular meshwork, ciliary body, and retina. The eye should be regularly examined for evidence of recurrent disease. Although recurrent lesions generally are treated in the same way as primary lesions, the margins of excision and the degree of cryotherapy need to be increased because of the small but not negligible potential for the development of invasive carcinoma. Early evidence suggests that application of topical mitomycin-C, adjunctively in cases of recurrence or primarily in instances in which surgical excision cannot be performed, may be a safe and effective treatment modality.[35]

Primary corneal epithelial dysplasia is a relatively rare condition that predominantly involves the corneal epithelium, with disproportionately little or absent lesional involvement of the limbus. The involved corneal epithelium appears frosted or opalescent, with either fimbriated, serpiginous, scalloped, geographic, or smooth edges, and usually without a fibrovascular pannus. The corneal lesions may be single or multiple and abut the limbus or form islands away from the limbus. These lesions may show extensive waxing and waning alterations in shape and size over months to years.[36] Cytologically, the involved epithelium shows signs of atypia and dysmaturation. Treatment consists of simple scraping of the corneal epithelium, taking special care not to damage the basement membrane protective barrier. Any associated limbal mass or lesion should be excised, leaving wide margins, with the option for additional cryotherapy left to the discretion of the surgeon. Recurrences are common.

Invasive squamous cell carcinoma can arise from squamous dysplasia or carcinoma in situ if the underlying basement membrane barrier is broken. The underlying Bowman’s layer and corneal stroma, or the subepithelial conjunctival tissues, may be invaded. Treatment consists of wide excision of the lesion with inclusion of the involved corneal stroma and sclera by lamellar dissection. Extensive cryotherapy of the lateral and deep margins is indicated, more aggressively than for the noninvasive situations. Cryotherapy reduces the recurrence rate of these lesions from 40% to under 10%.[37] Scleral, intraocular, or orbital invasion also may occur. Involvement of the uvea or trabecular meshwork may afford the neoplastic cells access to the systemic circulation. Fortunately, regional metastasis is rare[38] and widespread systemic metastasis is even rarer. Deaths from this type of tumor are extremely uncommon. Enucleation is indicated for intraocular invasion, and exenteration is indicated in orbital extension.





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13. Arey LB, Cavode WM. The method of repair in epithelial wounds of the cornea. Anat Rec. 1943;86:75–82.


14. Soong HK. Penetrating keratoplasty for ocular surface disease. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea, Vol. 3. St. Louis: Mosby Yearbook; 1996:1781–8.


15. Nishida T, Nakagawa S, Awata T, et al. Fibronectin promotes epithelial migration of cultured rabbit cornea in situ. J Cell Biol. 1983;97:1653–7.


16. Fujikawa LS, Foster CS, Harrist TJ, et al. Fibronectin in healing rabbit corneal wounds. Lab Invest. 1981;45:120–9.


17. Soong HK, Hassan T, Varani J, et al. Fibronectin does not enhance epidermal growth factor-mediated acceleration of corneal epithelial wound closure. Arch Ophthalmol. 1989;107:1052–4.


18. Tseng SCG, Maumenee AE, Stark WJ, et al. Topical retinoid therapy for various dry-eye disorders. Ophthalmology. 1985;92:717–27.


19. Ubels JL, Edelhauser HF, Austin KH. Healing of experimental corneal wounds treated with topically applied retinoids. Am J Ophthalmol. 1985;95:353–8.


20. Soong HK, Parkinson WC, Bafna S, et al. Movements of cultured corneal epithelial cells and stromal fibroblasts in electric fields. Invest Ophthalmol Vis Sci. 1990;31:2278–82.


21. Kaufman HE. Epithelial erosion syndrome: metaherpetic keratitis. Am J Ophthalmol. 1964;57:983–7.


22. Taylor HR, Kimsey RA. Corneal epithelial basement membrane changes in diabetics. Invest Ophthalmol Vis Sci. 1981;20:548–53.


23. Bisla K, Tanelian DL. Concentration-dependent effects of lidocaine on corneal epithelial wound healing. Invest Ophthalmol Vis Sci. 1992;33:3029–33.


24. Dass B, Soong HK, Lee B. Effects of proparacaine on actin cytoskeleton of corneal epithelium. J Ocul Pharmacol. 1988;4:187–94.


25. Goldman JN, Dohlman CH, Kravitt BA. The basement membrane of the human cornea in recurrent epithelial erosion syndrome. Trans Am Acad Ophthalmol Otolaryngol. 1969;73:471–81.


26. Khodadoust AA, Silverstein AM, Kenyon KR, Dowling JE. Adhesion of regenerating corneal epithelium: the role of the basement membrane. Am J Ophthalmol. 1968;65:339–48.


27. Kenyon KR, Fogle JA, Stone DL, Stark WJ. Regeneration of corneal epithelial basement membrane following thermal cauterization. Invest Ophthalmol Vis Sci. 1977;16:292–301.


28. Brown NA, Bron AJ. Recurrent erosion of the cornea. Br J Ophthalmol. 1976;60:84–96.


29. Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman’s layer and stroma. Surv Ophthalmol. 1978;23:71–122.


30. Werblin TP, Hirst LW, Stark WJ, et al. Prevalence of map–dot–fingerprint change in the cornea. Br J Ophthalmol. 1981;65:401–9.


31. Kenyon KR. Recurrent corneal erosion: pathogenesis and therapy. Int Ophthalmol Clin. 1979;19:169–75.


32. McLean EN, MacRae SM, Rich LF. Recurrent erosion. Treatment by anterior stromal puncture. Ophthalmology. 1986;93:784–8.


33. Judge D, Payant J, Frase S, Wood TO. Anterior stromal micropuncture: electron microscopic changes in the rabbit cornea. Cornea. 1990;9:152–60.


34. Soong HK, Farjo QA, Meyer RF, Sugar A. Diamond burr superficial keratectomy for recurrent corneal erosions. Br J Ophthalmol. 2002;86:296–8.


35. Frucht-Pery J, Sugar J, Baum J, et al. Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology, 1997;104:2085–93.


36. Waring GO, Ross AM, Ekins MB. Clinical and pathological description of 17 cases of corneal intraepithelial neoplasia. Am J Ophthalmol. 1984;97:547–59.


37. Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctival tumors and squamous cell carcinomas. Am J Ophthalmol. 1983;95:359–63.


38. Zimmerman LE. The cancerous, precancerous, and pseudocancerous lesions of the cornea and conjunctiva. Corneoplastic surgery. In: Rycroft PV, ed. Proceedings 2nd Annual International Corneoplastic Conference. London: Pergamon Press; 1969:547–55.

One comment on “Chapter 56 – Corneal Epithelium

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