J CATARACT REFRACT SURG - VOL 32, SEPTEMBER 2006

Development of late-onset subepithelial corneal

haze after laser-assisted subepithelial

keratectomy with prophylactic

intraoperative mitomycin-C

Case report and literature review

Mujtaba A. Qazi, MD, Troy W. Johnson, OD, Jay S. Pepose, MD, PhD

We present a case of dense, visually significant reticular haze that developed approximately 17months after uneventful laser-assisted subepithelial keratectomy with mitomycin-C (MMC). Thepatient was successfully treated with manual debridement coupled with phototherapeutic kera-tectomy and intraoperative MMC.

J Cataract Refract Surg 2006; 32:1573–1578 Q 2006 ASCRS and ESCRS

Laser-assisted subepithelial keratectomy (LASEK) offers analternative technique of laser vision correction for individ-

uals who are not ideal candidates for laser in situ keratomi-

leusis (LASIK) based on corneal curvature, central corneal

pachymetry, orbital anatomy, or the presence of corneal

dystrophies or surface irregularity. Laser-assisted subepi-

thelial keratectomy improves the safety of refractive proce-

dures and can provide visual outcomes similar to those of

photorefractive keratectomy (PRK) and LASIK.1–4 How-ever, several potential side effects have been described

with LASEK, including the development of visually signif-

icant corneal haze.5

The term haze is used to describe alterations in corneal

transparency caused by refractive surgery.6 Corneal haze

Accepted for publication April 5, 2006.

From the Pepose Vision Institute (Qazi, Pepose); the Departmentof Ophthalmology and Visual Sciences (Qazi, Pepose), Washing-ton University School of Medicine; and the University of MissouriSchool of Optometry (Johnson), St. Louis, Missouri, USA.

Supported in part by research grants from the Midwest CorneaResearch Foundation, St. Louis, Missouri, USA.

No author has a financial or proprietary interest in any productmentioned.

Corresponding author: Jay S. Pepose, MD, PhD, Pepose Vision In-stitute, 16216 Baxter Road, Suite 205, Chesterfield, Missouri63017, USA. E-mail: jpepose@peposevision.com.

Q 2006 ASCRS and ESCRS

Published by Elsevier Inc.

and associated myopic regression, with potential loss ofbest corrected visual acuity (BCVA), have been attributed

to aggressive wound healing involving an influx of stromal

keratocytes and replacement with extracellular matrix

(ECM) elements.7–9 It is postulated that preserving an epi-

thelial flap along with the basement membrane structure

over an ablated stromal bed reduces the risk for corneal

haze and regression compared with the risk with PRK. Basic

science and clinical investigations attribute the protectivemechanism of the LASEK flap to the reduction in: stromal

infiltration of tear-film cytokines, the release of preformed

cytokines from damaged corneal epithelia, and subepithe-

lial keratocyte apoptosis.

Transient, mild corneal haze can occur after LASEK but

usually fades after several months with minimum sequelae.

Lin et al.10 show that deeper ablations increase the risk for

haze formation. We have reported that corneal haze afterLASEK (without prophylactic mitomycin-C [MMC]) can

evolve into reticular anterior scarring resulting in loss of

BCVA.11

Attempts to mitigate the risk for haze formation after

LASEK involve the prophylactic use of topical MMC

intraoperatively. Mitomycin-C is an alkylating agent12

that inhibits proliferation of subepithelial keratocytes.13,14

The prophylactic use of intraoperative topical MMC hasbecome routine for many surgeons in cases of high

correction or deep ablation with LASEK. Its use, however,

does not eliminate the risk for haze formation. We report

0886-3350/06/$-see front matterdoi:10.1016/j.jcrs.2006.04.027

1573

CASE REPORTS: LATE-ONSET SUBEPITHELIAL CORNEAL HAZE AFTER LASEK WITH MMC

a patient who developed significant subepithelial haze

more than 1 year after LASEK with intraoperative MMC.

This was successfully treated by manual debridement,

phototherapeutic keratectomy (PTK), and intraoperative

MMC.

CASE REPORT

A 23-year-old Asian man was evaluated for laser refractivecorrection of high compound myopic astigmatism before theavailability of phakic intraocular lenses in the United States.The preoperative BCVA was 20/16 in each eye, with a manifest re-fraction of�12.00�2.00� 10 in the right eye and�11.50�1.25� 157 in the left eye (Table 1). The keratometric readings inthe right and left eye by Orbscan (Bausch & Lomb, Inc.) were43.8/42.1@4 and 43.9/42.5@163, respectively. The central cornealthickness by 50 MHz ultrasonic pachymetry (Cornea-Gauge Plus,Sonogage) was 523 mm in the right eye and 517 mm in the left eye.Due to the large refractive error and thinner than average corneas,LASEK was recommended after the potential risks, benefits, andalternatives had been discussed.

The patient had bilateral, sequential LASEK with the Star S2excimer laser (193 nm, 160 mJ/cm2; Visx, Inc.) using a large op-tical zone (6.5 mm) with a blend of approximately 8.0 mm inboth eyes. The epithelial flap was created after ethanol 20% (dehy-drated ethyl alcohol) was applied for 30 seconds. The total abla-tion depth was 155 mm in the right eye and 151 mm in the lefteye, according to the laser platform. Following laser application,MMC 0.02% was applied to the central cornea with a presoakedMerocel sponge (Becton Dickinson) for 2 minutes and then irri-gated copiously with balanced salt solution (BSS). After the epi-thelial flap was repositioned, a soft bandage lens was placed ineach eye. The patient was treated with topical ciprofloxacin0.3% (Ciloxan) 4 times daily in each eye for 1 week, with preser-vative-free artificial tears and oral analgesics as needed.

On day 1, the binocular visual acuity was 20/100 with well-centered bandage contact lenses bilaterally. At 4 days, the contactlenses were removed and the uncorrected visual acuity (UCVA)was 20/200 in the right eye and 20/80 in the left eye. Irregularepithelium was noted in both eyes without areas of sloughing,and there were no signs of subepithelial haze. At this time, pred-nisolone acetate (Econopred Plus 1%) was prescribed 4 timesdaily, with a plan to begin tapering after 1 month. At 1 month,trace corneal haze was noted in both eyes. The haze completely

Table 1. Timeline of dense subepithelial haze formation after LASEK with

adjuvant, single-dose intraoperative mytomycin C (MMC) 0.02%

Left Eye UCVA BSCVASpherical

Equivalent Haze

Preoperative 20/CF 20/16 –12.13 06 months post LASEK 20/16 20/16 Plano 09 months post LASEK 20/16 20/16 Plano C0.517 months post LASEK 20/40 20/32 –1.00 C411 months post

debridement/MMC/PTK20/25 20/25 Plano C0.5

UCVA Z uncorrected visual acuity, BSCVA Z best spectacle-corrected

visual acuity, CF Z counting fingers, PTK Z phototherapeutic

keratectomy

J CATARACT REFRACT SUR1574

resolved by the 10-week visit, at which time the UCVA was 20/20in both eyes. The topical steroid was discontinued 14 weekspostoperatively.

The patient was seen at 17 months with a complaint of a grad-ual, painless decrease in vision in the left eye over the previous 2 to3 weeks. The UCVA was 20/20 in the right eye and 20/40 in theleft, with a BCVA of 20/32 in the left eye. Biomicroscopy of theright eye was unremarkable, but there was dense central subepi-thelial haze (grade 4/4) in the left eye, with dimensions of2.4 mm � 3.2 mm, obscuring iris details. Topical steroids (PredForte 1%) 4 times a day and cyclosporine (Restasis 0.05%) 2 timesa day were prescribed in the left eye. At the next follow-up visit,19 months postoperatively, there was no improvement in UCVAor BCVA in the left eye. Manual debridement with MMC 0.02%and PTK was therefore scheduled for the left eye.

After informed consent had been obtained, gentle debride-ment (Crescent blade, Alcon, Inc.) was used to manually removemost of the central haze. Phototherapeutic keratectomy (6.0 mmdiameter) was then performed with the Visx Star 3 laser to polishthe stromal surface using carboxymethylcellulose 1.0% (Cellu-visc) as a masking agent. A Merocel sponge soaked with MMC0.02% was placed over the central cornea for 2 minutes. Afterthe cornea was copiously irrigated with BSS, a soft contact lenswas applied.

On day 1, topical Econopred Plus 1% and moxifloxacin hy-drochloride 0.5% (Vigamox) were prescribed 4 times a day inthe left eye. The UCVA was 20/125 in the left eye, and C1 hazewas noted (Figure 1). Once again, the topical steroid was gradu-ally tapered over several months. Topical Restasis twice a day inthe left eye and oral vitamin C 500 twice a day were also pre-scribed. The UCVA improved to 20/32 by the 3-month post-debridement visit, with trace residual haze observed onbiomicroscopy (Figure 2). At 11 months, the patient’s lastrecorded visit, the UCVA was 20/16 in the right eye and hadimproved to 20/25 in the left eye with a manifest refraction of

Figure 1. One day after manual debridement plus intraoperative MMC

and PTK, residual reticular subepithelial haze (grade C1) is seen centrally.

G - VOL 32, SEPTEMBER 2006

CASE REPORTS: LATE-ONSET SUBEPITHELIAL CORNEAL HAZE AFTER LASEK WITH MMC

C0.25�0.50� 179 (BCVA 20/25). The patient denied any signif-icant complaints, and only mild haze was noted.

DISCUSSION

Corneal haze after photoablation is a well-documented

risk and has been widely investigated. Most series involving

the treatment of low to moderate myopia with LASEK with-

out prophylactic MMC describe low levels (0% to 13%) of

haze formation, generally peaking at the third postopera-tive month and resolving by the twelfth month.1,3–5,15–20

Other series involving the treatment of moderate to high

myopia report visually significant haze formation in 8%

to 10% of LASEK eyes.21,22 Kim et al.23 report 7.5% of

146 eyes (mean preoperative spherical equivalent of

�8.01 diopters [D] 6 1.85 [SD]) with C3 haze, 17.8%

with C2 haze, and 31.5% with C1 haze 12 months after

LASEK. Lin et al.10 show that the duration of haze afterLASEK depended on the severity of the haze: C1 haze

resolved after 4.0 6 2.2 months, while C2 haze resolved

after 5.5 6 3.3 months. Haze formation peaked at 3 months

in their cohort of 90 LASEK eyes.

In LASEK, a viable epithelium is believed to limit ker-

atocyte transformation into cells actively involved in the

production of ECM and collagen.3,5,7,9,24 Transmission

electron microscopy of the LASEK flap shows an intact ep-ithelial cellular layer, with some discontinuity and irregu-

larities in the basement membrane.3 Gabler et al.25

observe that the corneal epithelial flap remained vital for

Figure 2. Further resolution of haze 3 months after manual debridement

with intraoperative MMC and PTK.

J CATARACT REFRACT SUR

up to 45 seconds while exposed to alcohol 20%. The plane

of alcohol-assisted dissection of the epithelial layer was be-

tween Bowman’s and the lamina densa.

Several authors have determined that surgically in-

duced injury to the corneal epithelium plays a significant

role in subsequent subepithelial fibrosis. Nakamuraet al.26 have demonstrated subepithelial haze after LASIK

if the epithelium is denuded intraoperatively. Epithelial dis-

ruption results in the release of preformed cytokines and

secretion of newly formed cytokines, including interleu-

kin-1, transforming growth factor (TGF)-b, interleukin 6,

and epidermal growth factor.7,27–29 These cytokines medi-

ate epithelial keratocyte interactions, initiating epithelial

regeneration and keratocyte apoptosis.27 The actions of cy-tokines, enzymes such as metalloproteinases, inflammatory

cells, and free radicals in the subepithelial stroma disrupt

the highly organized matrix of collagen fibrils, leading to

alteration of corneal clarity.30,31

The wound modulating properties of the epithelial

flap were observed in white leghorn chick eyes that had

LASEK.32 Less keratocyte apoptosis was seen in the central

superficial stroma than in the peripheral stroma, perhapsbecause the epithelial flap served as a plug and barrier

against the influx of tear cytokines into the central stroma.

An albino rabbit model comparing LASEK and PRK showed

that at higher ablations (�7.00 D), LASEK induced less ker-

atocyte apoptosis, myofibroblast transformation, and chon-

droitin sulfate synthesis.33 Laube et al.34 confirmed less

keratocyte apoptosis in rabbit eyes after LASEK than after

PRK. In another animal model of PRK, amniotic membraneapplication to the stromal bed reduced subepithelial haze

grading by reducing the expression of IL-1.35 Lee et al.16

correlate lower haze gradings with lower tear fluid trans-

forming growth factor-b1 in the early days after LASEK

than after PRK.

In clinical studies, Carones et al.2 show lower haze

rates in eyes deepithelialized with alcohol 20% than in

those deepithelialized manually, presumably because ofless disruption of the epithelial cell layer. Lee et al.16

show lower haze rates at 1 month in LASEK eyes, with al-

cohol-assisted flap formation, than in PRK eyes. Autrata

and Rehurek36 confirm lower haze grading in 108 LASEK

eyes than in 108 PRK eyes 1 to 24 months after surface

ablation.

Risk factors for the development of corneal haze after

photoablation include large treatments,10 atopy, autoim-mune conditions,37 or high ultraviolet (UV) radiation.

Our patient did not have a history significant for these

risk factors except deep ablation. Lin et al.10 found that if

the ablation depth/corneal thickness ratio was greater

than 0.18, there was a higher chance of developing 1Chaze or more. They also identified an ablation depth of

100 mm or deeper as increasing the risk for haze formation.

G - VOL 32, SEPTEMBER 2006 1575

CASE REPORTS: LATE-ONSET SUBEPITHELIAL CORNEAL HAZE AFTER LASEK WITH MMC

Using their criteria, our patient would have had a greater

than 92.5% chance of developing corneal haze of at least

1C. However, according to the findings in several of the

above-cited studies, we would most likely have observed

haze within the first 6 months. Our case revealed the onset

of advanced haze 16 to 17 months postoperatively. The pa-tient denied local trauma, corneal erosion, or acute con-

junctivitis. He had been wearing UV-protective sunglasses

on a regular basis and had been using topical lubricants

as needed. As such, the etiology of the late-stage haze for-

mation remains unidentified.

Intraoperative strategies to reduce the risk for postop-

erative haze formation aim to limit epithelial injury. With

alcohol-assisted techniques, this requires keeping the ex-posure time of alcohol to a minimum, as higher concentra-

tions and duration of exposure lead to a reduction in the

number of viable cells in the epithelial flap. In our experi-

ence, 18% to 20% alcohol for 20 seconds provides safe and

complete epithelial flap creation. Vinciguerra et al.38 rec-

ommend the butterfly LASEK technique with smoothing

to minimize epithelial trauma and haze formation. This in-

volves the retraction of both halves of the alcohol-assistedepithelial sheet from the center to the periphery, along

with the application of a hyaluronic acid masking agent

that is removed with PTK. An alcohol-free technique in

which a methylcellulose gel is used to create the epithelial

sheet.5,20 Pallikaris et al.39 report the use of an automated

epikeratome to form the epithelial flap, with preservation

of normal epithelial and basement membrane structure,40

in which 97% of eyes had trace haze grading or less3 months after photoablation.

Additionally, intraoperative, single-dose MMC has

been used as adjuvant therapy to prevent haze formation af-

ter LASEK. The long-term effects of using this drug for cor-

neal prophylaxis are unknown. Frequent topical use of

MMC is associated with significant ocular toxicity, includ-

ing scleral melt.41 A single intraoperative application of

MMC has the advantages of full compliance, minimumside effects, and controlled drug delivery. Carones et al.42

randomized 60 consecutive PRK eyes (preoperative myopia

range �6.00 to �10.00 D) into 2 groups: 1 received a

2-minute intraoperative application of MMC (0.2 mg/mL)

and the other did not. They conclude that the prophylactic

MMC group had lower haze rates (0% of MMC eyes versus

63% of control eyes with haze higher than C1 at 6 months),

better UCVA and BCVA results, and more accurate refrac-tive outcomes than those achieved in the control group.

Camellin43 reports that the use of a brushstroke of intra-

operative MMC 0.01% after alcohol-assisted LASEK with

smoothing significantly decreased subepithelial haze com-

pared with a control group that did not receive intraopera-

tive MMC. He cautions, however, that the use of MMC was

associated with greater overcorrection and higher corneal

J CATARACT REFRACT SURG -1576

surface aberrations at 1 month and 1 year. Kottler and

Dick44 recommend MMC use in LASEK enhancements.

The question of repeated use of MMC remains unan-

swered and needs to be fully discussed during the informed

consent process. A concentration- and duration-dependent

effect on stromal keratocyte density has been shown in rab-bit eyes following a single application of MMC, with greater

MMC exposure affecting deeper stromal layers45 and endo-

thelium.46 However, Lee et al.47 report no statistically sig-

nificant decrease from preoperative level in endothelial

cell densities measured by specular microscopy in 1011

human eyes following PRK with intraoperative MMC. To

limit the potential risks of MMC exposure, they adjusted

the exposure time of intraoperative MMC as a function ofablation depth and used an annular-shaped sponge for par-

acentral application of MMC, as originally described by

Jain et al.48 Koch reserves repeat MMC for patients who de-

veloped haze during their initial surface ablation proce-

dure, eyes with corneal surgery prior to the initial surface

ablation, and enhancement procedure ablation depth

greater than 20 mm (D.D. Koch, MD, ‘‘Second Surface Abla-

tion with MMC,’’ Journal of Cataract & Refractive SurgeryToday, February 2006, pages 53–54).

Postoperative pharmacologic strategies to reduce the

risk for post-LASEK haze involve the use of topical cor-

ticosteroids, nonsteroidals, and ascorbic acid, among

others.5,9,20 Topical and systemic ascorbate have been

shown to reduce the deleterious effects of UV-radiation ex-

posure and free-radical injury to corneal tissue.49–51 Cam-

ellin1 advocates the use of topical autologous serum 4 timesdaily for 1 week if the LASEK flap is disrupted, and Yee and

Yee20 apply autologous serum intraoperatively and postop-

eratively. Lee et al.52 report that fixing a strip of amniotic

membrane at the inferior limbus immediately after LASEK

in 94 eyes resulted in shorter reepithelialization times, bet-

ter refractive and visual outcomes, and lower corneal haze

than in eyes that had a bandage contact lens only. Addi-

tional modalities such as keratocyte apoptosis blockers29

and vector gene therapy53 may assist with the treatment

of subepithelial haze after LASEK in the future.

Once haze has developed, surgical management is sim-

ilar to that after PRK.54–56 Partal et al.19 report 1 eye of a 27-

year-old woman with a preoperative spherical equivalent of

�7.25 D and an ablation depth of 178 mm who developed

C2 to 3 haze that was treated with PTK and MMC with re-

duction of haze on subsequent visits. Camellin1 reports aneye in which the epithelium sloughed 2 days after LASIK

and the cornea later developed C4 haze, which was treated

with repeat LASEK plus PTK. Mirza et al.11 illustrate the

use of manual debridement coupled with PTK and intra-

operative MMC for the treatment of subepithelial scarring

after LASEK. The present case highlights the use of the

same strategy in a young patient who developed haze

VOL 32, SEPTEMBER 2006

CASE REPORTS: LATE-ONSET SUBEPITHELIAL CORNEAL HAZE AFTER LASEK WITH MMC

despite the intraoperative use of MMC and an aggressive

postoperative topical steroid regimen.

The identification of late-onset corneal haze after

LASEK despite the use of intraoperative MMC poses the

question of the causative agents or mechanisms of this

phenomenon. One could argue that the use of MMC itselfcould alter the timeline for introduction of apoptotic cyto-

kines, resulting in a delayed response. Randomized masked

prospective controlled trials are needed to fully evaluate the

efficacy and safety of routine prophylactic use of intraoper-

ative MMC during LASEK, as well as the optimum concen-

tration and duration of treatment. However, such trials may

require a large enrollment to give the study sufficient power

in light of the relatively low incidence of haze without pro-phylaxis following LASEK and an acceptable beta (type II)

error limit. Quantitative risk factors, such as those identi-

fied by Lin et al.,10 provide clinical guidelines for estimat-

ing the risk for developing corneal haze after LASEK and

providing recommendations for alternative surgical op-

tions, such as phakic and pseudophakic intraocular lenses

or corneal inlay procedures.

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