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ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-10025-1200 |
Corneal Collagen Cross-linking (CXL) Only vs CXL Combined with INTACS: 12-month Follow-up Data
1Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Leinster, Ireland
2–4Department of Ophthalmology, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
Corresponding Author: Brendan K Cummings, Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Leinster, Ireland, Phone: +011 872655254, e-mail: brendancummings.eyes@gmail.com
How to cite this article: Cummings BK, Kaur M, Zikry J, et al. Corneal Collagen Cross-linking (CXL) Only vs CXL Combined with INTACS: 12-month Follow-up Data. Int J Kerat Ect Cor Dis 2024;11(1):1–6.
Source of support: Nil
Conflict of interest: Dr Yaron Rabinowitz is associated as the Editorial Board member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this editorial board member and his research group.
Received on: 08 August 2023; Accepted on: 29 November 2023; Published on: 13 November 2024
ABSTRACT
Purpose: To present 1-year data comparing the efficacy of the combination of CXL and INTACS vs CXL only in the treatment of keratoconus.
Methods: The chart records of 25 eyes of 19 patients with keratoconus treated with CXL and INTACS between January 2011 and May 2013 were retrospectively reviewed. The outcomes of this combined procedure were compared with the outcomes of 143 eyes of 109 patients treated by CXL only. The following parameters were studied and outcomes were evaluated at 12 months postoperatively: uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), keratometry (Max K and Average K), and spherical equivalent.
Results: Uncorrected visual acuity at 12 months following CXL+INTACS was significantly better than CXL only, in terms of lines gained. Uncorrected vision in the CXL+INTACS group improved by 1.7 lines more than in the CXL only group (p = 0.024). While the CXL+INTACS group, on average, gained 0.08 lines more than the CXL only group at 12 months postoperatively, this difference was not statistically significant (p = 0.1). The maximum keratometric value was significantly reduced by both CXL only and CXL+INTACS; however, there was, on average, a 2.45D greater flattening of KMAX in the CXL+INTACS group when compared with the CXL only group (p = 0.00003).
Conclusion: Both groups (CXL only and CXL+INTACS) demonstrated significant improvements in UCVA, BSCVA, and keratometry. However, there were statistically significant greater improvements in UCVA lines gained, keratometry, and spherical equivalent in the CXL+INTACS group compared with the CXL only group.
Keywords: Athens protocol, Astigmatism, Collagen corneal cross-linking, Cornea, Cornea biomechanic, Cornea ectasia, Corneal collagen cross-linking, Intacs, Intrastromal corneal rings, Keratoconus.
INTRODUCTION
Keratoconus is a progressive ectasia of the cornea resulting from noninflammatory thinning of the corneal stroma.1 Over time, there may be a progressive loss of vision due to the irregular astigmatism and myopia induced from the progressive corneal thinning.2 In most instances vision is improved with rigid contact lenses but approximately 10–20% ultimately progress to the point where they need a corneal transplant.3,4 INTACS implantation has been demonstrated to improve vision and corneal collagen cross-linking (CXL) has been shown to slow the progression of the disease, as such both these treatments are good options prior to corneal transplantation in appropriately selected patients.5,6 The condition exerts a negative impact on quality of life, causing significant visual acuity reduction due to the progressive changes of the disease.7–10 Although not yet FDA approved in the United States, corneal CXL has gradually become a dependable treatment tool and first line of treatment for keratoconus in the rest of the world. Early reports on the effectiveness of CXL treatment was first reported in 2003, and the procedure has been shown to be effective in preventing progression of keratoconus in up to 70% of eyes.11,12
Implantation of intrastromal corneal ring segments (ICRSs) has been shown to improve visual acuity in patients with keratoconus.13 This improvement in visual acuity has been shown to be stable at 5 years in patients with stable keratoconus; however, ICRSs do not prevent progression and do not provide lasting benefits in visual acuity in patients with progressive KC.14 According to a prospective, comparative, randomized consecutive study by Coskunseven et al. implantation of ICRS followed by CXL results in greater improvement of keratoconus than CXL followed by ICRS.13
Logic would suggest, therefore, that the percentage of patients benefiting from stable improvements in visual acuity gained by the implantation of INTACS could be increased if keratoconus stabilizing CXL was also performed. In the same way, if INTACS are also performed on patients receiving CXL, those patients might benefit from an increase in visual acuity as well as a stabilization of their condition, preventing the need for a corneal transplant.
Due to its impact on patient quality of life, improvement in visual acuity could potentially be a primary goal in the treatment of keratoconic patients. Finding a treatment plan that provides the patient with stabilization or regression of keratoconus as well as improvement in visual acuity may be important to delivering optimum patient care. This paper compares outcomes, in terms of visual acuity, keratometric values, and refraction of CXL alone vs CXL combined with INTACS implantation at 12 months.
STUDY DESIGN AND PATIENT POPULATION
This cohort study included all patients who consecutively underwent a CXL or CXL+INTACS procedure for keratoconus at the Cornea Genetic Eye Institute in Los Angeles, California, United States of America, from January 2011 to May 2013.
Inclusion criteria for the CXL or CXL+INTACS treatment were documented keratometric progression of at least 1 diopter in the previous 6 to 12 months, a centrally clear corneal a minimal corneal thickness of 400 µm and at least 450 µm at the 7-mm optical zone prior to ultraviolet-A irradiation, a mesopic pupil size of <6.5 mm, no pregnancy or breastfeeding in the past 6 months, and no history of previous ocular disease or surgery. The following parameters were measured in all patients preoperatively and at 1 year postoperatively: refraction, uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), and keratometry (K) readings (max K and average K) (Table 1).
| Pre-op parameter | CXL only | CXL+INTACS |
|---|---|---|
| No. of patients | 143 | 25 |
| Male-to-female ratio | 21:10 | 19:6 |
| Age (y) | 32.5 ± 11.9 | 32.6 ± 14.5 |
| Sphere (D) | −1.39 ± 3.84 | −4.18 ± 2.34 |
| Cylinder (D) | −3.04 ± 1.85 | −3.49 ± 1.86 |
| SE (D) | −2.87 ± 3.94 | −5.70 ± 2.54 |
| UCVA (logMAR) | 0.84 ± 0.56 | 1.04 ± 0.53 |
| BSCVA (logMAR) | 0.27 ± 0.23 | 0.38 ± 0.29 |
| KMAX | 49.59 ± 5.27 | 53.04 ± 5.12 |
| KAVG | 46.95 ± 4.8 | 50.03 ± 4.83 |
The CXL and CXL+INTACS treatments were performed in accordance with the tenets of the Declaration of Helsinki and local laws regarding research using subjects.
To perform cross linking in the USA an IDE was obtained from the FDA for the Peschke Meditrade device below. The study was approved and monitored by the Western IRB.
PREOPERATIVE EVALUATION
Keratoconus was diagnosed or confirmed by Videokeratography (Tomey TMS 4, Tomey, Japan) and slit-lamp examination. Corneal thickness measurements were obtained by optical coherence tomography (OCT) using the Optovue device. Manifest and Snellen refractions were also carried out and documented. Patients were educated on their condition and an informed discussion between patient and doctor was performed before the patient decided on their treatment of choice.
METHODS
Procedure for Patients Undergoing CXL Only
The procedure performed is epithelium-off (epi-off) cross-linking and the procedure is as follows: Topical anesthesia of proparacaine HCL 0.5% was administered to the eye every 5 minutes for 3 doses immediately before the procedure. A central mark was placed over the epithelium with a felt tipped pen.
Epithelium Removal
The central 9 mm of the corneal epithelium is removed ensure that the riboflavin penetrates the stroma in order to achieve a high level of UVA absorption. This is achieved by one of two different methods:
Alcohol was applied for 45 seconds into a 9-mm ring placed on the cornea and then washed off; the central 9 mm of epithelium was then removed by a blunt spatula (87/143 eyes).
Using the VISX S4 excimer laser, the central 6.5 mm of the epithelium was ablated in the PTK mode to a depth of 50 µm; the peripheral epithelium out to 9 mm was then removed by a blunt spatula (56/143 eyes).
Riboflavin Administration
Riboflavin drops (0.1%) were then instilled onto the cornea every 2 minutes for 30 minutes until the riboflavin had saturated the corneal stroma. The patient’s corneal pachymetry was measured to ensure there was at least 400 µm of tissue present before UV-A irradiation (if the corneal pachymetry was <400 µm, hypoosmolar riboflavin drops were applied to swell the cornea to at least 400 µm prior to ultraviolet-A irradiation). The patients were examined at the slit lamp to ensure that riboflavin had saturated the corneal stroma and that there was a green flare in the anterior chamber before UV-A irradiation.
UV-A Irradiation
Pilocarpine was administered to cause pupillary miosis. The UV-X radiation system (UV-X; Peschke Meditrade, Switzerland) is calibrated. UV-A irradiation (UVA light of 370 nm wavelength) is applied at 3.0 mW/cm2 for 30 minutes, while the riboflavin administration is continued every 2 minutes.
After the CXL treatment, a topical antibiotic drop (Ciprofloxacin 0.3%) is instilled followed by placement of a bandage soft contact lens. The patient is given topical antibiotic, nonsteroidal anti-inflammatory [acular LS (ketorolac tromethamine, Allergan)], and frequent lubricating drops to use postoperatively. Oral analgesics are given as needed. Topical steroid drops (prednisolone acetate 1%) are started at postoperative day 5 and the bandage contact lens is removed when the epithelium is healed, usually by day 4–7. Postoperative examinations are done at day 1, week 1, and months 1, 3, 6, and 12, or as necessary in between, and then yearly.
PROCEDURE FOR PATIENTS UNDERGOING CXL+INTACS
Topical anesthesia of proparacaine HCL 0.5% was administered to the eye every 5 minutes for 3 doses immediately before the procedure.
Channel Creation – Femtosecond Laser (IntraLase) Assisted Technique
A drop of tetracaine was applied to the eye. The center of the pupil was marked using a felt tipped pen. The suction ring was lowered onto the cornea and centered on the point previously marked to show the preoperative position of the center of the pupil. The following laser settings were used on all patients who underwent data analysis: channel depth 400 pm, entry incision length 1.4 mm, entry incision width 1 mm, channel size inner diameter 6.6 mm, and outer diameter 7.4 mm.11 This effectively creates a 0.4 mm channel size, which is 0.05 mm larger than the size of the INTACS.
Epithelium Removal
The entry wound and channel creation takes 12 seconds. Once completed, the suction ring was removed and alcohol was applied for 45 seconds into a 9 mm ring placed on the cornea and then washed off; the central 9 mm of epithelium is then removed by a blunt spatula.
Riboflavin administration is followed by slit lamp examination and UV-A Irradiation as described above.
INTACS Insertion
The cornea is hydrated with a balanced saline solution and the entry wound is opened with a Sinskey hook (Medicon, Denmark). The channels are also inspected for patency by inserting the Sinskey hook into the channels. The Sinskey hook is then used to elevate the entry lip of the circular channel and the inferior INTACS segment is placed beneath the Sinskey hook and carefully pushed forward with the INTACS holder until the edge of the INTACS has been advanced to 1 mm from the entry wound. The incision entry is closed with a single 10-0 nylon suture placed at 100% corneal depth and sutured tight.
Immediately Post-op
After the procedure was completed a topical antibiotic drop (Ciprofloxacin 0.3%) was administered followed by application of a bandage soft contact. Postoperative topical medications given were prednisolone acetate 1% (Pred Forte; Alcon Laboratories, Ft Worth, Tex) every hour, ketorolac tromethamine 0.5% (Acular; Allergan, Irvine, Calif), and gatifloxin 0.3% (Zymar, Allergan) four times daily for the first day and tapered as necessary over 1 week.
RESULTS
UCVA
UCVA (LogMAR) at 12 months following CXL only improved from 0.84 ± 0.56 to 0.68 ± 0.46 at 12 months postoperatively. This was a significant improvement of 0.16 ± 0.58 on average (p = 0.001).
Lines of uncorrected vision improved by 1.1 ± 3.34 on average at 12 months post CXL only (p = 0.0001).
UCVA (LogMAR) at 12 months following CXL+INTACS improved from 1.04 ± 0.53 to 0.62 ± 0.42 at 12 months postoperatively. This was a significant improvement of 0.42 ± 0.51 on average (p = 0.0007).
Lines of vision improved by 2.8 ± 3.38 on average at 12 months post CXL+INTACS (p = 0.001).
UCVA (LogMAR) at 12 months following CXL+INTACS was significantly better than CXL only in terms of lines gained with uncorrected vision in the CXL+INTACS group gaining, on average, 1.7 lines more than the CXL only group (p = 0.024).
BSCVA
BSCVA (LogMAR) at 12 months following CXL only improved from 0.27 ± 0.23 to 0.19 ± 0.19 at 12 months postoperatively. This was a significant improvement of 0.08 ± 0.2 on average (p = 0.0015).
Lines of best corrected vision improved by 0.9 ± 1.95 on average at 12 months post CXL only (p = 0.0007).
BSCVA (LogMAR) at 12 months following CXL+INTACS improved from 0.38 ± 0.29 to 0.22 ± 0.18 at 12 months postoperatively. This was a significant improvement of 0.16 ± 0.3 on average (p = 0.02).
Lines of vision improved by 1.7 ± 3.09 on average at 12 months post CXL+INTACS (p = 0.016).
While the CXL+INTACS group, on average, gained 0.08 lines more than the CXL alone group at 12 months postoperatively, this difference was not significant (p = 0.1).
K Max (KMAX)
KMAX at 12 months following CXL only improved from 49.59D ± 5.27 to 48.43D ± 4.77 at 12 months postoperatively. This was a significant improvement of 1.16D ± 2.91 on average (p = 0.0001).
KMAX at 12 months following CXL+INTACS improved from 53.04D ± 5.12 to 49.43D ± 4.98 at 12 months postoperatively. This was a significant improvement of 3.61D ± 1.8 on average (p = 0.00000001).
The maximum keratometric value was reduced significantly by both CXL only and CXL+INTACS, however, there was, on average a 2.45D greater flattening of KMAX in the CXL+INTACS group when compared with the CXL only group (p = 0.00003).
K Average (KAVG)
KAVG at 12 months following CXL only improved from 46.95D ± 4.8 to 46.05D ± 4.15 at 12 months postoperatively. This was a significant improvement of 0.9D ± 5.46 on average (p = 0.001).
KAVG at 12 months following CXL+INTACS improved from 50.03D ± 4.85 to 46.92D ± 4.35 at 12 months postoperatively. This was a significant improvement of 3.11D ± 1.71 on average (p = 0.00000001).
The average keratometric value was reduced significantly by both CXL alone and CXL+INTACS, however, there was, on average a, significant 2.21D greater flattening of KAVG in the CXL+INTACS group when compared with the CXL only group (p = 0.00003).
Sphere
Sphere at 12 months following CXL only improved from −1.39D ± 3.84 to −0.93D ± 3.41 at 12 months postoperatively. This was a significant improvement of 0.46D ± 2.75 on average (p = 0.0072).
Sphere at 12 months following CXL+INTACS improved from −4.18D ± 2.34 to −1.38D ± 3.99 at 12 months postoperatively. This was a significant improvement of 2.8D ± 3.47 on average (p = 0.00062).
While the spherical measurements of both groups improved significantly at 12 months postoperatively, patients in the CXL+INTACS group improved, on average by 2.34D more than those who had CXL only. This difference is significant (p = 0.0003).
Cylinder
Cylinder at 12 months following CXL only improved from −3.04DC ± 1.85 to −2.92DC ± 1.86 at 12 months postoperatively. This was an insignificant improvement of 0.12DC ± 2.13 on average (p = 0.34).
Cylinder at 12 months following CXL+INTACS improved from −3.49DC ± 1.86 to −2.94DC ± 1.68 at 12 months postoperatively. This was an insignificant improvement of 0.55DC ± 2.45 on average (p = 0.61).
While the cylindrical measurements of neither group improved significantly at 12 months postoperatively, patients in the CXL+INTACS group improved, on average by 0.43DC more than those who had CXL only. This difference is not significant (p = 0.96).
Spherical Equivalent
Spherical equivalent at 12 months following CXL only improved from −2.87D ± 3.94 to −2.24D ± 3.45 at 12 months postoperatively. This was a significant improvement of 0.63D ± 3.17 on average (p = 0.008).
Spherical equivalent at 12 months following CXL+INTACS improved from −5.7D ± 2.54 to −2.71D ± 3.7 at 12 months postoperatively. This was a significant improvement of 2.99D ± 3.41 on average (p = 0.00046).
While the spherical equivalent measurements of both groups improved significantly at 12 months postoperatively, patients in the CXL+INTACS group improved, on average by 2.36D more than those who had CXL only. This difference is significant (p = 0.0017).
DISCUSSION
The CXL+INTACS produced a greater flattening of the keratoconic cornea than CXL only. This manifest as a significantly higher number of uncorrected lines gained at 12 months postoperatively.
The analysis of the effect of CXL only and CXL+INTACS on KMAX at 12 months with reference to Pre-op KMAX yielded some interesting findings, with the greatest improvement in KMAX occurring in patients with a KMAX ≥ 58 D. While logic suggests that the higher the KMAX, the more room there is for improvement, Koller et al. suggest that a cut-off of 58 D be used when evaluating patients for CXL.15 Our findings would suggest that, perhaps, this cut-off point may in fact be higher. At 12 months postoperatively, a significant difference in change in UCVA was shown between patients treated with CXL only vs patients treated with CXL+INTACS; however, there was not a significant difference in change in BSCVA at 12 months between the two groups. The goal treatment for a patient with keratoconus is to attempt to avoid the need for corneal transplant, and to rehabilitate the patient and even though >95% of patients who underwent CXL+INTACS will require spectacles or corrective contact lenses postoperatively, those glasses will be lighter for patients in the CXL+INTACS group, and because of the significant flattening of the cornea, patients in this group should also experience more comfortable and tolerable contact lens wear. Combining INTACS insertion with CXL does not, in most cases, leave the patient glasses free. It does, however, in theory, allow patients to use lighter, cheaper glasses, and allow them to achieve optimum refraction using more comfortable and tolerable contact lenses.
It is important to weight up these advantages of CXL+INTACS over CXL only with the increased risk for complications with the addition of INTACS to the treatment plan. Although none of the patients in the CXL+INTACS group included in this study suffered post-operative complications (those that did were excluded due to them having additional ophthalmic interventions postoperatively), the complications of INTACS are typically more severe and include extrusion, placement into the anterior chamber, infection, and inflammation. Of the patients 27 who underwent CXL+INTACS and were accessible for this study, 2 had to be excluded (1 for INTACS removal, 1 for INTACS repositioning).
AUTHOR CONTRIBUTION
Conception and design (YSR); data collection (JZ, MK, BKC); analysis and interpretation of data (BKC); writing the manuscript (BKC, YSR); critical revision of the manuscript (YSR) (Figs 1 to 5).
Fig. 1: CXL only: K values at pre-op and 12 months demonstrating a flattening of ≈ 1 diopter
Fig. 2: CXL+INTACS: K values at pre-op and 12 months demonstrating a flattening of ≈ 4 diopters
Fig. 3: Chance of gaining, losing, or having no change in lines at 12 months vs pre-op
Fig. 4: Chances of regression, stabilization or progression of keratoconus at 12 months postoperatively
Fig. 5: Effect of CXL only and CXL+INTACS on KMAX at 12 months with reference to pre-op KMAX
ORCID
Brendan K Cummings https://orcid.org/0009-0000-6367-2195
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