CHAPTER 7

Collagen Shrinkage and Crosslinking Procedures

Keratorefractive surgical procedures aim to alter the refractive power of the cornea by changing its shape. Various methods are used to alter corneal curvature, including incising or removing corneal tissue or implanting artificial material into the cornea. Procedures that change the character of the corneal collagen have also been developed. This chapter focuses on 2 such procedures: corneal collagen shrinkage and corneal collagen crosslinking.

Collagen Shrinkage

History

The idea of using heat to alter the shape of the cornea was first proposed by Lans, a Dutch medical student, in 1898. When Lans used electrocautery to heat the corneal stroma, he noticed astigmatic changes in the cornea. In 1975, Gasset and Kaufman proposed a modified technique known as thermokeratoplasty to treat keratoconus. In 1984, Fyodorov introduced a technique of radial thermokeratoplasty that used a handheld, heated Nichrome needle designed for deeper thermokeratoplasty. The handheld probe contained a retractable 34-gauge wire heated to 600°C. For a duration of 0.3 second, a motor advanced the wire to a preset depth of 95% of the corneal thickness. Fyodorov used different patterns to treat hyperopia and astigmatism.

However, excessive heating of the cornea resulted in necrosis and corneal remodeling, and regression and unpredictability of treatment limited the success of this technique. It is now known that the optimal temperature for avoiding stromal necrosis while still obtaining corneal collagen shrinkage is approximately 58°–76°C. Human collagen fibrils can shrink by almost two-thirds when exposed to temperatures in this range, as the heat disrupts the hydrogen bonds in the supercoiled structure of collagen. In the cornea, the maximal shrinkage is approximately 7%. When higher temperatures are reached (>78°C), tissue necrosis occurs.

Neumann AC, Fyodorov S, Sanders DR. Radial thermokeratoplasty for the correction of hyperopia. Refract Corneal Surg. 1990;6(6):404–412.

Laser Thermokeratoplasty

In the 1990s, numerous lasers were tested for use in laser thermokeratoplasty (LTK). Only the holmium:yttrium-aluminum-garnet (Ho:YAG) laser reached commercial production and received US Food and Drug Administration (FDA) approval. The Ho:YAG laser produces light in the infrared region at a wavelength of 2100 nm and has corneal tissue penetration to approximately 480–530 µm.

Two different delivery systems were investigated: a contact system and a noncontact version. One noncontact system approved by the FDA in 2000 used a slit-lamp delivery system to apply 8 simultaneous spots at a wavelength of 2.1 µm at a frequency of 5 Hz and a pulse duration of 250 µsec.

The system was approved for the temporary correction of 0.75–2.50 D of hyperopia with less than 1.00 D of astigmatism. The initial interest in LTK later waned, primarily because of the significant refractive regression that frequently occurred. Few LTK units, if any, remain in clinical use.

Conductive Keratoplasty

In the past decade, radiofrequency has reemerged as a method of heating the cornea. In 2002, the FDA approved the ViewPoint CK system (Refractec, Irvine, CA) for the temporary treatment of mild to moderate hyperopia with minimal astigmatism. In 2004, conductive keratoplasty (CK) received FDA approval for treatment of presbyopia in the nondominant eye of a patient with an endpoint of –1.00 to –2.00 D.

The nonablative, collagen-shrinking effect of CK is based on the delivery of radiofrequency energy through a fine conducting tip that is inserted into the peripheral corneal stroma (Fig 7-1). As the current flows through the tissue surrounding the tip, resistance to the current creates localized heat. Collagen lamellae in the area surrounding the tip shrink in a controlled fashion and form a column of denatured collagen. The shortening of the collagen fibrils creates a band of tightening that increases the curvature of the central cornea.

Figure 7-1 Schematic representation of an eye undergoing conductive keratoplasty, which delivers radiofrequency energy to the cornea through a handheld probe inserted into the peripheral cornea. (Courtesy of Refractec, Inc.)

For the treatment of hyperopia, the surgeon inserts the tip into the stroma in a ring pattern around the peripheral cornea. The number and location of spots determine the amount of refractive change, with an increasing number of spots and rings used for higher amounts of hyperopia. The CK procedure is performed using topical anesthesia and typically takes less than 5 minutes. The collagen shrinkage leads to visible striae between the treated spots, which fade with time (Fig 7-2).

Figure 7-2 One month after a 24-spot conductive keratoplasty treatment in a patient with +2.00 D hyperopia, the spots are beginning to fade. Three sets of 8 spots each were applied at a 6.0-, 7.0-, and 8.0-mm optical zones. (Courtesy of Refractec, Inc.)

Patient selection

The Refractec system is FDA approved for the temporary reduction of spherical hyperopia in patients 40 years or older with a spherical equivalent of +0.75 to +3.25 D and ≤0.75 D of astigmatism. The treatment is not advised for use in patients who have undergone radial keratotomy, and it is not FDA approved for use in patients with keratoconus, ectatic disorders, or significant irregular astigmatism. An upper limit of +1.50 D (spherical equivalent) appears to be the current treatment ceiling for this technology, and repeat applications over time or increased number of spots does not seem to enhance or increase that limit.

Safety

In the principal FDA clinical trial to date, no patient had a worse outcome than 20/40 visual acuity, and none lost more than 2 lines of vision. One patient of a total of 391 had >2.00 D of induced cylinder, and no patient with a preoperative corrected distance visual acuity (CDVA; also called best-corrected visual acuity, BCVA) of ≥20/20 had <20/25 at 1 year. Although induced cylinder of >2.00 D is an FDA safety variable, smaller amounts of induced cylinder were apparent. At 1 year, 6% of patients had >1.00 D of induced cylinder. The magnitude of the induced cylinder decreased with time. No central corneal haze was noted at 12 months, and endothelial cell counts were similar before and after the study.

Results

The clinical trial included 12-month data for 401 eyes; mean cohort age was 55.3 years (range, 40.2– 73.9 years). The mean cycloplegic spherical equivalent was +1.86 ± 0.63 D. By 12 months postoperatively, 92% of study patients had achieved uncorrected distance visual acuity (UDVA; also called uncorrected visual acuity, UCVA) of 20/40 or better, 74% achieved 20/25 or better, and 54% had 20/20 or better. By 24 months postoperatively, 93% of study patients had achieved UDVA of 20/40 or better, 76% achieved 20/25 or better, and 52% had 20/20 or better. There was a slow, continued drift toward increasing hyperopia, with regression of +0.21 D and +0.48 D at 12 and 24 months, respectively. Overall, there was a 20% loss of effect after 2 years. This loss of effect is probably a combination of true regression and the normal hyperopic drift that occurs as people age. The results in the FDA CK trial for presbyopia were similar.

Despite initial reports of refractive stability, long-term follow-up has revealed regression and/or lack of adequate effect with CK. In a long-term (mean, 73.1 months; range, 44–90 months) follow-up of patients enrolled in the phase 3 multicenter trial of CK, Ehrlich and Manche found nearly complete regression of treatment effect in the 16 eyes (of the original 25 eyes) available for follow-up.

Ehrlich JS, Manche EE. Regression of effect over long-term follow-up of conductive keratoplasty to correct mild to moderate hyperopia. J Cataract Refract Surg. 2009;35(9): 1591–1596.

Hersh PS. Optics of conductive keratoplasty: implications for presbyopia management. Trans Am Ophthalmol Soc. 2005;103:412–456.

Kymionis GD, Kontadakis GA, Naoumidi TL, Kazakos DC, Giapitzakis I, Pallikaris IG. Conductive keratoplasty followed by collagen cross-linking with riboflavin-UV-A in patients with keratoconus. Cornea. 2010;29(2):239–243.

McDonald MB. Conductive keratoplasty: a radiofrequency-based technique for the correction of hyperopia. Trans Am Ophthalmol Soc. 2005;103:512–536.

Other applications

Other potential off-label uses also exist for CK. In cases of overcorrected myopic LASIK and myopic photorefractive keratectomy (PRK), CK can be used to correct hyperopia. In these procedures, CK obviates the need to lift or cut another flap. In one report, CK was used to treat both keratoconus and post-LASIK ectasia. Although corneal irregularities improved immediately, with some improvement in visual acuity, some cases showed regression of effect at 1 month. Larger studies with additional follow-up are needed.

In postcataract or postkeratoplasty patients with astigmatism, CK can be used to steepen the flat axis, because each spot is individually placed. The overall effect is still a myopic shift, so CK is particularly useful when the spherical equivalent is hyperopic. In a study of 16 patients who had CK for hyperopia after cataract surgery, 1-year follow-up data showed that CK for low to moderate postcataract hyperopia was effective and safe.

Some surgeons have also used CK in combination with collagen crosslinking in an attempt to correct the corneal curvature abnormalities in keratoconus.

Conductive keratoplasty appears to have advantages both in cost and in allowing flexible (offlabel) treatment patterns because the tip can be placed anywhere on the cornea. More experience and long-term data will be required to determine how important CK will be in the refractive surgeon’s armamentarium. Currently, however, its use remains fairly limited because of the high rate of refractive regression.

Alió JL, Ramzy MI, Galal A, Claramonte PJ. Conductive keratoplasty for the correction of residual hyperopia after LASIK. J Refract Surg. 2005;21(6):698– 704.

Claramonte PJ, Alió JL, Ramzy MI. Conductive keratoplasty to correct residual hyperopia after cataract surgery. J Cataract Refract Surg. 2006;32(9):1445– 1451.

Kolahdouz-Isfahani AH, McDonnell PJ. Thermal keratoplasty. In: Brightbill FS, ed. Corneal Surgery: Theory, Technique, and Tissue. 3rd ed. St Louis: CV Mosby; 1999.

Kymionis GD, Kontadakis GA, Naoumidi TL, Kazakos DC, Giapitzakis I, Pallikaris IG. Conductive keratoplasty followed by collagen cross-linking with riboflavin-UV-A in patients with keratoconus. Cornea. 2010;29(2):239–243.