RES can be associated with trauma or anterior corneal dystrophies, including epithelial [Franceschetti type, epithelial rosette dystrophy, map, dot, fingerprint (Cogan’s) dystrophy], basement membrane (Meesman’s dystrophy, Reis-Bückler’s dystrophy), and stromal (lattice, granular, and macular) dystrophies. RES provoked by trauma is also referred to as macroform RES, whereas spontaneous RES, more likely to be associated with a corneal dystrophy, is referred to as microform (4). The likelihood of recurrence of symptoms in patients with trauma induced RES was estimated to be 1:150 (5,6,7). Severity, frequency, and length of recurrences of corneal erosions varies widely. The symptoms may last from 1 to 4 hours in case of microform RES and from 1 to 21 days in case of macroform RES (4).

The exact etiology and pathogenesis of RES are not well understood, but several structural, biochemical, and functional abnormalities have been reported. The ultrastructural changes associated with RES include abnormal basal epithelial cell layer, abnormal epithelial basement membrane, absent or abnormal hemidesmosomes, and loss of anchoring fibrils (4,6,7). Binucleated cells and multinucleated giant cells have been found in the corneal epithelium (10). Tonofibrils, prominent in the abnormal epithelial cells, are probably responsible for forming these binucleated cells (8). Interestingly, all layers of the epithelium in patients with RES are infiltrated with neutrophils (8). Proteases released from lysozymes of these neutrophils are responsible for proteolytic degradation of the underlying basement membrane (9) and stroma (3). Additionally, matrix metalloproteinase-9, a collagenase produced by neutrophils as well as by corneal epithelial cells and macrophages (10), is overexpressed and is involved in degradation of the epithelial basement membrane (10,11).

Confocal microscopy in patients with RES associated with anterior membrane dystrophies discloses a spectrum of structural changes in the basal epithelium, basement membrane, Bowman’s layer, anterior stroma, and corneal neurons (12,13). Whether these structural changes represent an abnormal matrix as a consequence of upregulated matrix metalloproteinase activity remains unclear (14). Interestingly, these abnormalities can be found on confocal microscopy even in eyes that do not present signs of anterior corneal dystrophy on slit-lamp examination (12).

In case of trauma, the initial injury causing corneal abrasion is commonly a slicing type injury, caused by a fingernail, edge of a paper, tree branch, or bush. The severity of the trauma is usually minor (15,16). Corneal injuries induced by fingernail are particularly at high risk of progressing to RES (4). It is noteworthy that the older ophthalmology literature refers to RES as “fingernail keratitis” (17). Injuries with paper, fingernails, or plant materials were estimated to be five times more likely to induce RES than injuries with harder and sharper objects such as metal, glass, or rock (18). On the other hand, corneal trauma involving penetration into deeper stroma is less likely to induce RES (19,20).

Following the injury, the corneal epithelial defect is filled rapidly by epithelial cells sliding from adjacent epithelial basal layers onto the surface of the epithelial defect. After the epithelial defect is completely covered with one layer of epithelium, the epithelial cells begin mitosis and production of suprabasal epithelial cell layers (21). Sliding of basal epithelial cells can occur over either preexisting basement membrane or bare stromal collagen (22). If the
basement membrane remains intact after trauma, the new epithelial cell layer becomes firmly adherent within a week (22). However, if the injury involves removal of basement membrane, the strength of epithelial adherence can be altered for more than 2 months (22).

Patients with RES typically have a basement membrane problem (21). The absence of hemidesmosomes (and in some cases the absence of entire thickness of basement membrane) are the main electron microscopic characteristics of RES. Thinning and splitting of basement membrane can also be present (26,27). Collagen VII, another component of basement membrane, is one of the major components of the epithelial anchoring system (23,24). Not surprisingly, patients with epidermolysis bullosa, a mucocutaneous autoimmune disease characterized by autoantibodies to collagen VII, can develop RES (25).

An abnormally flat basal epithelial cell layer suggests that the epithelial cells may be responsible for abnormal production of and attachment to the basement membrane (21). The presence of a high number of mitochondria with abnormal shape in the basal epithelial cells, seen on electron microscopy as intracellular vacuoles, suggests an abnormal metabolic activity in these cells and supports the idea of the pathogenic role of basal epithelium in RES (21,22).

The epithelial defect in patients with RES is covered with epithelial cells within 1 to 3 days after injury, uneventfully, but several weeks later the attachment of the basal epithelial cell layer becomes loose. The loosely attached epithelium in this area can cause clinical symptoms, generally worse in the morning, upon awakening, with sudden pain, photophobia, and tearing. Alternatively, the tearing away of the epithelium may occur at the moment of transition from deep sleep to rapid-eye-movement (REM) sleep, with resultant pain that awakens the patient.

The appearance of the cornea on slit-lamp examination between the episodes of clinical symptoms may be normal. Sometimes, however, various degree of epithelial or subepithelial edema, located in the area of former erosion, may be seen during the asymptomatic intervals. This edema may be subtle (minimal bedewing) (21), discernible only with retroillumination. Alternatively, a fine linear subepithelial opacity in a shape of fine bubbles or a distinct subepithelial bulla may be visible (21).

Although the therapy of RES is palliative rather than curative, it should be emphasized to the patient that although the disease and therapy may represent a considerable annoyance, it is typically not vision threatening (31). A spectrum of therapeutic interventions has been described for RES (Table 31-1), and some of these are widely accepted today. Typically, a stepladder approach, beginning with conservative measures and moving to invasive intervention, is followed. Adjuvant therapy added to a treatment program may provide significant benefit. For example, adding cycloplegics may offer additional relief of symptoms. And although keratoconjunctivitis sicca is not believed to be a cause of RES, it can be an important coconspiracy factor that must be eliminated when successfully managing RES. Patients who do not respond favorably to preservative-free artificial tears may benefit from punctal occlusion (32). Simple elimination of dry eye may lead to a major improvement of RES in some cases (32). Topical steroids, another adjuvant to RES therapy, can be used to suppress the inflammatory component and reduce the epithelial infiltration with neutrophils (29). Systemic tetracycline antibiotic therapy and lid hygiene are indicated in patients with RES who also have meibomian gland dysfunction (29). In fact, meibomian gland dysfunction has been identified as a common disorder associated with RES (28,29). According to one report, 83% of patients with RES recalcitrant to conservative treatment had documented meibomian gland dysfunction, and 73% had acne rosacea (28). Most of these patients had the corneal abnormality located to the inferior and middle thirds of the cornea (28,30). A relationship of RES to menstruation further supports the role of meibomian gland dysfunction (4,30), because sex hormones have been shown to participate in regulation of sebaceous gland secretion (31).