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

INTRODUCTION

Keratoconus remains a common indication for corneal transplantation surgery.1 Ectasia usually develops during adolescence and progresses slowly thereafter, with a minority of affected patients requiring corneal transplantation.2,3 The popularity of keratorefractive surgery and technological advances have contributed to an increased awareness of sub-clinical or forme fruste keratoconus.

The fear of inducing, or of worsening pre-existing corneal ectasia by performing keratorefractive surgery has hastened our search for better diagnostic tools which detect subtle corneal abnormalities indicative of early ectasia. However, the diagnosis of forme fruste keratoconus remains particular difficulty. Corneal topography has become mandatory for all patients contemplating refractive surgery but in spite of improved software programmes it has not yet been perfected. A number of guidelines exist to help detect topographical evidence of ectasia but these alone are often insufficient to allow a definitive diagnosis to be made. Aberrometry records the higher order aberrations of the eye and has been found to have a role in the detection of corneal ectasia.4-7 More specifically vertical coma is increased in both early (Figures 4.1A and B) and advanced (Figures 4.2A and B) ectasia.8,9 However, increased vertical coma in the presence of normal topography and low clinical suspicion is not diagnostic of ectasia and this finding should only be considered in addition to other factors and not as an isolated finding. More recently, new technology has been developed which records corneal hysteresis, a reflection of the corneal viscoelastic properties and is thought to provide an indication of its biomechanical integrity.10 The Reichert Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo NY, USA) can be used clinically to measure corneal hysteresis (CH) in addition to the corneal resistance factor (CRF) which reflects the overall resistance of the cornea. Kirwan et al examined both CH and CRF in normal eyes and eyes with forme fruste and advanced keratoconus.11 Both parameters were found to be significantly lower in eyes with advanced keratoconus compared with normal and forme fruste keratoconus (FFKC) eyes, while no

1 6 difference was found between the latter two groups

when pachymetry matched. Due to significant overlap in both CH and CRF across all 3 groups, they concluded that this instrument was not useful as a single test in the detection of early ectasia.

Laser in situ keratomileusis (LASIK) has been performed on more than 17 million people worldwide, but a dramatic increase in the reported incidence of keratoconus has not occurred.12 Binder reported 85 eyes with post LASIK ectasia.13 Faraj et al reported that 78% of patients with post LASIK have pre-existing forme fruste keratoconus, a preoperative central corneal thickness <500 µm or underwent treatment for high myopia with a residual stromal bed <250 µm.14 More recently Randleman et al15 established risk factors for the development of post LASIK ectasia which included those high-lighted by Faraj et al in addition to topographical abnormalities and young age at surgery. Other factors such as a history of eye rubbing, unstable refraction, a family history of ectatic eye disease and increased elasticity may also be predictive factors.

Current practice involves performing corneal topography and aberrometry on all patients undergo LASIK or laser epithelial keratomileusis (LASEK). There is also a universal practise adopted by many ophthalmologists where a flap is not cut when the preoperative corneal thickness is <500μm. In many cases of post LASIK ectasia no apparent risk factors are evident. The question must be asked if the keratorefractive surgery was responsible for inducing the ectasia or if its development was inevitable whether or not the surgery had been performed. Wang et al reported a case of bilateral ectasia after unilateral LASIK in which ectasia appeared 20 months post operatively following a small amount of tissue removed in the LASIK eye. This was followed sometime later by the development of ectasia in the unoperated eye.16

A number of patients re-present some years following refractive surgery following redevelopment of myopia. In many, this is due to regression or myopic progression but myopic due to the development of keratoconus may also be the underlying cause. As mentioned above, in some patients analysis of the pre operative topography may show subtle signs of forme fruste keratoconus but in some the original topography is deemed to be entirely normal. Other factors must then be considered such as creation of an excessively

thick flap at the time of surgery thus resulting in an excessively thin residual stromal bed. Greater reliability of newer keratomes and performance of intraoperative pachymetry should help avoid this problem. The development of anterior segment ocular coherence tomography (OCT), has made it possible to measure the thickness of the original flap and indeed the residual stromal bed in cases of post LASIK ectasia. In cases where these are found to be within acceptable limits, and in the absence of topographical abnormalities, it is likely that the keratorefractive surgery did not induce the ectasia and that the development of ectasia was inevitable. This serves to reinforce the fact that the pathogenesis of this keratoconus remains poorly understood. There are a number of morphological and functional differences between normal and keratoconic eyes and the paucity of cross-linking between collagen molecules is now the basis for crosslinking using riboflavin.17

The emphasis on diagnosis and treatment of keratoconus has gained huge momentum in recent times. Clearly in some cases with established disease corneal topography and aberrometry are diagnostic. It is that cohort of patients where suspicion of early form fruste disease arises, particularly those who wish to undergo refractive surgery that pose the main clinical dilemma. Undoubtedly the development of post LASIK ectasia is a serious matter and has medico-legal implications. It is clear that better diagnostic software that removes the uncertainty of diagnosis is required. Currently available topography machines, aberrometors and the ocular response analyzer while useful, still fall short of what is needed. Apart from this, certain criteria regarding patient selection and treatment should be adhered to in order to minimize risk. In particular large treatments in corneas with 500µ thickness should be avoided. There should be a move to cutting thin flaps and if there is any doubts particularly in patients with mild to moderate myopia LASEK should be the treatment of choice. Many surgeons perform intra-operative pachymetry and this is to be encouraged. A few of the newer technologies allow for the creation of flaps as thin as 80µm but as yet have no hard data on the efficacy of such flaps.

Cross-linking is a new and innovative treatment for corneal ectasia.18 It could be a major advance if it

halts the progression of keratoconus and avoids or delays the need for corneal transplantation surgery. However, long-term data on the efficacy of crosslinking is required. Ng et al (personal communication), have applied cross-linking to the corneas of a number of patients with keratoconus and subsequently performed LASEK on these eyes. They report initial success and if this is the case it may be a new and exciting long-term innovative treatment. Forme fruste keratoconus and post LASIK ectasia strike fear in many refractive surgeons and the possible emergence of better diagnostic software and a possible non-invasive medical treatment would be a welcome new development.

REFERENCES

1.Kang PC, Klintworth GK, Kim T, Carlson AN, Adelman R, Stinnett S, Afshari NA. Trands in the indications for penetrating keratoplasty, 1980-2001. Cornea 2005;24:801-03.

2.Tuft SJ, Moodaley LC, Gregory WM, Davison CR, Buckley RJ. Prognostic factors for the progression of keratoconus. Ophthalmology 1994;101:439-47.

3.Kennedy RH, Bourne WM, Dyer JA. A 48-year clinical and epidemiologic study of keratoconus. Am J Ophthalmol 1986;101:267-73.

4.Holland DR, Maeda N, Hannush SB, Riveroll LH, Green MT, Klyce SD, Wilson SE. Unilateral keratoconus. Incidence and quantitative topographic analysis. Ophthalmology 1997;104:1409-13.

5.Rao SN, Raviv T, Majmudar PA, Epstein RJ. Role of Orbscan 2 in screening keratoconus suspects before refractive corneal surgery. Ophthalmology 2002;109:1642-46.

6.Auffarth GU, Wang L, Volcker HE. Keratoconus evaluation using orbscan Topography System. J Cataract Refract Surg 2000;26:222-28.

7.Maguire LJ, Bourne WM. Corneal topography of early keratoconus. Am J Ophthalmol 1989;108:746-48.

8.Maeda N, Fujikado T, Kuroda T, Mihashi T, Hirohara Y, Nishida K, Watanabe H, Tano Y. Wavefront aberrations measured with Hartmann-Shack sensor in patients with keratoconus. Ophthalmology 2002;109:1996-2003.

9.Alio JL, Shabayek MH. Corneal higher order aberrations: A method to grade keratoconus. J Refract Surg 2006;22:539-45.

10.Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005;31:156-62.

11.Kirwan C, O’Malley D, O’Keefe M. Corneal hysteresis and corneal resistance factor in Keratoectasia: Findings using the Reichert Ocular Response Analyzer. Ophthalmologica

12.Condon PI. Will Keratectasia be a major complication for LASIK in the long-term? J Cataract Refract Surg 2006;32:2124-32.

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

14.Faraj HG, Gatinel D, Chastang PJ, Hoang-Xuan T. Corneal ectasia after LASIK. J Cataract Refract Surg 2003;29:220.

15.Randleman J, Woodward M, Lynn M, Stulting RD. Risk assessment for ectasia after corneal refractive surgery. Ophthalmology 2008;115:37-50.

16.Wang JC, Hufnagel TJ, Buxton DF. Bilateral keratectasia after unilateral laser in situ keratomileusis: A retrospective diagnosis of ectatic corneal disorder. J Cataract Refract Surg 2003;29:2015-18.

17.Wollensak J, Buddecke E. Biochemical Studies on human corneal proteoglycans – A comparison of normal and keratoconic eye. Graefes Arch Clin Exp Ophthalmol 1990;228:517-23.

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

POST-LASIK CORNEAL ECTASIA

Corneal ectasia remains one of the most insidious complications after laser in situ keratomileusis (LASIK). Ectasia of the cornea is a progressive anterior shift of the cornea that is associated with central steepening and thinning, myopic shift, astigmatic changes and visual symptoms. Ectasia after LASIK is visionthreatening and is one of the most difficult complications to manage, requiring a penetrating keratoplasty in severe cases. Reported incidence of post-LASIK ectasia ranges from 0.12 to 0.66%.

RISK FACTORS

Currently recognized risk factors for the development of post-LASIK ectasia include high myopia, low residual stromal bed from excessive ablation or thick flap creation and preoperative topographic abnormalities, including forme fruste keratoconus and pellucid marginal corneal degeneration. Ectasia can also rarely occur in patients without identifiable risk factors.

The current literature does not define a specific residual corneal thickness that would place an eye at risk for ectasia. By comparing the biomechanical properties of keratoconic corneas with normal corneas Andreassen et al. estimate that for the normal cornea, a residual stromal bed thickness less than 250 µm might produce a cornea with a tangential elastic modulus comparable to that of a keratoconic cornea. Barraquer suggests a 300 µm thickness of stress-bearing cornea. He also advised against lamellar surgery in corneas with less than 450 µm of total thickness and those with steep keratometry readings. In a literature review, Faraj et al. report that 78% of ectasia cases were forme fruste keratoconus or highly myopic eyes with an RSB less than 250 µm after LASIK and that 11% had an RSB greater than 250 µm but with a total corneal thickness less than 500 µm preoperatively. However, there have been reports of postoperative ectasia after a residual bed thickness over 250 µm is confirmed.

Forme fruste keratoconus as defined by the Rabinowitz criteria is a risk factor for post-LASIK ectasia. Pellucid marginal corneal degeneration suspects are also at increased risk. Preoperative posterior float elevations greater than 40 mm may

2 2 signify increased ectasia risk. It is wise to avoid LASIK

in patients with asymmetric inferior corneal steepening or asymmetric bowtie patterns with skewed steep radial axes above and below the horizontal meridian.

THERAPEUTIC OPTIONS

The two principal approaches to the management of corneal ectasia include restoration of vision by optical means to obviate irregular astigmatism, such as the use of rigid gas permeable contact lenses, and in more severe cases, restoration of tectonic integrity of the cornea by interventional means. In recent years, a variety of treatment modalities have emerged, and include methods to increase corneal rigidity, such as a novel collagen cross-linking approach, or the use of intrastromal implants, and recent techniques in central and peripheral lamellar keratoplasty. Current therapeutic options for iatrogenic keratectasia include:

1.Rigid contact lenses

2.Conductive keratoplasty

3.INTACS

4.Cross-link

5.Lamellar keratoplasty

6.Penetrating keratoplasty

7.Combination therapies.

COLLAGEN CROSS-LINKING

Cross-linking is a widespread method in the polymer industry to harden materials and also in bioengineering to stabilize tissue. Although various methods including glutaraldehyde cross-linking are in clinical use in other medical specialties, the method most extensively studied for corneal use is ultraviolet A (UV-A)/ riboflavin collagen cross-linking. This utilizes UV-A at 370 nm to activate riboflavin, generating reactive oxygen species that induce covalent bonds between collagen fibrils. In animal studies, collagen cross-linking by the combined riboflavin/UV-A treatment induced a significant increase in corneal rigidity by approximately 70%. In human, ultraviolet cross-linking treatment appears to be able to halt progression of corneal ectasia in keratoconus patients.

SURGICAL TECHNIQUES

After topical anesthesia, central corneal epithelium is removed within a 8 mm diameter. A 0.1% riboflavin solution (10 mg riboflavin-5-phosphate in 10 ml

dextran 20% solution) is applied every 5 min until the stroma was penetrated and aqueous is stained yellow. The irradiation is performed at working distance of a 10 cm for 30 min using a UVA double diode at 370 nm and an irradiance of 3mW/cm2 (equal to a dose of 5.4 J/cm2). The required irradiance is controlled in each patient directly before the treatment to avoid a potentially dangerous UVA overdose. The parameters of the irradiation treatment must not be modified because of the risks for serious side effects.

RESULTS

Clinical Results

The most important study about the use of cross-linking in iatrogenic keratectasia after LASIK came from Hafezi et al. In this case series, ultraviolet cross-linking treatment appears to be able to halt and even partially reverse iatrogenic corneal ectasia after LASIK with a follow-up of up to 25 months. In 90% of the eyes, BSCVA significantly increased, cylinder decreased. In all cases, researcher reported a reduction in the maximum K readings 12 months after cross-linking. 2 D or more difference between preoperative and postoperative K reading was present in 50% of the eyes treated. These results are comparable to that of cross-linking for corneal ectasia in keratoconus patients in which slight flattening of the cornea of up to 2D and 1.66 line increase in BSCVA were observed.

Biomechanical Results

Using a microcomputer-controlled biomaterial testing machine biomechanical stress–strain measurements showed an impressive increase in corneal rigidity of 71.9% in porcine and 328.9% in human corneas and Young’s modulus by the factor 1.8 in porcine and 4.5 in human corneas after cross-linking.

COMBINED TREATMENTS

Since collagen cross-linking alone does not normalize corneal curvature, attempts have been made to combine it with other surgical modalities. Chan et al. describe cross-linking treatment immediately after INTACS insertion, with a statistically significant greater mean change in cylinder (2.73D) and K steep (1.94D) compared with INTACS alone. While these results

appear promising, further studies evaluating safety, stability of effect and the effect of combination treatment with intrastromal implants are needed. In addition, combination of cross-linking technology with other modalities such as the various forms of lamellar keratoplasty may provide additional yields for ectasia patients.

POTENTIAL COMPLICATIONS AND PREVENTIONS

In early postoperative period, a temporary corneal haze similar to haze after photorefractive keratectomy can develop. This superficial haze disappeared only gradually despite intensive therapy.

Histopathologic and confocal microscopic studies revealed that 300 mm deep stroma is depopulated of keratocytes after cross-linking therapy. Repopulation of this area takes up to 6 months. As long as the cornea treated has a minimum thickness of 400 mm the corneal endothelium will not experience damage, nor will deeper structures such as lens and retina. To prevent damage to the endothelium, the lens or the retina, safe clinical application of X-linking must respect the following criteria:

1.For diffusion of riboflavin throughout the corneal stroma, the epithelium should be removed.

2.Riboflavin solution should be applied for at least 5 minutes allowing riboflavin to permeate through the cornea before the UV irradiation (during the UV exposure, the riboflavin serves as both a photosensitizer and a UV blocker)

3.The UV irradiance must be homogenous and before each treatment, the desired irradiance of 3 mW/cm2 should be controlled with a UVA meter.

4.Cornea must have a minimal central thickness above 400 mm to protect the endothelium.

REFERENCES

1.Randleman JB. Post-laser in-situ keratomileusis ectasia: Current understanding and future directions. Curr Opin Ophthalmol 2006;17(4):406-12. Review.

2.Tan DT, Por YM. Current treatment options for corneal ectasia. Curr Opin Ophthalmol 2007;18(4):284-9. Review.

3.Spörl E, Huhle M, Kasper M, Seiler T. [Increased rigidity of

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

5.Wollensak G, Iomdina E. Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol 2008;11. [Epub ahead of print]

6.Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen cross-linking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg 2007;33(12):2035-40.

7.Wollensak G. Cross-linking treatment of progressive keratoconus: New hope. Curr Opin Ophthalmol 2006;17(4):356-60.

8.Chan CC, Sharma M, Wachler BS. Effect of inferiorsegment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007;33(1):75-80.

9.Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: In vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007;35(6):580-82.

10.Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23(1):43-49.