To evaluate the incidence of epithelial ingrowth (EI) following femtosecond LASIK (f-LASIK) flap relift.

This retrospective case series enrolled patients who underwent post-refractive enhancement surgery at a single independent outpatient health facility in Canada. Patients 18 years or older who underwent refractive enhancement surgery between July 2021 and December 2022 were eligible. We excluded patients with a history of cataract or refractive lens exchange surgery. Follow-ups were conducted at 1 week, 1 month, 3 months, 6 months, and 1 year postoperatively. The primary outcome was the incidence of EI following f-LASIK flap relifts. Secondary outcomes included other complications and visual outcomes 12 months postoperatively.

Among the 103 included eyes, EI was reported in 41% of patients at some point in the follow-up period, with most EI present at one month and not requiring treatment. EI was three times less likely to develop if the enhancement was performed within one year of the original surgery (OR 0.31, P
                     =0.023), and was 5–6 times more likely to develop if it was performed after three years (OR=0.17, P
                     <0.001). Successful treatment of EI by flap lift with sutures (n
                     =2) and Nd:YAG laser (n
                     =2) was performed in 4 eyes.

Only a small number (n
                     =4) of EI post-flap lifts required treatment, and the procedure generally provided excellent long-term visual outcomes. Thus, f-LASIK flap lift is a safe option for refractive enhancement, even several years following the original surgery.

Évaluer l’incidence de l’invasion épithéliale (IE) après un relèvement du volet LASIK au laser femtoseconde (f-LASIK).

Cette série de cas rétrospective a inclus des patients ayant subi une chirurgie de retouche réfractive dans un établissement de santé indépendant au Canada. Les patients âgés de 18 ans et plus ayant subi une retouche réfractive entre juillet 2021 et décembre 2022 étaient éligibles. Les patients ayant des antécédents de chirurgie de la cataracte ou d’échange de cristallin réfractif ont été exclus. Les suivis ont été effectués à 1 semaine, 1 mois, 3 mois, 6 mois et 1 an après l’opération. La mesure principale des résultats était l’incidence de l’IE après le relèvement du volet f-LASIK. Les critères secondaires incluaient d’autres complications et les résultats visuels à long terme (12 mois après l’opération).

Parmi les 103 yeux inclus, une IE s’est développée chez 41 % des patients au cours de toute la période de suivi, la plupart des cas apparaissant à un mois et ne nécessitant pas de traitement. L’IE était trois fois moins susceptible de se développer si le relèvement était effectué dans l’année suivant la chirurgie initiale (OR 0,31, p
                     =0,023), et 5–6 fois plus susceptible de se développer s’il était effectué après trois ans (OR=0,17, p
                     <0,001) suivant la chirurgie initiale. Un traitement réussi de l’IE par relèvement du volet avec sutures (n
                     =2) et laser Nd :YAG (n
                     =2) a été réalisé sur 4 yeux.

Seul un petit nombre (n
                     =4) de cas d’IE après relèvement du volet ont nécessité un traitement, et la procédure a généralement permis d’obtenir d’excellents résultats visuels à long terme. Ainsi, le relèvement du volet f-LASIK est une option de retouche réfractive sûre, même plusieurs années après la chirurgie initiale.

# Introduction

Approximately 10–14% of patients receiving refractive surgery with laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) undergo enhancement procedures to optimize visual outcomes [1]. Although complications from primary surgeries are well-documented, there is limited research on complications from enhancement procedures, particularly following primary femtosecond laser LASIK (f-LASIK) surgeries [2].

Epithelial ingrowth (EI) is notably more common with flap relifts, which is believed to be caused by epithelial cell migration towards the flap-stromal interface during flap creation [1,3,4]. Several risk factors for EI have been identified, including the type of surgical instrumentation used for flap creation (microkeratome versus femtosecond), the time elapsed since primary LASIK, and patient age [1].

Studies generally advise against lifting microkeratome-created LASIK flaps more than 3 years after the primary procedure [5,6]. Yet, it is uncertain whether the risk for EI significantly escalates before the three-year benchmark when lifting f-LASIK flaps. This case series evaluated the incidence of epithelial ingrowth and other complications after f-LASIK flap lift, as well as an assessment of long-term visual outcome.

# Patients and methods

This study was approved by the Queen's University Health Sciences and Science Research Ethics Board (TRAQ # 6040034) and conformed with the latest revision of the Declaration of Helsinki.

## Design and participants

We conducted a retrospective case-series which enrolled 103 eyes who underwent f-LASIK flap relift surgery between July 2021 and December 2022. All procedures were carried out at an out-of-hospital independent health facility comprising 2 surgeons on the included participants.

Patients 18 years or older who had received primary uncomplicated LASIK were included in this study. Patients were excluded if they did not have complete medical records or if they had previously undergone a refractive enhancement procedure. We also excluded patients if they had a history of ocular comorbidities, cataract, or refractive lens exchange surgery. For each patient, patient demographics (age, gender, date of surgery, operated eye), details of the original refractive surgery, pre-enhancement refraction, target refraction, bandage contact lens status, and achieved refractive outcomes were collected.

## Primary femtosecond laser LASIK procedure

The surgical approach was decided by the treating surgeon for each respective patient.

The IFS Advanced Femtosecond Laser (Johnson & Johnson) was used to create the flap, with all flap diameters between 8.5 and 9.0mm and depth 90–105 microns. Excimer laser correction was performed using a wavefront-guided ablation pattern (iDesign System) on the VISX S4 Laser (Johnson & Johnson).

## Refractive enhancement procedures

It is standard practice at this refractive surgical center for all enhancements to be performed by flap lift, except in cases of low residual stromal bed thickness. The surgical technique involved first identifying the flap edge using an intralase flap lifter. The flap edge was then lifted in both directions from the hinge, and an irrigating cannula used to lift the flap back. After laser treatment was completed, a dry weck-cel sponge was used to gently wipe the peripheral stromal bed clear of epithelial cells. The flap was then carefully reflected back in position, and the interface irrigated. A bandage contact lens was occasionally used if there was significant loose epithelium.

## Epithelial ingrowth incidence and treatment procedures

This study considered both the overall prevalence of epithelial ingrowth as well as the prevalence of epithelial ingrowth requiring treatment. Anecdotally, our surgeons frequently see mild degrees of epithelial ingrowth at the flap edge with f-LASIK flap relifts. Most cases do not require treatment unless there is a reduction in uncorrected visual acuity, foreign body sensation, and/or spread of epithelial cells into the central visual axis. When treatment was indicated, we offered either flap lift with suturing or neodymium-doped yttrium aluminum garnet (Nd:YAG) laser treatment. In cases of extensive epithelial ingrowth and/or ingrowth involving the central visual axis, flap lift with sutures was advised. Flap lift alone was not offered due to the high recurrence rate.

## Analysis

The primary outcome measure of our study was the rate of epithelial ingrowth following f-LASIK flap relift at 1 week, 1 month, 3 months, and 12 months postoperatively. Secondary outcomes included the incidence of other complications as well as postoperative refractive outcomes at 1-year post-enhancement.

The data collected from the electronic medical records were input in an Excel spreadsheet (Microsoft Corp., Redmond, WA, USA). Data analysis was performed using RStudio (Version 2023.12.1+402) alongside R software (R Foundation for Statistical Computing, Vienna, Austria). The packages employed for data analysis were “tidyverse”, “dplyr”, “stringr” and “ggplot2”. Figures were created using Prism 8 (GraphPad, CA, USA). A Kolmogorov-Smirnov test was performed to examine the data for distribution normality. For complication rates and standard visual outcomes, data was presented as a percentage. For refractive outcomes, means and standard deviations (SD) were calculated, and a paired t-test was performed to evaluate statistically significant differences where applicable.

# Results

This study included a total of 103 eyes that underwent refractive enhancements. The baseline demographics and visual parameters are summarized in Table 1
                     . The cohort consisted of 66% females, with a mean age of 41.4±11.8 years. The mean time between primary and enhancement procedures was 4.8±3.9 years (range: 2 months to 14 years).

## Complications

The flap lift was successful in 100% of the cases included in this study. Following f-LASIK flap lift, EI was observed in 41% of eyes across all follow-up periods, peaking at 38% of eyes at the one-month follow-up. The risk of EI was significantly correlated with time since original surgery, as presented by the Odds Ratios (OR) (Table 2
                        ).

Epithelial ingrowth was 3 times more likely to develop if the enhancement was performed more than a year following the original surgery (OR=0.31, P
                        <0.05), and approximately 6 times more likely if performed more than 3 years following the surgery. The OR at 3-and-5 years were comparable (OR=0.17, P
                        <0.001 and OR=0.20, P
                        <0.001, respectively).

Of all the EI observed, only a total of 4 cases required intervention. All treatments for EI were successful. There were 2 cases in the same individual requiring flap lift with sutures 3 months post-enhancement, with complete resolution of symptoms and visual acuity. Another 2 individuals developed EI in their operated eye, with both visual acuity and foreign body sensation being resolved after two rounds of Nd: YAG laser treatment. All 4 cases had their original surgery at least 5 years before retreatment (range: 5.4–10.7 years).

Other postoperative complications included microstriae (8%) and haze (3%), none of which required treatment.

## Visual outcomes

Standardized visual and refractive outcomes at 12 months are presented in Fig. 1
                        .

The visual outcome parameters (i.e., accuracy, stability, safety, efficacy, and predictability) are outlined in Table 3
                        .

At the 12-month follow-up, 60% of eyes had an uncorrected visual acuity (UCVA) of 20/20 or better and 85% of eyes had a UCVA of 20/40 or better. Flap relifts were safe (<1% loss of two or more lines of best-corrected visual acuity) and predictable (96% of eyes at
                        ±
                        1.0D from target SE), with excellent accuracy and stability after 12 months.

# Discussion

The study's primary aim was to shed light on the incidence of EI after f-LASIK flap lifts. Although EI is a rare complication following primary LASIK, flap lifting retreatment has been shown to increase the incidence of EI [1]. Our findings reveal a three-fold increase in the risk of developing EI when more than a year has elapsed since original surgery compared to procedures performed before the one-year mark. This is a novel practice-changing finding of the study. Previous studies published in the literature have shown that there is an increased incidence of EI as more time elapses since the original surgery, identifying 3-years and 5-years as times where this risk is significant [7,8]. Indeed, we observed a pronounced increase in EI incidence when the enhancement occurs beyond three-or-five-years following the original surgery. Notably, there appears to be a “plateau” effect after three years, with similar incidence at three-and-five years. In previous reports, the incidence of epithelial ingrowth has been reported to be higher in enhancements following primary hyperopic as opposed to primary myopic treatment [1,6]. In our series, we observed a trend towards a threefold higher risk of epithelial ingrowth with primary hyperopic treatment compared to myopic treatment. However, due to the limited sample size of primary hyperopic cases, the confidence interval was wide (OR=0.31; 95% CI [0.0269–2.318], P
                     =0.21). We observed no differences in the risk of epithelial ingrowth between hyperopic and myopic retreatments (OR=1.0, P
                     >0.05).

The overall incidence of EI in our study was 41%, situating our findings at the upper spectrum of reported rates in the existing literature (0.02%–44%) [3,8–18]. The reason for this is likely multi-factorial, but can be primarily attributed to the extended duration since the original surgery, a well-documented risk factor for EI [5,7,8]. For example, in another study evaluating exclusively f-LASIK flap lifts, the overall EI rate was 8.3% [2]. However, they excluded all cases where more than 2 years had elapsed since primary surgery. Conversely, in our study, the mean time elapsed since primary f-LASIK was 4.8±3.9 years. When paralleled with a study that assessed enhancements conducted at least 5 years following both microkeratome and femtosecond LASIK, the incidence of EI was 42.85%, aligning closely with our findings [18]. It's important to contextualize these findings within the broader landscape of refractive surgery, where previous studies have suggested that enhancements following f-LASIK tend to have a lower prevalence of EI compared to those post-microkeratome LASIK [19]. This was attributed to the geometry of microkeratome-created flaps, which might offer a conduct path for epithelial cells to migrate to the stromal interface. However, the characteristics of femtosecond flaps—its smaller and thinner profile and increased fibrosis or scarring at the flap margin—introduce unique challenges [18]. The increased fibrosis can theoretically make flap relifting more difficult, an observation supported anecdotally by the greater resistance encountered during these procedures despite the 100% relift success rate. Moreover, the fibrotic changes may intensify over time, contributing to the formation of gaps between the flap and the peripheral cornea post-relift and providing a potential avenue for EI. This highlights the need for careful consideration of the time elapsed since original surgery when planning refractive enhancement. Finally, we considered the presence of any EI rather than clinically significant EI reported in other studies; most cases seen represented small amounts of EI at the flap edge which did not require treatment.

Clinically relevant epithelial ingrowth was not common in our cohort (n
                     =4, 3.8%). Additionally, management with the Nd: YAG laser minimized the need for further surgical intervention (n
                     =2, 1.9%). The rate of eyes requiring surgical intervention is consistent with those previously reported in the literature (1.34%–4.38%) [8,18,20]. All 4 cases requiring treatment in our sample had their enhancement surgery at least five years following their primary f-LASIK. All treatments for EI were successful in resolving symptoms and achieving a UCVA of at least 20/20 in the affected eye. Two of our cases were treated with two sessions of Nd: YAG laser micropunctures, a novel treatment approach for EI first described in 2008 [21]. Our study showcases yet again the efficacy of Nd: YAG laser as a non-invasive alternative treatment to the traditional flap lift with sutures.

The secondary purpose of this study was assessing the visual outcomes following f-LASIK flap lift.

Overall, our findings highlight that, at the 12-month follow-up, the f-LASIK flap lift exceeds FDA benchmarks for parameters of efficacy, safety, predictability, accuracy and safety of treatment [7]. Thus, our results suggest that lifting femtosecond LASIK flaps for enhancements is safe even years after surgery, and is a viable alternative to PRK to expedite patient recovery and reduce postoperative discomfort.

Our study, while providing valuable insights into the outcomes of f-LASIK flap lifts, is subject to limitations that merit consideration. Firstly, the small sample size prevented a subgroup analysis comparing these outcomes between hyperopic and myopic retreatments. Also, this study did not incorporate patient-reported outcome measures, which are increasingly recognized as critical in the field of ophthalmology [22]. Despite these limitations, we believe that our study contributes to the growing body of evidence on refractive surgery outcomes and underscores the importance of considering the timing of enhancement procedures in the management of EI. Future studies with larger sample sizes, prospective designs, and comprehensive outcome measures are warranted to confirm and expand upon our findings.

# Conclusion

In conclusion, our findings delineate a progressive increase in the risk of EI after f-LASIK flap lifts, starting as early as one year post-operatively and escalating further at three years. Interestingly, no additional increase in incidence was observed at the five-year mark, but all instances requiring clinical intervention occurred when more than five years had elapsed since primary LASIK. Importantly, the rate of clinically relevant EI was low, and even when EI developed, interventions such as flap lift and Nd: YAG laser treatments were successful in achieving symptom relief and excellent visual outcomes.

# Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

# Author contributions

All authors contributed equally to the conception and design of this study. M.R.G. was primarily responsible for acquisition and analysis of data. All authors contributed to the interpretation of the data. All authors contributed to drafting the manuscript, revising it critically, and approving the final version submitted.