The impact of interrupted corneal collagen crosslinking (CXL) treatment.

PURPOSE: To evaluate progression of keratoconus in patients where CXL treatment was interrupted due to insufficient swelling of the cornea. METHODS: A retrospective review was conducted of all patients with keratoconus diagnosis who underwent CXL at the Department of Ophthalmology, Örebro University Hospital (USÖ) during the years 2010-2017. In total 377 eyes of 280 patients were screened for inclusion. In 17 eyes (15 patients), the treatment was interrupted due to insufficient swelling of the cornea. Patient journals were reviewed and keratometry examinations were analysed for long-term progression. RESULTS: Eleven eyes (nine patients) were included in the study. Five eyes showed no signs of progression after the interrupted CXL treatment. In one eye progression continued, however, first after a period of a number of years, indicating a delayed course of clinical progression. CONCLUSION: This study indicates that debridement of the corneal epithelium and riboflavin administration without intense UVA radiation may slow or arrest the progression of keratoconus, likely due to photosensitisation from ambient light.

Effect of accelerated high-fluence riboflavin and rose bengal-mediated corneal cross-linking on resistance to enzymatic digestion.

PURPOSE: This study evaluated the effect of high-fluence accelerated corneal cross-linking on the resistance to enzymatic digestion, assessing two chromophore/light combinations: riboflavin/UV-A light (RF/UV-A) and rose bengal/green light (RB/green). METHODS: Freshly prepared ex-vivo porcine corneas (n = 189) were divided into 8 groups groups. Group A corneas were unirradiated controls without chromophore soaking (A0), or soaked with riboflavin (A1) or rose bengal (A2). Group B corneas underwent accelerated epi-off RF/UV-A CXL at fluences of 5.4 J/cm² (B1), 10 J/cm² (B2), or 15 J/cm² (B3). Group C corneas underwent accelerated epi-off RB/green CXL at fluences of either 10 J/cm² (C1) or 15 J/cm² (C2). Following CXL, all corneas were digested in 0.3% collagenase-A solution, and the time until complete dissolution was measured. RESULTS: Non-irradiated controls exposed to RF and RB enhanced corneal resistance to collagenase digestion, with RB having a stronger effect than RF. RF/UV-A-treated corneas showed significantly increased digestion resistance with increasing fluence levels. RB/green-treated corneas displayed enhanced digestion resistance with each increase in fluence up to 10 J/cm²; a 15 J/cm² fluence yielded similar digestion resistance times to a 10 J/cm² fluence, suggesting a plateau effect in accelerated RB/green CXL protocols. CONCLUSIONS: When compared to standard-fluence treatments, high-fluence accelerated epi-off CXL using both riboflavin and rose bengal significantly increases resistance to enzymatic digestion. The optimal settings for clinical protocols might be 15 J/cm² (30 mW/cm² for 8 min 20 s) for RF/UV-A and 10 J/cm² (15 mW/cm² for 11 min 7 s) for RB/Green Light.

The relationship between keratan sulfate glycosaminoglycan density and mechanical stiffening of CXL treatment.

The corneal stroma is primarily composed of collagen fibrils, proteoglycans, and glycosaminoglycans (GAGs). It is known that corneal crosslinking (CXL) treatment improves mechanical properties of the cornea. However, the influence of stromal composition on the strengthening effect of CXL procedure has not been thoroughly investigated. The primary objective of the present research was to characterize the effect of keratan sulfate (KS) GAGs on the efficacy of CXL therapy. To this end, the CXL method was used to crosslink porcine corneal samples from which KS GAGs were enzymatically removed by keratanase II enzyme. Alcian blue staining was done to confirm the successful digestion of GAGs and uniaxial tensile experiments were performed for characterizing corneal mechanical properties. The influence of GAG removal and CXL treatment on resistance of corneal samples against enzymatic pepsin degradation was also quantified. It was found that removal of KS GAGs significantly softened corneal tensile properties (P < 0.05). Moreover, the CXL therapy significantly increased the tensile stiffness of GAG-depleted strips (P < 0.05). GAG-depleted corneal buttons were dissolved in the pepsin digestion solution significantly faster than control samples (P < 0.05). The CXL treatment significantly increased the time needed for complete pepsin digestion of GAG-depleted disks (P < 0.05). Based on these observations, we concluded that KS GAGs play a significant role in defining tensile properties and structural integrity of porcine cornea. Furthermore, the stiffening influence of the CXL treatment does not significantly depend on the density of corneal KS GAGs. The findings of the present study provided new information on the relation between corneal composition and CXL procedure mechanical effects.

Evaluation of risk factors for treatment failure in canine patients undergoing photoactivated chromophore for keratitis - corneal cross-linking (PACK-CXL): a retrospective study using additive bayesian network analysis.

BACKGROUND: Infectious keratitis is a common ophthalmic condition in canine patients. Sequelae can include keratomalacia and corneal perforation, a vision threatening outcome. Photoactivated chromophore for keratitis - corneal cross-linking (PACK-CXL) is a non-surgical, adjunctive treatment method for infectious keratitis. The goal of this retrospective, multicenter study was to determine risk factors for treatment failure following PACK-CXL in canine patients suffering from suspected infectious keratitis. Medical records from four veterinary ophthalmology services were reviewed, and information related to patient demographics, ophthalmic findings, the PACK-CXL protocol used, and epithelialization time was collected and analyzed. Due to the potential for intervariable relationships, an additive Bayesian network (ABN) analysis was performed to evaluate these complex relationships. RESULTS: Records for 671 eyes (668 dogs) were included in the analysis. Based on the ABN, in the population included here, patients who underwent an accelerated PACK-CXL protocol were less likely to experience treatment failure versus patients treated with a slow protocol. Mutual dependencies between exposure variables were identified by ABN, which would have been overlooked using classical regression. Corneal re-epithelialization time was shortened following PACK-CXL combined with topical medical therapy compared to PACK-CXL alone. CONCLUSIONS: No risk factors associated with treatment failure were identified in the population included in the present study. Canine patients may benefit from the use of accelerated PACK-CXL protocols, especially when combined with topical antibiotics and anti-collagenolytic therapy. The reasons for this apparent positive impact on treatment outcome remain unclear.

Use of corneal cross-linking beyond keratoconus: a systemic literature review.

PURPOSE: The success of corneal collagen cross-linking in altering keratoconus' clinical course has driven a search for further uses of this procedure. This literature review aims to analyze the scientific evidence available for the benefit of cross-linking in the management of ophthalmic diseases other than progressive keratoconus or ectasia induced by corneal refractive procedures. METHODS: A systemic literature review. RESULTS: We reviewed 97 studies. We found that collagen cross-linking can limit the progression of several other corneal ectasias, thus reducing and limiting the need for keratoplasty. Collagen cross-linking also can reduce the refractive power of the cornea and can be considered for a moderate degree of bacterial keratitis or when the organism is unidentified, which is refractive to antibiotics alone. However, the comparative rarity of these procedures has limited the extent of evidence. In fungal, Acanthamoeba, and herpes virus keratitis, the evidence is inconclusive of the safety and efficacy of cross-linking. CONCLUSION: Current clinical data is limited, and laboratory data has not fully correlated with published clinical data.

The effect of accelerated pulsed high-fluence corneal cross-linking on corneal endothelium; a prospective specular microscopy study.

BACKGROUND: Corneal collagen cross-linking (CXL) is a procedure utilized for halting keratoconus progression with different approved protocols. The current study aimed to assess the corneal endothelial changes following the relatively new accelerated pulsed high-fluence protocol of epithelium-off corneal cross-linking for the treatment of mild to moderate keratoconus. METHODS: This prospective case series study enrolled 45 eyes of 27 patients with mild to moderate progressive keratoconus who underwent accelerated pulsed high-fluence CXL (pl-ACXL, 30 mW/ cm2 UVA at 365 nm wavelength, 8 min pulsed mode 1 s on / 1 s off with a total energy of 7.2 J/ cm2). The main outcome measures were corneal endothelial changes assessed by specular microscopy at 3 and 6 months postoperatively including endothelial cell density (ECD), coefficient of variation, percentage of hexagonal cells, average, minimum and maximum endothelial cell sizes. Demarcation line depth was assessed 1 month following surgery. RESULTS: The mean age of the studied sample was 24.89 ± 7.21. The mean preoperative ECD (2944.6 ± 247.41 cell/mm2) showed non-significant reduction at 3 and 6 months postoperatively (2931.03 ± 253.82 and 2924.7 ± 224.88 cell/mm2, respectively, P-value = 0.361). There were no significant changes in the mean coefficient of variation, percentage of hexagonal cells, average, minimum and maximum endothelial cell sizes at 3 and 6 months following pl-ACXL (P-value > 0.05). The mean demarcation line depth 1 month after pl-ACXL was 214 ± 17.43 µm. CONCLUSIONS: Corneal endothelial changes following accelerated pulsed high-fluence CXL were minimal with stability of endothelial cell count and non-significant morphological changes. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04160338 (13/11/2019).

Repeated sessions of PACK-CXL WA for the treatment of resistant bacterial keratitis: a retrospective study.

OBJECTIVE: The aim of this work is to evaluate the safety and efficacy of repeated sessions of photo-activated chromophore for keratitis-cross linking (PACK-CXL) window absorption (WA) for the treatment of resistant bacterial keratitis (BK). PATIENTS AND METHODS: This is a retrospective clinical cohort study. Thirty eyes with clinically suspected and lab-confirmed bacterial keratitis, resistant to appropriate antibiotic therapy- which was modified by sensitivity reports- for 2 weeks with failure of epithelialization for 4 weeks after the standard anti-microbial therapy (SAT) together with one setting of PACK-CXL WA were included. If after the first session of PACK-CXL, there is a start of improvement in the form of reduction of the size of corneal ulcer and stromal infiltrates together with the start of epithelialization on clinical examination and AS-OCT, another session of PACK-CXL WA was performed after one week, and so on, till the complete healing and resolution of bacterial keratitis and confirmation by negative bacterial culture. Identification of the micro-organisms was done by lab study before and after treatment. Corneal healing was evaluated by corneal examination and anterior segment OCT (AS-OCT). RESULTS: Thirty eyes of 30 patients were recruited in this study. They were 16 males and 14 females, their mean age was 44.3 ± 5.38 years. The mean ulcer size was 3.96 ± 1.87 (mm3), while the mean size of stromal infiltrates was 4.52 ± 2.24 (mm3). PACK-CXL WA treatment was performed an average of 2.87 times for the 30 eyes. Complete healing and resolution (Successful treatment) was observed in 27 eyes (90%) of cases and failure of epithelialization was observed only in 3 eyes (10%). Complete corneal healing was reported in the second month postoperatively in 90% of eyes. CONCLUSION AND RECOMMENDATION: PACK-CXL WA may be a promising, non-invasive treatment option for resistant bacterial keratitis. It may have a synergistic effect with standard antimicrobial treatment (SAT). Also, it can overcome the antibiotics resistance that has become rapidly spreading worldwide. Repeated sessions of PACK-CXL WA may be more effective for the treatment of resistant bacterial keratitis till complete epithelialization and resolution of BK than a single session with few complications. However, further prospective and comparative studies to support the results are needed.

Short-Term Effect of Conventional Versus Accelerated Corneal Cross-Linking Protocol on Corneal Geography and Stability.

Purpose: To determine the 6-month effect of conventional (CXL30) and accelerated cross-linking with a UVA intensity of 9 mW/cm2 (CXL10) on corneal stability and to investigate whether there was a difference in ABCD grading system parameters regarding the two different procedures. Methods: Twenty-eight eyes of 28 patients with a documented keratoconus (KN) progression were included. Patients were selected to undergo either epi off CXL30 or CXL10. At the baseline and the follow-up visits after one (V1), three (V2), and six months (V3), the patients underwent complete ophthalmic examination and corneal tomography. Results: In the CXL30 group, all the parameters from the ABCD grading system significantly changed from baseline to V3; parameter A decreased (p = 0.048), B and C increased (p = 0.010, p < 0.001), and D decreased (p < 0.001). In the CXL10 group, there were no changes in parameters A (p = 0.247) and B (p = 0.933), though parameter C increased (p = 0.001) and D decreased (p < 0.001). After an initial decline after one month, visual acuity (VA) recovered on V2 and V3 (p < 0.001), and median maximal keratometry (Kmax) decreased in both groups (p = 0.001, p = 0.035). In the CXL30 group, there were significant changes in other parameters; average pachymetric progression index (p < 0.001), Ambrósio relational thickness maximum (ARTmax) (p = 0.008), front and back mean keratometry (p < 0.001), pachymetry apex (PA) (p < 0.001), and front elevation (p = 0.042). However, in the CXL10 group, there were significant changes only in ARTmax (p = 0.019) and PA (p < 0.001). Conclusion: Both epi-off CXL protocols showed similar short-term efficacy in improving VA and Kmax, halting the progression of KN, and both similarly changed tomographic parameters. However, the conventional protocol modified the cornea more significantly.

Determination of efficacy of repeated CXL and probable risk factors in patients with progressive keratoconus.

PURPOSE: To evaluate the efficacy of Repeated CXL (Re-CXL) and determine probable risk factors that lead to Re-CXL in patients with progressive keratoconus. METHOD: In this retrospective study, the medical records of patients who had been re-operated in our center between 2014 to 2020 due to progressive keratoconus were evaluated; seven eyes of seven patients had undergone Re-CXL procedure. Pre- and post-treatment variables were recorded and analyzed using IBM SPSS Statistics software. RESULTS: The mean interval between the 1st and 2nd CXL was 49.71 months (range 12-72 months). Out of 7 patients for whom Re-CXL was considered necessary, eye rubbing was detected in 6 patients. Six patients were very young with a mean age of 13 years at primary CXL and 16.83 years at Re-CXL. Visual acuity and astigmatism did not change significantly after the Re-CXL procedure (p-values = 0.18, 0.91, respectively). When measurements of these indices prior to Re-CXL and post Re-CXL were compared, K1 (p-value = 0.01), K2 (p-value = 0.01), Kmean (p-value = 0.01), and Kmax (p-value = 0.008) changed significantly. As to pachymetry (p-value = 0.46), it did not change significantly. Kmax value regressed in all eyes after Re-CXL. CONCLUSION: Re-CXL procedure was effective in halting the progression of disease. As to the risk factors, eye rubbed-related mechanism like eye rubbing and VKC, lower age, and pre-operative Kmax value > 58 D are the risk factors of Re-CXL procedure.

Corneal cross-linking guards against infectious keratitis: an experimental model.

BACKGROUND: PACK-CXL (photo-activated chromophore for keratitis-corneal cross-linking) is an alternative option in treatment of corneal infections. It inhibits corneal melting by increasing the stromal resistance, besides the microbicidal effect of photo-activated riboflavin. METHODS: Corneal infection with Pseudomonas aeruginosa and Staph aureus bacteria was induced in 20 eyes of 10 rabbits after 6 weeks of corneal cross-linking in half of the eyes, while the other acted as control group. Clinical and corneal histopathological examination was done to evaluate the extent of inflammation, ulceration, organism penetration, and depth of corneal stromal affection. RESULTS: The control eyes developed severe inflammation compared to the cross-linked eyes. Corneal melting occurred in 6 eyes in the control versus none in cross-linked group. Histopathological examination showed that the inflammation was confined to the superficial part of the stroma with localization of the inflammation in the cross-linked eyes in contrast to the control eyes that showed deep infiltration. CONCLUSION: PACK-CXL provides infection localization through increasing the corneal rigidity and resistance to enzymatic digestion, even in the absence of the riboflavin microbicidal role. So, early PACK-CXL is worth to be considered in the IK treatment algorithm.

Transepithelial corneal crosslinking with oxygen enhancement and pulsed light for progressive ectasia: one-year results.

PURPOSE: To evaluate the efficacy and safety of transepithelial accelerated crosslinking (TE-ACXL) using pulsed light and supplemental oxygen. METHODS: Thirty eyes of 30 consecutive patients with progressive keratoconus or post-LASIK ectasia were enrolled in a prospective non-comparative study conducted at the Magrabi Eye Center (Jeddah, Saudi Arabia). All eyes underwent TE-ACXL with supplemental oxygen. Primary outcome measures were the mean change in corrected distance visual acuity (CDVA) (logMAR) and maximum keratometry (max K) from preoperatively to 12 months postoperatively. Secondary outcome measures included change in manifest refractive spherical equivalent (MRSE), refractive cylinder, keratometry, symmetry index (SI), center-surrounding index (CSI) and ectasia index (EI) of the anterior and posterior corneal surfaces, corneal and epithelial thickness at corneal vertex and thinnest location, corneal densitometry, corneal high order aberrations (HOA) and endothelial cell density (ECD). RESULTS: Mean age was 29.6 ± 8.2 years. At 1 year, the follow up rate was 93.3%. CDVA improved statistically significantly at 12 months (p = 0.027). Measures of corneal keratometry or pachymetry did not change significantly (p < 0.05). Postoperatively, a demarcation line was documented in 78.6% eyes at 1 month, and in 12 (42.9%) eyes at 12 months. The mean depth of the demarcation line was 341.9 ± 49.4 µm. Corneal densitometry increased significantly at 1- and 3-months (p < 0.05) and returned to normal levels at 6- and 12-months postoperatively. CONCLUSION: TE-ACXL with oxygen supplement is effective at halting the progression of corneal ectasia for at least 1 year and can be a refractive neutral procedure.

Three-years outcomes of simultaneous photorefractive surgery and customized corneal cross-linking for keratoconus.

PURPOSE: To report the efficacy of customized cross-linking (CXL) in halting progression of keratoconus when combined with photorefractive procedures. METHODS: Seven eyes from 7 patients with documented progressive keratoconus were treated with customized CXL (customized ultraviolet-A irradiance pattern centered on the maximum posterior elevation with total energy levels ranging from 5.4 up to 10 J/cm2 , and an energy fluence of 9 mW/cm2) combined with photorefractive procedures. Four patients underwent simultaneous transepithelial photorefractive keratectomy (T-PRK) plus customized CXL, and three patients underwent simultaneous transepithelial phototherapeutic keratectomy (T-PTK) plus customized CXL. Tomographic parameters (Kmax, pachymetry of the thinnest point and maximal elevation of posterior float and regularization index) and best spectacle-corrected visual acuity (BSCVA) were compared preoperatively and 3 years postoperatively. RESULTS: All eyes showed a decrease in the maximal curvature Kmax, and none of eyes showed progression. Six eyes showed a flattening of 3 or more diopters (D). On average, Kmax decreased by - 4.8 ± 2.5 D, and the BSCVA improved by 0.04 ± 0.07 logarithm of the minimal angle of resolution. The mean value of regularization index was 8.7 ± 3.8 D. Mild corneal haze occurred in two eyes, and superficial apical scar occurred in one eye. None of the eyes had a vision-threatening complication. CONCLUSION: Customized CXL combined with photorefractive procedure (T-PRK/T-PTK) resulted in long lasting flattening effect and strong regularization of keratoconic corneas along with improvement of BSCVA over a 3-year follow-up.

The bactericidal effect of two photoactivated chromophore for keratitis-corneal crosslinking protocols (standard vs. accelerated) on bacterial isolates associated with infectious keratitis in companion animals.

BACKGROUND: Bacterial corneal infections are common and potentially blinding diseases in all species. As antibiotic resistance is a growing concern, alternative treatment methods are an important focus of research. Photoactivated chromophore for keratitis-corneal crosslinking (PACK-CXL) is a promising oxygen radical-mediated alternative to antibiotic treatment. The main goal of this study was to assess the anti-bactericidal efficacy on clinical bacterial isolates of the current standard and an accelerated PACK-CXL treatment protocol delivering the same energy dose (5.4 J/cm2). METHODS: Clinical bacterial isolates from 11 dogs, five horses, one cat and one guinea pig were cultured, brought into suspension with 0.1% riboflavin and subsequently irradiated. Irradiation was performed with a 365 nm UVA light source for 30 min at 3mW/cm2 (standard protocol) or for 5 min at 18mW/cm2 (accelerated protocol), respectively. After treatment, the samples were cultured and colony forming units (CFU's) were counted and the weighted average mean of CFU's per µl was calculated. Results were statistically compared between treated and control samples using a linear mixed effects model. RESULTS: Both PACK-CXL protocols demonstrated a significant bactericidal effect on all tested isolates when compared to untreated controls. No efficacy difference between the two PACK-CXL protocols was observed. CONCLUSION: The accelerated PACK-CXL protocol can be recommended for empirical use in the treatment of bacterial corneal infections in veterinary patients while awaiting culture results. This will facilitate immediate treatment, the delivery of higher fluence PACK-CXL treatment within a reasonable time, and minimize the required anesthetic time or even obviate the need for general anesthesia.

Impact of keratoconus stage on outcome after corneal crosslinking.

BACKGROUND: This study aimed to analyze if the outcome after corneal crosslinking (CXL) in progressive keratoconus patients depends on the stage at which the procedure is performed. This knowledge would help to improve success of CXL and to define surgery indications in those patients. METHODS: In this retrospective study, 124 consecutive eyes of 100 patients with progressive keratoconus undergoing corneal CXL at the University Eye Hospital Tübingen were included. The eyes were graded according to modified Krumeich stages depending on induced myopia or astigmatism, corneal radii, minimum corneal thickness, and morphological changes. The observation period covered November 2008 to September 2018. Preoperatively, 12 and 24 months after CXL, the best corrected visual acuity (BCVA) was determined and astigmatism as well as tomographic parameters (Kmax, Kmin, central corneal thickness (CCT), minimum corneal thickness (MCT)) were measured by means of a Scheimpflug camera system. RESULTS: BCVA results showed significant differences between the modified Krumeich stages at 12 months (p = 0.014) and at 24 months postoperatively (p = 0.032). Also, astigmatism differed significantly among the stages at 24 months after CXL (p = 0.023). However, no significant differences regarding astigmatism were detectable after 12 months. In terms of Kmax, Kmin, CCT, and MCT, no significant differences between the Krumeich stages were observed. CONCLUSIONS: BCVA showed a significantly higher improvement after CXL in the early stage of keratoconus compared to a higher stage. However, the postinterventional tomographic values did not differ significantly between the different modified Krumeich stages. The significantly higher improvement in BCVA after CXL in the early stage might indicate that earlier intervention provides a higher subjective benefit to the individual. Further studies with larger sample sizes are needed to confirm these findings.

Update on the genetics of keratoconus.

In the past few years we have seen a great acceleration of discoveries in the field of keratoconus including new treatments, diagnostic tools, genomic and molecular determinants of disease risk. Recent genome-wide association studies (GWAS) of keratoconus cases and population wide studies of variation in central corneal thickness and in corneal biomechanical properties confirmed already identified genes and found many new susceptibility variants and biological pathways. Recent findings in genetic determinants of familial keratoconus revealed functionally important variants and established first mouse model of keratoconus. Latest transcriptomic and expression studies started assessing novel non-coding RNA targets in addition to identifying tissue specific effects of coding genes. First genomic insights into better prediction of treatment outcomes are bringing the advent of genomic medicine into keratoconus clinical practice.

Corneal riboflavin gradients and UV-absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1 to 0.5.

Avoiding damage of the endothelial cells, especially in thin corneas, remains a challenge in corneal collagen crosslinking (CXL). Knowledge of the riboflavin gradients and the UV absorption characteristics after topical application of riboflavin in concentrations ranging from 0.1% to 0.5% could optimize the treatment. In this study, we present a model to calculate the UV-intensity depending on the corneal thickness. Ten groups of de-epithelialized porcine corneas were divided into 2 subgroups. Five groups received an imbibition of 10 min and the other five groups for 30 min. The applied riboflavin concentrations were 0.1%, 0.2%, 0.3%, 0.4% and 0.5% diluted in a 15% dextran solution for each subgroup. After the imbibition process, two-photon fluorescence microscopy was used to determine fluorescence intensity, which was compared to samples after saturation, yielding the absolute riboflavin concentration gradient of the cornea. The extinction coefficient of riboflavin solutions was measured using a spectrophotometer. Combining the obtained riboflavin concentrations and the extinction coefficients, a depth-dependent UV-intensity profile was calculated for each group. With increasing corneal depth, the riboflavin concentration decreased for all imbibition solutions and application times. The diffusion coefficients of 10 min imbibition time were higher than for 30 min. A higher RF concentration and a longer imbibition time resulted in higher UV-absorption and a lower UV-intensity in the depth of the cornea. Calculated UV-transmission was 6 percentage points lower compared to the measured transmission. By increasing the riboflavin concentration of the imbibition solution, a substantially higher UV-absorption inside the cornea is achieved. This offers a simple treatment option to control the depth of crosslinking e.g. in thin corneas, resulting in a lower risk of endothelial damage.

Compaction of very thin corneas from ultraviolet A riboflavin-vitamin E transepithelial cross-linking.

The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of transepithelial (epi-on) cross-linking. Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 µm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured. The average percent change in pachymetry was -0.43% ± 0.38% (maximum -1.06%) in the shielded half. Pachymetry change was -6.2% ± 2.2% (maximum 12%) in the cross-linked halves. In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was -5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.

Multi modal imaging in corneal edema after corneal collagen cross-linking (CXL); a case-based literature review.

BACKGROUND: Keratoconus (KCN) is a common ectatic disorder of the cornea. Corneal collagen cross-linking (CXL) is used as an effective option to slowdown the disease progression. Although CXL is considered a safe procedure, corneal endothelial damage, especially in corneal thickness of less than 400 µm, has been reported. CASE PRESENTATION: A 25-year-old man known case of KCN was referred with complaints about blurred vision and discomfort of the right eye 3 days after performing CXL. The preoperative thinnest point was 461 µm. His presenting BCVA was CF at 1 m. Examination showed central corneal edema and stromal haziness. ASOCT demonstrated increased central corneal thickness and very deep CXL line. In the confocal scan, anterior stroma showed hyper-reflective lines without recognizable cells and nerves, the middle stroma showed rare active and edematous keratocytes and a hyper-reflective reticular pattern with elongated keratocytes and needle-like structures involving the posterior stroma indicated increased depth of CXL. To manage the patient, debridement of loosened epithelium was done. Non-preservative steroid 1% eye drop was prescribed frequently. The corneal edema was completely resolved during 2 months with no need for surgical procedure and BCVA of 20/30 in his right eye. CONCLUSION: The corneal thickness of more than 400 µm cannot guarantee the absence of corneal edema after corneal collagen cross-linking, which can pertain to several factors such as inadvertently using of higher energy as well as the incorrect observance of all guidelines, instructions, and other precautions, even by a trained surgeon.

Effect of corneal cross-linking on endothelial cell density and morphology in the peripheral cornea.

BACKGROUND: To compare the endothelial cell density and morphology in the peripheral cornea before and after corneal cross-linking (CXL). METHODS: This study evaluated thirty-one eyes of 31 patients who were treated with standard CXL for progressive keratoconus. Preoperatively and 6 months postoperatively, we compared the corneal endothelial cell density (ECD), the coefficient of variation in cell size (CV), and the percentage of hexagonal cells (HEX), in the peripheral regions of the cornea, using a non-contact specular microscope (EM-3000, Tomey). RESULTS: All keratoconic eyes in this series were measurable in the peripheral regions. No significant differences were found in the peripheral ECD preoperatively and 6 months postoperatively at each point (Wilcoxon signed-rank test, superior, p = 0.16, nasal superior, p = 0.12, temporal superior, p = 0.17, inferior, p = 0.37, nasal inferior, p = 0.28, temporal inferior, p = 0.17). The mean percentage of the ECD loss was 1.3, 1.3, 1.0, 1.4, 0.7, and 1.4%, respectively. No significant differences in the peripheral CV or HEX were found preoperatively and 6 months postoperatively at each point. CONCLUSIONS: Standard CXL does not cause significant changes in endothelial cell density, polymegethism, or polymorphism, in the peripheral regions of the cornea. It is suggested that CXL is a minimally invasive surgical approach for progressive keratoconus, even in terms of peripheral endothelial cells. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (000031162).

Simultaneous photorefractive keratectomy and accelerated collagen cross-linking in high-risk refractive surgery (Tehran protocol): 3-year outcomes.

PURPOSE: To evaluate safety and efficacy of performing simultaneous photorefractive keratectomy (PRK) and collagen cross-linking (CXL) in myopic patients with preoperative risk factors for developing keratectasia. METHODS: Seventeen eyes of 15 patients with at least one of the following risk factors were recruited: central keratometry (Kmax) between 48 and 50, difference between inferior, superior corneal power (I-S value) between 1.4 and 1.9 and corneal thickness between 450 and 480 µm. Upon final stage of standard PRK, 0.02% mitomycin was applied for 30-50 s, and then, accelerated CXL was performed for 5 min. Pre- and postoperative Oculus Pentacam® imaging for keratometry values, measurement of uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were done for all patients. RESULTS: Mean follow-up time was 32.08 ± 7.79 months (range 25-49 months). Mean age of patients was 28.78 ± 3.80 years. Mean postoperative spherical equivalent was + 0.19 ± 0.42 (- 0.5 to + 1.0 [D]). Mean UDVA and CDVA improved from 0.9062 ± 0.485 log MAR and 0.0148 ± 0.043 log MAR to 0.0173 ± 0.040 log MAR and 0.0057 ± 0.023 log MAR, respectively (P = 0.011, P = 0.735). Mild degree of early postoperative stromal haze was seen which did not persist more than 6 months. There was no late stromal haze, corneal ectasia or other major postoperative complication in the follow-up period. CONCLUSION: Combined PRK and accelerated CXL is an efficient and safe procedure for high-risk refractive surgery candidates, with no increased risk of persistent corneal haze.