15th Annual Comangement Report: An Introduction to Corneal Collagen Cross-Linking

Corneal collagen cross-linking may reduce or eliminate the progression of ectasia in patients with keratoconus.

By Karen K. Yeung, O.D., and Barry A. Weissman, O.D., Ph.D.

Goal Statement:

Keratoconus is an asymmetric, bilateral, progressive ectasia of the cornea that affects approximately one in 2,000 people. Current “conventional” treatment options for keratoconus include both rigid gas permeable contact lenses and penetrating keratoplasty. Unfortunately, neither of these options treat the underlying cause of ectasia. Corneal collagen cross-linking (CXL), however, is a relatively recent procedure currently under investigation to determine if it can slow, stabilize, or even possibly reverse the progression of corneal ectasia in patients with keratoconus.

Faculty/Editorial Board:

Karen K. Yeung, O.D., and Barry A. Weissman, O.D., Ph.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID 27906-AS. Please check with your state licensing board to see if this approval counts towards your CE requirement for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Neither Dr. Yeung nor Dr. Weissman have any relationships to disclose.

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Keratoconus is an asymmetric, bilateral, progressive ectasia of the cornea that affects approximately one in 2,000 people.^1,2 Compared to normal corneas, the mechanical stability of keratoconic corneas are decreased because of increased pepsin digestion and fewer collagen cross-links.³

Current “conventional” treatment options for keratoconus include both rigid gas-permeable contact lenses and penetrating keratoplasty. Unfortunately, neither of these options treat the underlying cause of ectasia, and therefore cannot stop the progression of keratconus.

Corneal collagen cross-linking (CXL), however, is a relatively recent procedure currently under investigation to determine if it can slow, stabilize, or even possibly reverse the progression of corneal ectasia in patients with keratoconus.⁴

Introduction to CXL

CXL increases the rigidity of the cornea by inducing additional cross-links within or among collagen fibers using ultraviolet-A (UVA) light and riboflavin. The UV light reacts with the riboflavin to cause covalent bond formations between the corneal fibers.

It must be noted, however, that although some ophthalmologists are performing CXL “off-label,” the procedure is not currently FDA approved. FDA approved clinical trials are underway in the U.S. to determine its safety and efficacy.

First studied in a series of timeand dose-response assays on rabbit and porcupine eyes, researchers found a 70% to 300% increase in corneal rigidity after CXL.^4-7 The first CXL procedures on keratoconic human patients, however, only date to 1998. In fact, the first clinical application with CXL was used to treat corneal melt.⁸

In 2003, research showed that CXL appeared to halt the progression of keratectasia.⁹ Subsequent studies with limited follow-up data supported these findings.^10,11 Additionally, a controlled, prospective study of CXL’s effect on keratectasia patients that was completed in early 2009 showed that corneal shape appears to undergo a process of regularization, evoluting toward a more “normal” shape during the first year after treatment.¹²

Procedure

A standard CXL procedure begins with the administration of an anesthetic, followed by debridement of the central 7mm to 9mm of the cornea to allow uniform diffusion of the riboflavin into the stroma.⁹ Next, riboflavin 0.1%, suspended in a dextran T500 20% solution is applied and allowed to permeate the cornea before UVA irradiation.

Riboflavin is reapplied every five minutes during a 30-minute irradiation period. Following treatment, a topical antibiotic ointment is applied until corneal reepithelialization is achieved.⁹ Bandage soft contact lenses can be used for pain management and/or to enhance healing.

UVA irradiation has a toxic effect on cell viability and can cause keratocyte and corneal endothelial cell destruction or death, as well as possible lens and retinal damage.^9,13,14 Additionally, it is suggested that CXL treatment be restricted to the anterior 250µm to 350µm of the stroma. Thus, CXL is not recommended for patients whose corneas are thinner than 400µm.¹³ Because 85% to 90% of the UVA radiation is absorbed in the anterior 400µm of the cornea, the procedure should spare the patient’s deeper corneal structures, crystalline lens and retina.¹⁴

Pathophysiology

Histologically, CXL facilitates covalent bond formations between collagen fibers and increases collagen fiber diameter. Together, these processes result in greater collagen rigidity in the anterior 200µm of the cornea.^14,15 Additionally, CXL promotes a possible resistance to pepsin digestion, which may be an important consideration for keratoconus patients who exhibit elevated collagenase activity.^16-18

Immediately following the procedure, CXL causes several corneal changes, such as edema, superficial nerve loss, cellular modifications and isolated endothelial damage.¹⁹ In one study of five patients who underwent CXL, confocal microscopy suggested that all corneal layers were affected to some degree.^20,21

Still, no significant endothelial changes were documented upon measurement of cell density and hexagonality at the one-year follow-up. Further, no collateral damage to the unexposed limbal areas was documented, and the epithelium regenerated completely within four days with use of a soft bandage contact lens.²² However, keratocyte apoptosis up to 300µm deep in the stroma has been documented in some CXL patients.¹³

Disconnected corneal nerves regenerate within six months after the procedure, which allows for partial return of corneal sensitivity. The nerve plexus gradually improves, but is not well defined until one year after the procedure. In two years, the number of nerve fibers increases and interconnections begin to resemble their preoperative structure. Also, there is increased reflectivity of the extracellular matrix, enlarged keratocytes, extracellular deposits and remodeling of the endothelial layer.^13,20-22

Mid- and anterior stromal keratocytes start repopulating within two to three months following CXL; however, this process is not complete until month six. The posterior stroma (beyond 300µm to 350µm deep) also experiences an increase in keratocyte density at one to three months post-op.

In the mid and anterior stroma, there is increased density of the extracellular matrix with active keratocyte nuclei at three to six months. The repopulated keratocytes are thought to form new, well-structured collagen and more compact lamellar interconnections, resulting in improved structural integrity.

One study showed that riboflavin/UVA collagen CXL-induced cellular wound healing mechanisms and altered the normal structure and cellularity of the cornea during three years of continuous followup.¹⁹

CXL appears to be histologically similar for patients who have ectasia secondary to keratoconus or a LASIK procedure.²¹

Adverse Effects of CXL

Though long-term complications from CXL have not yet been extensively studied and documented, reports of several short-term complications do exist.

• Treatment failure. CXL failure is largely defined as keratoconic progression following treatment. One study of 117 eyes from 99 patients who underwent CXL documented a failure rate of 7.6% at one-year follow-up.²³ The results also indicated that 2.9% of eyes lost two or more lines of Snellen visual acuity. Additionally, sterile infiltrates were noted in 7.6% of eyes, and corneal scars were present in 2.8% of eyes.

The researchers concluded that risk factors for CXL failure included a preoperative patient age of 35 years or older, an entering spectacle-corrected visual acuity better than 20/25 and a maximum keratometry reading greater than 58.00D.²³

• Postoperative infection/ulcer. Debriding the corneal epithelium theoretically exposes the cornea to microbial infection. Indeed, there have been reports of Acanthamoeba keratitis development secondary to corneal melt five days after CXL treatment, as well as multiple corneal infiltrates, avascularized corneal scar and a permanent reduction in visual acuity secondary to bacterial keratitis three days after CXL.^24-27 Reactivated herpetic keratitis and neurodermatitis have also been reported following CXL.^28,29

One study reported four cases of severe keratitis in a group of 117 keratoconic eyes treated with standard CXL.³⁰ The four patients exhibited signs of ciliary redness, anterior chamber cells and central keratic precipitates. Additionally, they demonstrated white infiltrates both at the edge of and within the CXL treatment zone 24 hours post-op. Also, best-corrected visual acuity was reduced in two of four cases.

• Stromal haze. One study indicated that 14 of 163 eyes developed significant stromal haze that decreased patients’ best-corrected visual acuity one year after CXL.³¹

Another study documented stromal haze in five of 44 patients within six months of undergoing CXL.²²

There has been debate as to whether stromal haze is a normal finding after CXL because of its frequency.³² However, most cases of postoperative stromal haze resolve within one year. CXLinduced stromal haze extends into about 60% of the stroma, compared to PRK-induced haze, which is strictly subepithelial.³³ The haze may be associated with the depth of CXL into the stroma as well as the amount of keratocyte loss.^22,23,33 Patients with advanced keratoconus may have a higher risk for stromal haze development after CXL due to steeper and thinner corneas.³¹

• Increased IOP. One study showed transient increases in intraocular pressure one week, one month, three months and six months after CXL.³⁴ Another study showed an average postoperative IOP increase of 2mm Hg.²⁹ In an in vitro model of human corneas, IOP was also increased.³⁵

It is important to note, however, that a Goldman applanation tonometer may not be the best device to use in the follow-up of patients after CXL because its measurements are subject to changes in corneal rigidity. Future studies are needed to determine the best way to monitor IOP in post-CXL patients.

Treatment Variations

• CXL with and without epithelial removal. Current studies are determining whether the epithelium should be partially or completely removed during the CXL procedure. Because tight junctions between superficial cells of the corneal epithelium prevent the permeation of riboflavin, complete debridement of the epithelium may be necessary to ensure adequate and uniform stromal saturation of riboflavin during the procedure.^7,9 A homogenous distribution of riboflavin also restricts the cytotoxic damage to 200µm of stromal depth and minimizes the risk to the endothelium.³⁶

Partial grid-pattern epithelial removal limits the riboflavin uptake in a non-homogenous manner, which may adversely affect the efficacy of CXL.³⁷

If a surgeon removes only the superficial epithelium with an excimer laser, patients often experience more postoperative pain.³⁸ Additionally, the patient might require prolonged riboflavin application to achieve standard corneal saturation.³⁸

CXL without epithelial debridement (C3R) may reduce the risk of infection because the epithelium remains intact. But, one laboratory study confirmed that C3R has a 20% reduction of CXL biomechanical effects and may compromise deeper parts of the eye.^39,40

• Hypo-osmolar riboflavin. Currently, CXL is contraindicated for patients with corneas thinner than 400µm. However, by temporarily expanding thin corneas using a hypo-osmolar riboflavin solution, one study suggested that more patients with corneas less than 400µm thick could be candidates for CXL.⁴¹ Theoretically, this procedure would protect the underlying endothelium for thinner corneas. Clearly, more clinical follow-up is still necessary to determine if this procedure is as effective as standard CXL.

• ß-nitro alcohols. Because UVA causes keratocyte and corneal endothelial cell toxicity, the use of short-chain aliphatic ß-nitro alcohols in lieu of UVA-riboflavin to cross-link collagen tissue might be a viable alternative.⁴² Currently being evaluated on porcine globes, ß-nitro alcohols would render UVA radiation unnecessary, allowing patients with both thick and thin corneas to undergo cross-linking.

• Flash-linking. Results from one recent study advocate the use of surface wave elastometry to quickly cross-link collagen fibers.⁴³

Also currently being evaluated on porcine eyes, this technique may stiffen the cornea and require just 30 seconds of UVA exposure.

Long-Term Results

Data on the long-term results of CXL are currently limited to a maximum four years. One study followed 241 eyes of 130 patients who underwent CXL for six years (average follow-up of 26.7 months). At three-year follow-up, 33 eyes remained in the study. Improvement in bestcorrected visual acuity by at least one line occurred in 58% of eyes and decreased astigmatism (average 1.54D) was noted in 54% of eyes.²⁴ (No trends were recorded after three years of follow-up due to the small number of remaining patients.)

These results are supported by other data that suggest CXL leads to corneal flattening, with a reduction in myopia, astigmatism, coma and spherical aberrations.^29,44 In a prospective study of 23 eyes, the authors found that progression of keratoconus was halted in all treated eyes, exhibiting a 2.00D reduction of maximum keratometry in 70% of patients.⁹ Endothelial cell density and lens transparency remained the same. The full extent of kerectasia regression after CXL is still unknown because of limited follow-up data.

Other Applications for CXL

In addition to keratoconus, corneal cross-linking may be used to correct iatrogenic keractasia secondary to LASIK, to treat corneal melt or as an adjunct therapy in intrastromal ring implantation.^8,45-47 In fact, research that evaluated the efficacy of C3R on keratoconic eyes after Intacs implantation found that the procedure had an additive effect in improving best-corrected visual acuity and steep keratometry measurements.^48,49

Some researchers have also proposed an adjunctive role for CXL in the treatment of corneal infection, because the procedure enhances corneal resistance against enzymatic degradation.¹⁶

CXL is being developed as a new procedure to slow, stop or possibly reverse the progression of several corneal ectasias. Long-term studies are still necessary to determine both the success and adverse side effects of CXL. Additional studies are also needed to evaluate the long-term biomechanical effect of CXL.

Currently, there is no effective way to measure collagen turnover, so postoperative stability remains a concern.⁴⁰ More studies are also needed to identify potential contraindications, such as severely advanced age, corneal shape and/or present stage of ectasia.

Promising long-term results may expand CXL to developing countries where penetrating keratoplasty incurs more risks and costs than in the United States.⁹ Perhaps there will be a time when all patients with ectasia are treated with CXL. In the meantime, however, your keratoconic and post-refractive surgery ectasia patients will still require your care. So, don’t put away your rigid gas-permeable lenses just yet!

Dr. Yeung is a director of optometry at the University of California, Los Angeles Arthur Ashe Student Health Center. Dr. Weissman is chief of contact lens service and professor of ophthalmology at the Jules Stein Eye Institute at the University of California, Los Angeles.

References

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