This article is more than 5 years old. Information may no longer be current.
Many issues regarding cross-linking remain unclear
There has been an explosion of interest in keratoconus in recent times, along with an “apparent” increase in the prevalence of this condition.
This can be attributed to several factors, including a possible increase in the screening of patients due to the popularity of corneal refractive surgery, with possible self-selection of patients with early cones and suboptimal spectacle and soft contact lens vision who opt to undergo a refractive procedure. When patients present for screening, the availability of better devices to image corneal shape — both the anterior and posterior surfaces — increases the detection of this condition in its early stages, something that was not possible until the advent of sophisticated topographers.
Management options have increased, with newer contact lens systems that attempt to better conform to the altered corneal shape in these eyes and provide better comfort. With scleral contact lenses, even advanced cones can now be managed. When a patient fails contact lenses or desires independence from them, the use of intrastromal rings and the combination of excimer corneal reprofiling using topography guidance can be considered, often in conjunction with implantable Collamer lenses (STAAR Surgical), although the effort is often to improve visual function, without attempting for “perfect” unaided vision.
However, arguably the most important advance in keratoconus management in recent times has been the use of collagen cross-linking to “freeze” the corneal shape, preventing further deterioration. Since its inception, cross-linking has undergone numerous modifications in technique and parameters, and it is in now used in conjunction with some of the other methods mentioned to “lock in” the effects of these procedures. Finally, when all else fails, deep anterior lamellar keratoplasty, which preserves the patient’s endothelium, is used, and this has increased in popularity with the use of the big bubble technique. In heavily scarred corneas, however, the penetrating graft remains a useful option.
Given the ease of performance of the cross-linking procedure, it is perhaps not surprising that it has rapidly gained favor among ophthalmic surgeons, even those who do not have a cornea subspecialty interest. The increased use by multiple surgeons has also spawned numerous variations, and hence, this is a topic with many areas that deserve further attention. The round table in this issue describes some of these controversies.
Patient selection has been an area of interest because the procedure offers the best results when performed in “ideal” patients. Areas of debate in this context include optimal corneal thickness, maximal keratometry, and performance of the procedure in the presence of pre-existing scars, in children, in those with active ocular surface allergies and in those who have corneal distortion that does not permit optimal visual restoration with spectacles or contact lenses. Finally, while most studies require definite prospective evidence of keratoconus progression before inclusion, in the real world, whether this is required in an 18-year-old with documented changes in his vision and refraction — per the patient and obvious cones on topography — is questionable. Of course, the same may not be applicable in a 35-year-old in whom the natural history of the condition indicates that the progression is likely to be slowing down or stopping.
Once it has been decided to perform the procedure, there are numerous variations possible with regards to the parameters used during the procedure. The type of riboflavin used has seen numerous changes, particularly with respect to the addition of epithelial toxins that allow the penetration of riboflavin through the intact epithelium. This has been initiated because of the significant pain factor that epithelium-off cross-linking produces in the initial postoperative period. Similarly, the open epithelium can result in an increased occurrence of corneal infections, and particularly in those with allergies, they can take prolonged time to heal, with the resultant complications. However, proponents of the original epithelium-off technique argue that while riboflavin can pass through the chemically altered epithelium, this may not be true for the ultraviolet light applied. This is an ongoing controversy with both camps providing data that at least partially support their claims. In order to achieve more efficient corneal saturation, the use of wells, with pooled riboflavin, rather than drops has been suggested. An increase in riboflavin concentration has also been proposed, although this is yet to gain popularity.
While the total energy that should be delivered to the cornea during the procedure is not debated, the relationship between power and time has seen alterations. Because the 1-hour duration of the original Dresden procedure was felt to be too long, the accelerated procedure, which works by invoking the Bunsen-Roscoe law of reciprocity for photochemical reactions, has been introduced. The law states that equivalent effects can be produced by titrating intensity and time in a given system, as long as the total radiant energy level is attained. Hence, the procedure is now performed by using 30 mW/cm2 for a duration of 3 minutes, in lieu of the original protocol requiring 3 mW/cm2 for 30 minutes, thereby significantly reducing the treatment time. A deeper analysis of the actual photochemical events during the procedure, however, indicates that in a biological system as in the cornea, for the type 2 reaction to occur, a significant amount of oxygen species are required, and excessively shortening treatment time may affect the procedure because there is not enough time for oxygen regeneration in the tissues, which is another area of controversy.
To address this issue, there has been a move to provide the ultraviolet light in a pulsed manner instead of in a continuous beam. Similarly, the actual beam profile that is ideal for cross-linking is debated because a Gaussian profile may result in suboptimal energy delivery at the periphery of the beam. A beam profile that addresses this issue is now available, and as seen in the discussions, it is possible that, in time, a topography-guided profile may also be available. There is also discussion as to whether centering the procedure on the thinnest part of the cornea, rather than on the center, would help improve efficiency, although this would then require alterations in technique to protect the limbal epithelium and stem cells, which is already a matter of concern.
The postoperative treatment protocols are varied, but the most significant area of concern is the lack of robust metrics to evaluate the outcomes of the procedure. There are issues with using current methods of corneal evaluation, especially in the more severely distorted corneas, and while visual improvement is a good measure of success, assessing the corneal architectural changes and structural changes has proven more challenging, despite the application of Placido and Scheimpflug topography, aberrometry, confocal microscopy and optical coherence tomography technology toward this end.
Hence, while it is clear that collagen cross-linking does offer clinical benefits and increases the surgeon’s ability to better deal with keratoconus, and that the procedure is increasingly being performed, it is also equally clear that many, if not all, aspects of the procedure have significant issues that remain unclear. Finally, based on the round table discussion, in which experts have highlighted current gaps in knowledge about this procedure and indicated areas for further research, it is possible that, although cross-linking is currently a single approach, in time it may evolve as multiple variations that may need to be rationally applied to particular subsets of keratoconus patients to increase both the efficacy and the safety of treatment.
References:
Rao SK. Indian J Ophthalmol. 2013;doi:10.4103/0301-4738.116071.
Richoz O, et al. Transl Vis Sci Technol. 2013;doi:10.1167/tvst.2.7.6.
Vinciguerra P, et al. Ophthalmology. 2009;doi:10.1016/j.ophtha.2008.09.048.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; +852-3997-3266; fax: +852-3996-8212; email: dennislam.gm@gmail.com.
Disclosure: The authors have no relevant financial disclosures.