Management of Corneal Ectasia after LASIK with Phototherapeutic Keratectomy Combined with Photorefractive Keratectomy and Collagen Cross-Linking

Background To evaluate the efficacy of phototherapeutic keratectomy (PTK) combined with photorefractive keratectomy (PRK) and riboflavin with ultraviolet-A collagen cross-linking (CXL), performed sequentially on the same day, in the management of corneal ectasia after LASIK. Methods This retrospective review comprised consecutive patients with corneal ectasia after LASIK. The patients were administered PTK and PRK on the previous corneal flap, and CXL was given on the same day by the same surgeon. The main outcome measures included age, sex, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), spherical equivalent refraction, cylinder equivalent refraction, steep and flat keratometries (K), central corneal thickness (CCT), endothelial cell count, corneal haze, and ectasia stability. Mean follow-up period was 6, 12, and 24 months. Results Sixteen eyes of twelve patients were included in the study. Twenty-four months after administration of PTK combined with PRK and CXL, a significant improvement in UDVA was observed. Mean cylinder equivalent refraction was significantly reduced at 6, 12, and 24 months postoperatively. However, no significant reduction was observed in spherical equivalent refraction. A significant reduction in the flat K and steep K values was observed. No significant change in mean CCT value was observed. Mean endothelial cell count and morphology were unchanged between preoperative and postoperative patients. In addition, no obvious corneal haze was observed. Conclusions PTK combined with PRK and CXL on the same day is a safe and effective treatment in improving visual acuity in selected patients with corneal ectasia after LASIK.


Introduction
Corneal ectasia after LASIK is characterized as the progressive thinning and steepening of cornea, resulting in refractive aberrations and severe visual loss [1]. All excimer laser procedures can weaken corneal biomechanics because of removing the corneal tissue. Several parameters such as high myopic corrections, thin corneas, and residual corneal thickness <250 µm are considered as major risk factors for corneal ectasia [2].
ere are many traditional treatments for corneal ectasia after LASIK, including rigid gas permeable contact lenses and intracorneal ring segments; however, the most frequently used method is corneal transplantation [3]. In recent years, various studies have demonstrated that corneal CXL with no loss in corneal transparency can stiffen the cornea.
Several studies have reported the efficacy of corneal CXL as a new treatment for postoperative ectasia [4].
During CXL treatment, the epithelium is removed to permit the absorption of riboflavin solution into the corneal stroma [5]. Excimer laser phototherapeutic keratectomy (PTK) is used to remove the epithelium prior to the refractive surgery [6]. Several combined procedures have been proposed to enhance the efficacy of CXL; however, the most effective method is the combined photorefractive keratectomy (PRK) followed by CXL [7]. Kanellopoulos used transepithelial PTK to remove corneal epithelium before topography-guided PRK and CXL in patients with keratoconus [8]. Studies have shown that PRK can reduce irregular astigmatism and the refractive error, providing patients with improved visual outcomes. e corneal flap is commonly presented in patients with corneal ectasia after LASIK. Randleman et al. reported that the mean measured flap thickness is 138 µm [9]. In our study, the corneal epithelium was removed with PTK. e patients were administered PRK to ablate the corneal tissue in the corneal flap, avoiding the remaining corneal tissue under the flap ( Figure 1). e aim of PRK is to normalize the cornea by reducing irregular astigmatism while treating part of the refractive error. Since the corneal tissue of the flap is ablated, we can avoid removal of a significant amount of corneal stroma, thereby maintaining the biomechanical integrity and the thickness of the cornea. However, PTK has not been evaluated in combination with PRK and CXL for the visual enhancement in patients with corneal ectasia after LASIK. e purpose of our study was to evaluate the efficacy of PTK combined with PRK and CXL performed sequentially on the same day in the management of corneal ectasia after LASIK.

Patient Selection.
Patients with corneal ectasia after LASIK from the Department of Ophthalmology, Provincial Hospital affiliated to Shandong University, Jinan, China, were included in the study. Once the diagnosis of corneal ectasia after LASIK was confirmed (see the following section), written informed consent was obtained from all the patients. e study was approved by the ethics committee of the Provincial Hospital affiliated to Shandong University, Jinan, China.
A diagnosis of corneal ectasia was carried out for patients with progressive corneal steepening associated with an increasing myopic and/or astigmatic refractive error two or more months after LASIK surgery. e findings were combined with increasing inferior corneal steepening and thinning. Progression of the myopic refractive error with or without progression of the manifest astigmatism, decreasing uncorrected distance visual acuity (UDVA), loss of corrected distance visual acuity (CDVA), progressive inferior corneal steepening on topography, and/or decreasing inferior corneal thickness were observed in all the cases [10].

Clinical Examination.
e following evaluations were completed before and after the treatments: age, sex, UDVA, CDVA, refraction, keratometry (K), CCT, endothelial cell count, corneal haze on a scale of 0 to 4 (0 � clear cornea, 1 � mild haze, 2 � moderate haze, 3 � severe haze, and 4 � reticular haze (obstructing iris anatomy)), and ectasia stability as defined by stability in corneal topography [10]. UDVA and CDVA values were recorded in a 20-foot lane using high-contrast Snellen visual acuity testing. Topographical keratometry (K) readings were obtained by corneal topography (ALLEGRO TOPOLYZER VARIO WaveLight Erlangen, Germany). CCT was measured using ultrasound pachymetry (HANDY PACHYMETER SP-100; Nishi-ku, Nagoya 451-0051, Japan). Endothelial cell count was determined in the central cornea by specular microscopy. Slitlamp microscopy was used to confirm the presence of a LASIK flap and corneal haze.
2.2.1. PTK. PTK was used to remove epithelium in the previous corneal flap. After topical anesthesia with proparacaine eye drops, an excimer laser system with a wavelength of 193 nm (WaveLight EX500 Technologies, Erlangen, Germany) was used for the procedure. PTK ablation was performed using an 8.5 mm zone at intended depth of 50 µm in the previous corneal flap (Figure 1(a)).

PRK.
PRK was used to normalize the cornea by reducing irregular astigmatism while treating part of the refractive error.
e same surgeon performed all the procedures. PRK was used to ablate the tissue on the previous corneal flap. An excimer laser system with a wavelength of 193 nm (WaveLight EX500 Technologies, Erlangen, Germany) was used for the PRK procedure ( Figure 1(b)).

CXL.
Immediately after PRK, riboflavin (Medio-Cross riboflavin/dextran solution, 0.1%) was administered topically for 30 min at intervals of 2 mins. Penetration of the cornea and presence of riboflavin in the anterior chamber (riboflavin shielding) were monitored by slit-lamp examination. e cornea was illuminated for 30 min using a UV light lamp (UV-X 1000 system, IROC Innocross AG Co., Switzerland; wavelength 365 nm, irradiance 3 mW/cm 2 , total dose 5.4 J/ cm 2 ). Riboflavin administration was continued during UV illumination at the same time interval (Figure 1(c)).
After the treatment, a bandage contact lens was applied until the epithelium was completely healed. e patients were examined daily until the epithelium healed and at one, three, and six months postoperatively.

Statistical Analysis.
Snellen visual acuities were converted to LogMAR values for analysis. e 2-tailed paired ttest was performed. P value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS 18.0 (SPSS, Inc., Chicago, IL).

Results
Sixteen eyes of twelve patients (8 male and 4 female) with corneal ectasia after LASIK were included in the study. e mean patient age was 28.5 years (range: 12-43 years). Fifteen eyes had a central CCT analyzed by optical pachymetry (350 µm).
Topographic improvement ( Figure 4) and flattening of the cornea were observed, with a significant reduction in the steep K and flat K values (both P < 0.05; Table 1 Figure 5(b)).
Following the treatment, no serious complications related to any of the three treatments (PTK, PRK, or CXL) were reported during the follow-up period. Specifically, no eye developed corneal haze (Figure 7).

Discussion
Corneal ectasia is characterized by progressive thinning and steepening of the cornea, which can severely impact patients' vision. e most frequent incidence of iatrogenic corneal ectasia is attributed to LASIK [11]. e prevalence of myopia in China is high; many people have undergone surgery of LASIK. Until recently, corneal transplantation has been the most used treatment for corneal ectatic disorders. However, due to the difficult procedure with a long and uncertain visual recovery [12], its use has been limited. Various treatments have been used to postpone or replace the corneal transplantation.
e treatment of corneal ectasia includes two parameters: corneal biomechanical stability and optical improvement of the irregular cornea. e aim of our study was to develop a new technique to treat patients with corneal ectasia after LASIK and improve both corneal stability and functional vision. Reaching functional vision consists of improving UDVA and CDVA and normalization of corneal topography, which indicates that patients are less dependent on contact lenses in order to achieve higher postoperative vision quality. In recent years, many effective tools have been used to treat patients with keratoconus and corneal ectasia. Several combined procedures have also been used to treat corneal ectasia. ese methods include intracorneal ring segment implantation (ICRS), phakic intraocular lenses (pIOL), and a phakic toric implantable collamer lens (ICL) combined with CXL. ese techniques have different levels of affecting the cornea or anterior chamber structure. But our research can achieve the smallest damage on the eye.   Furthermore, most reports of treating patients with corneal ectasia after LASIK had less number of cases and shorter follow-up times. CXL is a relatively new technique used for the stabilization of ectatic disorders [13,14]. e technique is based on the absorption of UVA radiation by the cornea after the riboflavin is taken in absorbed by the stroma. is technique can increase the corneal strength and stability by inducing cross-links at the corneal stroma [15]. However, the technique does not increase the visual function of the patient. e need for further refractive correction is required for patients with CXL [16].
PTK uses an excimer laser ablation to remove the epithelium and smoothen the anterior irregular cornea [17,18].
However, it has been used in combination with CXL for the visual restoration in keratoconus when administered on the same day [19]. PRK is an alternative treatment to improve vision in selected cases of mild keratoconus. e aim of PRK is to remodel the shape of the cornea and decrease irregular astigmatism. It has been demonstrated that patients may benefit substantially even with a relatively small correction due of the corneal thickness limitations [20].
In our study, the epithelium was removed by PTK instead of traditional mechanical or alcohol-led epithelial removal.
rough this method, the corneal flap can be preserved completely. After the epithelium removal, the patients with corneal ectasia were administered PRK and CXL on the same day. is is the first reported case where series of patients with corneal ectasia were treated with PTK combined with PRK and CXL performed sequentially on the same day. e major consideration in the planning of this procedure was the postoperative corneal thickness. e corneal flap includes the corneal epithelium, Bowman layer, and corneal stroma. Randleman et al. evaluated fifty eyes of 29 patients' flap thickness in eyes with corneal ectasia after LASIK. e mean measured flap thickness was 138 µm ± 26 µm (SD) (range: 90-220 µm) [9]. In our current study, the epithelium was removed by PTK. e PTK ablation was performed using an 8.5 mm zone at a depth of 50 µm. A maximum ablation depth of 80 µm was chosen for all cases to achieve a decrease in astigmatism and to avoid removing the corneal tissue beyond the corneal flap that would jeopardize the biomechanical integrity of the cornea. Our results showed that without removing corneal stroma, the vision could be corrected in patients with corneal ectasia.
Our results showed that the treatment was relatively safe, effective, and predictable. Patients treated with simultaneous PTK, PRK, and CXL showed a rapid and significant improvement in UDVA at the 24-month follow-up. Mean cylinder equivalent refraction was significantly reduced at 6, 12, and 24 months postoperatively. However, at three intervals, the spherical equivalent refractions were not significantly reduced. Topographic evaluation of these patients showed marked improvement of irregularity. A significant reduction in the flat K and steep K values was observed. Mean CCT changed from 416 ± 42.5 µm preoperatively to 393 ± 38.0 µm at 24 months postoperatively. However, the change was not significant. Moreover, no significant change was observed in mean endothelial cell count and morphology in preoperative and postoperative groups. e change may be explained by either corneal structural changes, continuous epithelial remodeling, or even the patient's adaptation to the new optical conditions.

Conclusion
In conclusion, no serious complications or side effects of the treatments were observed in any participant. Simultaneous PTK and PRK treatments followed by CXL seem to be a promising treatment for patients with corneal ectasia. Administering this technique with careful observance of safety could offer patients with corneal ectasia after LASIK an opportunity to gain functional vision, avoid long-term  complications such as use of contact lens, and reduce the need for corneal transplantation. Significant improvement in clinical vision and the stability of the ectasia during the postoperative follow-up lead us to believe that the simultaneous approach of PTK, PRK, and CXL may offer an alternative solution to corneal ectasia after LASIK.

Limitations
However, we should pay attention to the corneal flap thickness that is limited, so this method is not suitable for patients with high astigmatism. In addition, the longer follow-up and larger patient sample are is also required to validate the safety and stability of the combined treatment procedure.

Data Availability
e data used to support the findings of this study have been deposited in the public repository (https://figshare.com/ articles/k1_datas/6610646).

Conflicts of Interest
e authors declare that they have no conflicts of interest.