Advances in the technology of corneal cross-linking for keratoconus.

Corneal cross-linking (CXL) with ultraviolet-A (UVA) and riboflavin was introduced over 15 years ago and has been widely adopted as a treatment for keratoconus. Several studies have demonstrated the safety and efficacy of the procedure performed according to a standard protocol. Recent scientific and technological advances have highlighted the opportunity for optimization of the CXL procedure through modifications to this protocol. Advances in the technology of CXL include new riboflavin formulations, higher irradiance UVA sources, and programmable UVA illumination patterns. Several laboratory and clinical studies demonstrate that these modifications may provide equivalent treatment effect in shorter total treatment times. Additionally, although the original purpose of CXL was to stabilize the cornea and prevent further visual loss in keratoconus, patient-specific computational modeling and customized CXL with programmable UVA treatment patterns demonstrate the potential for CXL to be used as a means of improving corneal topography to maximize visual rehabilitation in patients with keratoconus. This review aims to provide an overview of these advances in CXL technology designed to optimize the efficiency or efficacy of the clinical CXL procedure.

Corneal cross-linking versus conventional management for keratoconus: a lifetime economic model.

AIMS: To assess the cost-effectiveness of corneal collagen cross-linking (CXL) versus no CXL for keratoconus in the United States (US). METHODS: A discrete-event microsimulation was developed to assess the cost-effectiveness of corneal cross-linking (CXL, Photrexa + KXL combination product) versus no CXL for patients with keratoconus. The lifetime model was conducted from a US payor perspective. The source for CXL efficacy and safety data was a 12-month randomized, open-label, sham-controlled, multi-center, pivotal trial comparing CXL versus no CXL. Other inputs were sourced from the literature. The primary outcome was the incremental cost per quality-adjusted life year gained. Costs (2019 USD) and effects were discounted 3% annually. The impacts of underlying uncertainty were evaluated by scenario, univariate, and probabilistic analyses. RESULTS: Starting at a mean baseline age of 31 years and considering a mixed population consisting of 80% slow-progressors and 20% fast-progressors, the CXL group was 25.9% less likely to undergo penetrating keratoplasty (PK) and spent 27.9 fewer years in advanced disease stages. CXL was dominant with lower total direct medical costs (-$8,677; $30,994 versus $39,671) and more QALYs (1.88; 21.80 versus 19.93) compared to no CXL. Considering the impact of reduced productivity loss in an exploratory scenario, CXL was associated with a lifetime cost-savings of $43,759 per patient. CXL was cost-effective within 2 years and cost-saving within 4.5 years. LIMITATIONS: Limitations include those that are common to similar pharmacoeconomic models that rely on disparate sources for inputs and extrapolation on short-term outcomes to a long-term analytical horizon. CONCLUSIONS: Keratoconus is a progressive and life-altering disease with substantial clinical, economic, and humanistic consequences. The economic value of cross-linking is maximized when applied earlier in the disease process and/or younger age, and extends to improved work productivity, out-of-pocket costs, and quality of life.

Inhibiting the neuronal isoform of nitric oxide synthase has similar effects on the compensatory choroidal and axial responses to myopic defocus in chicks as does the non-specific inhibitor L-NAME.

In birds, the choroid plays a role in the visual regulation of eye growth, thickening in response to myopic defocus, and thinning in response to hyperopic defocus, in both cases moving the retina towards the image plane. This response is rapid, occurring within hours of the defocus stimulus. These changes are consistently associated with slower changes in the sclera, that result in the appropriate changes in axial elongation, decreasing growth in response to myopic defocus and increasing it in response to hyperopic defocus. The molecular mechanisms underlying the scleral response involve changes in the synthesis of extracellular matrix molecules, however, those underlying the changes in choroidal thickness are not known. However, evidence suggests that it may involve the gaseous signal molecule nitric oxide, as nitric oxide is a potent smooth muscle relaxant, and injections of the non-specific nitric oxide synthase inhibitor L-NAME transiently inhibits the thickening response. Interestingly, it also dis-inhibits ocular growth, in accordance with a mechanistic link between the two responses. If nitric oxide is part of the signal cascade underlying the visual regulation of eye growth, it would be important to ascertain the source of the molecule. As a first step towards doing so, we used various more specific NOS inhibitors and studied their effects on the choroidal and growth responses. Birds (7-12 days old) were fitted with +10 D lenses on one eye. On that day, single intravitreal injections (30 microl) of the following inhibitors were used: nNOS inhibitor N(omega)-propyl-L-arginine (n=12), iNOS inhibitor L-NIL (n=16), eNOS/iNOS inhibitor L-NIO (n=15), non-specific inhibitor L-NMMA (n=30) or physiological saline (n=18). Ocular dimensions were measured using high-frequency A-scan ultrasonography at the start of the experiment, and at 7, 24 and 48 h after. We found that the nNOS inhibitor N(omega)-propyl-L-arginine had the same inhibitory effects on the choroidal response, and dis-inhibition of the growth response, as did L-NAME; neither of the other inhibitors had any effect except L-NMMA. We conclude that the choroidal compensatory response is influenced by nNOS, possibly from the intrinsic choroidal neurons, or the parasympathetic innervation from the ciliary and/or pterygopalatine ganglia.

Lasik Xtra® Provides Corneal Stability and Improved Outcomes.

A new procedure which combines LASIK and corneal cross-linking (Lasik Xtra®) has been proposed as an alternative to traditional LASIK. It is aimed at restoring strength to the cornea, increasing stability in visual outcomes, increasing the accuracy of the refractive correction, and potentially lowering enhancement rates. This article reviews the current clinical evidence which has been published on the topic and reviews both the safety and efficacy argument for the procedure.

Consecutive laser in situ keratomileusis and accelerated corneal crosslinking in highly myopic patients: preliminary results.

PURPOSE: To report the preliminary results of an evaluation of the safety and predictability of Lasik Xtra, a technique combining laser in situ keratomileusis (LASIK) and accelerated corneal crosslinking, in highly myopic patients. METHODS: In this consecutive comparative case series, 70 consecutive eyes undergoing LASIK for correction of high myopia (-8.00 D to -19.00 D manifest refractive spherical equivalent) were prospectively recruited and treated with Lasik Xtra and compared with a retrospective consecutive control group of 64 eyes who had undergone LASIK alone for correction of high myopia. The follow-up was 3 months. Outcome measures included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and refraction. RESULTS: A total of 61% of LASIK only eyes achieved UDVA of 20/25 or better, compared to 98% of Lasik Xtra eyes (p<0.001) at 3 months. A greater percentage of eyes were within ±0.50 of the intended correction in the Lasik Xtra group (88%) than in the LASIK only group (65%) at 3 months (p = 0.005). Linear regression of the scatterplot of attempted versus achieved correction reveals a coefficient of determination of 0.83 in the LASIK only group vs 0.99 in the Lasik Xtra group. A trend (p = 0.051) towards greater refractive drift in the LASIK group (-0.13 D) vs the Lasik Xtra group (-0.04 D) was observed. No adverse events were observed in either group. CONCLUSIONS: Lasik Xtra did not reduce the refractive accuracy of the LASIK procedure. The addition of crosslinking may induce early stabilization of the cornea after LASIK, improving the predictability of refractive outcomes in highly myopic subjects.

Evaluation of epithelial integrity with various transepithelial corneal cross-linking protocols for treatment of keratoconus.

Purpose. Corneal collagen cross-linking (CXL) has been demonstrated to stiffen cornea and halt progression of ectasia. The original protocol requires debridement of central corneal epithelium to facilitate diffusion of a riboflavin solution to stroma. Recently, transepithelial CXL has been proposed to reduce risk of complications associated with epithelial removal. Aim of the study is to evaluate the impact of various transepithelial riboflavin delivery protocols on corneal epithelium in regard to pain and epithelial integrity in the early postoperative period. Methods. One hundred and sixty six eyes of 104 subjects affected by progressive keratoconus underwent transepithelial CXL using 6 different riboflavin application protocols. Postoperatively, epithelial integrity was evaluated at slit lamp and patients were queried regarding their ocular pain level. Results. One eye had a corneal infection associated with an epithelial defect. No other adverse event including endothelial decompensation or endothelial damage was observed, except for epithelial damages. Incidence of epithelial defects varied from 0 to 63%. Incidence of reported pain varied from 0 to 83%. Conclusion. Different transepithelial cross-linking protocols have varying impacts on epithelial integrity. At present, it seems impossible to have sufficient riboflavin penetration without any epithelial disruption. A compromise between efficacy and epithelial integrity has to be found.

Inhibiting the transient choroidal thickening response using the nitric oxide synthase inhibitor l-NAME prevents the ameliorative effects of visual experience on ocular growth in two different visual paradigms.

It is generally accepted that the increase in choroidal thickness in response to myopic defocus in chicks acts to move the retina towards the image plane. It may also constitute part of the signal cascade in the visual regulation of eye growth. To test this, we used the nitric oxide synthase inhibitor l-NAME to inhibit the defocus induced choroidal thickening under two different visual conditions, and looked at the effects on ocular growth rate. Exp. 1: Deprivation/Vision: chicks were monocularly deprived of form vision with translucent diffusers from day 6 to day 9. In the middle of each day the diffusers were removed for 2 h. One group received an intravitreal injection of 30 microl l-NAME (16 micromole; n=12) prior to the vision, a second group received injections of physiological saline (n=11). Exp. 2: Recovery/Vision: chicks were made myopic by form deprivation from day 6 to day 10. On days 11 to 14 the diffusers were removed for 2 h per day for 4 days to allow eyes to "recover" from the myopia. One group received an injection of l-NAME prior to vision (n=8), the other saline (n=6). Refractive errors were measured with a refractometer at the start (days 6 and 11) and end (days 10 and 15, respectively) of both experiments. Ocular dimensions were measured with high frequency A-scan ultrasonography at the start and end, and on the third experimental day immediately before and after the period of vision. Choroidal retinoic acid synthesis was measured by HPLC. Finally, NO production and scleral proteoglycan synthesis were measured in eyes wearing positive lenses 6 and 24h after an injection of l-NAME. l-NAME prevented the transient vision-induced choroidal thickening in both experiments. Furthermore, l-NAME inhibited the protective effect of brief daily vision: eyes became significantly more myopic than saline controls (exp. 1: -9 D vs -2.7D; exp. 2: -0.9 D vs +4.3 D; p<0.005 for both) and grew faster (change in lens-sclera: exp. 1: 295 vs 158 microm; exp. 2: 147 vs 39 microm; p<0.05 for both). Notably, l-NAME inhibited the growth of the anterior chamber (exp. 1: 88 vs 185 microm; exp. 2: 147 vs 254 microm; p<0.01 for both). Injections of l-NAME after the periods of vision had no effect on growth at the back of the eye, but still had an inhibitory effect on the anterior chamber. Retinoic acid levels in the drug-injected choroids were significantly decreased compared to controls. In eyes responding to positive lenses, l-NAME inhibited NO synthesis and disinhibited scleral glycosaminoglycan synthesis 6h after the injection. In summary, preventing the transient vision-induced increases in choroidal thickness altered ocular growth rate in a consistent manner under two different visual conditions, in both preventing the vision-induced reduction in growth rate. This supports the hypothesis that visually-induced changes in choroidal thickness play a role in the visual regulation of ocular growth.