Journal of Refractive Surgery

Original Article 

Safety and Efficacy of Simultaneous Corneal Collagen Cross-linking With Topography-guided PRK in Managing Low-grade Keratoconus: 1-year Follow-up

Waleed S. Tuwairqi, MD; Mazen M. Sinjab, MD, PhD

Abstract

PURPOSE:

To evaluate 1-year visual and topographic outcomes and safety and efficacy of corneal collagen cross-linking (CXL) combined with topography-guided photorefractive keratectomy (TG-PRK) to achieve near emmetropia in eyes with low-grade keratoconus.

METHODS:

Twenty-two eyes from 15 patients (11 women, 4 men) were included in a prospective, nonrandomized, noncontrolled clinical study. Mean patient age was 26.6±6.07 years (range: 19 to 40 years). Inclusion criteria were low-grade keratoconus with evidence of progression, transparent cornea, corrected distance visual acuity (CDVA) 0.8 (decimal) or better, corneal thickness >440 μm, and maximum keratometry readings (K-max) <51.00 diopters (D). All patients underwent simultaneous TG-PRK with CXL. Study parameters were uncorrected distance visual acuity, CDVA, manifest refractive error, manifest and topographic (corneal) astigmatism, patient satisfaction, and efficacy and safety of the treatment. Follow-up was 1 year.

RESULTS:

After 1 year, statistically significant improvement was noted in all study parameters (P<.01). The safety and efficacy indices were 1.6 and 0.4, respectively. Patient satisfaction questionnaire showed that 91% were satisfied, 9% were not completely satisfied but believed they improved, and none were dissatisfied. Corneal topography demonstrated significant improvement in 55%, improvement in 36%, and minor improvement in 9% of cases. No cases progressed as evidenced by keratometry readings.

CONCLUSIONS:

Simultaneous TG-PRK with CXL is an effective and safe treatment with remarkable visual and topographic outcomes in patients with low-grade keratoconus who meet the recommended inclusion criteria.

Abstract

PURPOSE:

To evaluate 1-year visual and topographic outcomes and safety and efficacy of corneal collagen cross-linking (CXL) combined with topography-guided photorefractive keratectomy (TG-PRK) to achieve near emmetropia in eyes with low-grade keratoconus.

METHODS:

Twenty-two eyes from 15 patients (11 women, 4 men) were included in a prospective, nonrandomized, noncontrolled clinical study. Mean patient age was 26.6±6.07 years (range: 19 to 40 years). Inclusion criteria were low-grade keratoconus with evidence of progression, transparent cornea, corrected distance visual acuity (CDVA) 0.8 (decimal) or better, corneal thickness >440 μm, and maximum keratometry readings (K-max) <51.00 diopters (D). All patients underwent simultaneous TG-PRK with CXL. Study parameters were uncorrected distance visual acuity, CDVA, manifest refractive error, manifest and topographic (corneal) astigmatism, patient satisfaction, and efficacy and safety of the treatment. Follow-up was 1 year.

RESULTS:

After 1 year, statistically significant improvement was noted in all study parameters (P<.01). The safety and efficacy indices were 1.6 and 0.4, respectively. Patient satisfaction questionnaire showed that 91% were satisfied, 9% were not completely satisfied but believed they improved, and none were dissatisfied. Corneal topography demonstrated significant improvement in 55%, improvement in 36%, and minor improvement in 9% of cases. No cases progressed as evidenced by keratometry readings.

CONCLUSIONS:

Simultaneous TG-PRK with CXL is an effective and safe treatment with remarkable visual and topographic outcomes in patients with low-grade keratoconus who meet the recommended inclusion criteria.

From Elite Medical Center, Al Riyadh, Kingdom of Saudi Arabia.

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (W.S.T.); data collection (W.S.T.); analysis and interpretation of data (M.M.S.); drafting of the manuscript (M.M.S.); critical revision of the manuscript (W.S.T., M.M.S.); statistical expertise (M.M.S.); supervision (W.S.T.)

Correspondence: Mazen M. Sinjab, MD, PhD, PO Box 167 AlTal, Damascus, Syria. Tel: 963 9 3344 9660; Fax: 963 1 144 71220 ext 2; E-mail: mazen.sinjab@yahoo.com

Received: October 14, 2011
Accepted: February 21, 2012
Posted Online: March 26, 2012

Click here to read the Letter to the Editor.

New treatments available to patients with keratoconus include intrastromal corneal ring segment implantation,1,2 conductive keratoplasty,3 phakic intraocular lenses,4,5 and corneal collagen cross-linking (CXL).6

Collagen cross-linking has emerged as a promising technique to slow or stop the progression of keratoconus7 as well as postoperative LASIK ectasia.8 By modifying corneal stromal structure and increasing corneal strength and stability, CXL provides a new approach and when combined with techniques that improve visual acuity such as topography-guided photorefractive keratectomy (TG-PRK) may offer a useful surgical technique to treat patients with keratoconus and postoperative LASIK ectasia.9–12

In this study, we analyzed primary visual acuity and refractive and topographic outcomes over a 1-year postoperative period in patients with grade 1 and 2 keratoconus who underwent this simultaneously combined treatment.

Patients and Methods

Twenty-two eyes from 15 patients were included in this prospective, interventional, nonrandomized, noncontrolled study. All patients underwent simultaneous CXL with TG-PRK to correct their refractive error by one surgeon (W.S.T.) at Elite Medical Center, Riyadh, Kingdom of Saudi Arabia. All patients were adequately informed about the aim and expected results of this type of surgery. All patients signed a consent form and the study was approved by the local ethics committee.

Inclusion criteria were patients aged ⩾19 years, sagittal (axial) topography pattern consistent with keratoconus, an inferior-superior ratio >1.5 on topography mapping, stage 1 and 2 keratoconus according to Krumeich classification, corneal thickness >440 μm at the thinnest location, preoperative corrected distance visual acuity (CDVA) 0.8 (decimal) or better, and maximum keratometry readings (K-max) <51.00 diopters (D). Progressive keratoconus was defined as one or more of the following changes over a period of 6 months: an increase of ⩾1.00 D in K-max, an increase of ⩾1.00 D in manifest cylinder, and/or an increase of ⩾0.50 D in manifest refraction spherical equivalent (MRSE). Exclusion criteria were patients with a history of corneal surgery, delayed epithelial healing, and pregnancy or lactation during the course of the study.

Contact lens wearers were instructed to discontinue use for a minimum of 2 weeks before the preoperative eye examination and required confirmation of a stable refraction at two examinations that were at least 7 days apart. A stable refraction was determined as one in which the MRSE and keratometry measurements at the first visit did not differ by more than 0.75 D from the respective measurements at the second visit.

Surgical Technique of Simultaneous CXL and TG-PRK

All procedures were performed using the SCHWIND Amaris excimer laser system (software version 1.1.1008.140 and IRX 3.5.0.3; SCHWIND eye-tech-solutions, Kleinostheim, Germany) with the Schwind-Sirius topography system (CSO Inc, Florence, Italy) for TG-PRK followed by irradiation with the UV-X corneal collagen CXL system (IROC AG, Zurich, Switzerland). Cyclotorsion and offset pupil were automatically controlled.

A topical anesthetic agent was administered, and the central 9.0 mm epithelium was removed by mechanical debridement. Topography-guided PRK was performed on a 6.5-mm optical zone. The ablation depth was limited to achieving ±1.00 D of emmetropia and keeping at least 400 μm of stroma before proceeding with CXL, taking into account that the thickness of corneal epithelium is normally 50 μm. Mitomycin C 0.02 mg/mL was applied for 30 seconds. Corneal collagen CXL was performed according to the methodology described by Wollensak et al.13 Riboflavin (0.1% in 20% dextran T500 solution) was administered topically every 2 minutes for 30 minutes. Riboflavin absorption throughout the corneal stroma and anterior chamber was confirmed by slit-lamp examination.

Ultrasound pachymetry was performed when corneal thickness was <400 μm. An additional application of hypoosmolar riboflavin solution was performed for 10 minutes to swell the cornea to reach at least 400 μm.

The cornea was aligned and exposed to UVA 365 nm light for 30 minutes at an irradiance of 3.0 mW/cm2. During UVA exposure, isotonic riboflavin administration was continued every 2 minutes. Postoperatively, antibiotic and corticosteroid drops were administered, a bandage soft contact lens was placed, and the eye was reexamined at the slit-lamp. The contact lens was removed after the epithelial defect had closed (3 to 5 days postoperatively). Antibiotics and corticosteroid drops were continued four times daily for 7 days. Patients were followed for 12 months postoperatively and had complete examinations at 1, 3, 6, and 12 months.

Outcome Measures

Visual Acuity and Refraction. Uncorrected distance visual acuity (UDVA) and CDVA were measured preoperatively and postoperatively at 1, 3, 6, and 12 months. Visual acuity was recorded and analyzed as the logMAR value. Manifest refraction was performed preoperatively and 1, 3, 6, and 12 months postoperatively, and the MRSE and manifest astigmatism were analyzed.

Topography. Corneal topography was performed using the Schwind-Sirius Topographer for diagnosis, TG-PRK treatment, and follow-up. Topographic data were obtained preoperatively and 1, 3, 6, and 12 months postoperatively. The K-max values, average K values, flat K (K1) values, and steep K (K2) values as well as corneal astigmatism (simulated K) were recorded from the topography data. Postoperative changes in topographic pattern were graded depending on the shape of the anterior sagittal map and the inferior-superior symmetry as: 1) significant improvement, when the topographic shape and values approached normal limits; 2) improved, when the pattern improved in shape and values but was still graded as low-grade keratoconus; and 3) minor change, when minimal changes occurred in shape and values.

Efficacy and Safety Indices. Efficacy index was calculated by the ratio postoperative UDVA/preoperative CDVA (logMAR). Safety index was calculated by the ratio postoperative CDVA/preoperative CDVA (logMAR).

Patient Satisfaction. Patient satisfaction was determined depending on a special questionnaire and classified as: 1) satisfied, when the patient could read signs, drive at night, watch TV, and his/her function was acceptable; 2) improved, when the patient was satisfied most of the time but had difficulty with tasks requiring sharp vision, and would undergo the procedure again; and 3) dissatisfied, when the patient still had trouble driving, reading, and watching TV most of the time.

Statistical Analysis

GraphPad Prism version 5.03 (GraphPad Software Inc, La Jolla, California) was used to perform the statistical analysis. The results in outcome measures after 1 year were analyzed using the paired two-tailed design. The correlation between outcome measures after 1 year and preoperative demographics was studied using the Pearson correlation coefficient.

Results

All patients enrolled in the study completed 1-year follow-up. Mean patient age was 26.6±6.07 years (range: 19 to 40 years).

Regarding preoperative topographic patterns, both asymmetric bowtie inferior steep and inferior steep patterns were seen in 36.36% of eyes, whereas symmetric bowtie and claw pattern were found in 18.18% and 9.09% of eyes, respectively. One year postoperatively, most eyes were classified as improved or having had significant changes (55% and 36%, respectively) (Fig), whereas 9% of eyes had only minor changes.

Representative corneal topography A) before and B) after topography-guided photorefractive keratectomy followed by same-day corneal collagen cross-linking. The procedure applied bilaterally achieved flattening of the cone with subsequent reduction of topographic astigmatism compared to baseline.

Figure. Representative corneal topography A) before and B) after topography-guided photorefractive keratectomy followed by same-day corneal collagen cross-linking. The procedure applied bilaterally achieved flattening of the cone with subsequent reduction of topographic astigmatism compared to baseline.

The Table shows the pre- and 1-year postoperative demographics with significant changes (P<.01) occurring in all demographics. Table A (available as supplemental material in the PDF version of this article) shows the correlation between changes in UDVA and preoperative demographics. Only preoperative sphere (R=0.679, P<.01) and spherical equivalent (R=−0.682, P>.01) were significant. Contrary to UDVA, there was no significant correlation (P>.01) between changes in CDVA and preoperative demographics as shown in Table B (available as supplemental material in the PDF version of this article).

Pre- and Postoperative Demographics of Patients Undergoing CXL and TG-PRK

Table: Pre- and Postoperative Demographics of Patients Undergoing CXL and TG-PRK

The procedure was safe and moderately efficient with safety and efficacy indices of 1.6 and 0.4, respectively. The patient satisfaction questionnaire showed that 91% of patients were satisfied, 9% were not completely sat-isfied but believed they had improved, and none were dissatisfied.

Discussion

A relatively new surgical treatment used to strengthen the corneal tissue and stabilize the progression of the ectatic cornea is CXL with riboflavin and UVA radiation.13–15 A procedure with CXL treatment alone is capable of corneal stabilization, but topography and visual outcome show only minimal improvement14 as a result of apical keratometry reduction and consequent corneal regularization.16

A combination of CXL with techniques that improve visual acuity may offer a comprehensive treatment for patients with corneal ectatic disorders. A simultaneous approach of PRK followed by CXL seems to be capable of offering functional vision in patients with keratoconus.11 Kymionis et al17 reported encouraging results in a case of pellucid marginal degeneration that had simultaneous customized PRK and CXL treatment as did Spadea.18

In 2007, Kanellopoulos and Binder19 published a study on CXL with sequential TG-PRK as an alternative to penetrating keratoplasty for keratoconus. Their study showed significant clinical improvement and apparent stability >1 year after CXL. However, there were two potential limitations to their approach. First, an important portion of the stiffened cross-linked corneal tissue was removed by the PRK (potentially decreasing the possible benefits of the CXL). Second, the corneal ablation rate could be different in cross-linked corneas than in the virgin cornea (leading to unpredictable refractive results).

In 2009, Kymionis et al11 published a study of simultaneous topography-guided treatment followed by CXL. Their results were promising in halting the progression of keratoconus and achieving clinical improvement. In the same year, Kanellopoulos20 published a study that compared sequential with “same-day” simultaneous CXL and TG-PRK and concluded that the same-day procedure was superior to the sequential procedure in the visual rehabilitation of progressing keratoconus.

In our study, simultaneous customized PRK and CXL with riboflavin and UVA irradiation was performed. The aim of this combination was to remodel the irregular cornea and decrease the irregular astigmatism to enhance the final visual and refractive outcomes.

Postoperatively, significant improvements were noted in UDVA and CDVA, as well as significant flattening of the keratometric values. Other outcome measures have also shown significant improvement. The correlation between improvement in UDVA and preoperative demographics has shown no significant correlation except for the amount of spherical equivalent in general and the spherical component in particular. On the contrary, all correlations regarding the change in CDVA were insignificant.

Patient satisfaction may correspond to the improvement in the pattern of corneal topography. Changes in topographic patterns of keratoconus were seen in all (100%) cases but with different degrees. According to our classification, a significant improvement was noted in 36% of cases and no patient worsened (see Fig).

We designed our study to be subjective as well as objective. Therefore, we constructed a questionnaire in our clinic to estimate patient satisfaction (available as supplemental material in the PDF version of this article). The questionnaire has shown that 91% of patients were satisfied, 9% were not completely satisfied but believed they improved, and none were dissatisfied. This also may correspond to the changes in the pattern of corneal topography.

Combining CXL with TG-PRK is a safe and effective surgical visual revalidation modality in keratoconus. Continued stability of the good visual outcome and lack of progression of corneal ectasia may make this combined therapy an effective alternative to other invasive techniques for the treatment of ectatic disorders of the cornea. Our study, however, has two limitations: 1) it is limited to low-grade keratoconus, and 2) lacks data regarding the potential progression after 1-year postoperatively. Further studies are needed.

References

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Table A: Correlation Between Change in Uncorrected Distance Visual Acuity and Preoperative Demographics in Eyes That Underwent CXL and TG-PRKParameterrPValueSphere−0.679.001Manifest astigmatism−0.153.51Spherical equivalent−0.682.00Flat K (K1)−0.017.94Steep K (K2)0.048.84Topographic astigmatism (K2-K1)0.107.64

Table B: Correlation Between Change in Corrected Distance Visual Acuity and Preoperative Demographics in Eyes That Underwent CXL and TG-PRKParameterrPValueSphere0.043.85Manifest astigmatism−0.334.13Spherical equivalent−0.088.70Flat K (K1)−0.008.97Steep K (K2)0.187.41Topographic astigmatism (K2-K1)0.376.09

Pre- and Postoperative Demographics of Patients Undergoing CXL and TG-PRK

Parameter Preoperative 1-year Postoperative PValue
UDVA (logMAR) 1.72±2.32 −0.01±0.072 <.0001
CDVA (logMAR) −0.025±0.077 −0.04±0.063 <.0001
Sphere (D) −2.31±1.58 −0.15±0.94 <.0001
Manifest astigmatism (D) −2.23±1.32 −0.35±0.42 <.0001
Spherical equivalent (D) −3.42±1.74 0.05±0.73 <.0001
Flat K (K1) (D) 43.94±1.65 41.89±1.64 .0027
Steep K (K2) (D) 46.15±1.74 43.15±1.55 <.0001
Topographic astigmatism (K2-K1) (D) 2.22±0.9 1.26±0.7 <.0001
Authors

From Elite Medical Center, Al Riyadh, Kingdom of Saudi Arabia.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Mazen M. Sinjab, MD, PhD, PO Box 167 AlTal, Damascus, Syria. Tel: 963 9 3344 9660; Fax: 963 1 144 71220 ext 2; E-mail: mazen.sinjab@yahoo.com

Received: October 14, 2011
Accepted: February 21, 2012
Posted Online: March 26, 2012

10.3928/1081597X-20120316-01

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