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: [email protected].
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.
REFERENCES
1. Camellin M. Laser epithelial keratomileusis for myopia. J Refract Surg
2003; 19:666–670
2. Carones F, Fiore T, Brancato R. Mechanical vs alcohol epithelial
removal during photorefractive keratectomy. J Refract Surg 1999;
15:556–562
3. Azar DT, Ang RT, Lee J-B, et al. Laser subepithelial keratomileusis:
electron microscopy and visual outcomes of flap photorefractive
keratectomy. Curr Opin Ophthalmol 2001; 12:323–328
4. Claringbold TV II. Laser-assisted subepithelial keratectomy for the
correction of myopia. J Cataract Refract Surg 2002; 28:18–22
5. Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes,
and pathophysiology of LASEK: review of the literature. Surv Ophthal-
mol 2004; 49:576–602
6. Marshall J, Trokel SL, Rothery S, Krueger RR. Long-term healing of the
central cornea after photorefractive keratectomy using an excimer
laser. Ophthalmology 1998; 95:1411–1421
7. Baldwin HC, Marshall J. Growth factors in corneal wound healing fol-
lowing refractive surgery: a review. Acta Ophthalmol Scand 2002;
80:238–247
8. Kuo IC. Corneal wound healing. Curr Opin Ophthalmol 2004; 15:311–
315
9. Netto MV, Mohan RR, Ambrosio R Jr, et al. Wound healing in the cor-
nea; a review of refractive surgery complications and new prospects
for therapy. Cornea 2005; 24:509–522
10. Lin N, Yee SB, Mitra S, et al. Prediction of corneal haze using an abla-
tion depth/corneal thickness ratio after laser epithelial keratomileusis.
J Refract Surg 2004; 20:797–802
11. Mirza MA, Qazi MA, Pepose JS. Treatment of dense subepithelial
corneal haze after laser-assisted subepithelial keratectomy. J Cataract
Refract Surg 2004; 30:709–714
12. Verweij J, Pinedo HM. Mitomycin C: mechanism of action, usefulness
and limitations. Anticancer Drugs 1990; 1:5–13
13. Kim T-I, Tchah H, Lee S-A, et al. Apoptosis in keratocytes caused by
mitomycin C. Invest Ophthalmol Vis Sci 2003; 44:1912–1917
J CATARACT REFRACT SURG
14. Xu H, Liu S, Xia X, et al. Mitomycin C reduces haze formation in rabbits
after excimer laser photorefractive keratectomy. J Refract Surg 2001;
17:342–349
15. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK for the correction of
myopia and myopic astigmatism. J Cataract Refract Surg 2002; 28:
1343–1347
16. Lee JB, Choe C-M, Kim HS, et al. Comparison of TGF-b1 in tears follow-
ing laser subepithelial keratomileusis and photorefractive keratec-
tomy. J Refract Surg 2002; 18:130–134
17. Shahinian L Jr. Laser-assisted subepithelial keratectomy for low and
high myopia and astigmatism. J Cataract Refract Surg 2002; 28:
1334–1342
18. Bilgihan K, Hondur A, Hasanreisoglu B. Laser subepithelial keratomi-
leusis for myopia of �6 to �10 diopters with astigmatism with the
MEL60 laser. J Refract Surg 2004; 20:121–126
19. Partal AE, Rojas MC, Manche EE. Analysis of the efficacy, predictability,
and safety of LASEK for myopia and myopic astigmatism using the
Technolas 217 excimer laser. J Cataract Refract Surg 2004; 30:2138–
2144
20. Yee RW, Yee SB. Update on laser subepithelial keratectomy (LASEK).
Curr Opin Ophthalmol 2004; 15:333–341
21. Rouweyha RM, Chuang AZ, Mitra S, et al. Laser epithelial keratomileu-
sis for myopia with the autonomous laser. J Refract Surg 2002; 18:217–
224
22. Chalita MR, Tekwani NH, Krueger RR. Laser epithelial keratomileusis:
outcome of initial cases performed by an experienced surgeon. J Re-
fract Surg 2003; 19:412–415
23. Kim JK, Kim SS, Lee HK, et al. Laser in situ keratomileusis versus laser-
assisted subepithelial keratectomy for the correction of high myopia.
J Cataract Refract Surg 2004; 30:1405–1411
24. Shah S, Sebai Sarhan AR, Doyle SJ, et al. The epithelial flap for photo-
refractive keratectomy. Br J Ophthalmol 2001; 85:393–396
25. Gabler B, Winkler von Mohrenfels C, Lohmann CP. Laser epithelial ker-
atomileusis (LASEK): a histological study to investigate the vitality of
corneal epithelial cells after alcohol exposure. ARVO abstract 3222.
Invest Ophthalmol Vis Sci 2001; 42(4):S600
26. Nakamura K, Kurosaka D, Bissen-Miyajima H, Tsubota K. Intact corneal
epithelium is essential for the prevention of stromal haze after laser
assisted in situ keratomileusis. Br J Ophthalmol 2001; 85:209–213
27. Wilson SE, Mohan RR, Hong J-W, et al. The wound healing response
after laser in situ keratomileusis and photorefractive keratectomy; elu-
sive control of biological variability and effect of custom laser vision
correction. Arch Ophthalmol 2001; 119:889–896
28. Kaji Y, Soya K, Amano S, et al. Relation between corneal haze and
transforming growth factor-b1 after photorefractive keratectomy
and laser in situ keratomileusis. J Cataract Refract Surg 2001;
27:1840–1846
29. Kuo IC, Seitz B, LaBree L, McDonnell PJ. Can zinc prevent apoptosis of
anterior keratocytes after superficial keratectomy? Cornea 1997;
16:550–555
30. Corbett MC, Prydal JI, Verma S, et al. An in vivo investigation of the
structures responsible for corneal haze after photorefractive keratec-
tomy and their effect on visual function. Ophthalmology 1996;
103:1366–1380
31. Møller-Pedersen T, Cavanagh HD, Petroll WM, Jester JV. Stromal
wound healing explains refractive instability and haze development
after photorefractive keratectomy; a 1-year confocal microscopic
study. Ophthalmology 2000; 107:1235–1245
32. Lee JB, Javier JA, Chang J-H, et al. Confocal and electron microscopic
studies of laser subepithelial keratomileusis (LASEK) in the white
leghorn chick eye. Arch Ophthalmol 2002; 120:1700–1706
33. Esquenazi S, He J, Bazan NG, Bazan HEP. Comparison of corneal
wound-healing response in photorefractive keratectomy and
- VOL 32, SEPTEMBER 2006 1577
CASE REPORTS: LATE-ONSET SUBEPITHELIAL CORNEAL HAZE AFTER LASEK WITH MMC
laser-assisted subepithelial keratectomy. J Cataract Refract Surg 2005;
31:1632–1639
34. Laube T, Wissing S, Theiss C, et al. Decreased keratocyte death after
laser-assisted subepithelial keratectomy and photorefractive keratec-
tomy in rabbits. J Cataract Refract Surg 2004; 30:1998–2004
35. Wang MX, Gray TB, Park WC, et al. Reduction in corneal haze and ap-
optosis by amniotic membrane matrix in excimer laser photoablation
in rabbits. J Cataract Refract Surg 2001; 27:310–319
36. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy and
photorefractive keratectomy for the correction of hyperopia: results
of a 2-year follow-up. J Cataract Refract Surg 2003; 29:2105–2114
37. Cua IY, Pepose JS. Late corneal scarring after photorefractive keratec-
tomy concurrent with the development of systemic lupus erythema-
tosus. J Refract Surg 2002; 18:750–752
38. Vinciguerra P, Camesasca FI, Torres IM. Transition zone design and
smoothing in custom laser-assisted subepithelial keratectomy. J Cat-
aract Refract Surg 2005; 31:39–47
39. Pallikaris IG, Kalyvianaki MI, Katsanevaki VJ, Ginis HS. Epi-LASIK: pre-
liminary clinical results of an alternative surface ablation procedure.
J Cataract Refract Surg 2005; 31:879–885
40. Pallikaris IG, Naoumidi II, Kalyvianaki MI, Katsanevaki VJ. Epi-LASIK:
comparative histological evaluation of mechanical and alcohol-
assisted epithelial separation. J Cataract Refract Surg 2003; 29:
1496–1501
41. Rubinfeld RS, Pfister RR, Stein RM, et al. Serious complications of
topical mitomycin-C after pterygium surgery. Ophthalmology 1992;
99:1647–1654
42. Carones F, Vigo L, Scandola E, Vacchini L. Evaluation of the prophylac-
tic use of mitomycin-C to inhibit haze formation after photorefractive
keratectomy. J Cataract Refract Surg 2002; 28:2088–2095
43. Camellin M. Laser epithelial keratomileusis with mitomycin C: indica-
tions and limits. J Refract Surg 2004; 20:S693–S698
44. Kottler UB, Dick HB. Mitomycin C bei oberflachlichen Hornhautabla-
tionen mit dem Excimer-Laser: Eigene Erfahrungen und Literaturuber-
sicht. Klin Monatsbl Augenheilkd 2005; 222:499–504
J CATARACT REFRACT SURG1578
45. Chang S-W. Corneal keratocyte apoptosis following topical intraoper-
ative mitomycin C in rabbits. J Refract Surg 2005; 21:446–453
46. Chang S-W. Early corneal edema following topical application of
mitomycin-C. J Cataract Refract Surg 2004; 30:1742–1750
47. Lee DH, Chung HS, Jeon YC, et al. Photorefractive keratectomy with
intraoperative mitomycin-C application. J Cataract Refract Surg
2005; 31:2293–2298
48. Jain S, McCally RL, Connolly PJ, Azar DT. Mitomycin C reduces corneal
light scattering after excimer keratectomy. Cornea 2001; 20:45–49
49. Bilgihan A, Bilgihan K, Toklu Y, et al. Ascorbic acid levels in human
tears after photorefractive keratectomy, transepithelial photorefrac-
tive keratectomy, and laser in situ keratomileusis. J Cataract Refract
Surg 2001; 27:585–588
50. Bilgihan K, Bilgihan A, Akata F, et al. Excimer laser corneal surgery and
free oxygen radicals. Jpn J Ophthalmol 1996; 40:154–157
51. Stojanovic A, Ringvold A, Nitter T. Ascorbate prophylaxis for corneal
haze after photorefractive keratectomy. J Refract Surg 2003; 19:338–
343
52. Lee HK, Kim JK, Kim SS, et al. Effect of amniotic membrane after laser-
assisted subepithelial keratectomy on epithelial healing; clinical and
refractive outcomes. J Cataract Refract Surg 2004; 30:334–340
53. Song JC, McDonnell PJ, Gordon EM, et al. Phase I/II evaluation of safety
and efficacy of a matrix-targeted retroviral vector bearing a dominant
negative cyclin G1 construct (Md-dnG1) as adjunctive intervention for
superficial corneal opacity/corneal scarring. Hum Gene Ther 2003;
14:306–309
54. Majmudar PA, Forstot SL, Dennis RF, et al. Topical mitomycin-C for
subepithelial fibrosis after refractive corneal surgery. Ophthalmology
2000; 107:89–94
55. Vigo L, Scandola E, Carones F. Scraping and mitomycin-C to treat haze
and regression after photorefractive keratectomy for myopia. J Re-
fract Surg 2003; 19:449–454
56. Porges Y, Ben-Haim O, Hirsh A, Levinger S. Phototherapeutic keratec-
tomy with mitomycin C for corneal haze following photorefractive
keratectomy for myopia. J Refract Surg 2003; 19:40–43
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