Ординатура / Офтальмология / Английские материалы / Mastering Corneal Collagen Cross Linking Techniques (C3-R, CCL, CxL)_Garg_2009

INTRODUCTION

Emerging therapeutic corneal procedures such as ultraviolet collagen cross-linking are showing promise as possible adjunctive therapies to more familiar corneal reshaping techniques such as intracorneal segments for the treatment of keratoconus and LASIK ectasia.

We have begun calling these procedures corneoplastics. Corneoplastics are a group of techniques, most of them coming from refractive corneal surgery, that try to modify the corneal shape with a therapeutic purpose, and they are quickly emerging as the next frontier in corneal therapies. We are creating a new environment for the treatment of diseases that were untreatable before.

Corneoplastic techniques allow surgeons to model the structure of the cornea without having to resort to invasive techniques such as penetrating keratoplasty or lamellar grafting.

We are in a moment in which corneoplastic techniques are modeling techniques that can be used in different ways in order to create better corneal optics, to create better corneal topography, to improve the optical performance of the cornea for refractive purposes (Fig. 21.1). The first ophthalmologist to use the term corneoplastics was most likely Arun C Gulani, MD, from Jacksonville, Fla. Now, this concept is spreading abroad, becoming a new worldwide subspeciality allied to refractive and corneal surgery.1

COMBINING NEW AND OLD TECHNIQUES

Corneoplastic techniques can be broken down into biomechanical methods such as intracorneal segments

Figure 21.1: Corneoplastics concept

Figure 21.2: Corneoplastic techniques

or incisional techniques, elastic methods including ultraviolet collagen cross-linking and conductive keratoplasty (CK) and mixed methods such as excimer laser ablations or intracorneal lenses (Fig. 21.2).

Some of these methods are already well-known in their efficacy. Intracorneal segments, for example, are currently the best corneoplastic option for treating corneal pathologies such as keratoconus and LASIK ectasia.

On the other hand, one of the most promising new approaches for managing keratoconus and LASIK ectasia is collagen cross-linking, or C3-R, in which riboflavin is applied to the cornea (usually after epithelial removal) followed by about 30 minutes of UV light irradiation. This causes new bonds to form between adjacent collagen molecules in the cornea, increasing corneal rigidity as much as three or four times. In several recent studies this has not only stopped the progression of keratoconus, but has caused some degree of reversal and improved visual acuity in many eyes.2,3. The procedure is not yet approved by the US Food and Drug Administration, but has received the CE mark in Europe.

By combining this method with intracorneal segments, the efficacy of the implants can be enhanced beyond their current capabilities (Fig. 21.3).

Intracorneal segments have been used for keratoconus for more than 7 years, and these cases are more or less stable. Of course some of them were not ideal cases in the beginning. Although they did improve, some of them were followed by a residual

increase in the corneal steepness because the 135 keratoconus was advanced and was not stopped

Figure 21.3: Combined corneoplastic technique: Corneal scrapping followed by riboflavin instillation for cross-linking, 4 months after keraring implantation

completely by the ring. At this moment the combination of UV cross-linking to these cases is adding rigidity and strength to the cornea, and stopping this process that was slowed after the rings in some cases.

The ideal result of combining these procedures would be to avoid procedures such as corneal grafts. You can never guarantee the outcome of a corneal grafting technique, and moreover, keratoconus may relapse on a corneal graft. This is the state of the art at this moment in the treatment of keratoconus, but it is far from ideal, far from being defined as a solution in young patients, because keratoconus may relapse in them.

The most desirable situation is to find an alternative to corneal grafting. It is important to notice that at the

end, it is possible that few patients will require penetrating keratoplasty. But, if we can delay a penetrating keratoplasty in a keratoconus patient for one or two decades, this could be consider the main objective for corneoplastics; because the risks of corneoplastic procedures such as intracorneal rings and cross-linking are so minimal when we compare to related risks of penetrating keratoplasty.

UNFINISHED BUSINESS

While these techniques are showing promise, there is much to be learned and modified. For example, while researchers are eagerly anticipating the various applications of UV collagen cross-linking, they are also aware that UV light is toxic to the ocular structures, making it necessary to explore alternative energy options. We can anticipate in the future other sources of energy will be substituted for UV light and will not be as potentially harmful.

In addition, the biomechanical qualities of the cornea pose challenges to the accurate application of combined techniques. Understanding the behavior of corneal tissue following corneoplastic procedures is complicated by its intricate structure.

By the present time one of the structures of the eye which can be damage by UV light are the limbal steam cells, protecting them using a limbal shield is recommended. We use a cellulose sponge ring over the limbus to protect the steam cells during UV light exposure (Fig. 21.4).

When is the best time to approach for combine cross-linking and intracorneal rings and for keratoconus?

At the Instituto Oftalmológico Novavision in Mexico City we have been doing the manual technique for

intracorneal rings implantation (either Intacs or Keraring) for 8 years, and for the last 5 years we use IntraLase femtoseconds technology to carve the channels for intracorneal rings implantation to treat keratoconus and LASIK ectasia.

Since the beginning we noticed that this combination femoseconds laser and keraring provide us an excellent corneoplastic procedure, because we achieved better topographic and refractive results than expected. In fact, today we consider this combination as a partial refractive procedure for such irregular corneas.

Controversies arise at this point. When we need to cross-link, if we end with good topographic and refractive result? Few surgeons prefer to cross-link first and then proceed with rings implantation, others use simultaneous cross-linking and corneal ring implantation during the same day, and some surgeons like myself we rather to wait 3 to 4 months after intracorneal ring implantation for cross-linking.

I consider this adjunctive procedure especially for two indications: First in the case of residual myopic refractive error after femtoseconds laser and

intracorneal ring implantation, and second when we face to an unstable cornea after intracornreal ring implantation.

At the present time, our preferred technique for cross-linking after intracorneal rings is to use excimer laser for a 40 microns of PTK at 7 mm of optical zone, followed first by 20 minutes of riboflavin instillation, one drop each 2 minutes, and second 20 minutes of UV light exposure using riboflavin installation each 2 minutes.

The best approach for corneoplastics philosophy in keratoconus is to consider first intracorneal rings to remodel heavely irregular corneas like in the case of Pellucid Marginal Degeneration, and second crosslinking after to improve stability.

It is vital to recognize that important mechanical remodeling is only feasible with intracorneal rings, because reduction of corneal central power is only 2 diopters at 24 months after cross-linking, besides, crosslinking itself, is not capable of improving irregular topography in the case of Pellucid Marginal Degeneration. An example of mechanical remodeling with intracorneal rings is presented, followed by crosslinking (Fig. 21.5).

Figure 21.5: Corneoplastics using combine technique for pellucid marginal degeneration: Only one inferior Keraring segment followed by crosslinking. Orbscan dual map axial topography map shows three principles of corneoplasics: Improving

COMBINING TREATMENTS

EXPERIENCES

Given the early success of the C3-R treatment, researchers in the United States and around the world are investigating the effectiveness of combining it with other existing approaches. Wachler compared C3-R with Intacs to Intacs alone as a treatment for keratoconus.4 They found that you can get an augmented effect by combining the treatments. They first placed the intacs, and then applied the riboflavin treatment. The intacs with C3-R group showed significantly greater flattening in K-steep and K-average than in the Intacs-only group, as well as significantly greater reduction in manifest cylinder. However, the changes in BCVA and UCVA were not statistically significantly different between the two groups.4,5

CROSS-LINKING AND PRK

One of the most promising uses of the C3-R procedure is in combination with a modified version of PRK. In about 200 of the 300 cases Kanellopoulos has used the cross-linking technique followed some months after by PRK, using the WaveLight topography-guided laser platform to normalize the shape of the cornea.6

This procedure combines a myopic PRK over the apex of the cone with a segment of hyperopic PRK at the opposite side of the cornea (Fig. 21.6). The combination flattens the ectatic part of the cornea and steepens the part of the cornea that’s very flat. As a result, you’re removing very little tissue but making the cornea smoother.

Kanellopoulos notes that this type of PRK is a specialized intervention because treating the refractive

error isn’t necessarily the goal. The goal is to normalize the cornea as much as possible to increase BSCVA. BSCVA increases if you decrease the amount of irregular astigmatism. So the number one treatment target is cylinder, and to improve the irregular astigmatism and the number two target is correcting some of the sphere. More importantly, that eye does not need a cornea transplant.

Some surgeons might argue that this could be done using wavefront-guided technology. In mild cases of ectasia that’s true. However, a wavefront-guided system will try to ablate tissue until it’s all equal, so it removes three times as much. Tissue reserve is a big issue in ectasia cases.

Kanellopoulos has manifested, one surprising effect of the cross-linking treatment is that corneal tissue reacts differently to laser ablation, which is an issue if the cornea is cross-linked before ablation. In cross-linked corneas consistently get more refractive result than expected. He hasn’t yet found a formula to compensate for the difference. As we know, keratoconus requires very irregular ablations. However, undercorrecting by 25 percent is recommended to play it safe. Once it

was clear that this sequential approach of cross-linking first followed by PRK 6 months after, it has been safe and effective combination, now the procedures can be taken simultaneously the very same day.

REFERENCES

1.Alio J. Corneoplastics emerging as the newer frontier in corneal therapies. Ocular Surgery News Europe/AsiaPacific Edition. 2007.

2.Wollensak G. Cross-linking treatment of progressive keratoconus: New Hope. Curr Opin Ophthalmol 2006;17:4:356-60.

3.Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Para surgical therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking of corneal collagen: Preliminary refractive results in an Italian study. J Cataract Refract Surg 2006;32:5:837-45.

4.Chan CCK, Sharma M, Boxer Wachler BS. The effect of inferior segment Intacs with and without corneal collagen cross-linking with riboflavin (C3-R) on keratoconus. J Cataract Refract Surg 2007;33:75-80.

5.Kent C. Update: Managing and predicting ectasia. Review Ophthalmology 2007;14.

6.Kanellopoulos. Perfecting Cross-linking with PRK. IntraLase users meeting. ASCRS Chicago 2008.

INTRODUCTION

A number of new technologies are becoming available to cornea and refractive surgeons for the treatment of corneal irregularities such as keratoconus and postLASIK Keratectasia and irregular astigmatism.The new approaches involve corneoplastics procedures to remodel the cornea through mechanical techniques (intracorneal rings), biochemical techniques (crosslinking), and mixed methods (laser ablation).

Corneal collagen cross-linking represents a new therapeutic option for delaying or halting keratoectasia in progressive keratoconus and post-LASIK ectasia. The basic technique was developed in Dresden in 1998 by Wollensak, Spoerl and Seiler, however, it was not until 2003 that the first clinical trial data in 22 first patients was published by the same authors.1

Collagen cross-linking described by Seiler might halt and even slightly reverse the progression of keratoconus.The aim of this technique is to strengthen lamellar fibers, thereby restoring the cornea’s structural integrity.

The aim of the present chapter is to describe the different techniques for cornea collagen cross-linking that have been described:

•Original Seiler cross-linking technique

•Caporossi cross-linking technique

•Kanellopoulos IntraLase cross-linking technique

•Sánchez-León modified post-LASIK ectasia crosslinking technique

•PTK cross-linking technique

•Simultaneous topo-guided PRK and cross-linking

Keratoconus is a condition in which the tensile strength of the cornea’s lamellar fibers diminish to about half of their normal values, causing the cornea to assume a conical shape with an off-centre apex, and resulting in irregular astigmatism. The condition generally first appears when a patient is between 10 and 20 years of age. In most cases the deformation of the cornea progresses up to a certain point and then stops as mysteriously as it began.When this occurs, the condition is called forme fruste keratoconus.

However, in the case of “frank” keratoconus the condition becomes progressively worse for several decades, perhaps even for the lifetime of the patient, although the progression slows over time. Topography studies suggest that forme fruste keratoconus has an incidence of about 5:1000, while progressive keratoconus has an incidence of about 1- 2:1000. With

collagen cross-linking it may be possible to transform the progressive form of keratoconus into the more benign, forme fruste keratoconus.

SEILER CROSS-LINKING TECHNIQUE

Collagen cross-linking stiffens collagen by creating new chemical bonds between collagen molecules. It occurs naturally as a consequence of ageing and diabetes. In fact, type 1 diabetes provides complete protection against keratoconus. 2

After experimenting with several techniques to induce collagen cross-linking in human corneal tissue, Seiler and his associates decided that the application of riboflavin (vitamin B2) combined with UV radiation offered the most favorable safety/efficacy ratio. In that technique the ultraviolet light causes riboflavin to release oxygen radicals, which in turn create new crosslinking bonds between lamellar fibers and within the collagen molecules.

Seiler’s procedure involves the scraping of the epithelium from the central 9.0 mm of the cornea, the application of riboflavin in 20% dextrane, and irradiation of the area with 3mW/cm2 of ultraviolet light at a wavelength of 365 nm for 30 minutes (Figure 22.1). Based on animal experiments and early clinical experience they found that these parameters happened to be the best combination for an optimal stiffening (1.5-fold) and maximal safety. Moreover, in vitro und in vivo-experiments showed that with the current parameters there was no apoptosis of endothelial cells if the corneal thickness was at least 400 microns.

CLINICAL TRIAL CONFIRMS EFFICACY OF COLLAGEN CROSS-LINKING

Clinical results so far suggest that not only does the collagen cross-linking achieved in this way halt the

141

Figure 22.1: Seiler cross-linking original technique

progression of keratoconus, but it also causes keratoconic corneas to assume a more normal shape with consequent improvements in visual acuity. In a study involving 26 eyes of 25 keratoconus patients who underwent the cross-linking treatment, corneal topography showed progression halted in every case after a follow-up of one to five years (mean 2.4 years). In addition, maximal K-readings decreased by a mean of 1.38 D (p<0.01) and were significantly reduced in 65% of the cases. Furthermore, visual acuity improved by a mean of 1.3 lines (p< 0.01). Today, it is possible by medical and therapeutic means to transform keratoconus into the forme fruste state.3

CAPOROSSI CROSS-LINKING TECHNIQUE SIENA EYE CROSS PROJECT

The technique of Riboflavin UV-A collagen crosslinking 4,5 involves the photo-polymerization of corneal collagen by increasing chemical interand intra-helical bond formation. This mechanism of molecular cross-linking allows the cornea to build strength and a resistance to ectasia. The mechanism of hardening and thickening the cornea is mediated by a photodynamic reaction between the photosensitizer Riboflavin 0.1 % / Dextrane 20% solution (Ricrolin; Sooft, Italy) and low-dose UV-A irradiation (3 mW/ cm2 ) with a total exposure time of 30 minutes. The release of reactive oxygen species (ROS) during the reaction stimulates covalent bond formation between collagen fibers.

At the University of Siena, the UV-A irradiation is delivered by a solid state UV-A illuminator named CBM. (Caporossi-Baiocchi-Mazzotta) X-Linker VEGA, which is CE-marked.5,8

WHAT IS DIFFERENT ABOUT SIENA EYE CROSS PROJECT?

The only difference on the illuminators between the Siena project and the Dresden original technology was in the energy stabilizing system (CM controller). The new illuminator was designed to obtain a timely, homogeneous irradiation, thus avoiding the emission peak and energy decrease related to battery pack systems.

In 2005 the “CBM X linker” was created (Caporossi-Baiocchi-Mazzotta cross-linker),6,8 and the 142 aim of this new technology was to obtain the most

circular illumination spot and the biggest and most constant in its diameter. In order to do this, they increased the cross-linkable area to 11 mm, by using an illuminator made of a five UV-A LED array (37010), mounted on a heat sink system in the source head of the equipment and powered by a stabilized circuit to provide an energy equal to a safe and efficient value (5.4 J/cm2 , thus 3.0 mW/cm2 as power density).

A second goal of the project was to increase the working distance up to 1.5-1.8 cm to operate more efficiently on the cornea. A further goal was to achieve a sharper focus and improved adjustment control of the UV-A spot. This particular feature was obtained by inserting two low-power red laser sources into the optical head, thus not interfering with the “therapeutic” wavelength, as aiming-beam function.8

To achieve direct control of the whole procedure and of the focusing function, they inserted a micro- color-camera into the center of the UV-A array to show, in real-time mode, the correct aiming-beam alignment so that we could control the correct centering of the irradiated area. The “live” picture is shown on an LCD monitor mounted on the control unit of the equipment8 (Figure 22.2).

This particular visual-control feature plays a very important role in maintaining constant UV-A irradiation. This is particularly important because a

Figure 22.2: The “live” picture is shown on the LCD monitor, mounted on the control unit of the new CBM-VEGA. The monitor also shows the elapsed time and the current step of the procedure

±1 mm defocus can diminish the energy provided to the corneal tissue by 8-10%. A 0.2 mm decentration can cause the same decrease in energy, while a 0.5 mm increase in decentration is associated with a 20% decrease in the energy that reaches the corneal apex.

The monitor displays important information for the surgeon during the procedure, such as the current stage of the operation, device calibration, staining phase with related timer from 10 to 30 minutes, and elapsed treatment time for each five-minute step (steps one to six). Finally, a new feature is the camera-coaxial fixation point, which makes ocular alignment fixation easier for the patient.

THE RESULTS

Since 2004, 44 eyes were treated, each affected by growing keratoconus, clinically and instrumentally reported. The mean age of patients was 23.2 years of age (between 14 and 42 years). All patients in this Eye Cross Study were treated in accordance with the Siena Eye Cross protocol (Dresden modified) with crosslinking Riboflavin UV-A.5-7

Patients were followed up to 24 months postoperatively. Temporary haze was observed in a few cases (15%; four within the first three months, one case after six months), however, this disappeared after one month of therapy with preservative-free topical steroids. The most common side effect reported during the first postoperative month was temporary corneal edema (15 days/three months), which disappeared progressively after steroid and topical NSAID administration. No delayed re-epithelialization or endothelial damage was apparent during the 24-month follow-up period, and there were no incidences of keratoconus worsening in any of the treated eyes during follow-up. An average decrease in K-reading of around 1.5 D was observed.

The average, top-line results achieved in the 44 eyes of the Siena Eye Cross Study are shown in Table 22.1. On the whole, all eyes demonstrated refractive stability 24 months after treatment, without any clinical or instrumental signs of the disease returning.

KANELLOPOULOS INTRALASE CROSSLINKING TECHNIQUE

There is an international controversy about if the procedure will induce cross-linking of the corneal

Table 22.1: Data collected after 24 months from 44 eyes treated in accordance with the Siena Eye Cross protocol (Dresden modified) with cross-linking Riboflavin UV-A

collagen fibers if we remove or not remove the epithelium. Some researches are in favor of leaving the epithelium intact in order to achieve a faster visual rehabilitation and diminish of the symptoms. Kanellopoulos has promoted a new technique especially designed for an early disease or forme fruste keratoconus, using the IntraLase femtoseconds laser to create a corneal pocket at 100 microns depth, and only 5’ of side cut, then instilling a one-time, onedose amount of 0.1% riboflavin in that pocket. With these technique we would be able to cross-link the cornea selectively, 60 microns above the pocket and 200 microns below without having to remove the corneal epithelium Figures 22.3A to D. Kanellopoulos’ team has been experimenting with cutting down the amount of time needed for the procedure. They are experimenting with delivering the same energy in a shorter amount of time by doubling the fluence. They have found that 7 milliwatts per square centimeter may be a reasonable means of cutting down on the treatment time, going from 30 minutes to 15 with the same total irradiance of about 5.5 joules.9

METHODS

•10 keratoconic cornea were cross-linked utilizing

•7mW ’ 15 minutes UVA irradiation of 370 nm wavelength (5.2 joules)

•Intracorneal 0.1% riboflavin instillation assisted by a 100 micron in depth and 7 mm in diameter pocket created with the IntraLase femtoseconds laser (5 degree side cut).