28

Use of Autologous Serum to Reduce Haze After LASEK

Steven B.Yee, MD, Ning Lin, MD, OD, Alice Z.Chuang, PhD, and

Richard W.Yee, MD

Hermann Eye Center, University of Texas Health Science Center at

Houston,

Houston, TX

BACKGROUND

In years past, excimer laser photorefractive keratectomy (PRK) has been a popular surgical modality for the correction of myopia. The postoperative pain, corneal haze, and slower visual rehabilitation after PRK prompted a large number of patients to select laser in situ keratomileusis (LASIK) instead. However, LASIK involves cornea flap creation, repositioning, and a healing process and, accordingly, flap-associated complications and aberrations compromised visual outcome. In addition, LASIK may not be suitable for patients with high myopia, thin corneas, or large pupils. Additional concern regarding loss of the LASIK flap may be a relative contraindication to individuals who are at higher risk for ocular trauma (law enforcement, military personnel, emergency medical personnel, and athletes in contact sports). To overcome the previously mentioned limitations and to enhance visual recovery, a new refractive surgery technique was developed, laser epithelial keratectomy (LASEK), with promising results (1–4). After application of 18% to 20% ethanol on the corneal epithelium for 25 to 45 seconds, a superiorly hinged epithelial flap is created and laser ablation is then performed. The epithelial flap is then replaced and a bandage contact lens is applied.

LASEK offers a major advantage over LASIK in that no true flap is created. Accordingly, flap-associated complications and aberrations arising from LASIK flap creation are avoided. Patients with thin corneas, large pupils, or those who may sustain ocular trauma (and loss of a LASIK flap) could also benefit from LASEK. The uncorrected visual acuity of postoperative LASEK and LASIK are comparable.

HAZE

As in PRK, haze (loss of corneal transparency) is a major postsurgical complication of LASEK. Histopathologically, haze is characterized by the confluence and activation of keratocytes (fibroblasts), and the accumulation of abnormal collagen and other substances in the extracellular matrix (5–7). The development of haze after PRK has been associated with increased cellular reflectivity from high numbers of wound-healing

keratocytes (17). The proliferative capability of keratocytes isolated from a corneal haze has been found to be significantly greater than that of keratocytes from normal cornea in tissue cultures (8, 9).

Haze is associated with a decrease in contrast sensitivity, development of halos and glare, decrease in the predictability of the correction of refractive error, and regression of acquired correction (3–11). Several animal studies have shown reduction of corneal haze by a single intra-operative application of topical mitomycin C (10), by postoperative application of topical synthetic inhibitor of metalloproteinase (11), tranilast (8), collagenase inhibitors (10% ascorbate, 0.1 M cysteine, 0.37% EDTA, and 1% tetracycline) (12), and plasmin inhibitors (aprotinin) (13). The use of corticosteroids in the modulation of haze has yielded equivocal results. Corticosteroids either have had no effect on haze (9,13) or have appeared to reduce the incidence of haze (14). Use of corticosteroids entails the well-known untoward effects of elevation of intraocular pressure (IOP) and risk of cataract. Oral supplementation with vitamin A (25,000 IU retinol palmitate) and vitamin E (230 mg α-tocopheryl nicotinate) may reduce haze formation in humans after PRK (15). Intact corneal epithelium has been shown to play an important part in curbing haze and in the differentiation of myofibroblasts in corneal wound healing (16). Corneal haze has been shown to be correlated with ablation depth. Haze is seen more frequently and is denser in high myopes. In the −3.00-diopter (D) groups, haze appears to be maximal at approximately 3 months, whereas in the −6.00-D group, haze is maximal at 5 to 6 months (9).

There is a correlation between increased ablation depth/corneal thickness (AD/CT) ratio (e.g., more than 0.18) and an increased incidence of corneal haze (21). Fortunately, the treatment and control groups were well-matched, with each group containing eyes with low AD/CT and eyes with high AD/CT ratios.

Serum has been used effectively as treatment for intractable aqueous-deficient dry eyes (18). Serum is the fluid portion of blood that is devoid of clotting factors and cellular components. It has been used in cell cultures for many years. The growth factors and other components found in serum may help cell adhesion, cell migration, cell proliferation, wound healing, and remodelation. Serum is known to be rich in epithelial growth factor (EGF) and other components known to accelerate corneal epithelial wound healing through stimulation of cell proliferation and of migration and antipoptotic effects (22). Autologous serum has been efficacious in the treatment of persistent corneal epithelial defects in dry eyes associated with Sjogren syndrome (19,20).

OUR EXPERIENCE

All consecutive patients undergoing LASEK procedure for refractive errors at the Hermann Eye Center, The University of Texas Health Science Center at Houston, from 1999 to 2002 were included in our study. The LASEK procedures were performed by a single surgeon (R.W.Y.) using an Alcon Autonomous LADARVision 4000 Excimer Laser (Alcon Laboratories, Fort Worth, TX).

During the initial patient encounter, a complete medical and ophthalmic history was taken (including the history and stability of refractive error). A complete eye examination was also performed, including the determination of visual acuity (both uncorrected and

LASEK, PRK, and excimer laser stromal surface ablation 356

best-corrected), manifest refraction, and cycloplegic refraction. The cycloplegic refraction was performed after topical administration of phenylephrine 2.5%, tropicamide 1.0%, and cyclopentolate 0.5%. Corneal topography and pachymetry were obtained on all patients, as well.

Eleven consecutive patients undergoing LASEK using a modified Camellin LASEK procedure received a 20% autologous serum solution (in balanced salt solution) as eye drops. During the surgery, two drops of the autologous serum solution was administered to the cornea before and after repositioning the epithelial flap. The patient applied one drop of serum solution as an ophthalmic drop six times per day for 4 days. On postoperative day 0, the patient started the serum solution 3 hours postoperatively. If reepithelialization was not completed by postoperative day 4, the patients continued administration of the serum solution for an additional 1 to 2 days until completion of reepithelialization and removal of the bandage contact lenses.

The control group was a historical control. These patients also underwent LASEK (same modified Camellin LASEK technique as the “serum” group) and had complete haze data in each follow-up. The control group patients were participants in another study investigating LASEK patients and haze formation in relation to the ablation depth/cornea thickness ratio. The sole difference between the “serum” group and the control group was the use of autologous serum eye drops in the “serum” group. The two groups (“serum” and control) were matched for age and for amount of refractive error.

LASEK TECHNIQUE

After standard preparation, draping and placement of an eyelid speculum, the cornea is marked at the 3 o’clock and 9 o’clock positions. A stencil is used to mark the area at 6 o’clock. Using a 60-to 80-µm trephine, epithelial microtrephination is performed resulting in a 60-degree to 80-degree hinge at the 12 o’clock location. An alcohol well/alcohol cone (whose circumference is greater than that of the incision) is then placed over the eye and filled with an 18% ethanol solution. The alcohol solution is left in place for 45 seconds. A weck sponge is then used to remove the alcohol solution, followed by rinsing with balanced salt solution. Epithelial detachment is then performed using an epithelial hoe followed by a flap spatula. The epithelial flap is then folded back at the 12 o’clock position. After small spot excimer treatment is completed, the flap is then repositioned with a fine cannula and/or a small spatula. A bandage soft contact lens is then applied to the cornea to keep the flap in place until completion of re-epithelialization (normally 3 to 5 days).

After LASEK, patients were examined daily or every other day until reepithelialization is accomplished. Thereafter, the patients were examined at 1 week, 1 month, 3 months, 6 months, and 12 months postoperatively. Assessment of visual acuity (both uncorrected and best-corrected) and slit-lamp examination were included in each visit. In addition to performing the standard slit-lamp examination, the post-LASEK corneas were also evaluated for corneal haze by two independent evaluators (Fig. 1). The ratings for corneal haze from the two evaluators were averaged and recorded. The relative scale is as follows:

0=no haze

0.5+=trace haze

1+=mild easily, easily seen on slit-lamp biomicroscopy 2+=moderate haze

3+=marked haze, iris details still visible 4+=severe haze, iris details obscured

Figure 1 An example of haze. (A) 0.50+ haze. (B) 1.0+ haze.

Serum Preparation

Twenty milliliters of the patient’s blood is collected in two red top tubes (no preservatives, no wax) and centrifuged at 4,000 rpm for 4 minutes. Using sterile technique, the serum is then drawn off and diluted with balanced salt solution to arrive at a final concentration of 20%. The autologous serum solution is then packaged into individual single-use ampoules and stored at −80°F until the day of surgery, when it is thawed at room temperature. The patient is then instructed on the use of the autologous serum eye drops and is advised to store the eye drops in a refrigerator at 40°F.

Statistical Methods

For each eye, the AD/CT ratio was computed and categorized into high or low AD/CT based on AD/CT ratio being less than or greater than 0.18. The maximum haze during the postoperative follow-up was recorded for each eye. If the maximum haze was equal to or greater than 1+, the eye was categorized into the haze group. Otherwise, it was included in the no haze group. The baseline characteristics, age, refractive error, AD, and AD/CT are reported as mean ±SD are compared between two groups using two-sample t tests. Categorical variables are reported as frequency (%). The Fisher exact test was used to examine significant differences in distribution or in frequency between the groups. Stepwise logistic regression was further used to compare the treatment effects and other baseline characteristics (age, refractive error, and AD/CT).

LASEK, PRK, and excimer laser stromal surface ablation 358

All statistical computations were accomplished with SAS for Window NV, version 6.12 (Cary, NC). A p value of 0.05 was regarded as significant.

RESULTS

A total of 106 LASEK-treated eyes from 63 patients were included in this study. Of these, 21 (20%) LASEK-treated eyes from 11 patients received 20% autologous serum treatment; 85 (80%) LASEK-treated eyes from 52 patients did not receive serum treatment.

The age of patients in the treatment group ranged from 27 to 45 years (mean age was 38.2±5.1 years), and the age of the control group ranged from 24 to 67 years (mean age was 40.9±9.6 years). There were no statistical differences in age range between the treatment and the control groups (P=0.10).

The mean refractive error for the treatment group was −5.23 (±2.02) D. The mean refractive error for the control group was −5.46 (±3.74) D. There were no statistical differences in the mean refractive error between the treatment and control groups (P=0.70).

The mean follow-up duration was 306±66 days for the treatment group and 192 ±107 days for the control group.

The mean ablation depth for the eyes receiving treatment was 74.70±22.93—m, with a mean AD/CT ratio of 0.14±0.04. The mean ablation depth for eyes not receiving treatment was 93.0±45.0 µm, with a mean AD/CT of 0.18±0.09. There were no statistical differences in mean ablation depth and in AD/CT between the treatment and control groups (P=0.07 and 0.08, respectively); 45 (42%) eyes had a high AD/CT ratio (AD/CT > 0.18).

Fifty-eight percent had a low AD/CT ratio. Of the high AD/CT eyes, seven (16%) eyes received serum and 38 (84%) eyes received no treatment. Of the eyes with low AD/ CT ratio, 14 (23%) received serum treatment and 47 (77%) received no treatment. There were no statistical differences in distribution of high or low AD/CT between treatment groups (P=0.46, Fisher exact test).

It was found that in eyes with both high and low AD/CT ratios, the use of autologous serum was associated with a lower incidence of corneal haze. This lower incidence of haze with serum use was statistically significant in eyes with high AD/CT ratio with a p value of 0.0068.

Although a lower incidence of corneal haze was associated with autologous serum use in eyes with low AD/CT ratio, this finding was not considered statistically significant with a p value of 0.5803 (Fig. 2).

The stepwise logistic regression analysis showed that the significant factors associated with developing haze were high AD/CT ratio (odds ratio=103, p <0.001) and the nonuse of serum treatment. The use of serum drops was associated with the significant reduction of corneal haze after LASEK (Fig. 3).

Figure 2 Comparison of maximal corneal haze between serum group and nonserum group. Among 85 nonserum-treated eyes, 47 eyes were in the lower ratio group (AD/CT ratio <0.18) and 38 eyes were in higher ratio group (AD/CT ratio ≥0.18). Forty-two of 47 eyes (89%) in the no serum/lower ratio group developed no corneal haze during the follow-up period. Only five of 47 eyes (11 %) in the no serum/lower ratio group showed 1+or more haze. In the no serum/higher ratio group, 35 of 38 eyes (92%) developed 1+or more corneal haze during follow-up period. In the no serum/higher ratio group, three of 38 eyes (8%) had no corneal haze. Among 21 serum-treated eyes, seven eyes were in the higher ratio group and 14 eyes were in the lower ratio group. Three of seven eyes (42%) in the autologous serum/higher ratio group had no corneal haze during the follow-up period. In the autologous serum/lower ratio group, all 14 eyes were free of corneal haze.

LASEK, PRK, and excimer laser stromal surface ablation 360

Figure 3 Comparison of average corneal haze between serum-treated group and nonserum-treated group. The average corneal haze in the serumtreated group was 0.54±0.18 (range from 0 to 1+). While in the nonserumtreated group, the average corneal haze was 0.79±0.61 (range from 0 to 2+). Autologous serum was identified as a significant factor (p=0.0005) in developing corneal haze by using the stepwise logistic regression.

DISCUSSION

LASEK is becoming increasingly popular since its introduction to the United States in 1999. LASEK appears to be a safe and efficacious alternative to LASIK, even in patients with higher amounts of myopia (21). LASEK has also been shown to be superior to LASIK in terms of postoperative topographical results and in the correction of cylinder error (second-order astigmatism) (22). In contrast to LASIK, LASEK avoids the use of a microkeratome and thus avoids the complications associated with flap creation. In contrast to PRK, LASEK offers the advantage of less postoperative pain and less time required for re-epithelialization. LASEK is particularly attractive to patients with thin corneas, high myopia, flat corneas, and those prone to ocular trauma (e.g., police officers, members of the armed forces, participants in contact sports).

LASEK shares with PRK the potential complication of corneal haze. Corneal haze may result in: (1) decrease in the predictability of correction/refraction; (2) reduction in the quality of vision; (3) decrease in contrast sensitivity; (4) increase in cornea irregularity; (5) regression of visual acuity; and (6) an increase in recovery time. Corneal haze remains the most important factor in the determination of LASEK outcome. Although it is believed that the risk of corneal haze is lower for LASEK than for PRK, there does remain the real risk of corneal haze among LASEK patients.

Our grading is based on the appearance of the corneal haze on slit-lamp biomicroscopy. It is compatible with the system proposed by Hanna (23). Serum (e.g., fetal calf) has played a prominent role in promoting cell growth in culture. Tsubota et al. demonstrated that fetal calf serum accelerated corneal epithelial cell migration in vitro (19).

There are many precedents for the clinical use of autologous serum. Autologous serum has been successfully used in the rehabilitation of the ocular surface in patients with severe dry eye caused by ocular pemphigoid, Stevens-Johnson syndrome, and Sjögren syndrome. The rationale for using autologous serum is based on the observation that factors present in tears are also present in serum, but not in commercially available artificial tears (20). Autologous serum has also been found to be efficacious in the therapy of persistent epithelial defects (25).

The selection of 20% autologous serum came about from the successful use of 20% autologous serum by Tsubota et al. (20). Although the exact mechanism of how autologous serum may decrease corneal haze is not well-understood, there are numerous components in serum that may play a role in the decrease of corneal haze. The serum components believed to promote epithelial healing are EGF, basic fibroblast growth factor (bFGF), and fibronectin (25).

EGF found in human tears and serum has proven efficacious in the healing of corneal abrasions (27). The bFGF and acidic fibroblast growth factor (aFGF) have been shown to promote faster healing of epithelial defects in rabbit corneas (26).

In our study, patients with AD/CT ratio of more than 0.18 were at greater risk for corneal haze. We found that the use of 20% autologous serum (intra-operatively and also as postoperative eye drops) reduced the incidence of corneal haze, regardless of the AD/ CT ratio.

We demonstrated that 20% autologous serum may be of benefit to patients undergoing LASEK. The use of serum was correlated with a lower incidence of corneal haze. Given

LASEK, PRK, and excimer laser stromal surface ablation 362

that corneal haze is a major factor in LASEK outcome and that the use of the patient’s own serum under proper settings not associated with major untoward effects, one could make the case for use of 20% autologous serum in LASEK patients with high AD/CT ratios.

REFERENCES

1.Shah S, Sebai Sarhan AR, Doyle SJ, Pillai CT, Dua HS. The epithelial flap for photorefractive keratectomy. Br J Ophthalmol; 2001; 85(4):393–396.

2.Kornilovsky IM. Clinical results after subepithelial photorefractive keratectomy (LASEK). J Refract Surg; 2001; 17(2 Suppl):S222–S223.

3.Scerrati E. Laser in situ keratomileusis vs. laser epithelial keratomileusis (LASIK vs. LASEK). J Refract Surg; 2001; 17(2 Suppl):S219–S221.

4.Lee JB, Seong GJ, Lee JH, Seo KY, Lee YG, Kim EK. Comparison of laser epithelial keratomileusis and photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg; 2001; 27(4):565–570.

5.Malley DS, Steinert RF, Puliafito CA, Dobi ET. Immunofluorescence study of corneal wound healing after excimer laser anterior keratectomy in the monkey eye. Arch Ophthalmol; 1990; 108(9):1316–1322.

6.Fantes FE, Hanna KD, Waring GO 3rd, Pouliquen Y, Thompson KP, Savoldelli M. Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys. Arch Ophthalmol; 1990; 108(5):665–675.

7.Fitzsimmons TD, Fagerholm P, Harfstrand A, Schenholm M. Hyaluronic acid in the rabbit cornea after excimer laser superficial keratectomy. Invest Ophthalmol Vis Sci; 1992; 33(11): 3011–3016.

8.Moller-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(7):1235–1245.

9.Okamoto S, Sakai T, Iwaki Y, Tobari I, Hamano S. Effects of tranilast on cultured rabbit corneal keratocytes and corneal haze after photorefractive keratectomy. Jpn J Ophthalmol; 1999; 43(5):355–362.

10.Gartry DS, Kerr Muir M, Marshall J. The effect of topical corticosteroids on refraction and corneal haze following excimer laser treatment of myopia: an update. A prospective, randomized, double-masked study. Eye; 1993; 7(Pt 4):584–590.

11.Xu H, Liu S, Xia X, Huang P, Wang P, Wu X. Mitomycin C reduces haze formation in rabbits after excimer laser photorefractive keratectomy. J Refract Surg; 2001; 17(3):342–349.

12.Chang JH, Kook MC, Lee JH, Chung H, Wee WR. Effects of synthetic inhibitor of metalloproteinase and cyclosporin A on corneal haze after excimer laser photorefractive keratectomy in rabbits. Exp Eye Res; 1998; 66(4):389–396.

13.Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg; 2002; 18(3):217–224.

14.Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology; 1999; 106(10):1984–1989.

15.Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, Shimmura S. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol; 1999; 83:390–395.

16.Pastor JC, Calonge M. Epidermal growth factor and corneal wound healing: a multicenter study. Cornea; 1992; 11:311.

17.Moller-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 Jul; 107(7):1235–45.

18.Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 2001 Apr; 42(5):948–56.

19.Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology 1999 Oct; 106(10):1984–9.

20.Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, and Shimmura S. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999; 83: 390–395.

21.Rouweyha RM, Chuang AZ, Mitra S, Phillips CB, Yee RW. Laser epithelial keratomileusis for myopia with the autonomous laser. J Refract Surg 2002 May–Jun; 18(3):217–24.

22.Smolek MK, Yee RW, McDonald MB, Klyce SD, Nguyen L, Stokes JP. A Comparison of LASEK, PRK, and LASIK Topographies and Wavefront Analysis.

23.Hann KD, Pouliquen YM, Waring GO II, et al. Corneal wound healing in monkeys after repeated excimer laser photorefractive keratectomy. Arch Ophthalm 1992; 110:1286–1291.

24.Geerling G, Daniels JT, Dart JK, Cree IA, Khaw PT. Toxicity of natural tear substitutes in a fully defined culture model of human corneal epithelial cells. Invest Ophthalmol Vis Sci 2001 Apr; 42(5):948–56.

25.Poon AC, Geerling G, Dart JK, Fraenkel GE, and Daniels JT. Autologous serum drops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol 2001; 85:1188–1197.

26.Fredj-Reygrobellet D, Plouet J, Delayre, et al. Effects of a FGF and bFGF on wound healing in rabbit corneas. Curr Eye Res 1987; 6:1205–9.

27.Pastor JC, Calonge M. Epidermal growth factor and corneal wound healing: a multicenter study. Cornea 1992; 11:311.

29

LASEK After Corneal and Intraocular

Procedures

Puwat Charukamnoetkanok, MD and Dimitri T.Azar, MD

Massachusetts Eye and Ear Infirmary, Schepens Eye Research Institute,

Harvard Medical School

Boston, MA

The goal of refractive surgery is to correct refractive error, allowing patients to be independent of spectacles or contact lens. Ideally, surgeons aim to accomplish this goal with a single procedure. However, variability in biological response to laser or incisional procedures compromise postoperative predictability and stability. Therefore, retreatment or enhancement is often necessary to achieve satisfactory results. Patients’ preoperative characteristics such as relatively thin cornea may also dictate that a combined procedure be performed to save the tissue and reduce the risk of postoperative ectasia. Various ocular surgeries may affect the refractive status of the eye. Refractive surgery has been increasingly used to improve the postoperative refractive errors. This chapter discusses the possible roles for LASEK after corneal surgeries.

LASEK RETREATMENT

If the decision for enhancement is made at a relatively short period of time after the primary procedure, the retreatment of LASEK is relatively simple and straight-forward. The surgeon recreates the epithelial flap by applying alcohol in a similar manner to that of the original procedure. However, after prolonged wound healing, the re-elevation of the epithelial flap may be difficult. The surgeon may need to apply alcohol for longer duration. An alternative is to perform transepithelial photorefractive keratectomy (PRK) for laser subepithelial keratomileusis (LASEK) enhancement after prolonged wound healing.

LASEK AFTER PRK

LASEK procedure can be used for enhancement of the patient who underwent PRK. These patients already experienced postoperative discomfort and delayed visual recovery associated with PRK. Therefore, they may be more open to the possibility of similar procedure and possibly reduced discomfort associated with LASEK. The epithelial flap has been shown to be viable after brief alcohol exposure (1). The presence of this protective layer may provide optimal environment for corneal wound healing (2).

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Regression caused by epithelial hyperplasia or higher aberrations induced by abnormal stromal fibrosis may also be reduced.

As with the case of retreatment after LASEK, surgeon may encounter difficulty in reelevation of epithelial flap, especially after prolonged periods after the primary procedure. Thus, there may be a need for longer duration of alcohol application.

LASEK AFTER LASIK

PRK has been used after laser in situ keratomileusis (LASIK) in the treatment of extremely high myopia either simultaneously (3) or as a two-stage procedure (4). Guell et al. (5) reported the use of intraepithelial PRK, in which a photoablation was performed directly in the epithelium, without damage to Bowman’s membrane, to treat regression after LASIK. Eight of the 21 eyes (38%) were emmetropic at 6 months and 11 (52.4%) had a refraction between −0.50 and +0.50 diopters (D). Refraction was stable from the second week to the first year, with no significant differences among the mean standard errors (SEs) at 10 days, 6 weeks, 6 months, and 12 months. As a treatment of incomplete LASIK flaps, Bond et al. suggested performing 180 to 220 phototherapeutic keratectomy (PTK) pulses, then proceeding with PRK as if the flap had never been created (6,7).

It is observed that haze formation is significantly greater in PRK after LASIK compared to that seen in primary PRK (8,9). This higher risk of haze may be the result of laser impact on the Bowman’s layer of a previously ablated cornea.

LASEK may be considered when a surgeon contemplates a retreatment of residual refractive errors in patients with high myopia who have thin corneas to allow for sufficient stromal bed thickness. In theory, LASEK should offer comparable visual outcomes to those of PRK after LASIK.

LASEK AFTER RK

It has been reported that the need for retreatment after radial keratotomy (RK) ranges from 30% to 33% of cases (10). The Perspective Evaluation of Radial Keratotomy (PERK) study (11) reported that after 10 years of treatment, 25% to 30% of patients who underwent RK had hyperopia. PERK also revealed that as many as 43% of post-RK patients had hyperopic shift of 1 D or more. Furthermore, the same study reported that 17% of eyes had a residual myopia of greater than 1 D.

LASIK has been used to treat residual myopia and astigmatism, as well as hyperopic shift after RK (12–15). There is a theoretical risk associated with applying suction to post-RK cornea. However, it has been shown that the use of suction is relatively safe in these eyes (16).

One of the challenges of performing LASIK in an eye that had RK is the “pizza slice” effect. This complication occurs when the incisions extend inside the 8 to 9 mm of the central cornea. After the microkeratome cut, the flap separates into triangular shape as a result of inadequate healing of the RK incision. Even seemingly well-healed incisions may contain epithelial plugs on close inspection by slit-lamp examination. These epithelial plugs within RK incisions can lead to epithelial in-growth and precipitate

“pizza slice” effect. Other complications include epithelial in-growth, interface wrinkling, central-island flap tear or dislocation, and infection.

Surface ablation procedure such as LASEK is an excellent alternative to avoid pizza slice effect after RK. The epithelial flap can still be easily manipulated to cover the stroma, should the pizza slicing effect occurs. The bandage contact lens provides added stability to the flap.

In a large multicenter retrospective study of PRK after RK, Azar et al. (17) found that patients with lower original and residual myopia (6 D or less) achieved better visual outcomes after PRK than did those with higher myopia. The amount of myopic correction achieved using RK was not predictive of the amount of myopic correction using PRK. Several studies have demonstrated lower predictability of the refractive outcomes in patients who underwent PRK after RK compared to those with no previous surgery (18– 23). It remains to be seen if LASEK after RK will lead to a more optimal wound-healing response and enhance the postoperative predictability.

Yong et al. reported a five-fold to 10-fold increase in haze formation after performing PRK after RK. Because several reports have suggested that LASEK resulted in less haze than PRK (2,24,25), it is not unreasonable to extrapolate that LASEK may also lead to less haze formation after RK. However, an adjunctive use of mitomycin C may be considered in the case of high residual refractive error.

LASEK AFTER INTRAOCULAR SURGERY

Astigmatism is often induced after scleral buckling surgery, trabeculectomy, extracapsular cataract extraction, and penetrating keratoplasty. Despite the advances in intraocular surgical techniques, many patients still have to endure suboptimal vision, compared to their visual potential, because of corneal irregularities (26,27). A myriad of factors exert influences on postoperative refractive error and astigmatism. In penetrating keratoplasty, the antemortem corneal curvature of the donor, trephination, graft sizing, and suturing techniques have profound effects on the final result.

The possibility of using refractive surgery to eliminating postoperative astigmatism after intraocular surgery has profound implications. The popularity of refractive surgery has raised the patients’ expectation regarding the optical result of their surgery. In elderly patients, the contact lens alternative is often not accepted because the patient may not be able to tolerate a contact lens.

LASIK have been performed after penetrating keratoplasty (PK) and other intraocular surgical procedures (28–33). The optimal time to perform refractive surgery is still debatable. To ensure postoperative stability, it is important to delay the refractive surgery as much as possible after the intraocular procedure. The presence of a good wound scar and the stable refraction and topography for at least 3 months after vitrectomy, scleral buckling, extracapsular cataract extraction (ECCE), and keratoplasty may be necessary before LASIK surgery (29).

Most of the LASIK complications after intraocular surgery occur during dissection of the flap. The high intraocular pressure exerted during the application of the suction ring may lead to wound dehiscence. In patients with steep corneas after PK, the risks of flap

LASEK, PRK, and excimer laser stromal surface ablation 368

complications (such as incomplete flap, buttonhole, or free flap) are increased after LASIK.

PRK has been used to treat myopia and astigmatism after intraocular surgery (34–39). Complications from PRK after PK include regression (34,37) and haze (34,37,38). There were two single case reports of graft rejection associated with surface ablation using excimer laser. One case was an endothelial rejection diagnosed 2 weeks after PRK for recurrent lattice corneal dystrophy 6 years after the original PK (40). Another case involved endothelial rejection occurring 5 days after using excimer laser for treatment of myopia and astigmatism in a 3-year-old graft (41). In both cases, the rejections were successfully reversed without loss of corneal clarity by prompt treatments with corticosteroid. It was unclear whether the rejections were precipitated by the excimer laser, soft contact lens placement, epithelial ablation, or changes in the patient’s medical regimen (40).

Stulting et al. (42) prospectively investigated the effect of excimer laser PRK for myopia on the corneal endothelium in 142 eyes. They concluded that for the correction of up to 6.0 D of myopia, PRK does not cause detectable changes in central corneal endothelial cell density, but it does cause a transient, modest loss of peripheral corneal endothelial cells at 1 year. Central endothelial cell density remained stable at any of the postoperative examinations. The peripheral cell density decreased 4.1% (P=0.003) at 3 months and 6.2% (P=0.0001) at 1 year. However, the peripheral cell density was not significantly different from the preoperative value at 2 years. The decrease in peripheral endothelial cell density at 1 year correlated with the amount of attempted correction, but there was no correlation between attempted correction and the change in central or peripheral endothelial cell density 2 years postoperatively.

There is a theoretical risk of damaging or loss of endothelial cells as a consequence of elevated intraocular pressure. LASEK avoids the potential endothelial damages from raised intraocular pressure during the flap cutting.

Because LASEK does not require cutting of the flap, it eliminates most of the risks of performing refractive surgery after PK. Despite potential beneficial wound healing response in LASEK, there is still a risk of postoperative haze, especially in treatment of high refractive errors. It is also important to realize that the goal of refractive surgery after PK is not necessary to obtain good uncorrected visual acuity by eliminating most of the refractive errors but to lessen the amount of astigmatism and anisometropia.

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