SURVEY OF OPHTHALMOLOGY VOLUME 53 � NUMBER 1 � JANUARY–FEBRUARY 2008

MAJOR REVIEW

Recurrent Corneal Erosion SyndromeSujata Das, MS, FRCS (Glasg.),1 and Berthold Seitz, MD, FEBO2

1Bhubaneswar Eye Institute, Bhubaneswar, Orissa, India; and 2Universitatsklinikum des Saarlandes,Klinik fur Augenheilkunde, Homburg/Saar, Germany

Abstract. Recurrent corneal erosion syndrome is a chronic relapsing disease of the cornealepithelium characterized by repeated episodes of sudden onset of pain usually at night or upon firstawakening, accompanied by redness, photophobia, and watering of the eyes. Individual episodes mayvary in severity and duration. These symptoms are related to corneal deepithelialization in an area inwhich the epithelium is weakly adhered. It is a frustrating disorder for both the patient and thephysician. In the majority of cases, the acute episode is managed by patching, and cycloplegic andtopical antibiotic ointment, with prophylactic application of gels during daytime and ointment at nightto prevent further erosion. In a minority of cases these measures are insufficient and may needalternative treatment modalities including therapeutic contact lens wear, anterior stromal puncture,superficial keratectomy, Nd:YAG, and most effectively, excimer laser therapy (phototherapeutickeratectomy). (Surv Ophthalmol 53:3--15, 2008. � 2008 Elsevier Inc. All rights reserved.)

Key words. anterior stromal puncture � excimer laser ablation � phototherapeutickeratectomy � recurrent corneal erosion � superficial keratectomy

I. History

Recurrent corneal erosion syndrome (RCES) hasbeen recognized as a disease entity for over 100years. It is a chronic relapsing disease of the cornealepithelium characterized by repeated episodes ofsudden onset of pain usually at night or upon firstawakening, accompanied by redness, photophobiaand watering of the eyes. The first report waspublished in 1872 by Hansen.36 He termed thedisease as ‘‘intermittent neuralgic vesicular kerati-tis.’’ Von Arlt published about the same phenome-non two years later.99 Both recognized antecedenttrauma. Szili in 1900 reported epithelial irregulari-ties and gray dots associated with recurrent ero-sion.91 Vogt in 1921 described fine white dots onBowman’s layer, fluorescein staining lines, and anirregular epithelial surface with localised edemausing a slit-lamp.98 Stood in 1901 suggested that

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trauma to the corneal epithelium and anteriorstroma resulted in an inability of the new epitheliumto form normal attachments to the injured anteriorBowman’s layer.87

II. Epidemiology and Clinical Features

Brown and Bron published a case series of 80patients with RCES in an age range of 24--73 years(highest prevalence between the third and fourthdecade).7 Mean age at the time of presentation was42 years with a slight male predominance (56%).Microform erosions were seen in 56% of cases. Thefemale patients with history of trauma were mostlydue to scratches from a baby’s finger. They foundthat microform erosions were most common in thespontaneous cases, whereas macroform and com-bined microform and macroform variants were most

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commonly of traumatic origin. The interval betweenfirst recurrence and initial abrasion varied from 2days to 16 years. Family history suggesting dominantinheritance was found only in 3% of cases. In 10% ofcases the disease appeared bilaterally. The frequencyof recurrences varied considerably and ranged fromminor recurrences each morning to major recur-rences separated by months. Recurrences lastedfrom one to four hours in microform lesions andfrom 1--21 days in macroform lesions. Pain was themost common symptom followed by watering of theeye and blurred vision. Common site of erosion wascentral just below the pupil. Superficial cornealdystrophy was found in 78% of patients between 51and 60 years of age. Intraepithelial microcysts werea common finding in healed corneas being presentin 59% of eyes. Franceschetti described a familialtype of recurrent erosion with an autosomaldominant inheritance pattern.25 Laibson andKrachmer reported familial occurrence of recurrenterosion associated with dot-map fingerprint dystro-phy of the cornea.55

Wood has included 25 eyes of 22 patients withRCES for microdiathermy treatment.104 There were16 women and 6 men with an age range between 26and 66 years and a mean age of 44 years. History ofinjury was present in 18 eyes. Fingernail injury wascommon. Ten eyes with injury developed RCESwithin six months and the residual eight eyesdeveloped RCES between 1 and 15 years aftertrauma.

Hope-Ross et al had evaluated 30 patients withrecalcitrant corneal erosion with an age range of 27to 77 years, and a mean age of 45 years.43 Womenwere more (57%) commonly involved than men(43%). Combinations of macro- and microformerosion were most common (77%). Fingernailinjury was the most common cause (16%) of initialcorneal abrasion. Positive family history was presentin two patients. Tiredness, menopause, menstrua-tion, and alcohol were recognized to be aggravatingfactors. Of the 17 women in the study, 41%identified hormonal events such as menstruation,pregnancy, and menopause. Tear film debris andreduced tear break-up time were found in all cases.Microcysts were the most common abnormality inpatients. Fifty-six percent of patients suffered sharppain accompanied by lacrimation on waking up.Seventeen percent of patients suffered only duringnight-time and awoke from sleep due to pain in theeye.

Hykin et al presented a series of 117 patients witha history of RCES with a mean age of 38 years (range14 to 80 years).44 Seventy-five cases had a history ofshallow corneal injury, 23 cases had epithelialbasement membrane dystrophy (EBMD), and eight

had both. They concluded patients with EBMD ora trauma-related focal epithelial basement mem-brane abnormality were more likely to present withchronic recurrent symptoms than trauma-relatedcases with no abnormality. Heyworth et al did a four-year review for the same cohort of patients andfound traumatic etiology to be less likely to sufferchronic recurrent erosion syndrome than those withEBMD.38

Riedy et al did a retrospective review of 104patients (68 women, 36 men) with a mean age of 43years.77 History of trauma was present in 45% ofpatients, 29% had EBMD, and 17% had both. Morethan 87% of erosions occurred in the inferior thirdof the cornea.

Williams and Buckley found that 35% cases withRCES due to map-dot-finger print dystrophy hada Hudson-Stahli line in the affected segment. Incontrast, RCES of traumatic origin did not demon-strate such a predominant localisation.100

III. Etiology and Pathogenesis

Cogan believed that in his patients with bullouskeratopathy, hypotonicity of the tears allowed thecorneal epithelium to become more edematous atnights, causing it to worsen.12 Chandler also thoughtthat this mechanism would explain the predominantoccurrence of erosions in the morning.11

Recurrent corneal erosion syndrome may beeither primary or secondary, depending on whetherthe defect in the epithelial basement membrane isintrinsic or acquired (Table 1). In the majority ofpatients with RCES, trauma is the initiating factor,especially trauma from a scratch that damages ordestroys the corneal basement membrane. Primarydystrophic disorder is further classified according tothe predominant location of the dystrophy withinthe cornea. EBMD is a frequent cause of RCES.Epithelial basement membrane dystrophy includesentities such as Cogan’s microcystic dystrophy(map-dot fingerprint dystrophy) and so-called non-traumatic recurrent erosion.105 The other causesmay be due to Reis-Bucklers, lattice, as well asmacular and granular dystrophy. Secondary causesthat may lead to RCES include chemical andthermal injuries, previous herpetic keratitis, meibo-mian gland dysfunction,43 ocular rosacea,1 diabetesmellitus, Salzmann’s nodular degeneration,103 bandkeratopathy, previous bacterial ulceration, kerato-conjuctivitis sicca, and epidermolysis bullosa. Typi-cally microform erosions occur with spontaneousattacks associated with EBMD whereas macroformerosions are associated with traumatic etiology.Some individuals in families with lattice dystrophy

RECURRENT CORNEAL EROSION SYNDROME 5

manifest recurrent epithelial erosions without clin-ically identifiable stromal involvement. In theabsence of epithelial erosions, the dystrophic lesionsaffect vision minimally. Nocturnal lagophthalmoshas been reported to be associated with RCES.88

It is believed that damage to superficial squamouscells of the epithelium due to corneal exposure isresponsible for RCES. It is hypothesized thatsaccades during early morning REM (rapid eyemovement) sleep phase intensify the condition ofnutritionally deficient cornea during night, espe-cially in the case of previously damaged cornealepithelium in conjunction with corneal dystrophy ormicrotraumas.40

Association of RCES with juvenile X-linked Alportsyndrome has been reported. A survey among 39patients with Alport syndrome revealed that six of

TABLE 1

Classification of Etiology of RCES

(A) PRIMARY(1) Epithelial basement membrane dystrophy

(i) Cogan’s microcystic (map-dot-finger)dystrophy

(2) Dystrophy involving Bowman’s layer(i) Reis-Bucklers dystrophy(ii) Thiel-Behnke dystrophy

(3) Stromal dystrophy(i) Lattice dystrophy(ii) Macular dystrophy

(iii) Granular dystrophy(4) Endothelial dystrophy

(B) SECONDARY(1) Degeneration

(i) Band keratopathy(ii) Salzmann’s nodular degeneration

(2) Trauma(i) Traumatic epithelial abrasions(ii) Chemical and thermal injury

(3) Eyelid pathology(i) Entropion(ii) Ectropion

(iii) Floppy eyelid(iv) Lagophthalmus(v) Meibomian gland dysfunction

(vi) Blepharitis(4) Following ocular infection

(i) Bacterial keratitis(ii) Viral keratitis

(5) Following refractive surgery(i) Laser in situ keratomileusis(ii) Photo-refractive keratectomy (RCES rare)

(6) Systemic causes(i) Diabetes mellitus(ii) Epidermolysis bullosa

(iii) Juvenile X-linked Alport’s syndrome(7) Miscellaneous

(i) Keratoconjuctivitis sicca(ii) Bullous keratopathy

(iii) Idiopathic(iv) Munchhausen syndrome

them had suffered from RCES.84 One case of RCESwas reported to be due to self-inflicted injury(Munchhausen syndrome).92 Removal of cornealepithelium during vitrectomy is one of the causes ofRCES. Recurrent corneal erosion syndrome hasbeen reported after laser refractive surgery. It mayrarely occur after photorefractive keratectomy(PRK)75 and following laser in situ keratomileusis(LASIK). Typically, after PRK, as after photother-apeutic keratectomy (PTK), the epithelium adhereseven stronger than before the laser treatment. AfterLASIK RCES may be due to corneal neuropathy thatoccurs after cutting the flap in addition to theepithelial manipulation at the edge of the flap.Sometimes undiagnosed EBMD may have beenpresent before LASIK. LASIK can induce or pre-cipitate RCES;95 thus, it seems to be important tominimize epithelial damage during LASIK to pre-vent RCES afterwards.

The ultrastructural changes which reduce adhe-sion of the corneal epithelium include a deficientepithelial basement membrane, the absence andabnormality of hemidesmosome, and the loss ofanchoring fibrils. The importance of the anchoringsystem in maintaining epithelial adhesion has longbeen established and a defective anchoring systemhas been incriminated in recurrent corneal erosionand other anterior basement membrane disor-ders.53 The anomalous production of basementmembrane and connective tissue material withinand under the corneal epithelium can disrupt theattachment. Abnormal deposition of normal base-ment membrane is believed to be one of thepathogenetic roles of RCES. A possible cause forthe pathologic changes observed in RCES isdegradation of the epithelial attachment complexesby matrix degrading enzymes. Increased level oractivity of several members of the matrix metal-loproteinase (MMP) enzyme family, includingMMP-2 and MMP-9 have been reported in patientswith recurrent erosion.1,29 MMP-2 expression isupregulated in human epithelium with RCEScompared to normal control samples. Immunoloc-alization studies suggest that MMP-2 is concentratedin basal epithelial cells where it may play animportant role in degradation of the epithelialanchoring system and recurrent epithelial slippageand erosion.29

The apparent cause of RCES is failure ofepithelial cells to regain tight adhesive contacts tothe underlying corneal stroma after trauma inEBMD; it is the failure of the epithelial cells tomaintain tight adhesion to a defective basementmembrane. Cell adhesion molecules of the integrinfamily are in large part responsible for the adhesionof the corneal epithelium to the stroma. A mouse

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model for the study of RCES has implicated role ofa-9 b-1 integrin in progression of the disease.74

IV. Histopathology

Goldman et al described the first electron micro-scopic study of post traumatic recurrent erosion.34 Inthis study, segmental absence of hemidesmosomesand basement membrane was demonstrated. Thenormal columnar basal epithelial cells were flattenedadjacent to the defective basement membrane.Intercellular edema was seen at all levels of theepithelium. Tripathy and Bron found that theepithelium was extremely thickened and pale, sec-ondary to intercellular and intracellular edema usinglight and electron microscopy in a case of bilateral so-called ‘‘nontraumatic recurrent erosion.’’96 Electronmicroscopic examination of the pale cells demon-strated desmosomal attachments with decreasedintercellular digitations and intercellular clefts. Inaddition, hemidesmosomes were reduced or absentin the area of pale epithelial cells.

Fogle et al found subepithelial fibrocytic cells andfibrillogranular material in so-called ‘‘nontraumaticrecurrent erosion.’’21 They also demonstrated intra-epithelial extension of redundant basement mem-brane. Basement membrane complexes werefrequently discontinuous and a decreased numberof anchoring fibrils was noted.

Kenyon et al described three categories ofultrastructural abnormalities in eyes with RCES52

(Kenyon et al, Invest Ophthalmol Vis Sci [Suppl]21:39, 1981). First, in diabetic patients and patientswith map-dot-fingerprint changes, multilaminarbasement membranes were found attached to thebasal epithelial cells. Secondly, posttraumatic re-current erosion was characterized by basal cellrupture, absence of basement membrane adherentto the epithelium, and segmental appearance ofnew basement membrane. They speculated that thiscondition might be due to delayed synthesis ofa new basement membrane following trauma. Thethird mechanism was a basement membrane-stro-mal substrate adhesion abnormality, which occurredin postinfectious recurrent erosions. This wascharacterized by synthesis of basement membraneand by the appearance of an amorphous debrisadherent to the basal cell surface.

Aitken et al examined 25 samples of slidingepithelium from 23 patients of RCES by bothconventional light and transmission electron mi-croscopy.2 They found binucleated and multinucle-ated cells within all layers of the epithelium. Theseparation of the anchoring system occurred eitherbelow the level of anchoring plaques or at the level

of the epithelial cell membrane. Normal anddegenerated polymorphonuclear leucocytes werefound within and between the epithelial cells andwithin the anchoring layer.

V. Diagnosis

A history of previous trauma to the involved eye,recurrent episodes of pain on awakening, anda ragged, greyish-staining area of the epitheliumconstitute major diagnostic criteria. However, it maybe difficult in subtle cases with only focallyaggregated intra-epithelial whitish dots. Carefulhistory of previous trauma and keen slit-lampexamination with indirect illumination is indispens-able in those cases. Broad, angled slit-beam exam-ination and retroillumination examination afterdilatation of the pupil helps to diagnose signs ofbasement membrane dystrophy or the reparativestage after previous erosion. Loosely adherentepithelium can be identified at the slit lamp(Fig. 1) using a qualitative cellulose sponge test,wherein the topically anaesthetized corneal epithe-lium is touched with the tip of a cellulose sponge.10

If the corneal epithelium is easily pushed up intofolds with minimal pressure or easily debrided withminimal effort, then the epithelium is considered tobe loose.

Computerized videokeratography adds a new toolfor identification of difficult cases. Small well-defined areas (1 to 1.5 mm) of markedly reducedcorneal power (O2 diopter) were identified morecommonly in eyes with RCES and those eyes thathad sustained corneal epithelial trauma previ-ously.65 Variable corneal epithelial thickness afterwound healing in RCES may induce irregular

Fig. 1. Slit-lamp photograph showing loosely adherentepithelium in a case of RCES (Courtesy of Prof. Dr.Reinhard, Freiburg).

RECURRENT CORNEAL EROSION SYNDROME 7

astigmatism best imaged on videokeratography. Insome eyes that may be the only indication for RCESif map-dot-finger prints like alteration cannot beobserved. This is also of significance if refractiveprocedures can be planned. The surface asymmetryindex (SAI: measure of difference in corneal powerat every ring 180� apart, over entire corneal surfacecovered with rings) and the surface regularity index(SRI: measure of local fluctuations in centralcorneal power, circle of 4.5-mm diameter aroundthe center of entrance pupil) may be considerablyincreased in those eyes with RCES.102

In vivo confocal microscopy of corneas with RCESor EBMD has shown deposits in basal epithelialcells, subbasal microfolds and streaks, damagedsubbasal nerves, or altered morphology of theanterior stroma.79 However, confocal microscopycannot replace biomicroscopy in making diagnosisof RCES.

VI. Treatment

A. HISTORICAL APPROACHES

Since the description of RCES by Hansen,a plethora of therapeutic options have beenplanned to alleviate the symptoms and prevent therecurrences. Therapy of recurrent erosion withbland or antiseptic ointment began in 1898.36

Franke in 1906 treated 60 eyes with recurrenterosion with three-year follow-up.27 He removedthe epithelium and applied fresh chlorine waterfollowed by sodium chloride rinsing solution. Fifty-eight patients were primarily cured and only tworequired a second treatment.

Schreiber in 1914 used a hypertonic ointmentand pressure patching for 5 to 8 days, followed bydaily use of 3% boric acid ointment.81 Fleischanderlin 1954 recommended the use of 20% zinc sulphateointment.20 Atropine, quinine, topical anaesthesia,patching, and arsenic drops were used in the early1900s.33,39,97,99 Thygeson in 1959 had only a 60%cure rate of recurrent erosion using iodine cau-tery.94 Francois and Neetons26 in 1953 and Leigh56

in 1959 reported the use of lamellar keratoplasty inextremely difficult cases.

Foulks used mild hypertonic dextran polysaccha-ride solution for 10 patients with recurrent cornealerosion unresponsive to conventional therapy.23

Nine of 10 patients responded with improved visionand resolution of symptoms. It is widely believedthat hypertonic saline is preferable to paraffinointment. However, its exact therapeutic role isnot known clearly but may be due to osmoticdehydration of the epithelium.

In 1984 Wood described diathermy for treatmentof recurrent corneal erosion.104 He indented thecornea with a fine-pointed 2-mm or 3-mm diathermyneedle withdrawing when cautery just blanched thecorneal epithelium. He treated 25 eyes of 22patients with a mean post-treatment follow-up of1.6 years. All of the patients had subjective improve-ment after treatment, but 11 eyes remained symp-tomatic. This procedure is likely to induce irregularastigmatism and focal scars. This mode of treatmentis no longer practiced.

B. CONSERVATIVE MANAGEMENT

The basic principle of treatment of RCES is toincrease the adhesion of the epithelium to theunderlying stroma. This may be due to increase ofhemidesmosomes and anchoring fibrils or due topromotion of fibrosis.

1. Topical and Systemic Medication

The vast majority of patients respond to topicalmedication such as lubricating drops, gels, andointments. This medication often has to be used fora longer period of time. They serve to preventrecurrent erosions by keeping the eye lubricatedduring rapid eye movement and while opening theeye in the morning. Hyperosmotic agents are triedin an effort to minimize epithelial edema. Patchingduring acute attack with lubricant or antibioticointment helps to resolve the attack in a largenumber of patients.

Inhibitors of matrix metalloprotienase-9, cortico-steroids, and doxycycline were tried for treatment ofRCES. Therapy with a combination of medicationthat inhibit metalloproteinase-9 produced rapidresolution and prevented further recurrences.17

Although the vast majority of patients can besuccessfully treated with conventional managementa small group of patients fail to respond. Hope-Rosset al had conducted a prospective randomizedcontrolled trial to know the efficacy of oraltetracycline and oral tetracycline with topical pred-nisolone in the treatment of recalcitrant RCES.42

They concluded that lid hygiene and oral tetracy-cline twice daily for 12 weeks with or without topicalprednisolone for the first 7 days is beneficial in themanagement. Oral tetracycline administered in lowdoses is effective in the management of meibomiangland dysfunction. The authors believed that mei-bomian gland dysfunction was a causative factor inthe pathogenesis of RCES. Oral tetracycline may actby inhibition of the production of extra-cellularenzymes by ocular flora or inhibition of the synthesisof lipid by meibomian gland.16 It has an anti-inflammatory action independent of antimicrobial

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effect and has been shown to bind to conjunctiva andgoblet cells.15 Oral tetracycline, in low doses, iseffective in controlling meibomian gland dysfunctionand needs to be continued at least for three months.76

Prolonged treatment may be required in cases ofblepharitis associated with acne rosacea.

Beinitez-del-Castillo et al had used eye dropscombining 250 mg/ml of substance P-derivedpeptide with 1 mg/ml of insulin-like growth factor-Ifour times a day for two months in a patient withtraumatic erosion in the acute stage.6 They reportedthat complete epithelial resurfacing was achievedeleven days after the start of treatment and that norecurrence occurred during an 11-month follow-up.As corneal innervation is important for the mainte-nance of corneal structure and function, thismedication has been tried before in neurotrophickeratitis.8,69

2. Autologous Serum

Autologous serum is effective and safe in reducingthe number of recurrences experienced by patientswith RCES. Beinitez-del-Castillo et al used autolo-gous serum for three months in 11 eyes of 11patients, with acute macroform corneal erosionswho had suffered several relapses despite receivingseveral other treatments.14 Autologous serum islargely similar in composition to that of tears andprovides the ocular surface with basic nutrients forepithelial renewal.19 Fibronectin promotes epithe-lial cell migration and anchorage, 28 the lipidpresent in serum acts as a substitute for lipidcomponents produced by meibomian glands, andprealbumin contributes to the stability of thelacrimal film.35 Holzer et al treated 25 eyes withrecurrent corneal erosion with autologous serumafter transepithelial PTK.41 It was administered sixtimes daily for six weeks. Eighty percent of eyesrecovered without further corneal erosion. Ingeneral autologous serum treatment is consideredto be safe. The only adverse effect associated with itsuse was described by McDonnell et al who detectedimmunoglobulin deposits on the cornea of a patienttreated for a persistent epithelial defect due toherpes simplex keratitis.64 In principle, with serumthere is a risk of infection. However, there is nopublished literature, most likely because autologousserum is usually used in conjunction with topicalantibiotics.

3. Therapeutic Contact Lenses

Therapeutic contact lenses provide symptomaticrelief and encourage healing of the epithelium. Itshould be tried after primary modalities of treat-ment have failed. In recalcitrant posttraumatic cases

it may be used especially if an excimer laser is notavailable. A high water content large-diameter lens ispreferable according to Liu and Buckley.58 The lensshould be fitted fairly tightly with movement of nomore than 1 mm on upgaze. If the patient is free ofsymptoms for a period of three months the lensshould be removed. It has been found that re-currences are fairly common in dystrophic casesafter removal of the lenses. It is well known thatmicrobial keratitis may complicate contact lens weardespite prophylactic antibiotic eye drops. Patienttolerance to the lenses varies particularly in diabeticsand post-herpetic patients. Use of Bausch andLomb’s PureVision57 contact lens and Focus Nightand Day49 lenses have been reported to be safe andeffective when used as continuous-wear for thera-peutic purpose. A period of six weeks is consideredto be the minimum period for lens wear on the basisof time taken for epithelial basement membraneremodelling. Overnight use of scleral contact lenseshas been reported to be effective in RCES due toocular surface disorders.93 Collagen corneal ban-dage lenses have also been reported to acceleratereepithelialization and to prevent relapses of re-current erosions.101

C. SURGICAL MANAGEMENT

1. Superficial Keratectomy

In 1983, Buxton and Fox reported 13 patientswho were treated with superficial keratectomyfollowed by a bandage contact lens.9 They per-formed a total superficial epithelial keratectomyfrom limbus to limbus with a razor blade fragmentor a diamond knife. Dystrophic epithelium andbasement membrane were peeled in one continu-ous sheet leaving undisturbed Bowman’s layer(Fig. 2). Areas of persistent abnormality weretreated with a variable speed diamond drill thatwas applied lightly until a uniform surface had beenobtained. Eleven of their patients were relieved.According to Brown and Bron debridement alone isno more effective than medical treatment alone.Debridement of loose epithelium hastens resolutionof the acute episode but has not been shown toprevent recurrences.7 In addition, superficial kera-tectomy from limbus to limbus may damage thestem cells.

Soong and co-workers have found diamond burrsuperficial keratectomy to be an effective and safemethod of treatment.85 In a retrospective review of54 eyes of 47 patients they found recurrence inthree eyes. In cases of erosion located close to orwithin the visual axis the entire central cornea wasgently polished with a fine diamond burr usingmultiple even circular movements, taking care not

RECURRENT CORNEAL EROSION SYNDROME 9

to induce an irregular topography. In order toassure uncomplicated epithelialization a narrow 1--2mm rim of corneal epithelium was left intact in thecircumferential periphery unless visible erosion wasseen in that area.

Sridhar et al compared the efficacy of diamondburr polishing of Bowman’s layer to PTK for RCESassociated with EBMD.86 Fifteen eyes of 14 patientsunderwent PTK and 27 eyes of 25 patients un-derwent epithelial debridement and diamond burrtreatment. Recurrence of painful erosion was seenin four eyes (26.7%) in the PTK group in contrast tothree eyes (11.1%) in the diamond burr polishinggroup. In the PTK group, mild haze was seen in five(35.7%) eyes, whereas it was seen in seven eyes(25.9%) in the other group. They concluded thatdiamond burr polishing seems to have advantagesover PTK being simpler, less expensive, and pro-ducing less haze.

2. Anterior Stromal Puncture

McLean and co-workers had first described thetechnique of anterior stromal puncture (ASP) in1986.66 They used a 20-gauge disposable hypoder-mic needle under the slit-lamp to make multiplepunctures through loose epithelium and Bowman’slayer into the anterior half of the stroma. Theytreated 21 eyes of 18 patients in the area where theepithelium had sloughed or appeared to be loosefrom underlying basement membrane. Approxi-mately 15--25 punctures were spaced 0.5 mm to1 mm apart. The direction of the needle was

Fig. 2. Photograph showing superficial keratectomywhere dystrophic epithelium along with basement mem-brane is peeled in one continuous sheet (Courtesy of Prof.Dr. Reinhard, Freiburg).

perpendicular to the corneal plane and enoughpressure was exerted to indent the cornea one-quarter to one-third depth of the anterior chamberin order to achieve adequate penetration. Therationale of their approach was derived from theobservation that recurrent erosion often followsrelatively insignificant superficial corneal traumabut only rarely result from stromal laceration orembedded foreign bodies. It was believed that thebreaching of Bowman’s layer stimulated a moresecure bonding of the epithelium to the underlyingbasement membrane, Bowman’s layer, and stroma.The healing process following anterior stromalpuncture has been investigated in rabbit models.48

It has been found that basement membrane re-production occurred much more rapidly thanfollowing diathermy. This was thought to occurbecause the corneal epithelial cells were immedi-ately exposed to type-I collagen, whereas followingdiathermy, new type-I collagen has to be secreted onthe necrotic collagen before the corneal epitheliumwill secrete basement membrane.

One of the major concerns with regard to thesafety of ASP was corneal perforation. Anotherconcern was scarring due to deep stromal penetra-tion, which may affect vision especially when itinvolves the visual axis. However, ASP can be a safeand effective therapy if performed under anoperating microscope.78 Rubinfeld et al designeda specially bent needle for use on a disposablehandle.80 Smaller gauge needles have been used tominimize scarring but deeper incisions were re-ported with 27-gauge or 30-gauge needles. Analysisof corneal specimens where multiple cornealpunctures were made with 23-, 25-, 27-, and 30-gauge needles seven days prior to corneal graftsupported the use of the larger 23- and 25-gaugeneedles. It was also found that an insertion depth of0.1 mm was sufficient to cause fibrocytic reaction.50

Two angulations in the shaft of the standardizedneedle tip keep the needle tip out of patient’s viewduring the procedure thus minimizing anxiety andthe risk of headjerk reaction. Recently, this pro-cedure was reported to be used for recurrenterosion after LASIK, which helped in resolvingsecondary diffuse lamellar keratitis.62 However,performing ASP immediately after LASIK may causeflap displacement.

The advantages of ASP over PTK include thefollowing: (a) it can be easily performed in theoffice setting with simple equipment; (b) it has a lowrisk of inducing visually significant scarring andchanges in refractive power; and (c) it causes onlyminimal discomfort. However, if performed over thepupil, ASP may induce multifocal scars and irregulartopographic changes.

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3. Nd:YAG Laser Stromal Puncture

Geggel used Nd:YAG laser to create anteriorcorneal stromal micropuncture for the treatment oftraumatic RCES.31 He believed that laser punctureswere more reproducible, shallow, and translucent.Nd:YAG laser was focused at the basement-mem-brane zone after epithelial debridement. The energylevel was between 1.8 and 2.2 mJ and spots wereplaced in rows approximately 0.20 to 0.25 mm apart.He treated three patients successfully and theyremained symptom-free for 4 to 6 months. Katz etal used 0.4--0.5 mJ pulses to treat Bowman’s layerthrough an intact epithelium.51 They called it‘‘Nd:YAG photo-induced adhesion’’ because it didnot consistently puncture the anterior stroma. Theytreated eight patients in whom the symptoms hadresolved after treatment, during a mean follow-uptime of 21.2 months. This method may not becommonly recommended based on 11 treated eyes.

4. Phototherapeutic Keratectomy

During the mid 1980s clinical excimer lasersbecame available and offered a new approach tothe treatment of superficial corneal pathologies.Excimer laser ablation is a safe and effectivetreatment for refractory recurrent erosion syn-drome. The reported rate of success, regardingalleviation of symptoms and prevention of recur-rence of epithelial erosion, ranges between 74% and100%. This variability may be explained by thevariety of indication and treatment modalities ofPTK. Treatment of recurrent erosions due to traumahas a higher success rate than treatment for cornealdystrophies.46 Dausch et al reported success rate of74.4% in 74 eyes with RCES due to trauma treatedwith PTK.13 O’Brart et al reported that 4 out of 17eyes (23.5%) experienced recurrent episodes 3--6months after PTK and two have subsequently beenretreated, one of whom has been free of symptomsfor 12 months following retreatment.71 Postopera-tive best corrected visual acuity was unaltered innine eyes and improved by at least one line in eighteyes. Both Forster et al22 and Algawi et al3 reportedthat none of their patients had experienced a de-tectable recurrence of corneal erosion after PTKalthough few of their patients still complained aboutforeign body sensation. Ohman et al reported that20 of 76 treated eyes (26.3%) had recurrencesfollowing PTK.73 Morad et al reported a similarsuccess rate of 83% in their patients.67 Lohman andco-authors, who treated their patients during a symp-tom-free interval, reported a higher success rate of96%.60 However, the 3- to 12-month period offollow-up precludes drawing definite conclusionabout the superiority of this method. Cavanaugh

et al reported a 13.5% recurrence rate in patientswith anterior basement membrane dystrophy whohad recurrent corneal erosion.10 One of the fiveeyes which underwent repeat treatment requireda third procedure. In their study all recurrencespresented within six months after PTK. Retreatmentwith PTK appears to be successful for patients withmacro-erosions complicating recurrent corneal ero-sion syndrome who failed conservative managementwith ocular lubricants and a primary PTK.61 Ohmanand Fagerholm evaluated the effect of excimer laseron wound-healing in patients having RCES.72 Theydemonstrated that treatment with excimer laserafter epithelial removal was significantly better thanepithelial removal alone on the healing of recurrentcorneal erosions.72

The mechanism of action of excimer photoabla-tion in the treatment of recurrent erosion is un-known. It was the experience with PRK that firstsuggested a possible role of excimer laser photo-ablation in the treatment of recurrent erosions.Despite creating an iatrogenic corneal abrasion asa part of the PRK procedure, long-term problemswith instability of the epithelium did not occur. Themechanism by which excimer laser ablation preventsrecurrent erosion may lie in the strong bonds formedbetween the epithelial basement membrane andBowman’s layer postoperatively. Histological studiesof excimer laser-ablated monkey corneas have shownan increased accumulation of type-VII collagen(a major component of anchoring fibrils) andhemidesmosomes along the basement membraneof basal epithelial cells.63,89 Human studies haveindicated that the basal epithelial layer forms hemi-desmosomes and new basement membrane withintwo weeks of photoablation.59 In addition, thereappear to be undulations and excursions of stromalcollagen, as large as 4 mm, into the basal epitheliallayer.59 Such undulations would greatly increase thearea of attachment. Fountain et al have found thatfollowing excimer laser keratectomy the anchoringfibrils, hemidesmosomes, and the basal lamina donot completely normalize even after 15 months.24

Therefore, it seems to be imperative to follow thesepatients for at least 15 months after diffuse PTKbefore drawing any conclusion regarding the effectof this treatment on the recurrence. 24 Szentmaryet al found a significant increase in the number ofhemidesmosomes after PTK in corneas with superfi-cial stromal dystrophies.90

The technique of treatment varies widely. Excimerlaser can be used transepithelially32 or after de-bridement of the epithelium. In some studies focalablation was restricted to the affected zone ofepithelium, at a maximal depth of 40 mm, whenthere was no actual erosion.3,38,71 Alternatively, when

RECURRENT CORNEAL EROSION SYNDROME 11

a true erosion was present together with looseepithelial margins, the corneal area not covered withepithelium was treated at an ablation depth of 1--5 mm,in order to interfere as little as possible withBowman’s layer.13 Subsequently, the loose epitheliumbeyond the margin of erosion was treated directlywithin an area of one laser spot size of 1.5 mm, ata depth of 30--40 mm.13 Algawi et al3 and O’Brart et al71

reported that they mechanically removed the locallyloose epithelium, and subsequently a 20--30 pulseablation was applied to Bowman’s layer to achieve anablation depth of 5--7 mm. Kaplan-Messas et alpresented a study comparing the results of a focal toa diffuse method of treatment (Kaplan-Messas et al,Invest Ophthalmol Vis Sci 37: S574, 1996). In thelatter mode they shot 54 pulses spread over the entireBowman’s layer after total epithelial debridement, innine overlapping 6-mm diameter spots with a meanablation depth of 2 mm. Two eyes with focal PTK butno eye with diffuse PTK had recurrences. For RCES,PTK performed with low pulse energy and lownumber of pulses is considered as an effectivetreatment modality to achieve a fast and mostlydurable closure.82

Kremer and Blumenthal performed combinedPRK and PTK in myopic patients with recurrentcorneal erosions.54 First they corrected both myopiaand astigmatism taking 6 mm optical zone afterepithelial debridement out to the limbal area.Subsequently, the laser computer program waschanged to the PTK mode. The whole area ofBowman’s layer peripheral to the PRK zone wastreated by confluent 3.0-diameter circles of PTK ata depth of 6 mm.

Furthermore, PTK with an epithelial flap forrecurrent erosion syndrome has been reportedrecently.4,68 To reduce postoperative pain and toachieve faster visual rehabilitation, epithelium waspeeled and hinged at the 12 o’clock position likea LASEK flap. After laser ablation this flap wasplaced back to the stromal bed and a therapeuticcontact lens was put on to the eye. We do notrecommend this approach, because the pathologicalepithelium and the basement membrane are notremoved during such a procedure.

The other alternative is transepithelial PTK,where the laser ablation starts at the superficialepithelial layer.41 If there is an epithelial irregularity,the transepithelial technique will translate it toa stromal irregularity. In contrast, if there is a stromaldefect as a result of repeated corneal ulceration, thetransepithelial technique will tend to smoothen it.

Eschstruth and Sekundo compared the differentexcimer laser treatment options with an emphasison the aggressive PTK.18 They performed aggressivePTK with an ablation of 10--15 mm; and after a mean

follow-up time of 41.8 months a recurrence rate of6% without a change of visual acuity and a hyperopicshift of þ0.74 D were observed. They concluded thatin comparison to other forms of PTK such astransepithelial or conventional subepithelial PTK,aggressive PTK showed the lowest recurrence ratereported for a long-term follow-up.

Complications are minimal and typically notserious after PTK. Previous reports have demon-strated potential hyperopic shift following PTK.30,70

This has been associated with axial ablation toremove anterior stromal pathology and ablationdepths many times greater than that used for thetreatment of RCES. Lind et al have mentioned thatthe overall refractive change in 43 treated eyes forrecurrent corneal erosion was 0.69 diopters (Lindet al, Invest Ophthalmol Vis Sci 37: S572, 1996).Kaplan-Messas et al found a hyperopic shift of 0.87� 0.81 diopters in the ‘‘diffuse’’ treatment groupand 0.38 � 0.74 diopters in the ‘‘focal’’ treatmentgroup (Kaplan-Messas et al, Invest Ophthalmol VisSci 37: S574, 1996). However, this difference was notstatistically significant. Cavanaugh et al have founda trend towards hyperopia after PTK for recurrentcorneal erosion in anterior basement membranedystrophy.10 They have found a positive correlationbetween the amount of hyperopia and the numberof pulses applied. Best corrected visual acuityimproved after PTK in some cases due to decreasein irregular astigmatism. O’Brart et al found smallmyopic shift in refraction.71 They speculated thatthis may be due to a slight steepening in the centralcornea due to midperipheral stromal ablation.However, all of their patients had regular cornealtopography at six months with no apparent topo-graphical evidence of ablation zone or surfaceirregularities. Seitz et al have found no significantchanges in central keratometric power after PTKwith less than 5 mm of stromal ablation.82

Based on our experience and that of others,excimer laser PTK appears to offer a safe andeffective treatment for RCES (Table 2). We are ofthe opinion that subepithelial PTK should be triedin those cases who failed to respond to conservativemodes of treatment and application of therapeuticcontact lenses.

VII. Complications

Complications of RCES are infrequent, but mayinclude non-infectious anterior uveitis and stromalscarring. Acute stromal infiltrates are uncommonand suggest secondary microbial keratitis. Shoch etal described stromal infiltrates in five patients whohad RCES due to EBMD but with negative corneal

12 Surv Ophthalmol 53 (1) January--February 2008 DAS AND SEITZ

TABLE 2

Outcome of PTK Treatment in RCES

StudyNumber of Eyes

Treated

Follow-upPeriod

with Mean

Number ofEyes Successfully

Treated (%) Etiology

Time Interval ofRecurrence

SinceTreatment

Dausch et al12 74 6 to 50 months 55 (74) Trauma 8.4 � 9.3 monthsO’Brart et al71 17 6 to 24 months

(mean: 11months)

13 (76) Trauma,Spontaneous

3 to 6 months

Morad et al67 23 12 to 60 months(mean: 38months)

19 (83) -- --

Cavanaugh et al9 48 One year 43 (90) EBMD 0 to 6 monthsJain et al46 77 -- 71 (92) Trauma, Corneal

dystrophy,Idiopathic

--

Seitz et al82 116 Mean: two years 107 (92) Bullouskeratopathy,Trauma, Cogan’sepithelialdystrophy,Idiopathic

2 to 24 months(8 � 6months)

Kremer andBlumenthal54

16 24 to 32 months(mean: 31months)

16 (100) Trauma, EBMD

Lohman et al60 31 3 to 12 months 30 (97) Trauma, EBMD 2 weeksForster et al22 9 8 (89) TraumaOhman et al72 28 26 (93) Trauma

culture in three cases that were investigated.83 Incontrast, Luchs et al reported five patients whodeveloped an infiltrate associated with epithelialerosion with bacteria isolated in four of five eyes(Luchs et al, Invest Ophthalmol Vis Sci [Suppl] 36:S40, 1995). Ionides et al reported 11 patients withcorneal infiltration after recurrent epithelial ero-sion. Positive isolates were found in 16% of cases.45

Despite the intensity of infiltration the majority oflesions were culture negative. An epithelial erosionnot only bypasses the natural resistance of thecornea to infection but a large epithelial defect alsopermits the enhanced access of bacterial antigensand inflammatory cells into the stroma which mayproduce corneal infiltration and uveitis in sensitizedindividuals.

Diffuse lamellar keratitis (DLK) may occurmonths after LASIK as a result of a spontaneousrecurrent erosion.37 This may be due to outpouringof special cytokines such as hepatocyte growth factor(HGF) and keratinocyte growth factor (KGF) thatoccurs with injury to the epithelium. Severe re-current epithelial erosion with DLK has beenreported in a patient seven months after LASIKwho had intraoperative epithelial erosion in botheyes.5 Jeng et al have described three patients whohad epithelial defect intraoperatively and subse-quently developed DLK multiple times in the same

location of the same eye, always following an episodeof recurrent erosion.47 Nevertheless, the authorshave commented that DLK can occur in asymptom-atic patients who develop an intraoperative epithe-lial defect attributable to a suspected underlyingsub-clinical EBMD. It is important to note that RCESis a relative contraindication for LASIK because ofthe high risk of DLK post-LASIK due to spontaneousintraoperative erosion. These patients are better offwith PRK, which typically increase the strength ofepithelial adhesions. Repeated episodes eventuallylead to stromal destructions and irregular astigma-tism. Epithelial alterations may lead to irregularastigmatism that is easy to treat with abrasion andPTK. Unequivocally, patients with EBMD are betterdealt with PRK than LASIK because of high risk ofDLK.

VIII. Summary and Conclusions

Recurrent corneal erosion syndrome is commonlyencountered in ophthalmic practice. It is character-ized by disturbance of the epithelial basementmembrane resulting in defective adhesion andrecurrent breakdown of the epithelium. The condi-tion most commonly follows superficial cornealtrauma, especially a scratch. It may also occur in

RECURRENT CORNEAL EROSION SYNDROME 13

certain corneal dystrophies. Various treatmentmodalities have been tried to alleviate the symptomsas well as to prevent further recurrences. Today, newconservative modalities including autologous serumeye drops and surgical therapeutic modalities,especially PTK, and a rational stepwise approachcan help the vast majority of our patients with RCES.

We recommend excimer laser PTK in each eyewith four or more episodes of attack of traumatic ordystrophic origin after unsuccessful epithelial de-bridement and application of a therapeutic contactlens for at least two weeks.

IX. Method of Literature Search

The literature was searched using Medline, andarticles obtained from the bibliographies of thesepublications (1966--2006). We included referencesthat we considered to have a major contribution tothe understanding of recurrent corneal erosion.The search words used were recurrent corneal erosion,phototherapeutic keratectomy, excimer laser, anterior stro-mal puncture, superficial keratectomy. The abstracts ofthe non-English articles were also included.

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Outline

I. HistoryII. Epidemiology and clinical features

III. Etiology and pathogenesisIV. HistopathologyV. Diagnosis

VI. Treatment

A. Historical approachesB. Conservative management

1. Topical and systemic medications

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The authors reported no proprietary or commercial interest inany product mentioned or concept discussed in this article.

Reprint address: Dr. Berthold Seitz, Universitatsklinikum desSaarlandes, Klinik fur Augenheilkunde, Kirrberger Straße,D-66421 Homburg/Saar, Germany.

2. Autologous serum3. Therapeutic contact lens

C. Surgical management

1. Superficial keratectomy2. Anterior stromal puncture3. Nd:YAG laser stromal puncture4. Phototherapeutic keratectomy

VII. ComplicationsVIII. Summary and conclusions

IX. Method of literature search