Eyeworld

EW FEATURE 78 Update on crosslinking • September 2017 by Liz Hillman EyeWorld Staff Writer AT A GLANCE • Collagen crosslinking is best known for its ability to strengthen progres- sive keratoconic and ectatic corneas, but researchers and clinicians see refractive possibilities as well. • Customized crosslinking—targeting treatment to the area of most corne- al weakness—is showing promise in improving visual outcomes. • LASIK combined with crosslinking has been shown to improve refractive stability. • Crosslinking is also making strides in the correction of low myopia, hyperopia, and astigmatism. A look at applications for crosslinking beyond keratoconus C ollagen crosslinking has already established its value in its ability to halt progressive keratoconus and strengthen corneas weakened by post-refractive surgery ectasia. The quality of vision is not directly addressed though with the standard Dresden protocol, whose main purpose is simply biomechani- cal strengthening. However, research continues to progress on various fronts as to the potential refractive capabilities of crosslinking, including custom- ized crosslinking for keratoconus to promote more visual improvement, LASIK combined with crosslinking to strengthen the cornea, and cross- linking for the correction of refrac- tive error. Customized crosslinking Topography-guided crosslinking, zonal crosslinking, customized crosslinking: It goes by many names, but in short it describes the idea of targeting crosslinking treatment to the weakest area of the cornea. William Dupps, MD, PhD, Cleveland Clinic, Cleveland, led studies that modeled this idea, building on his group's research exploring the biomechanical origins of keratoconus. 1 "The premise is there is a weak- ening that occurs in the cornea that progresses over time," Dr. Dupps explained. Using clinical tomogra- Refractive opportunities for crosslinking continued on page 80 phy of a patient's eyes—one with keratoconus, the other without—Dr. Dupps said they created a virtual eye based on the real patient's corneal shape. In the unaffected eye model, they weakened a point on the cor- nea and saw curvature increase. "It developed a cone that was very similar to the one that had already manifested in the patient's other eye," he said. From there, the next step was to study how to approach therapy. Dr. Dupps said they researched how different treatments changed stiff- ness and thus corneal shape. In the model of an eye with a more central cone and another with an off-center cone, they looked at the differenc- es in response using the standard 9 mm global treatment vs. a more focal, or zonal, treatment centered on the steepest point. "We found that in the few cases we simulated, it predicted we would produce more than two times the amount of flattening of the steep- est portion of the cone compared to the standard treatment. Because this model incorporates the full 3-D shape of the cornea, we can pull out metrics that relate to the optical quality of vision. We computed aberrations like coma and spherical aberration and saw much larger decreases in coma with a zonal approach, which is the main aber- ration in keratoconus that we think degrades vision. "The take-home was that we should continue to explore the potential of more customized treatments to not only stabilize the disease, but in some cases to achieve more optical rehabilitation than we could with a standard treatment," Dr. Dupps said. This research has moved from the theoretical/model domain into some clinical cases. Matthias Elling, MD, senior physician, Ruhr Univer- sity Bochum, Bochum, Germany, pointed to research published in 2016 by Seiler et al. that found that 37% of eyes in the customized group (compared to 11% in the standard group) had 2 D or more of flattening at 1 year postop, as well as a better epithelial healing time, change in Kmax, and regularization. 2 Another paper published earlier this year showed similar safety of standard crosslinking compared to topog- raphy-guided but with a stronger flattening effect and better improve- ment in corrected distance visual acuity in the latter group. 3 When it comes to customized crosslinking, Dr. Dupps pointed to a couple of subtleties that he said could be important for this type of treatment. There are two different ways to calculate curvature of the cornea—axial curvature and tangen- tial curvature—which he said with keratoconus could give two very different locations for the steepest part of the cone. "We at least need to carefully report exactly what curvature metric is being used to guide [customized treatment] and then assess the out- comes in light of that," Dr. Dupps said. Dr. Dupps said there isn't a tool yet that identifies the weakest point of the cornea—steepest curvature point acts as a surrogate for now— but he said emerging tools like Brillouin microscopy and OCT elas- tography are in translational trials and could provide this information in the future. Dr. Elling pointed to a 2014 study that used Brillouin microscopy to show that stromal weakening in keratoconus is concen- trated in the region of the cone. 4 The other factor brought up by Dr. Dupps is how long the custom- ized treatment effect lasts. "Kerato- conus is a progressive condition. If you initially have a small zone of weakening, but then 20 years later you have progressive weakening of untreated peripheral corneal regions, the shape may continue to change. This might explain some cases of progressive central corneal flatten- ing after CXL, so there is a question of whether or not we should still be delivering some crosslinking treatment to the whole cornea while concentrating more treatment in the weakest area. That's another import- ant open question that needs further investigation," he said. "In terms of cons, a disadvan- tage [of customized crosslinking] that I can think of is that more physician input is required into de- termining the appropriate treatment pattern for each patient," Dr. Elling said. "However, this may become easier over time as the ophthalmic community gains experience with the procedure. "We have treated a few cases of irregular corneal astigmatism using this approach and have been very satisfied with the outcomes, partic- ularly in terms of visual improve- ment," Dr. Elling said. LASIK Xtra It's well established that LASIK can weaken the cornea and in some rare cases result in refractive drift or cor- neal ectasia. Crosslinking has been established to strengthen the corneal collagen bonds, so why not com- bine the two procedures? That's the concept behind LASIK Xtra (Avedro, Waltham, Massachusetts). "Published data on corneal crosslinking demonstrates that the procedure adds strength to the cornea, therefore the concept behind the combination procedure is an interesting one," Dr. Elling said, add- ing that he does not have personal experience with it, but noted that "the published literature supports the concept that CXL can add safety to the LASIK procedure, and that there is likely an improvement in refractive stability in highly myo- pic or hyperopic patients." He also mentioned other work that suggests better flap adhesion in these cases. 5–7 Anders Behndig, MD, professor and chief physician, Department of Clinical Sciences, head of the De- partment of Ophthalmology, Umeå University, Umeå, Sweden, offered his perspective on LASIK Xtra, calling it a "promising method for preventing iatrogenic ectasia after LASIK." "It has a theoretical rationale, and data are coming in supporting its clinical value. Furthermore, it ap- pears the method may have optical benefits, [such as] the stability of the postoperative refraction, but it's a bit early to say much about that," Dr. Behndig said. Though he doesn't have clini- cal experience with LASIK Xtra, Dr. Dupps said they've simulated it in computational models. The ques- tions they hoped to answer were whether additional flattening of the cornea with crosslinking would cause over or under corrections that would require physicians to change their nomogram for LASIK and if it would have a protective effect against ectasia. Dr. Dupps said there was less than a quarter diopter difference in the simulation between the LASIK

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