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

INTRODUCTION

Corneal refractive surgery advanced rapidly during the past two decades, due to the encouraging, predictable and stable results of corneal remodelling by photoablation using excimer lasers. A result of such advancement a new frontier of diagnostic equipments and tools became accessible to ophthalmic surgeon such as; corneal topographer, wavefront sensors, very high frequency optical coherence tomography (VHF OCT), and confocal microscopy. This technology aided in analysing not only the optical but also the structural properties of the cornea.

Recently the biomechanical properties of the cornea have been introduced as a new parameter in corneal refractive surgery, parameter that evaluates corneal characteristics from the biomechanical perspective; such as the corneal resistance factor, and corneal hysteresis. These parameters can be helpful for diagnosing certain corneal pathologies especially corneal ectatic diseases, were the biomechanical corneal characteristics are different from normal corneas.

TERMINOLOGY

Corneal Hysteresis

The term “Hysteresis” is derived from an ancient Greek word which means “coming behind”. It was first introduced into scientific vocabulary in 1890 by the Scottish physicist, Sir James Alfred Ewing. Hysteresis is a property of physical systems that do not instantly follow the forces applied to them, but react slowly, or do not return completely and instantaneously to their original state.

Corneal Resistance Factor

The static resistance component of the cornea which indicates the overall corneal resistance or simply the pressures “force” needed to applanate “deform” the cornea, this deformation is proportional to applied force and is expressed in mmHg (Fig. 2.1).

However, measuring the biomechanical properties in vivo is a challenging task, and has been approached by several methods,1-8 whether invasive as anterior Chamber saline injection and measuring ocular rigidity or non invasive as dynamic corneal imaging with

6 central indentation and dynamic bidirectional air

Figure 2.1: Corneal resistance factor which is the amount of pressure needed to flatten the anterior corneal surface

applanation. Pallikaris et al6 measured the ocular rigidity in living human eyes increasing the intraocular pressure by injecting a saline solution into the anterior chamber; while, Grabner et al7 used the dynamic corneal imaging method by central indentation to assess the individual elastic properties of eyes. Where as, Luce8 determined the biomechanical properties of the cornea using the Reichert ocular response analyzer (ORA), based on a dynamic bidirectional applanation process.

OCULAR RESPONSE ANALYZER ORA

The Ocular Response Analyzer, (ORA Reichert Ophthalmic Instruments, Depew NY) (Fig. 2.2) measures the corneal biomechanical properties by using a dynamic bidirectional air applanation process (non invasive method). It is composed of an air pump which applies a force on the anterior corneal surface (specific point) through a pressure transducer while an infrared light emitter is focused on the same point

Figure 2.2: Ocular response analyzer (ORA)

and the reflection of this infrared beam is monitored by a light intensity detector. This system records two applanation pressure measurements; one while the cornea is moving inward, and the other as the cornea returns. Due to its biomechanical properties, the cornea resists the dynamic air puff causing delays in the inward and outward applanation events, resulting in two different pressure values (Figs 2.3 and 2.4).

Figure 2.3: The infrared light intensity is maximally detected when the anterior corneal surface is applanated

Figure 2.4: ORA graph showing the difference in pressure between the In signal peek and the out signal peek which evaluates the viscoelastic property of the cornea (corneal hysteresis)

CORNEAL BIOMECHANICAL PROPERTIES IN NORMAL, KERATOCONIC EYES AND POSTLASIK EYES

In Prospective, conventional, comparative, interventional study,9 that reported the corneal biomechanical

properties in normal non complaining individual and keratoconic eyes using the ocular response analyzer ORA. The study included a total of 250 eyes divided into three groups: 164 normal eyes, 21 keratoconic eyes and 65 eyes that had undergone a corneal refractive surgery procedure to evaluate the effect of LASIK on the corneal biomechanical properties.

The author’s inclusion criteria were: for normal and post-refractive surgery groups, patients with any irregular patterns of corneal topography or history of ocular disease were not included; and for keratoconus group, only eyes with keratoconus with at least one clinical sign that was confirmed by corneal topography.

Results of this study, demonstrated that in the normal group, a decrease in the corneal biomechanical properties was observed in elder patients. This implies a loss of the elastic properties of the cornea with age, which coincides with the increase of ocular rigidity found by Pallikaris et al.6

As for the post LASIK surgery group, or the effect of excimer laser photoablation on the corneal biomechanical properties, a significant decrease in the biomechanical properties was found after the surgery. This result coincides with other studies1,7,10 and implies that the creation of the flap and the corneal thinning by ablation weaken the cornea and decreases its elastic properties. This could lead later to corneal ectasia after refractive surgery11,12. This can be an indicator for the importance of evaluating corneal biomechanical properties precisely the corneal hysteresis and resistance factor in screening refractive surgery candidates.

In keratoconic eyes, the corneal hysteresis (CH) and the corneal resistance factor (CRF) were significantly lower than in normal eyes and post LASIK surgery corneas. Low values of CH imply that the cornea is less capable of absorbing the energy of the air pulse, where as, low values of CRF, indicates the cornea rigidity is lower than normal.

REFERENCES

1.Jaycock PD, Lobo L, Ibrahim J, et al. Interferometric technique to measure biomechanical changes in the cornea induced by refractive surgery. J Cataract Refract Surg 2005;31:175-84.

2.Mamelok AE, Posner A. Measurements of corneal elasticity in relation to disease, using the Wiegersma elastometer.

3.Vaughan JM, Randall JT. Brillouin scattering, density and elastic properties of the lens and cornea of the eye. Nature 1980;284:489-91.

4.Kasprzak H, Forster W, von BG. Measurement of elastic modulus of the bovine cornea by means of holographic interferometry. Part I. Method and experiment. Optom Vis Sci 1993;70:535-44.

5.Wang H, Prendiville PL, McDonnell PJ, Chang WV. An ultrasonic technique for the measurement of the elastic moduli of human cornea. J Biomech 1996;29:1633-36.

6.Pallikaris IG, Kymionis GD, Ginis HS, et al. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci 2005;46:409-14.

7.Grabner G, Eilmsteiner R, Steindl C, et al. Dynamic corneal imaging. J Cataract Refract Surg 2005;31:163-74.

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

9.Ortiz D, Piñero D, Shabayek MH, et al. Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg 2007;33:1371–75.

10.Kamiya K, Miyata K, Tokunaga T, et al. Structural analysis of the cornea using scanning-slit corneal topography in eyes undergoing excimer laser refractive surgery. Cornea 2004;23:S59-S64.

11.Dupps WJ, Jr. Biomechanical modeling of corneal ectasia. J Refract Surg 2005;21:186-90.

12.Guirao A. Theoretical elastic response of the cornea to refractive surgery: Risk factors for keratectasia. J Refract Surg 2005;21:176-85.

INTRODUCTION

Although corneal ectasia (keratectasia) after laser in situ keratomileusis (LASIK) is reported uncommon, which is estimated to be 0.1%1to 0.66%,2 it is still an enigmatic and potentially devastating complication following laser in situ keratomileusis (LASIK).3 Abnormal collagen in addition to thin corneas may lead to progressive inferior corneal steepening, increase in myopia, irregular astigmatism, and loss of best corrected visual acuity. Unfortunately, the etiology of corneal ectasia is not fully known.

When contact lenses are no longer effective in preventing ectasia progression, there are some surgical management available, such as lamellar keratoplasty and intrastromal corneal ring segments. Various medical therapies did not differ significantly in decreasing the progression of ectasia. Hence, penetrating keratoplasty is another commonly performed surgical procedure for ectatic corneas. However, it is associated with many complications.4 Recently, Crosslinking seems to be one of the more effective means in the management of mild to severe cases.

It is essential that before the clinical treatment, the surgeon must correctly identify, assess, and understand the risk factors of corneal ectasia following laser in situ keratomileusis. Precise assessment is crucial in the management of corneal ectasia after laser in situ keratomileusis.

ASSESSMENT

Accurate detection of corneal ectasia is very important. A precise diagnosis of corneal ectasia may explain a patient’s symptoms postoperatively. A regression of refractive power may alter the postoperative management and treatment. Corneal ectasia is a direct contraindication for any enhancement surgeries and may detriment the cornea even further.

There may be no clinical symptoms in early stages. Although in some advanced cases, astigmatism may appear which may be detected by a refractive examination. Some patients may report acute onset of blurred vision. In the postoperative period, patients may frequently notice dramatic fluctuations in their vision3 and experience regression of their refractive surgical outcome.

Like early keratoconus, corneal ectasia is difficult 1 0 to detect using clinical tests. A useful tool for early

detection of keratoconus or keratectasia is pachymetry, which shows the relationship of the apical, central and thinnest part of the cornea. Corneal topography provides useful and accurate information with regards to the position of the ectasia. It also allows to detect the progression, and for early cases. Corneal topography is a diagnostic tool for corneal ectasia.

CORNEAL TOPOGRAPHY

Corneal ectasia has a similar clinical entity and topography with keratoconus and forme fruste keratoconus. Therefore, after LASIK, corneal ectasia has been reported in patients with keratoconus,5 and forme fruste keratoconus (FFKC).6,7 Also, the progression of ectasia can be most effectively evaluated via analysis of a series of corneal topographies.

Most diagnoses and assessments for keratoconus are based on anterior corneal curvature and elevation data derived from Placido-based corneal topography. But some mild degrees of post-LASIK keratectasia may be better detected at the level of the posterior corneal surface. The posterior corneal shape is mainly used for early recognition of this pathologic condition. Thus, it is prudent to be able to accurately evaluate any changes in the posterior cornea after LASIK.8,9

ORBSCAN

The Orbscan corneal topography system, which uses a placido device, can obtain the corneal curvature and has been used in refractive surgery for many years. It takes 40 slit sections of the cornea during two scans. The anterior and posterior corneal height profiles are reconstructed from these sections using threedimensional ray tracing with 9600 points. The Orbscan has been proven to provide useful and accurate information regarding the morphology and topographic changes related to keratoconus.10 Posterior topographic changes after LASIK are obviously, which has been well investigated.11,12

The risk of ectasia, which is highly suspected as corneal ectasia or keratoconus, is suggested as follows:13

•A variance of more than 1.00D in astigmatism between the eyes.

•Keratometric or corneal steepness on the mean power map.

•The posterior surface float is greater than 0.05 mm (The difference between the highest and lowest spots). Near the center of the posterior elevation map appears a dark reddish color. Wang et al12 have shown that the posterior elevation increases after LASIK. The increase is correlated with residual corneal bed thickness (Figure 3.1).

•Irregularity at 3 mm to 5 mm of the central cornea.

•The thinnest area of corneal thickness is more than 20 μm thinner than the thickness of the central cornea.

•The number of abnormal maps using the normal band scale. One abnormal map does not indicate forme fruste keratoconus or corneal ectasia. It is necessary to check after a few months. Two abnormal maps may indicate early keratoconus or corneal ectasia.

Recently however, some studies showed that Orbscan fails to correctly identify the posterior corneal

surface and can give incorrect diagnosis of post LASIK ectasia.14,15

We believe that corneal topography is an important complementary tool in the diagnosis of post LASIK ectasia. To fully evaluate these measurements, the clinician must look at the indices as a whole rather than at each individual values separately. The three components that are displayed (The elevation, curvature, and pachymetry) are designed to help in the analysis by comparing each one to another.

PENTACAM

Previous studies have reported that the Pentacam has a high degree of repeatability for the measurement of the posterior corneal curvature.16

The Pentacam is a rotating Scheimpflug camera with a higher depth of focus. It assesses the anterior chamber of the eye, the topographic corneal thickness, 1 1

corneal curvature, anterior chamber angle, and volume and height from up to 25,000 true elevation points. The system takes 50 pictures in a maximum of two seconds while rotating around a central point with a moveable eye.

Scheimpflug imaging differs from the Placido-based system in that it allows for the measurement of both the anterior and posterior corneal surfaces and the computation of a complete pachymetric map. The method of depicting elevation data and the subtracted reference shapes commonly uses a best-fit-sphere (BFS) and identifies a 4 mm optical zone centered on the thinnest portion of the cornea (exclusion zone). BFS is defined by utilizing all the valid data from within the 9 mm central cornea with the exception of the exclusion zone.17

The proposed screening parameters are:18,19

•Anterior elevation differences < +12μm are normal.

•Anterior elevation differences > +15μm are

•Anterior elevation differences + 12 ~ +15μm are suspicious.

•Similar numbers (about 5μm higher) apply to posterior elevation.

The confirmation can be made for forme fruste

keratoconus when the hot spot on the tangential map, relative pachymetry map and back elevation map, using the toric ellipsoid, are all at the same point. By Holliday’s experience,18 exceed -3.0% are significant for relative pachymetry, also for elevations of more than 15μm above the toric ellipsoid on the back elevation map (Fig. 3.2).

Other indices of the ectasia are the position of the thinnest point. At the beginning of the ectasia, the thinnest point is at central position. The thinnest point can transform from central position toward an eccentric position.

Several other parameters could also be extracted from corneal tomography examination. These include a faster and a more abrupt increase of the corneal

thickness spatial profile and the percentage of increase of thickness relative to normal corneas.17 Figure 3.3 shows a particular case of a patient with post-LASIK ectasia.

All of these can be used in a series of follow-up exams of the posterior corneal curvature in post-LASIK eyes. This will help to identify and predict keratectasia following LASIK. However, whether these measurements are more sensitive and specific than the classic Placido-based topography needs further investigation.

RISK FACTORS

After LASIK, there are many risk factors that may increase the probability of corneal ectasia. None of these factors are absolute predictors of corneal ectasia, but are correlated with its occurrence. Also, LASIK is not necessarily a causative or contributing factor to corneal ectasia seen postoperatively.20 Possible risk factors analyzed by Randleman et al3 include high

myopia, and thin preoperative corneal thickness. Some possible risk factors include:

•Forme fruste keratoconus (FFKC): Some ectasia after LASIK has been reported in patients with forme fruste keratoconus.6,7 One study showed 88% of affected eyes met the FFKC criteria.3 Therefore, screening and identifying patients with FFKC preoperatively is necessary.

•Keratoconus in one eye or a family history of keratoconus. Eyes with keratoconus are known to produce unpredictable refractive results and scarring after LASIK.21,22

•Residual stromal bed thickness after laser ablation was less than 250μm. Many studies have showed

that the residual stromal bed thickness of more than 250μm would possibly be safe. 1

•High myopia: Patients with high myopia require more tissue ablation during LASIK. This leaves them with a lower residual stromal bed thickness than

•Patients that have underwent enhancement after LASIK surgery. It has been proposed that multiple enhancements were correlated with ectasia.23 Enhancement after LASIK surgery may make residual stromal bed thinner.

•Asymmetrical cornea steepening.

•Asymmetrical astigmatism.

•High keratometric measurements: A higher risk of keratoectasia is suggested by K readings of 46D or more at the steepest point.13

•Age: With aging, the structure and shape of the cornea changes and may attribute to the development of ectasia.

•Patients who have genetic corneal dystrophies.24

Clinically, some of the patients who developed corneal ectasia may have multiple risk factors.

As technology continually advancing, the knowledge for assessing corneal ectasia following laser in situ keratomileusis continues to grow and criterion may be changed. Further studies are needed to provide more accurate and predictable treatment outcomes.

ACKNOWLEDGMENTS

We thank John Barkley OD, Thanh Nguyen OD and Tran Nguyen OD (Nova Southeastern University, FL, USA) for providing generous assistance and attentive correction of the language.

REFERENCES

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2.Pallikaris IG, Kymionis GD, Astyrakakis NI. Corneal ectasia induced by laser in situ keratomileusis. J Cataract Refract Surg 2001;27:1796-1802.

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

4.Tan BU, Purcell TL, Torres LF, et al. New surgical approaches to the management of keratoconus and post-LASIK ectasia. Trans Am Ophthalmol Soc 2006;104:212-20.

5.Clair-Florent M, Schmitt-Bernard C, Lesage C, Arnaud B. Keratectasia induced by laser in situ keratomileusis in keratoconus. J Refract Surg 2000;16:368-70.

6.Argento C, Cosentino MJ, Tytiun A, et al. Corneal ectasia after laser in situ keratomileusis. J Cataract Refract Surg 2001;27:1440–48.

7.Lafond G, Bazin R, Lajoie C. Bilateral severe keratoconus after laser in situ keratomileusis in a patient with forme

8.Chen D, Lam AKC. Intrasession and intersession repeatability of the Pentacam system on posterior corneal assessment in the normal human eye. J Cataract Refract Surg 2007;33:448–54.

9.Ciolino JB, Belin MW. Changes in the posterior cornea after laser in situ keratomileusis and photo refractive keratectomy. J Cataract Refract Surg 2006;32:1426–31.

10.Kim H, Joo CK. Measure of keratoconus progression using Orbscan II. J Refract Surg 2008;24:600-605.

11.Nilforoushan MR, Speaker M, Marmor M, et al. Comparative evaluation of refractive surgery candidates with placido topography, Orbscan II, Pentacam, and wavefront analysis. Cataract Refract Surg 2008;34:623– 31.

12.Wang Z, Chen J, Yang B. Posterior corneal surface topographic changes after laser in situ keratomileusis are related to residual corneal bed thickness. Ophthalmology 1999;106:406-09.

13.Karpecki PM. Bausch and Lomb Orbscan anterior segment analysis system. Wang M In: (Ed) Corneal topography in the wavefront era. Thoroare, USA:SLACK;2006:192-206.

14.Prisant O, Calderon N, Chastang P, et al. Reliability of pachymetric measurements using Orbscan after excimer refractive surgery. Ophthalmology 2003;110:511–15.

15.Matsuda J, Hieda O , Kinoshita S. Comparison of central corneal thickness measurements by Orbscan II and Pentacam after corneal refractive surgery. Jpn J Ophthalmol 2008;52:245–49.

16.Jain R, Dilraj G, Grewal SPS . Repeatability of corneal parameters with Pentacam after laser in situ keratomileusis. Indian J Ophthalmol 2007;55(5):341-47.

17.Belin MW, Khachikian SS, Arósio R. Keratoconus / Ectasia detection with the Oculus Pentacam: Belin/Ambrósio enhanced ectasia display. Highlights of ophthalmology 2007;55(6):5-12.

18.Maus M, Kröber S, Swardz T. Pentacam. In: Wang M. Corneal topography in the wavefront era. Thoroare, USA:SLACK;2006:281-93.

19.Holladay JT. Detecting forme fruste keratoconus with the Pentacam. Cataract and Refractive surgery today 2008;2:11-12.

20.Binder PS, Lindstrom RL, Stulting RD, et al. Keratoconus and corneal ectasia after LASIK. J Refract Surg 2005;21(6):749-52.

21.Buzard KA, Tuengler A, Febbraro JL. Treatment of mild to moderate keratoconus with laser in situ keratomileusis. J Cataract Refract Surg 1999;25:1600–09.

22.Ellis W. Radial keratotomy in a patient with keratoconus. J Cataract Refract Surg 1992;18:406–09.

23.Holland SP, Srivannaboon S, Reinstein DZ. Avoiding serious corneal complications of laser assisted in situ keratomileusis and photorefractive keratectomy. Ophthalmology 2000;107:640–52.

24.Rabinowitz YS. The genetics of keratoconus. Ophthalmol Clin N Am 2003;16:607-20.