Ординатура / Офтальмология / Английские материалы / Mastering Corneal Collagen Cross-linking Techniques (C3-R CCL CxL)_Garg, Kanellopoulos, O'Brart, Lovisolo, Pinelli_2008

MINIMAL CORNEAL THICKNESS

Special emphasis must be taken to ensure minimal corneal thickness preoperatively because of potential cytotoxic effects of UVA on corneal endothelial cells. Previous experimental studies in rabbit corneas have investigated dose-dependent cytotoxicity to the corneal endothelium.

surface irradiance according to the protocol described herein, may not be used in corneas thinner than 350 μm. This mimimal thickness should also be respected in human corneas. The laser treatment must

be applied with caution because more rigid corneas may have a different ablation depth-per-pulse than the untreated one. Indeed, it appears to result in overcorrections when these corneas are treated with excimer laser versus a normal PRK or LASIK procedure. For this reason, our recommendation is to use 7580% of the measured sphere and cylinder as a correction parameter when planning the ablation with T-CAT software. Larger comparative studies and longer followup is necessary in order to validate the long-term

efficacy of this combined treatment with UV/riboflavin 7 5

followed by topography-guided excimer laser treatment.10 The refractive and topographic stability of more than 3 years, however, appears to validate this minimally invasive treatment of iatrogenic keratectasia and leads us to believe that it may have an even wider application in the near future. We have utilized this modality in idiopathic keratoconus cases as well with similar results.11 As a cornea surgeon I do feel that UVA CCL may be the single most important introduction in cornea surgery and keratoconus and cornea ectasias in general over the last 25 years.

If our initial clinical experience holds true I the future follow up it may be able to significantly minimize the necessity for cornea transplantation in ectatic cornea disorders.

Can LASIK “ regressions” be a form of ectasia? I would like to present another case to you:

Six years ago, a 34-year-old female underwent LASIK for -11.00 D of myopia (Figs 13.3A to 3C). During the procedure a Moria M2 (Moria; Antony, France) microkeratome was used to create a 125-μm flap (calculated with subtraction pachymetry) and an Allegretto 200 Hz laser (Wavelight; Erlangen, Germany), with a planned 6-μm optical zone, was used to conserve tissue. Total treatment centrally was planned to 130 μm. The residual cornea bed measured 320 μm. For 5 years after the surgery, the patient was satisfied, and plano, with 20/20 visual acuity. The patient now presents 20/40 UCVA and 20/20 BSCVA, with eyes measuring -1.50 D and -0.75 D. No ectasia is evident on the topography and Oculus Pentacam (Oculus Optikgerate GmbH, Wetzlar, Germany).

The patient’s preoperative measurements: Central cornea thickness is approximately 460 μm.

I have relatively extensive experience in cases like this, as I have seen many patients treated for high myopia in the past. None of my cases have developed any corneal I have seen this type of LASIK regression many times in the past and have addressed the problem several different ways. In some cases, I have re-lifted the flap to do an additional enhancement, after measuring the flap thickness intraoperatively in order to avoid significantly reducing the postenhancement residual stromal bed. (Since 2000, I have tried to adhere to the guideline of 270 μm for residual stroma following LASIK). Another potential method of treatment for this patient would be to perform a

7 6 customized retreatment with asphericity adjustment

as an additive (Wavelight 400 Hz Allegretto Wave Eye- Q laser; Wavelight Laser Technologie AG, Erlangen, Germany). I would include a treatmentgoal of -0.50 D for the Q value (asphericity), in ordertoreduce spherical aberrations that are typically induced during the correction of high myopes. The hope is that the post-enhancement Q value would be less positive. Through past experience, we have learned that correction of -10.00 D shifts the 30o asphericity of the cornea from an average -0.30 D to ± 2, therefore inducing significant spherical aberrations. In the case of this patient, I chose not to use either of the previously mentioned options. Considering that the cornea was stable, I pulled from my experience with UVA collagen cross-linking as a means to rehabilitate ectatic corneas after LASIK. I proposed that the patient was experiencing a late biomechanical shift of the thinned cornea. The patient and I discussed the option of crosslinking the cornea and then enhancement, if necessary. I determined that performing an enhancement first may not be successful if the refraction continued to regress in the future. We therefore decided to proceed with collagen cross-linking with the PriaVision device (PriaVision, Menlo Park, California) for 30 minutes in conjunction with 1% riboflavin solution applied every 2 minutes to the surface of the deepithelialized cornea. Initially the patient was unsatisfied and experienced pain and discomfort for the first 10 days while the epithelium healed. That changed at 1-month followup, however, when we discovered her UCVA was back to 20/20 and her refractive error was -0.25 D. In the end, our patient achieved a VA of 20/15. I would therefore use this case to confirm previous reports on the biomechanical changes of the cornea following LASIK, and establish a significant biomechanical effect of the UVA cornea cross-linking to the operated cornea—with a change in the posterior cornea contour centrally and paracentrally (Figure 13.3C). This is a comparison map of the posterior cornea surface by the Wavelight Oculyzer (Pentacam). The first map on the left is the pre-UVA CCL posterior cornea surface devoid of any signs of ectasia. The middle map is the same posterior surface one month following UVA CCL. It is evident that there has been been a flattening change, more evident in the difference map on the right, The mid-periphery of the posterior cornea shows a “flattening” effect confirming the biomechanical change in this cornea following the collagen cross-

linking. This effect appears to have corrected the late regression of -1 Diopter.

I believe this case shows that any surprise regressions noted—even years—after LASIK could be biomechanical changes of the cornea, and could be treated by this minimally invasive alternative.

Figure 13.4 decribe a similar case: These are Pentacam comparison maps of a 27 y/o female that underwent LASIK for -10 OU 5 years ago

She had an enhancement fro -1.00 OU 3 years ago and deteriorated again to -1.5D

Instead of enhancement she underwent UVA CCL and the refraction regression reversed to plano. The pentacam comparison of pre and post UVA CCL for the sagittal curvature front (Fig. 13.4A) and posterior cornea elevation (Fig. 13.4B) shows the biomechanical change of cross-linking that produced the regression reversal.

Figure 13.4A

Figure 13.4B

Figures 13.4A and B: These are Pentacam comparison maps of a 27 y/o female that underwent LASIK for -10 OU 5 years ago. She had an enhancement fro -1.00 OU 3 years ago and deteriorated again to -1.5D Instead of enhancement she underwent UVA CCL and the refraction regression reversed to plano. The pentacam comparison of pre and post UVA CCL for the sagittal curvature front (Figure 13.4a) and posterior cornea elevation (Figure 13.4b) shows the biomechanical change of cross-linking that produced the regression reversal

7 9

REFERENCES

1.Binder, PS. Ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2003;29:2419-29.

2.Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK.Ophthalmology 2003;110(2):267-75.

3.Klein SR, Epstein RJ, Randleman JB, Stulting RD. Corneal ectasia after laser in situ keratomileusis in patients without apparent preoperative risk factors. Cornea 2006;25(4):388-403.

4.Kanellopoulos A, PeL Perry H, Donnenfeld E. Modified Intracorneal Ring Segment Implantations (Intacs) for the Management of Moderate to Advanced Keratoconus: efficacy and Complications. Cornea 2006;25:29-33.

5.Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet -a- induced collagen cross-linking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-27.

6.Seiler, T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea 2006;25:1057-59.

7.Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998;66:97-103.

8.Hafezi F, Mrochen M, Jankov M, Hopeler T, Wiltfang R, Kanellopoulos A, Seiler T. Corneal collagen cross-linking with riboflavin/UVA for the treatment of induced kerectasia after laser in situ keratomileusis 2007.

9.Kanellopoulos A. Management of post-LASIK ectasia with UVA collagen cross-linking followed by customized topography-guided PRK - an efficient approach to avoid corneal transplantation. Letter-to-the-editor in press Ophthalmology 2007.

10.Kanellopoulos AJ. Topography-guided Custom retreatments in 27 symptomatic eyes. J Refract Surg 2005;21:S513-18.

11.Kanellopoulos AJ, Pe L. Wavefront-guided Enhancements using the Wavelight Excimer Laser in Symptomatic Eyes Previously Treated with LASIK. J Refract Surg 2006;22:34549.

12.Kanellopoulos AJ, Binder PS. Collagen cross-linking (CCL) with Sequential topography-guided PRK. A temporizing alternative to penetrating keratoplasty. J of Cornea –in press

INTRODUCTION

The major causes of irregular astigmatism are corneal stromal degenerations (such as keratoconus and pellucid marginal degeneration) and post laser assisted in situ keratomileusis (Lasik) corneal ectasia. Keratoconus and pellucid marginal degeneration are bilateral, non-inflammatory diseases characterized by progressive corneal thinning and steepening, whereas ectasia is a serious postoperative late complication after refractive surgery.1,2

The treatment consists of spectacles, rigid contact lenses, intrastromal corneal ring segments (ICRS),3-29 corneal collagen cross-linking (CCL) with Riboflavin and Ultraviolet-A (UV-A)30-41 and when these treatment options are no longer effective, penetrating keratoplasty (PK).42 Expectations are limited, and consequences may be unpredictable, anatomically and functionally.1

INTRACORNEAL RING SEGMENTS’ AND IRREGULAR ASTIGMATISM

Intracorneal Ring Segments’ (Intacs, Addition Technology, Fremont, California, USA) are originally designed to correct low myopia.4 Refractive adjustment is achieved by flattening the central corneal curvature while maintaining clarity in the central optical zone. It is a removable and tissue-saving technique. Several studies have demonstrated the efficacy and the reversibility of ICRS in correcting myopia,4-6 but further reports revealed that ICRS are also suitable for keratoconic or post Lasik ectatic eyes since they increase corneal topographic regularity and patients’ uncorrected visual acuity (UCVA).

There are different types of ICRS, depending on their curvature, width, and zone of implantation all of them made of arc-like polymethyl methacrylate (PMMA). Intacs inserts have a crescent-shaped arc length of 150 degrees. Their inner diameter is 6.8 mm and the outer diameter is 8.1 mm, with a thickness which ranges from 0.25 to 0.45 mm in 0.05 increments. Last generation Intacs SK have an arc length of 150’, a width of 1.3 mm and are packaged in two thicknesses: 0.40 and 0.45 mm. The segment profile has an elliptical, edgeless shape providing a diffractive design to achieve reduced halo, glare and

8 2 increased quality of vision at the 6.0 mm optical zone.

KeraRings (Mediphacos, Belo Horizonte, Brazil) are newly developed segments that are characterized by a triangular cross-section that induces a prismatic effect on the cornea. Their apical diameter is 5 mm and the flat basis width is 0.6 mm with variable thickness (0.15to 0.30-mm with 0.5-mm steps) and arc lengths (90 degrees, 160 degrees, and 210 degrees). The optical zone provided by KeraRing segments is 5.0 mm in diameter.

Tunnel creation for segment implantation can be made manually using mechanical devices. This step of the procedure correlated with a number of possible complications such as epithelial defects, perforation, infectious keratitis, shallow or uneven or asymmetric segment placement, corneal stromal edema around the incision, extension of the incision toward the central visual axis or the limbus, and persistent incisional gaping.16-18 Alternatively, channel creation can be carried out with a femtosecond laser because it can deliver energy accurately to a precise depth in a programmed way making the procedure for many surgeons much safer, quicker and simplier.19-23

Clinical Outcomes

Colin et al24 in 2001 reported their one year followup after Intacs implantation in 10 patients with keratoconus. Spherical equivalent error and refractive astigmatism were reduced. At one year follow-up, uncorrected visual acuity (UCVA; approximately 20/ 50) was significantly better than pre-operative best spectacle corrected visual acuity (BSCVA approximately 20/200). Average BSCVA was improved by approximately two lines compared with baseline measurements. Topographic corneal shape was improved for all subjects.

In 2003, Siganos et al3 presented a prospective study of 33 keratoconic eyes treated with Intacs (mean follow-up 11.3 months). The mean UCVA and BSCVA improved significantly. Of 33 eyes, four eyes loss 1 to 2 lines of BSCVA, whereas 25 eyes experienced 1 to 6-line gain. Segments’ removed from 4 eyes and one eye underwent successful PKP.

In 2005, Hellstedt et al25 assessed the outcomes of 50 keratoconic eyes treated with Intacs. Both UCVA and BSCVA improved throughout follow-up. Visual functioning index improved from 61.6 ± 21.1 to 80.8

± 22.5. The mean change in corneal astigmatism was 2.9 ± 2.9 D at 6 months follow-up.

Alio et al26 presented in 2005 a prospective study of 26 keratoconic eyes divided in two groups based on their topographic findings. At one year, spherical equivalent error, mean keratometric values and refractive astigmatism were reduced significantly in both groups. In group 1, the mean UCVA improved from 20/100 to 20/32, whereas the mean BSCVA improved from 20/50 to 20/32. In group 2, the mean UCVA improved from 20/400 to 20/63, whereas the mean BSCVA improved from 20/50 to 20/32.

The European study11 published in 2006 documented a prospective study of Intacs for the management of keratoconus in 57 eyes. At 6-month evaluation, 78% of patients showed improvement of two lines or more in UCVA (p < 0.001). BSVCA of 20/ 40 or better improved from 53% of patients preoperatively to 74% of patients (p < 0.033). Manifest refraction spherical equivalent improved to 3.1 ± 2.5 D (p < 0.001) compared with the preoperative examination. Keratometry decreased a mean of -4.3 ± 2.8 D from the preoperative readings (p < 0.002).

Kymionis et al9 reported a long term retrospective series of 17 keratoconic eyes treated with Intacs. After 5 years spherical equivalent error was statistically significant reduced compared with the preoperative measurements, while UCVA, BSCVA improved in most patients.

In 2006, Ertan et al22 presented the outcomes of Intacs implantation using the femptosecond laser in a retrospective study of 118 eyes with keratoconus. At the end of the first postoperative year, 81.3% of eyes had improved UCVA and 73.7% had improved BSCVA. The mean keratometry decreased from 51.56 to 47.66 D and the mean spherical equivalent decreased from -7.57 to 3.72 D.

Rabinowitz et al12 pulished in 2006 a comparative study of Intacs insertion in keratoconic eyes using femptosecond laser or a mechanical spreader for tunnel creation. Both groups demonstrated significant reduction in average keratometry, spherical equivalent, refraction, UCVA, BSCVA, surface irregularity index and surface asymmetry index. Differences between groups were not statistical significant.

Kymionis et al15 reported in 2006 the long term follow-up (5 years) of Intacs for the management of post Lasik corneal ectasia in a retrospective study. At 5 years, the spherical equivalent error was reduced with

statistical significance. Pre-Intacs UCVA was 20/100 or worse in all eyes, whereas, at the last follow-up examination, six out of eight eyes had UCVA 20/40 or better. Two eyes (25%) maintained the pre-Intacs BSCVA, while the rest experienced a gain of one or two lines.

Alio et al,29 presented a prospective noncomparative case series to evaluate the potential of using Intacs to correct posterior ectasia LASIK. All cases showed marked improvement after segment implantation. Postoperatively, there was a reduction in the magnitude of the posterior and anterior corneal surface steepening, an increase in the topographical regularity index and a significantly enlargement of the optical zone.

In 2005, Mularoni et al28 evaluated the use of Intacs for the treatment of pellucid marginal degeneration in eight patients. At 12-month follow-up UCVA improved in all eyes and six eyes (75%) had a BSCVA of at least 20/25.

CORNEAL COLLAGEN CROSS-LINKING AND IRREGULAR ASTIGMATISM

The original idea was conceived at Dresden Technical University in the 1990s.31 The basic observation was the fact that young patients with diabetes almost never have keratoconus, because of the natural cross-linking effect of glucose, which increases corneal resistance in this patients.32-34 The clinical indications for collagen cross-linking are melting processes of the cornea and corneal thinning disorders such as keratoconus, pellucid marginal degeneration, and iatrogenic keratectasia after Lasik.

The technique of corneal collagen cross-linking consists in the photopolymerization of the stromal fibers by the radical formation effect of a photosensitizing substance (riboflavin) and UV light from a solid-state UVA source.31 Histopathological ex vivo studies revealed an increase in the diameter of the collagen fibers to a depth of 300 μm, greater resistance to enzyme breakdown (anticollagenase effect), apoptosis of keratocytes in the anterior and intermediate stroma and gradual repopulation by deep keratocytes.35

The formation of chemical bonds between the collagen fibrils accompanied by increasing collagen fibers diameter induces the biomechanical stability of 8 3

corneal collagen.36 Wollensak et al reported an increase of 328.9% in corneal rigidity in human corneas after cross-linking. The stiffening of the corneal collagen flattens the corneal apex which produces a total eye dioptric power reduction. This phenomenon can partially explain the improvement in patients’ uncorrected visual acuity. Changes in the best spectacle-corrected visual acuity are mainly related to the improvement in corneal symmetry demonstrated overall by the early coma reduction in the anterior corneal surface.

The main complication after corneal cross-linking is endothelial cell damage.37 Additionally there have been published cases of DLK38 in post CCL patient with ketatectasia after Lasik and herpetic keratitis with

Given the fact that collagen turnover is 2 to 3 years, more long term studies are essential to determine whether corneal cross-linking with riboflavin and UV- A have a long standing or a transient clinical effect.

INTACS COMBINED WITH CORNEAL COLLAGEN CROSS-LINKING AND IRREGULAR ASTIGMATISM

Intracorneal Ring Segments’ implantation and Corneal Collagen Cross-linking with Riboflavin and Ultraviolet- A as we described are minimally invasive techniques for the treatment of irregular astigmatism. Since ICRS insertion re-shapes the cornea and CCL inhibits or slows the progression of irregular astigmatism, a logical solution would be to combine the two treatment methods in order to synergize their effect (Fig. 14.1).

Chan et al29 studied the combination of Intacs with corneal collagen cross-linking with Riboflavin (C3-R) in 2007, in a retrospective, nonrandomized, comparative cases series comprising of 12 eyes of nine patients who had inferior segment Intacs placement without C3-R (Intacs only group) and 13 eyes of 12 patients who had inferior segment Intacs implantation and afterwards C3-R (Intacs with C3-R group). Intacs with C3-R had a significantly greater reduction in cylinder than the Intacs-only group (p < 0.05). Steep

Figure 14.1: Kerrarings implantation followed by UV-X in a keratoconic eye