A comparative analysis of the 1-year outcomes of modified Athens protocol versus Cretan protocol in the treatment of progressive keratoconus

Abstract

Background

This retrospective comparative cohort study aimed to compare the one-year outcomes of two modified surgical protocols, the Athens protocol followed by accelerated corneal cross-linking (ACXL) (topography-guided transepithelial photorefractive keratectomy [TG-TPRK] combined with ACXL) and the Cretan protocol followed by ACXL (transepithelial phototherapeutic keratectomy [TPTK] combined with ACXL), in patients with progressive keratoconus.

Methods

The study included 92 eyes of 67 patients (49 eyes/34 patients in the TG-TPRK-ACXL group; 43 eyes/33 patients in the TPTK-ACXL group). According to the TG-TPRK-ACXL ablation plan, TPTK was conducted on patients with a projected postoperative thinnest corneal thickness (TCT) of less than 400 μm. Visual acuity, refractive status, keratometry readings, corneal thickness, and keratoconus parameters were assessed preoperatively and 1-year postoperatively. Intraoperative ablation depth was also recorded. Generalized estimating equations (GEE) were applied to adjust for baseline characteristics and to compare the differences in ocular characteristic changes between the two groups after 1 year.

Results

Both groups showed significant improvement in uncorrected and best spectacle-corrected distance visual acuity (UDVA and BCVA) as well as a reduction in postoperative corneal curvature and irregularity index. After GEE correction, the TPTK-ACXL group showed a greater increase in BCVA (β = -0.117, P = 0.002). There were no significant variances between the two groups regarding changes in refractive error, corneal curvature, corneal astigmatism, and keratoconus parameters. Central and maximum ablation depths were thinner in the TPTK-ACXL group than in the TG-TPRK-ACXL group (P < 0.001). No serious intraoperative or postoperative complications were reported.

Conclusions

Both TPTK-ACXL and TG-TPRK-ACXL treatments have demonstrated efficacy in improving visual acuity and corneal regularity among keratoconus patients at the 1-year follow-up. TPTK-ACXL may be particularly beneficial for patients with poorer corneal conditions, potentially minimizing corneal thickness loss and serving as a substitute for TG-TPRK-ACXL.

Background

Keratoconus is a bilateral, progressively degenerative corneal condition characterized by corneal thinning and steepening, which ultimately impairs visual acuity. Progressive keratoconus is defined as: (1) steepening of the anterior corneal surface, (2) steepening of the posterior corneal surface, or (3) corneal thinning and/or accelerated thickness reduction [1]. Its therapeutic goals are to halt disease progression and improve functional visual outcomes [2]. The efficacy and safety of corneal cross-linking (CXL) in halting the progression of keratoconus have been extensively documented, leading to its recommendation as a standard treatment for progressive keratoconus in global consensus guidelines [1, 3]. However, the impact of CXL on best corrected visual acuity is minimal, often leading patients to rely on postoperative corneal contact lenses to enhance their visual acuity [4, 5].

In 2011, Kymionis introduced the concept of “CXL plus”, which combines CXL with adjuvant therapies to improve both stability and functional vision in patients with keratoconus [6]. Two commonly employed surgical procedures under the CXL plus approach are the combination of CXL with topography-guided transepithelial photorefractive keratectomy (TG-TPRK-CXL), known as the Athens protocol, and with transepithelial phototherapeutic keratectomy (TPTK-CXL), known as the Cretan protocol. Although the effectiveness of these two surgeries in stabilizing keratoconus and improving visual acuity has been confirmed [7–10], limited literature compares their efficacy.

Emerging techniques such as ray-tracing-guided ablation (RT t-PRK) [11] offer theoretical advantages by accounting for both anterior and posterior corneal aberrations. However, its clinical superiority over established protocols remains debated, with limited comparative long-term data.

In China, the Athens and Cretan protocols remain the mainstream surgical approaches for treating keratoconus. In this study, we adapted the Athens and Cretan protocols followed by ACXL to conduct a comparative analysis of their efficacy in improving corneal regularity and visual acuity. We applied generalized estimating equations (GEE) to assess the intervention outcomes, adjusting for the potential confounding effects of age, baseline data variability, and bilateral surgery.

Methods

According to the Helsinki Declaration, the study was approved by the ethics committee of Aier Eye Hospital, Jinan University (No. GZAIER2023IRB22). Patients diagnosed with progressive keratoconus who underwent TPTK-ACXL or TG-TPRK-ACXL surgery at Guangzhou Aier Eye Hospital were enrolled in this retrospective study. The diagnosis of keratoconus requires confirmation of posterior corneal ectasia and characteristic stromal thinning patterns detectable via corneal tomography or Scheimpflug imaging, following exclusion of non-inflammatory etiologies of corneal thinning [1]. In this study, the progression of keratoconus was defined as the occurrence of one or more of the following criteria over a period of 12 months: an increase of 1.00 diopter (D) or more in the maximum keratometry (Kmax), or a decrease of 10 micrometers (µm) or more in the thinnest corneal thickness (TCT). Exclusion criteria included the following: TCT less than 400 μm, active ocular infection or inflammation, previous ocular surgery, pregnancy or breastfeeding, and less than 1 year of postoperative follow-up. A total of 120 eyes were screened, and 28 eyes were excluded, including 20 eyes with incomplete follow-up and 8 eyes with preoperative TCT < 400 μm. Finally, 92 eyes were included.

Preoperative and postoperative evaluation

Baseline information and 1-year postoperative ophthalmological examination data were collected for all patients. These included uncorrected distance visual acuity (UDVA), best spectacle-corrected distance visual acuity (BCVA), manifest refraction (spherical error and cylindrical error), slit-lamp evaluation, and corneal tomography. The following parameters were evaluated using Pentacam (Oculus GmbH, Wetzlar, Germany): central corneal thickness (CCT), TCT, flat keratometry (Kf) and steep keratometry (Ks) of the anterior surface, Kmax of the anterior surface, corneal astigmatism and keratoconus parameters. The corneal epithelial thickness was measured using a Fourier-domain OCT system (RTVue, Optovue Inc., Fremont, CA, United States) before surgery. Before surgery, all patients underwent corneal topography (Keratron Scout, SCHWIND eye-tech-solutions, Germany), after which the examiner transmitted the topographic map to the laser surgical platform. Visual acuity was reported in logMAR and keratometry in diopters. Intraoperatively, the central, minimum, and maximum ablation depths were measured, including the thickness of corneal epithelium and part of stromal thickness.

Surgical procedures

All surgical procedures were consistently performed by two surgeons, Zheng Wang and Lu Xiong. Each patient underwent a systematic evaluation utilizing the TG-TRPK ablation algorithm to predict residual TCT. A clinical decision-making threshold of 400 μm was established, serving as a guideline for treatment selection: TPTK ablation was applied in cases with predicted residual TCT below this threshold, while TG-TRPK ablation was employed for those above. Following the implementation of these ablation strategies, none of the treated eyes were projected to exhibit a residual TCT below 350 μm, ensuring adherence to established safety margins. For patients with both eyes meeting the inclusion criteria, the surgical approach was also selected according to this criterion.

TPTK procedure. After administration of topical anesthesia of proxymetacaine hydrochloride 0.5% eye drops (Alcon Laboratories Inc, United States), transepithelial PTK ablation using an excimer laser system (Schwind Amaris 1050RS, SCHWIND eye-tech-solutions, Kleinostheim, Germany) was performed in a 7.0–9.0 mm zone at an intended depth of 50–60 mm according to the average corneal epithelial thickness outside the cone area. If the estimated remaining corneal thickness was less than 380 μm, only the stroma of the cone with an approximate optical zone of 2–3 mm was ablated. A spatula was then used to remove the rest of the corneal epithelium without ablation.

TG-TPRK procedure. Following topical anesthesia with 0.5% proxymetacaine hydrochloride eye drops (Alcon Laboratories Inc, United States), transepithelial PRK ablation with corneal wavefront-guided profiles using the Schwind Amaris 1050RS laser system (SCHWIND eye-tech-solutions, Kleinostheim, Germany) was performed. The epithelial ablation depth was determined based on epithelial thickness measurements at the cone apex, with an optical zone ranging from 5.0 to 6.0 mm. The target refraction, including both spherical and astigmatic components, was set to zero. The “Minimize +” mode was selected to automatically calculate and correct most higher-order aberrations (HOAs), prioritizing coma aberration reduction while maintaining the maximum stromal ablation depth within 50 μm. Mitomycin C was not administered during the procedure. Figures 1 and 2 illustrate the surgical design process using the Schwind Amaris 1050RS laser system.

Fig. 1.

The figure illustrates the corneal wavefront-guided procedure performed with the Schwind Amaris 1050RS laser system, where the “Minimize +” mode was utilized to reduce higher-order aberrations

Fig. 2.

The figure demonstrates the final laser ablation zone, with both target spherical and cylindrical powers set to zero

Accelerated CXL procedure. After the TPTK or TG-TPRK procedure, riboflavin (0.1% riboflavin sodium phosphate ophthalmic solution VibeX Rapid; Avedro, Inc, United States) was instilled on the center of the cornea every 2 min for approximately 10 min. The cornea was then irradiated for 4 min by ultraviolet light (30 mW/cm², KXL ultraviolet instrument, Avedro, United States) with a total energy delivered of 7.2 J/cm². A bandage soft contact lens (PureVision 2, Bausch & Lomb, Rochester, United States) was applied until complete epithelialization. After surgery, 0.5% levofloxacin eye drops (Santian Pharmaceutical co., LTD, Japan) were applied 4 times a day for one week. Fluorometholone 0.1% eye drops (Santian Pharmaceutical co., LTD, Japan) were applied 4 times a day on a tapering schedule for 1 month.

Statistical analyses

SPSS 20.0 statistical software (IBM Corp, Armonk, NY, United States) was used to analyze the data. All continuous data were reported as mean values ± standard deviation. The level of statistical significance was set at P < 0.05. The normality of the data was tested using the Shapiro-Wilk test. For normally distributed quantitative parameters, the mean values of baseline characteristics were compared between the two groups using the independent sample t-test. Medians and interquartile ranges for nonnormally distributed quantitative parameters were compared between the two groups using the Mann-Whitney U test. Categorical outcomes between the two groups were compared using the Chi-square. Within each group, the differences between pre- and postoperative values were assessed using either the paired t-test or the Wilcoxon signed-rank test, as deemed appropriate for the analysis. By utilizing GEE, the baseline characteristics including gender, age, visual acuity, refractive error and corneal tomography parameters were adjusted to analyze the differences in changes after 1 year between the two groups. During the GEE analysis, patients were categorized based on age: Group 1 was designated as 1 for individuals < 18 years old (juveniles), and Group 2 was designated as 2 for those ≥ 18 years old (adults); males were designated as 1, females were designated as 2; right eye surgeries were designated as 1, left eye surgeries were designated as 2; TPTK-ACXL procedures were designated as 1, TG-TPRK-ACXL procedures were designated as 2.

Results

Patient characteristics

A total of 92 eyes of 67 patients were included in the study, including 43 eyes of 33 patients who underwent TPTK-ACXL and 49 eyes of 34 patients who underwent TG-TPRK-ACXL. The average time from confirmed diagnosis of keratoconus to surgery was 1.16 ± 0.23 years in the TPTK-ACXL group and 1.32 ± 0.38 years in the TG-TPRK-ACXL group. The mean follow-up time after surgery was 1.78 ± 0.79 years in the TPTK-ACXL group and 1.85 ± 1.06 years in the TG-TPRK-ACXL group. The mean age at the time of surgery was 23.60 ± 6.14 years in the TPTK-ACXL group and 23.14 ± 5.34 years in the TG-TPRK-ACXL group.

Patient demographics at baseline and preoperative data of the two groups are included in Table 1. Age, sex, preoperative UDVA, corneal astigmatism and cylindrical error were well matched between the two groups at baseline. However, the TPTK-ACXL group exhibited higher keratometry steepness, thinner corneal thickness, greater irregularity in corneal morphology, greater spherical error, and worse BCVA compared to the TG-TPRK-ACXL group, due to the study’s design.

Table 1.

Patients’ demographics, preoperative and month 24 postoperative ocular characteristics in the TPTK-ACXL group and TG-TPRK-ACXL group

Parameters	TPTK-ACXL			TG-TPRK-ACXL
	Preoperative	1 Year	P a	Preoperative	1 Year	P a	P b
Age (y)	23.60 ± 6.14			23.14 ± 5.34			0.580
Sex (male: female)	29:4			30:4			1.000
Visual acuity (logMAR)
UDVA	0.91 ± 0.44	0.68 ± 0.39	< 0.001	0.81 ± 0.45	0.64 ± 0.37	< 0.001	0.286
BCVA	0.45 ± 0.35	0.20 ± 0.19	< 0.001	0.21 ± 0.20	0.15 ± 0.20	0.009	< 0.001
Refractive error (D)
Spherical error	−5.31 ± 3.47	−5.01 ± 3.60	0.295	−3.85 ± 2.79	−3.39 ± 3.52	0.004	0.018
Cylindrical error	−3.13 ± 2.34	−2.21 ± 1.71	0.022	−2.87 ± 2.26	−2.64 ± 1.96	0.441	0.546
Keratometry Readings (D)
Kf	47.46 ± 3.79	45.98 ± 3.38	< 0.001	44.67 ± 2.99	43.60 ± 3.21	< 0.001	< 0.001
Ks	51.37 ± 5.07	50.05 ± 4.56	< 0.001	48.61 ± 4.44	47.44 ± 4.43	< 0.001	0.004
Kmax	59.92 ± 7.70	54.13 ± 8.91	< 0.001	53.39 ± 7.39	50.75 ± 7.26	< 0.001	< 0.001
Corneal astigmatism	4.26 ± 0.40	3.91 ± 0.40	0.012	3.96 ± 0.36	3.84 ± 0.34	0.345	0.866
Cornea thickness (µm)
CCT	471.30 ± 35.36	445.45 ± 41.08	< 0.001	496.06 ± 27.78	474.80 ± 36.89	< 0.001	< 0.001
TCT	454.00 ± 36.70	425.57 ± 44.56	< 0.001	483.57 ± 28.23	454.98 ± 37.83	< 0.001	< 0.001
Keratoconus parameters
IS	6.52 ± 7.46	4.63 ± 3.00	< 0.001	3.24 ± 2.85	2.66 ± 2.66	0.002	< 0.001
ISV	92.84 ± 32.55	82.70 ± 32.30	< 0.001	62.37 ± 34.17	53.41 ± 31.05	< 0.001	< 0.001
IVA	0.87 ± 0.40	0.79 ± 0.41	< 0.001	0.61 ± 0.38	0.49 ± 0.32	< 0.001	0.003
IHA	30.36 ± 26.70	28.54 ± 27.21	0.633	30.49 ± 28.57	25.78 ± 22.73	0.084	0.919
IHD	0.13 ± 0.06	0.11 ± 0.07	< 0.001	0.08 ± 0.06	0.07 ± 0.05	< 0.001	< 0.001

TPTK-ACXL: Combined accelerated corneal cross-linking and transepithelial phototherapeutic keratectomy; TG-TPRK-ACXL: Combined accelerated corneal cross-linking and topography-guided transepithelial photorefractive keratectomy; UDVA: Uncorrected distance visual acuity; BCVA: Best spectacle-corrected distance visual acuity; Kf: Flat keratometry; Ks: Steep keratometry; Kmax: Maximum keratometry; CCT: Central corneal thickness; TCT: Thinnest corneal thickness; IHA: Index of height asymmetry; IS: Irregularity index; ISV: Index of surface variance; IVA: Index of vertical asymmetry; IHD: Index of height decentration

^aDifferences between preoperative and 1 year postoperative values in each group

^bDifference between the TPTK-ACXL and TGTPRK-ACXL groups before surgery

Visual acuity

Patients in both groups showed significant (P < 0.05) improvement in UDVA and BCVA after surgery at the 1-year follow-up visit (Table 1). After GEE correction, the TPTK-ACXL group exhibited more improvement in lines of BCVA compared to the TG-TPRK-ACXL group (β=-0.117, P = 0.002) (Table 2). Conversely, UDVA was found to be better in the TG-TPRK-ACXL group (β = 0.224, P = 0.002) (Table 2). BCVA was increased more than three lines in 12% in the TPTK-ACXL group and 3% in the TG-TPRK-ACXL group. No eyes lost more than one line (Fig. 3).

Table 2.

GEEs analysis for changes of UDVA, BCVA, spherical error, and cylindrical error after TPTK-ACXL and TG-TPRK-ACXL at 12 months postoperatively

Parameter	ΔUDVA (logMAR)			ΔBCVA (logMAR)			ΔSpherical error (D)			ΔCylindrical error (D)
	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value
TPTK	0.224	0.081 to 0.366	0.002	-0.117	-0.193 to -0.041	0.002	-1.117	-5.678 to 3.444	0.230	-0.664	-3.668 to 2.341	0.665
TGTPRK	0b			0b			0b			0b
< 18y	0.022	-0.171 to 0.215	0.823	-0.155	-0.303 to -0.008	0.039	0.622	-2.821 to 4.066	0.125	-3.757	-5.925 to -1.589	0.001
≥ 18y	0b			0b			0b			0b
Male	0.093	-0.066 to 0.252	0.249	0.047	-0.058 to 0.152	0.382	-0.176	-2.670 to 2.317	0.019	-0.840	-3.033 to 1.353	0.453
Female	0b			0b			0b			0b
UDVA (logMAR)	0.230	-0.090 to 0.549	0.158	-0.088	-0.211 to 0.035	0.160	1.152	-1.361 to 3.666	0.808	0.108	-3.022 to 3.239	0.946
BCVA (logMAR)	-0.289	-0.696 to 0.119	0.165	0.183	0.007 t0 0.359	0.042	0.475	-5.544 to 6.494	0.024	0.396	-5.089 to 5.882	0.887
Spherical error (D)	-0.012	-0.046 to 0.022	0.490	0.002	-0.014 to 0.019	0.788	0.129	-0.409 to 0.668	0.222	0.028	-0.295 to 0.351	0.865
Cylindrical error (D)	-0.006	-0.070 to 0.058	0.848	-0.016	-0.045 to 0.013	0.268	-0.102	-0.434 to 0.230	0.364	-0.014	-0.37 to 0.343	0.940
CCT (µm)	-0.014	-0.028 to 0.000	0.048	0.001	-0.005 to 0.006	0.784	0.032	-0.058 to 0.122	0.488	0.021	-0.082 to 0.124	0.688
TCT (µm)	0.015	-0.001 to 0.031	0.066	0.000	-0.006 to 0.006	0.891	0.048	-0.037 to 0.133	1.213	0.065	-0.048 to 0.178	0.256
Kf (D)	-3.289	-5.115 to -1.463	0.000	-0.357	-1.136 to 0.422	0.369	-8.745	-18.997 to 1.508	2.795	9.462	0.353 to 18.572	0.042
Ks (D)	3.336	1.463 to 5.209	0.000	0.419	-0.374 to 1.212	0.301	8.879	-2.965 to 20.722	2.159	-9.765	-19.182 to -0.348	0.042
Kmax (D)	-0.005	-0.051 to 0.042	0.840	0.019	-0.016 to 0.054	0.288	0.168	-0.437 to 0.773	0.296	-0.308	-1.091 to 0.475	0.440
IS	0.022	-0.046 t 0.090	0.532	0.009	0.001 to 0.018	0.031	-0.141	-0.912 to 0.629	0.129	-0.674	-1.53 to 0.181	0.122
Corneal astigmatism (D)	-3.213	-5.045 to -1.381	0.001	-0.369	-1.154 to 0.415	0.356	-8.954	-20.131 to 2.222	2.466	10.037	0.768 to 19.307	0.034
ISV	-0.021	-0.036 to -0.005	0.011	-0.016	-0.026 to − 0.006	0.002	0.008	-0.317 to 0.332	0.002	0.151	-0.105 to 0.408	0.248
IVA	1.180	-0.446 to 2.806	0.155	1.382	0.261 to 2.503	0.016	3.803	-40.802 to 48.407	0.028	-12.082	-33.531 to 9.368	0.270
IHA	-0.003	-0.008 to 0.003	0.299	-0.003	-0.006 to 0.000	0.095	-0.028	-0.054 to -0.002	4.332	-0.018	-0.045 to 0.01	0.210
IHD	2.478	-6.413 to 11.369	0.585	-4.553	-11.365 to 2.258	0.190	-17.425	-268.805 to 233.954	0.018	86.911	-14.746 to 188.568	0.094

^a The β-coefficient refers to how a dependent variable will change per unit increase in the predictor variable

^b Comparison reference group

Fig. 3.

Change in Snellen Lines of BCVA in both groups

Refractive error

In the TPTK-ACXL group, no statistically significant change was observed in spherical error at the 1-year follow-up compared to preoperative measurements (P = 0.295) (Table 1). However, a notable reduction in cylindrical error was observed (P = 0.022) (Table 1). In the TG-TPRK-ACXL group, spherical error decreased significantly 1 year after surgery compared with that before surgery (P = 0.004) (Table 1), but cylindrical error did not change significantly (P = 0.441) (Table 1). After GEE correction, there were no notable disparities observed in the spherical error and cylindrical error changes between the TPTK-ACXL and TG-TPRK-ACXL groups pre- and post-operatively (P > 0.05) (Table 2).

Keratometry readings and corneal thickness

At 12 months postoperatively, significant reductions in Ks, Kf, Kmax, CCT, and TCT were observed in both groups compared to baseline (P < 0.001) (Table 1). One year after surgery, the TPTK-ACXL group showed a significant decrease in corneal astigmatism (P = 0.012), while no significant change was observed in the TG-TPRK-ACXL group (P = 0.345) (Table 1). After GEE correction, there were no significant differences observed in Ks, Kf, Kmax, corneal astigmatism, CCT, and TCT changes before and after surgery between the TPTK-ACXL and TG-TPRK-ACXL groups (P > 0.05) (Tables 3 and 4). Figures 4 and 5 demonstrate the preoperative and 1-year postoperative corneal topographic changes in both eyes of the same patient, which underwent TG-TPRK-ACXL and TPTK-ACXL procedures, respectively.

Table 3.

GEEs analysis for changes of kf, ks, Kmax and corneal astigmatism after TPTK-ACXL and TG-TPRK-ACXL at 12 months postoperatively

Parameter	ΔKf (D)			ΔKs (D)			Δ Kmax (D)			ΔCorneal astigmatism (D)
	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value
TPTK	-0.037	-0.712 to 0.638	0.914	-1.415	-3.662 to 0.833	0.217	0.020	-2.92 to 2.96	0.989	-0.818	-2.123 to 0.487	0.219
TGTPRK	0b			0b			0b			0b
< 18y	0.034	-0.546 to 0.614	0.908	1.988	0.439 to 3.537	0.012	-1.259	-4.633 to 2.116	0.465	1.408	0.474 to 2.342	0.003
≥ 18y	0b			0b			0b			0b
Male	-0.161	-0.858 to 0.536	0.650	0.480	-1.235 to 2.195	0.583	2.722	-2.634 to 8.077	0.319	-0.035	-1.017 to 0.946	0.944
Female	0b			0b			0b			0b
UDVA (logMAR)	0.450	-0.312 to 1.213	0.247	-0.348	-1.678 to 0.981	0.608	-4.526	-9.918 to 0.866	0.100	-1.503	-2.709 to -0.298	0.015
BCVA (logMAR)	-1.221	-2.63 to 0.189	0.090	-2.578	-5.368 to 0.211	0.070	2.234	-4.161 to 8.628	0.494	0.115	-1.297 to 1.526	0.874
Spherical error (D)	-0.117	-0.23 to -0.004	0.042	-0.093	-0.345 to 0.159	0.468	-0.346	-0.744 to 0.051	0.088	0.138	-0.019 to 0.295	0.085
Cylindrical error (D)	0.164	0.046 to 0.283	0.006	-0.146	-0.35 to 0.057	0.158	-0.084	-0.837 to 0.669	0.827	-0.280	-0.452 to -0.108	0.001
CCT (µm)	0.015	-0.01 to 0.039	0.247	-0.061	-0.124 to 0.001	0.055	-0.112	-0.334 to 0.11	0.324	0.024	-0.04 to 0.088	0.465
TCT (µm)	-0.013	-0.04 to 0.013	0.326	0.007	-0.059 to 0.072	0.837	0.143	-0.113 to 0.398	0.273	-0.017	-0.061 to 0.027	0.446
Kf (D)	0.285	-3.643 to 4.214	0.887	8.019	2.988 to 13.05	0.002	10.501	-13.198 to 34.201	0.385	3.964	-1.834 to 9.763	0.180
Ks (D)	-0.179	-4.111 to 3.753	0.929	-7.793	-13.207 to -2.379	0.005	-10.451	-34.445 to 13.542	0.393	-3.672	-9.64 to 2.297	0.228
Kmax (D)	-0.160	-0.283 to -0.037	0.011	0.101	-0.262 to 0.465	0.585	-0.222	-0.896 to 0.452	0.519	0.074	-0.22 to 0.367	0.623
IS	-0.038	-0.063 to -0.013	0.003	0.351	-0.092 to 0.793	0.121	0.074	-0.231 to 0.378	0.635	0.085	-0.188 to 0.359	0.541
Corneal astigmatism (D)	0.463	-3.4 to 4.326	0.814	7.824	2.58 to 13.068	0.003	10.710	-13.168 to 34.587	0.379	3.581	-2.341 to 9.503	0.236
ISV	0.030	-0.019 to 0.078	0.227	-0.027	-0.16 to 0.106	0.693	0.086	-0.107 to 0.279	0.380	-0.002	-0.105 to 0.101	0.974
IVA	0.703	-3.771 to 5.177	0.758	9.765	-5.855 to 25.385	0.220	-10.810	-33.553 to 11.934	0.352	5.515	-3.119 to 14.15	0.211
IHA	0.006	-0.007 to 0.018	0.349	-0.003	-0.024 to 0.018	0.776	-0.072	-0.206 to 0.062	0.292	-0.015	-0.029 to -0.001	0.032
IHD	-7.598	-27.4 to 12.204	0.452	-81.003	-167.508 to 5.502	0.066	56.931	-97.327 to 211.188	0.469	-43.348	-83.064 to -3.632	0.032

^a The β-coefficient refers to how a dependent variable will change per unit increase in the predictor variable

^b Comparison reference group

Table 4.

GEEs analysis for changes of CCT, TCT and IS after TPTK-ACXL and TG-TPRK-ACXL at 12 months postoperatively

TPTK	ΔCCT (µm)			Δ TCT (µm)			Δ IS
	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value
TGTPRK	3.144	-25.199 to 31.488	0.828	-3.114	-13.128 to 6.9	0.542	-0.745	-2.691 to 1.201	0.453
< 18y	0b			0b			0b
≥ 18y	61.268	42.355 to 80.181	0.000	10.223	1.727 to 18.719	0.018	0.914	-0.428 to 2.255	0.182
Male	0b			0b			0b
Female	4.881	-21.519 to 31.282	0.717	1.405	-10.482 to 13.292	0.817	-0.838	-2.575 to 0.899	0.344
UDVA (logMAR)	0b			0b			0b
BCVA (logMAR)	-1.495	-24.696 to 21.705	0.899	1.003	-13.7 to 15.707	0.894	1.583	-0.966 to 4.132	0.223
Spherical error (D)	-38.001	-85.175 to 9.172	0.114	-18.667	-38.855 to 1.521	0.070	-0.421	-2.577 to 1.735	0.702
Cylindrical error (D)	-3.119	-6.812 to 0.573	0.098	-1.320	-3.105 to 0.465	0.147	0.060	-0.22 to 0.34	0.674
CCT (µm)	3.100	-0.085 to 6.285	0.056	0.313	-1.218 to 1.845	0.688	0.170	-0.092 to 0.432	0.204
TCT (µm)	-1.373	-2.234 to -0.512	0.002	-0.108	-0.557 to 0.341	0.638	-0.063	-0.173 to 0.047	0.263
Kf (D)	1.037	0.253 to 1.821	0.010	0.099	-0.385 to 0.583	0.689	0.077	-0.047 to 0.201	0.224
Ks (D)	53.797	-19.47 to 127.064	0.150	-25.046	-102.866 to 52.774	0.528	0.710	-8.894 to 10.314	0.885
Kmax (D)	-53.581	-129.916 to 22.754	0.169	25.121	-53.341 to 103.582	0.530	-0.372	-9.782 to 9.039	0.938
IS	6.008	-1.1 to 13.115	0.098	-0.154	-2.767 to 2.458	0.908	-0.179	-0.689 to 0.332	0.493
Corneal astigmatism (D)	7.515	-1.985 to 17.015	0.121	-0.287	-0.656 to 0.083	0.129	-0.022	-0.108 to 0.064	0.612
ISV	54.185	-21.197 to 129.566	0.159	-25.986	-103.8 to 51.828	0.513	0.447	-9.074 to 9.968	0.927
IVA	-1.721	-4.295 to 0.853	0.190	0.191	-0.74 to 1.121	0.688	0.036	-0.1 to 0.171	0.605
IHA	24.698	-210.017 to 259.413	0.837	-9.027	-94.146 to 76.093	0.835	-2.752	-14.584 to 9.08	0.649
IHD	0.169	-0.062 to 0.399	0.152	0.043	-0.111 to 0.196	0.586	0.022	-0.037 to 0.081	0.472
TPTK	-100.497	-1331.357 to 1130.363	0.873	3.578	-402.13 to 409.287	0.986	9.021	-36.038 to 54.08	0.695

Fig. 4.

Comparative maps of anterior corneal surface tangential curvature in the right eye of a 25-year-old male with bilateral progressive keratoconus: 1 year after TG-TPRK-ACXL surgery (A) vs. preoperative Pentacam imaging (B)

Fig. 5.

Comparative maps of anterior corneal surface tangential curvature in the left eye of the same patient: 1 year after TPTK-ACXL surgery (A) vs. preoperative Pentacam imaging (B)

Keratoconus parameters

Except for the index of height asymmetry (IHA), postoperative values of the irregularity index (IS), index of surface variance (ISV), index of vertical asymmetry (IVA), and index of height decentration (IHD) were significantly lower in both the TPTK-ACXL and TG-TPRK-ACXL groups compared to preoperative values at 12 months postoperatively (P < 0.001) (Table 1). After GEE correction, no significant difference was observed in IS, ISV, IVA, IHA, and IHD changes between the TPTK-ACXL and TG-TPRK-ACXL groups before and after surgery (P > 0.05) (Tables 4 and 5).

Table 5.

GEEs analysis for changes of ISV, IVA, IHA, and IHD after TPTK-CXL and TG-TPRK-CXL at 12 months postoperatively

Parameter	ΔISV			ΔIVA			Δ IHA			ΔIHD
	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value	β-coefficient	95% CI	P-value
TPTK	-1.791	-6.956 to 3.373	0.497	0.002	-0.079 to 0.083	0.962	3.615	-5.317 to 12.548	0.428	-0.004	-0.014 to 0.006	0.419
TGTPRK	0b			0b			0b			0b
< 18y	-0.994	-11.159 to 9.171	0.848	0.000	-0.114 to 0.115	0.998	-4.800	-12.26 to 2.661	0.207	-0.005	-0.023 to 0.013	0.608
≥ 18y	0b			0b			0b			0b
Male	5.135	-0.896 to 11.167	0.095	0.067	-0.002 to 0.136	0.057	6.798	-3.051 to 16.647	0.176	0.013	0.002 to 0.023	0.026
Female	0b			0b			0b			0b
UDVA (logMAR)	-1.286	-7.533 to 4.961	0.687	-0.054	-0.146 to 0.038	0.249	-1.145	-16.826 to 14.537	0.886	-0.010	-0.021 to 0.002	0.105
BCVA (logMAR)	-14.911	-26.981 to -2.841	0.015	-0.136	-0.332 to 0.059	0.172	-24.562	-43.393 to -5.731	0.011	-0.011	-0.035 to 0.013	0.388
Spherical error (D)	-0.425	-1.245 to 0.395	0.310	-0.003	-0.02 to 0.013	0.708	1.207	-1.882 to 4.297	0.444	-0.001	-0.003 to 0.001	0.330
Cylindrical error (D)	0.954	-0.116 to 2.023	0.081	0.006	-0.009 to 0.021	0.411	-0.316	-2.537 to 1.904	0.780	0.001	-0.001 to 0.003	0.447
CCT (µm)	0.303	0.064 to 0.543	0.013	0.004	-0.001 to 0.009	0.153	0.503	-0.206 to 1.212	0.164	0.001	0 to 0.001	0.063
TCT (µm)	-0.309	-0.566 to -0.052	0.018	-0.003	-0.009 to 0.002	0.251	-0.482	-1.235 to 0.271	0.210	-0.001	-0.001 to 0	0.135
Kf (D)	-17.171	-51.153 to 16.812	0.322	-0.441	-1.014 to 0.132	0.131	-23.448	-115.669 to 68.773	0.618	-0.040	-0.134 to 0.054	0.403
Ks (D)	19.782	-14.288 to 53.851	0.255	0.479	-0.097 to 1.055	0.103	26.954	-67.134 to 121.043	0.574	0.043	-0.051 to 0.137	0.369
Kmax (D)	-0.706	-2.143 to 0.732	0.336	-0.008	-0.026 to 0.01	0.412	0.447	-2.558 to 3.451	0.771	-0.001	-0.004 to 0.002	0.448
IS	-0.458	-0.726 to -0.19	0.001	-0.008	-0.014 to -0.002	0.010	-2.042	-4.421 to 0.338	0.093	-0.001	-0.002 to 0	0.002
Corneal astigmatism (D)	-17.133	-51.012 to 16.747	0.322	-0.444	-1.011 to 0.124	0.126	-28.467	-120.575 to 63.642	0.545	-0.040	-0.133 to 0.053	0.400
ISV	0.010	-0.4 to 0.42	0.962	-0.003	-0.007 to 0.002	0.235	-0.698	-1.908 to 0.513	0.259	0.000	-0.001 to 0.001	0.965
IVA	36.856	-4.803 to 78.515	0.083	0.392	-0.074 to 0.857	0.099	32.902	-60.571 to 126.375	0.490	0.027	-0.048 to 0.102	0.477
IHA	-0.025	-0.14 to 0.091	0.677	-0.001	-0.003 to 0	0.087	0.174	-0.136 to 0.484	0.272	0.000	0 to 0	0.101
IHD	-239.706	-453.187 to -26.225	0.028	-0.837	-3.844 to 2.17	0.585	56.071	-714.397 to 826.538	0.887	-0.084	-0.498 to 0.33	0.692

^a The β-coefficient refers to how a dependent variable will change per unit increase in the predictor variable

^b Comparison reference group

Age group analyses

GEE correction analyses revealed that adult patients exhibited more significant reductions in Ks (β = 1.988, P = 0.012), corneal astigmatism (β = 1.408, P = 0.003), TCT (β = 10.223, P = 0.018), and CCT (β = 61.268, P < 0.001) values than juveniles (Tables 3 and 4). In contrast, juveniles showed more significant improvements in BCVA (β = -0.155, P = 0.039) and a reduction in cylindrical error (β = -3.757, P = 0.001) (Table 2).

Ablation depth

In the TPTK-ACXL group, the mean central ablation depth was recorded as 52.96 ± 0.48 μm, whereas the mean maximum ablation depth was 57.05 ± 0.79 μm. In contrast, the TG-TPRK-ACXL group exhibited significantly higher values of 63.17 ± 1.04 μm and 83.51 ± 2.76 μm, respectively, for the central and maximum ablation depths (both P < 0.001) (Fig. 6).

Fig. 6.

Comparison of mean central ablation depth and mean maximum ablation depth between the two groups

Adverse events

None of the patients reported any serious intraoperative or postoperative complications or adverse events that resulted in loss of visual acuity. Post-operative mild corneal haze, not affecting visual acuity, was observed in 7 eyes (16.3%) in the TPTK-ACXL group and 6 eyes (12.2%) in the TG-TPRK-ACXL group. No additional steroid treatment was required beyond the standard protocol as all cases were graded as trace haze (Grade 0.5-1 on the Fantes scale [12]).

Discussion

Comparison of TG-TPRK-ACXL with other topography-Guided CXL protocols

Although supplemental rigid gas permeable (RGP) contact lens therapy remains the cornerstone of visual rehabilitation in keratoconus, there is growing interest in fully surgical approaches that combine CXL with adjunctive refractive procedures. These integrated interventions, collectively termed “CXL-plus” procedures, aim to simultaneously halt ectasia progression, mitigate HOAs and further enhance visual prognosis [2]. Critically, while these treatments do not eliminate the need for optical correction, they reshape the anterior corneal surface to convert an irregular, predominantly comatic astigmatism into a more regular refractive error. This regularization improves the efficacy of conventional spectacles and soft contact lenses by transforming complex aberrations into spherocylindrical defects that are more amenable to standard correction modalities [11]. TG-TPRK was the initial documented combined CXL procedure, known as the Athens protocol [13]. Kanellopoulos [7] presented a ten-year follow-up study on the outcomes of the Athens protocol in progressive keratoconus, demonstrating significant improvements in BCVA (0.59 ± 0.21 to 0.80 ± 0.17 decimal), as well as flattening of Ks from 50.57 ± 2.80 D to 45.87 ± 2.70 D and reduction in CCT from 468.74 ± 35.05 μm to 391.14 ± 40.07 μm in 144 eyes.

Most parameters in that study showed no significant changes over a period of 1 to 10 years, except for the Kmax value. This suggests that the surgical outcomes at 1 year can overall predict the long-term prognosis for keratoconus patients. In our study, TG-TPRK-ACXL also demonstrated favorable outcomes at 1 year postoperatively, with a BCVA from 0.21 ± 0.20 to 0.15 ± 0.20 (logMAR), Ks from 48.61 ± 4.44D to 47.44 ± 4.43 and CCT from 496.06 ± 27.78 μm to 474.80 ± 36.89 μm.

The Athens protocol involved performing a 6.5-mm, 50-µm PTK to remove the corneal epithelium, followed by topography-guided PRK to eliminate HOAs and up to 70% of cylinder and sphere, while not exceeding 50 μm, then the standard CXL treatment protocol (3 mW/cm²for 30 min) was carried out [13]. In our TG-TPRK procedure, we determined the epithelial ablation depth based on the epithelial thickness at the cone apex and focused on eliminating most of the HOAs particularly coma, without addressing any spherical or cylindrical power. And we used the accelerated CXL protocol (30 mW/cm² for 4 min). As such, the average central ablation, including the epithelial depth, for TG-TPRK was 63.17 ± 1.04 μm and the maximum ablation was 83.51 ± 2.76 μm. Subsequently, the stromal ablation depth was far less than 50 μm in our study when compared to the Athens protocol. The benefit of this approach includes optimizing the preservation of corneal stroma and enhancing postoperative corneal stability. Moreover, the accelerated CXL protocol shortened the exposure time, enhances treatment efficiency, and increases patients’ compliance with the surgery. Awwad et al. [14] demonstrated that 0.02% Mitomycin C application immediately after CXL led to increased anterior stromal haze reflectivity and larger haze area compared to CXL alone. Given the potential impact of haze on the visual quality of keratoconus patients, we did not use mitomycin C during the surgical procedure.

In a separate investigation [9] focusing solely on the removal of high-order aberrationsusing the Alcon WaveLight EX-500 laser, thirty-one keratoconus eyes underwent topography-guided PRK-CXL without significant visual improvement. In that study, alcohol-assisted epithelial debridement was used, which differs from our study, using uniform trans-epithelial laser removal, which may contribute to the difference in statistical improvement by generating a more uniform corneal surface. This difference, however, may also be due to the laser platform and profile used, as the WaveLight EX500 excimer laser system only corrects all HOAs, while in our study using the Schwind Amaris 1050RS laser, we selectively corrected only coma as the main aberration to minimize tissue consumption. Aberration profiles reveal that horizontal and vertical coma contributes approximately 63% of all HOAs in eyes with keratoconus [15].

Contrast of TPTK-ACXL and other PTK-CXL combinations

The “Cretan protocol”, on the other hand, combined technique of PTK and CXL, and this was first described by Kymionis et al. in 2010 [16]. Phototherapeutic Keratectomy utilizes excimer laser ablation to eliminate the epithelium and smoothen any irregularities on the anterior corneal stroma [16, 17]. Kymionis GD et al. [18] conducted a comparative study between TPTK-CXL and mechanical epithelial debridement combined with CXL, revealing that the TPTK group exhibited significant improvements in visual acuity and keratometric values, whereas no similar outcomes were observed in the mechanical epithelial removal group. Additionally, another study [19] reported similar findings that visual acuity improvement following TPTK-CXL was more pronounced compared to mechanical epithelial removal.

Furthermore, Xiangjun Chen et al. [20] conducted a review of 46 keratoconic eyes that underwent TPTK-ACXL and observed an improvement in BCVA from 0.25 ± 0.24 to 0.18 ± 0.22 logMAR (P = 0.002), as well as reductions in both Kmax from 50.58 ± 5.26 to 48.96 ± 4.00D (P < 0.001), with a mean follow-up period of 21.0 ± 7.6 months. Similar to our investigation, patients undergoing TPTK-ACXL also demonstrated a statistically significant enhancement in BCVA and a substantial reduction in Kmax, surpassing the findings reported by Xiangjun Chen et al. [20]. This observed difference could be attributed to the better corneal condition of patients undergoing TPTK-ACXL in our study. The mean TCT of patients undergoing TPTK-ACXL in our study was 454.00 ± 36.70 μm, whereas in Xiangjun Chen et al.‘s study [20], the average TCT of patients was just 390.8 ± 38.40 μm.

Additionally, we enhanced the Cretan protocol by determining the ablation depth based on average epithelial thickness outside the cone area and less ablation was performed if residual stromal thickness was less than 380 μm, aiming to maximize corneal stromal preservation, while optimizing correction of corneal irregularities, which followed by the accelerated CXL protocol. Rohit Shetty et al. [21] also reported that both TG-TPRK-CXL and topography-assisted TPTK-CXL were equally effective in improving UDVA and BCVA. However, TG-TPRK, as expected, resulted in a higher amount of intra-operative tissue ablation.

Comparative outcomes of TPTK-ACXL and TG-TPRK-ACXL

Few studies have compared TPTK-CXL and PRK-CXL, as patient selection for these two procedures generally differ significantly. As discussed previously, TPTK-CXL is usually recommended for patients with more severe keratoconus. Like in our study, TPTK-ACXL was indicated for individuals with an estimated post-ablation TCT of less than 400 μm. As a result, compared to the TG-TPRK-ACXL group, patients in the TPTK-ACXL group had more irregular corneas, steeper corneal curvature, and worse BCVA preoperatively. The GEE statistical analysis can effectively control baseline data variability between two groups, though concrete conclusions should not be drawn. Interestingly, our study observed comparable results when employing both TPTK-ACXL and TG-PRK-ACXL techniques. More specifically, the results showed more lines of BCVA improvement in the TPTK-ACXL group when compared to the TG-TPRK-ACXL group in post-operative year one. Though keratoconus HOAs, like coma, should theoretically degrade visual quality most significantly, we hypothesize that the excessive steepening at the apex of the cone, which is close to but often displaced from the visual axis, may be more visually impactful than anticipated. Therefore, simply reducing this steep area in keratoconus with TPTK-ACXL seems to have a profound visual effect.

Notably, even if optical aberrations are fully corrected, neural adaptation to pre-existing irregularities may limit visual acuity gains. For instance, adaptive optics (AO) simulations in normal eyes (Chen et al.) [20]. and keratoconus patients (Rocha et al.) [22]. demonstrated that partial aberration correction often yields better subjective vision than complete correction, likely due to neural recalibration.

While our study focused on the Athens and Cretan protocols, it is important to note that both TG-TPRK and TPTK-CXL procedures rely solely on anterior corneal topography for ablation planning, without accounting for the refractive contribution of the posterior corneal surface. This limitation may lead to suboptimal compensation of total corneal aberrations, as posterior corneal irregularities (e.g., divergent coma in keratoconus) can counteract anterior surface corrections. In contrast, emerging techniques such as ray-tracing-guided ablation, as reported in the literature by Mazzotta [11] in the first international largest case series and also in the case report published by Kanellopoulos [23], employ inverse optics principles to calculate total corneal power by tracing light rays through both anterior and posterior corneal surfaces. This method generates a refractive map that balances anterior and posterior aberrations, thereby minimizing stromal tissue removal and preventing overcorrections. Specifically, reverse ray-tracing algorithms simulate light propagation from the retina to the corneal surface, defining an ideal anterior corneal shape that neutralizes posterior surface aberrations. Such precision is particularly critical in keratoconus, where posterior ectasia significantly impacts optical quality.

Lastly, age plays a significant role in determining the effectiveness of CXL [24–26]. Our study findings indicate that adult patients exhibit better postoperative corneal flattening. This is consistent with the conclusions drawn by Soeters et al. [25] and Rebecca Farhat et al. [24]. On the other hand, a retrospective study found that the reduction of TCT in pediatric patients one year after CXL surgery was more significant compared to adults. However, a major limitation of this retrospective study was that five different crosslinking techniques were performed and analyzed together.

Limitations and future directions

To the best of our knowledge, our study is the first to compare the efficacy and safety of TG-TPRK-ACXL and TPTK-ACXL in progressive keratoconus after correcting baseline differences in contralateral eyes. However, it is crucial to acknowledge limitations of this study, such as the small sample size, and its retrospective nature. Moreover, post-operative wavefront analysis, specifically corneal and/or total HOAs around 3–4 mm, was not obtained and analyzed for direct comparison between the two groups. Moving forward, future prospective contralateral eye studies in moderate keratoconus patients with one eye receiving TPTK-ACXL and the other eye undergoing TG-TPRK-ACXL would further clarify if TPTK-ACXL may be a more superior surgical method than topographic guided TPRK with crosslinking. However, to establish clinical superiority and generalize these findings, rigorously designed randomized controlled trials (RCTs) with standardized protocols, larger cohorts, and longer follow-up periods are imperative.

In conclusion, both TPTK-ACXL and TG-TPRK-ACXL treatments demonstrate efficacy in enhancing visual acuity and corneal regularity among keratoconus patients, with a favorable safety profile. Keratoconus patients with excessive corneal apical steepening may benefit from TPTK-ACXL, which minimizes corneal thickness loss to serve as a potential substitute for TG-TPRK-ACXL.

Abbreviations

TG-TPRK

Topography-guided transepithelial photorefractive keratectomy

CXL

Corneal cross-linking

TPTK

Transepithelial phototherapeutic keratectomy

ACXL

Accelerated corneal cross-linking

GEE

Generalized estimating equations

D

Diopter

Kmax

Maximum keratometry

TCT

Postoperative theoretical thinnest corneal thickness

UDVA

Uncorrected distance visual acuity

BCVA

Best spectacle-corrected distance visual acuity

CCT

Central corneal thickness

Kf

Flat keratometry

Ks

Steep keratometry

HOA

Higher-order aberrations

IHA

Index of height asymmetry

IS

Irregularity index

ISV

Index of surface variance

IVA

Index of vertical asymmetry

IHD

Index of height decentration

AO

Adaptive optics

RCTs

Randomized controlled trial

Author contributions

JLH analyzed and interpreted the data, drafted the manuscript, and provided statistical expertise. JWW and IT designed the study and critically revised the manuscript. LX, BZ and XW collected data. ZW designed the study and critically revised the manuscript. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This retrospective study was approved by the Ethics Committee of Guangzhou Aier Eye Hospital (Approval No. GZAIER2023IRB22), and the study adhered to the Declaration of Helsinki. The requirement for informed consent was waived by the Ethics Committee of Guangzhou Aier Eye Hospital due to the retrospective nature of the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.