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To compare the changes encountered in corneal biomechanics and aberration profile following accelerated corneal collagen cross-linking (CXL) using hypo-osmolar and iso-osmolar riboflavin in corneal thicknesses of <400 and >400 microns, respectively. Methods: This is a prospective, interventional, comparative study involving 100 eyes of 75 patients with progressive keratoconus. Eyes were divided into two groups based on corneal thickness: group 1 included eyes with a corneal thickness of <400 microns who underwent hypo-osmolar CXL, and group 2 included eyes with a corneal thickness of >400 microns who underwent iso-osmolar CXL. Corneal biomechanical and aberration profiles were evaluated and compared between groups. Results: In group 1, all higher-order aberrations (HOA) except secondary astigmatism significantly decreased from baseline; however, in group 2, only coma and trefoil decreased. The corneal resistance factor and corneal hysteresis significantly improved in both groups, which was significantly greater in group 2 than in group 1. The change in inverse radius, deformation amplitude, and tomographic biomechanical index was significantly improved in group 2 as compared to group 1. Conclusion: Improvement in corrected distance visual acuity and decrease in HOA were significantly better in the hypo-osmolar CXL group; however, the improvement in biomechanical strength of the cornea was significantly better in the iso-osmolar group. [ABSTRACT FROM AUTHOR]

Introduction: Keratoconus is a non inflammatory disease characterised by progressive corneal thinning that results in a cone-like ectasia, irregular astigmatism, and decreased vision. Advanced disease can result in corneal scarring and blindness, necessitating penetrating keratoplasty. The only treatment believed to have the ability to stop or decrease the progression of keratoconus is Collagen Cross-Linking (CXL). Aim: To evaluate the efficacy of corneal collagen cross-linking with riboflavin (C3R) in patients with keratoconus by studying the outcomes in terms of Uncorrected Visual Acuity (UCVA), Best Corrected Visual Acuity (BCVA), manifest refraction, and corneal topography. Materials and Methods: A hospital-based prospective cohort study was conducted at the Regional Institute of Ophthalmology, Government Medical College, Thiruvananthapuram, Kerala, India from June 2017 to June 2018. Fifteen eyes of 12 patients who underwent corneal collagen cross-linking for progressive keratoconus were included. Routine ophthalmological examinations was done for all patients. Patients under the age of 35 years with progressive keratoconus, an average K value not exceeding 60 D, and who had not undergone any other surgical modalities of treatment were included in the study. Patients with scarred cornea or hydrops, active ocular infection, or pachymetry <400 µm were excluded. Detailed informed consent was obtained from all patients before surgery. Preoperative UCVA, BCVA cylinder, Spherical Equivalent (SE), and topography values were obtained. All patients were followed-up at three and six months postoperative period to look for changes in UCVA, BCVA, manifest refraction, and corneal topography. Data were expressed as the mean±Standard Deviation (SD) pre- and postoperatively and analysed statistically using the paired t-test, with p<0.05 considered statistically significant. Analysis was conducted using Statistical Package for Social Sciences (SPSS) version 16.0. Results: On follow-up at six months post-treatment, UCVA (log MAR) improved from 0.87±0.40 to 0.65±0.35 (p-value=0.001), and BCVA (log MAR) changed from 0.37±0.21 to 0.17±0.22 (p-value=0.001). K max decreased from 54.90±6.05 to 52.67±5.02 (p-value=0.001), and K min decreased from 48.14±4.24 to 45.93±4.07 (p-value=0.001). Astigmatism and SE also showed statistically significant improvement post-procedure (p-value 0.001 and 0.002, respectively). Astigmatism reduced from -3.50±1.58 to -2.90±1.37. SE reduced from -4.93±3.92 to -4.28±3.48. No significant complications were noted in any of the patients. Conclusion: The CXL is an effective procedure for stabilising the progression of keratoconus, thus reducing the burden of preventable blindness and the need for keratoplasty. [ABSTRACT FROM AUTHOR]

Purpose: To investigate Tumor necrosis factor alpha (TNF-α) levels in tears of mild-moderate keratoconus patients after high-dose oral riboflavin and direct sun UV-A exposure. Study Design: Quasi-experimental study. Place and Duration of Study: Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada, and Dr. Sardjito General Hospital, Yogyakarta, Indonesia, from December 2022 until April 2023. Methods: The TNF-α from tear of 8 patients (10 eyes) was evaluated before and after therapy. All patients received a high dose of oral riboflavin (800 mg/day) and direct UV-A exposure (≥15 minutes/day) for a total of three months of follow-up. The TNF-α expression in tears, visual acuity and the risk factors were examined at baseline until three months follow-up. Results: TNF-α levels in tears decreased significantly from baseline (6.74±1.39 pg/ml) to1st month (5.98±0.69 pg/ml; p=0.048). However, in the following months, the levels of TNF-α elevated in the 2nd month (6.29±0.84; p=0.390) and the 3rd month (6.20±0.95; p=0.177). Although re-elevated after two months, TNF-α concentration still decreased from the beginning of the study (6.74±1.39 to 6.20±0.95 pg/ml). The Uncorrected visual acuity and best corrected visual acuity were significantly improved from baseline to the last follow up (p = 0.02 and p = 0.026 respectively). Conclusion: There was a significant decrease of TNF-α l evels i n t ears o f mild-moderate keratoconus patients 1st month after therapy but no significant decrease in the subsequent follow-up. Furthermore, UCVA and BCVA values were improved. [ABSTRACT FROM AUTHOR]

Aim: To compare the effect of two different riboflavin solutions we use in the accelerated crosslinking (CXL) process on the pachymetry value. Materials and Methods: Patients who had accelerated CXL treatment with dextranfree riboflavin solution due to progressive keratoconus were retrospectively screened. Thirty-seven eyes of 27 patients (group 1) treated with Hydroxyl Propyl MethylCellulose (HPMC) and 0.1% riboflavin containing solution and 29 eyes of 23 patients (group 2) treated with D-alpha-tocopheryl polyethylene-glycol 1000 succinate (VE-TPGS) and 0.1% riboflavin containing solution were compared in terms of pachymetry changes during treatment. Results: In groups 1 and 2, the mean age was 23.92 ± 5.66 and 23.30 ± 4.89, respectively. Mean age, gender, initial keratometry values, mean central corneal thickness (CCT) before (p = 0.158) and after epithelial debridement (p= 0.320) did not differ significantly between the two groups (p>0.05). The CCT measured after riboflavin instillation was 453.22 ± 37.48 µm in the group 1 and 479.34 ± 38.54 µm in the group 2 (p=0.007). After instillation of riboflavin, according to the initial CCT, there was an average thinning of 21.57 ± 16 µm in the group 1 and 18.72 ± 22.13 µm thickening in the group 2 (p<0.001). According to the CCT measured after epithelial debridement, a thickening of 20.70 ± 21.77 µm in the group 1 and 62.76 ± 21.65 µm in the group 2 was observed (p<0.001). The rate of change of CCT after riboflavin instillation of significant differences existed between both groups (p<0.001). Conclusion: VE-TPGS, which is utilized to increase the cornea's permeability to riboflavin tissue during crosslinking treatment, significantly increases the corneal thickness compared to HPMC and provides a safer tissue thickness for ultraviolet A. [ABSTRACT FROM AUTHOR]

We employed the mechanical effect from 40 kHz ultrasound (US) to improve the delivery of riboflavin into corneal stroma for collagen crosslinking, which can benefit the treatment of keratoconus and other corneal ectasias. Experiments were conducted, first with porcine corneas ex vivo and then with New Zealand white rabbits in vivo, at varying mechanical index (MI) and sonication time. Results showed that 15 min of US applied on the cornea at MI = 0.8 in the presence of 0.5% of riboflavin solution enabled its delivery to deeper corneal stroma. Excessive heat was removed by a cooling setup to negate the thermal effect. The corneal absorption amount and penetration of riboflavin through cornea as detected by fluorotron, as well as the enhancement of corneal stiffness as measured by Young's modulus, were comparable to the conventional approach that requires complete corneal epithelium debridement. Histological analysis revealed minor exfoliation of superficial cell layers of corneal epithelium and loss of ZO‐1 tight junctions immediately after US. Full recovery of the corneal epithelium and restoration of tight junctions occurred in 3–4 days. The study shows that low‐intensity low‐frequency ultrasound (LILF US) is a less invasive alternative to the conventional epithelium‐off method for delivering riboflavin into the corneal stroma. [ABSTRACT FROM AUTHOR]

To evaluate long-term outcomes of corneal collagen crosslinking (CXL) using riboflavin and UV-A irradiation and to determine when to repeat CXL. In this retrospective consecutive interventional case series 131 eyes of 131 patients (95 male, 36 female, mean age 29.7 ± 11.4 years) between 2006 and 2016 received standard CXL (Dresden protocol, epithelium-off) for progressive keratoconus. Corrected distance visual acuity (CDVA) and corneal tomography (K1, K2, Kmax) were repeatedly recorded 1 year (n = 103 eyes) to 10 years (n = 44) postoperatively. Only one eye per patient was included. Paired t-test or Wilcoxon matched-pairs signed rank test was used for parametric and nonparametric data, respectively. 1–3 years preoperatively, median K2 significantly increased by 1.1 D (p < 0.001). Postoperatively, median K2 increased by 0.1 D after 1 year, then decreased over the remaining postoperative period by 0.85 D (p = 0.021). Kmax fluctuated without significant change. Median apical corneal thickness decreased by 16 µm (p = 0.012) after 5 years and then returned to preoperative values. Mean CDVA showed a significant improvement (decrease in logMAR 0.08 after 10 years, p = 0.010). CXL non-responders, defined by a postoperative increase in Kmax>2 D, increased from 16% after 5 to 33% after 10 years. Risk factors for non-response were young age, high astigmatism (>4.3 D), thin cornea (<480 µm), poor initial visual acuity (CDVA ≥0.3 D), and atopic dermatitis. 4 eyes were re-treated 3–4 years after first CXL without complications and keratoconus stabilized thereafter. CXL can slow or stop keratoconus progression. However, as the number of responders declines after 5 years, especially patients with risk factors may require re-treatment. [ABSTRACT FROM AUTHOR]

Purpose: To assess the 3-year clinical results of the 18 mW 7 J/cm2 transepithelial enhanced fluence pulsed light M accelerated crosslinking in the treatment of progressive keratoconus (KC) with chemically enhanced hyper-concentrated riboflavin solutions without iontophoresis and with air-room oxygenation. Setting: Siena Crosslinking Center, Siena, Italy. Methods: Prospective pilot, open non-randomized interventional study including 40 eyes of 30 young adult patients over 21 years old (10 simultaneous bilateral) with early (Stage I and II) progressive KC undergoing TE-EFPL 18 mW/7 J/cm2 ACXL (EFPL M TECXL). The 12 min and 58 s pulsed light (1 s on/1 s off) UV-A exposure treatments were performed with a biphasic corneal soaking using Paracel I 0.25% for 4 min and Paracel II 0.22% for 6 min riboflavin solutions and New KXL I UV-A emitter (Glaukos-Avedro, Waltham, USA) at an air room of 21% oxygenation. All patients completed the 3-year follow-up. Results: CDVA showed a statistically significant improvement in the third postoperative month (Δ + 0.17 d. e.) with a final gain of +0.22 d. eq. AK showed a statistically significant decrease in the sixth postoperative month (Δ − 1.15 diopters). K itmax showed a statistically significant decrease at 1-year follow-up (Δ − 1.3 diopters). The coma value improved significantly by the sixth month (Δ − 0.54 µm). MCT remained stable during the entire follow-up. No adverse events were recorded. Corneal OCT revealed a mean demarcation line depth at 282.6 ± 23.6 μm. Conclusions: Transepithelial enhanced fluence pulsed light M accelerated crosslinking with chemically enhanced riboflavin solution halted KC progression in young adult patients without iontophoresis and no intraoperative oxygen supplementation addressing the importance of increased fluence. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and safety of transepithelial diluted alcohol and iontophoresisassisted corneal cross-linking (DAI-CXL) and compare 24-month visual and topographic outcomes with accelerated CXL using hypo-osmolar riboflavin (A-CXL) in keratoconus patients with thin corneas (below 400 µm with epithelium). Methods: This retrospective study included keratoconus patients who underwent DAI-CXL or A-CXL. Uncorrected and corrected distance visual acuity (UDVA and CDVA) and data obtained from corneal topography were analyzed at baseline and 12 and 24 months of follow-up. Corneal demarcation line depth (DLD) at 1 month and corneal endothelial cell density (ECD) at 24 months were also evaluated. Results: The study included 25 eyes of 25 keratoconus patients (mean age: 25.48±6.69 years, male: 52%). DAI-CXL and A-CXL groups consisted of 13 and 12 patients, respectively. In both groups, median UDVA improved significantly at 24 months (p<0.05) whereas CDVA was similar despite a trend towards improvement. Median K-max decreased by 2.77 [interquartile range (IQR): 2.67] D and 2.24 (IQR: 4.38) D in DAI-CXL group (p=0.033) and A-CXL group (p=0.060), respectively. Corneal HOAs showed a significant improvement in only the DAI-CXL group (p=0.004). Average DLD was 237±67 µm in DAI-CXL and 242±57 µm in A-CXL (p=0.346). No significant changes in ECD were observed in both groups. Median follow-up changes in UDVA, CDVA, K-max, HOAs, and ECD were similar in the groups. Conclusions: We observed similar efficacy of transepithelial DAI-CXL to A-CXL in slowing down the progression of keratoconus in thin corneas without notable effects during a 24-month follow-up period. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the 5-year results of accelerated corneal collagen crosslinking (CXL) for progressive keratoconus and identify preoperative characteristics predictive of visual and topographic outcomes.Methods: A prospective interventional case series. Nineteen eyes of 19 patients receiving accelerated CXL with settings of 18 mW/cm2 for 5 min were included. Clinical and topographic parameters were assessed. Linear regression and logistic regression were used to compare the R2 and odds ratio (OR), respectively, between baseline characteristics and postoperative outcomes.Results: Corrected distance visual acuity (CDVA) remained stable from 0.28 ± 0.21 to 0.25 ± 0.18 logMAR (P = 0.486). The mean cylindrical refraction was stable (P = 0.119). The maximal keratometry (Kmax) decreased from 61.99 ± 10.37 to 59.25 ± 7.75 D (P < 0.001), flattening in the flattest and steepest meridians and mean keratometry were also observed (P ≤ 0.040). The mean anterior elevation at the apex reduced from 21.42 ± 16.69 to 18.53 ± 12.74 μm (P = 0.013) and changes in posterior elevation were non-significant (P = 0.629). Preoperative Kmax best predicted the postoperative change in Kmax (R2 = 0.55, P < 0.001) compared to the other baseline characteristics (P ≤ 0.028), whereas preoperative CDVA was the only significant predictor of postoperative change in CDVA (R2 = 0.41, P = 0.003). Accelerated CXL is less likely to fail in eyes with a steeper preoperative Kmax (OR = 0.74, P = 0.040) or greater posterior elevation at the apex (OR = 0.91, P = 0.042).Conclusion: Kmax significantly decreased following accelerated CXL. Eyes with worse preoperative CDVA and higher Kmax were more likely to have an improvement in visual acuity and corneal flattening. [ABSTRACT FROM AUTHOR]

[Display omitted] Corneal collagen crosslinking (CXL) is an effective method to halt the disease progression of keratoconus, a progressive corneal dystrophy leading to cone shaped cornea. Despite the efficacy of standard protocol, the concerning step of this procedure is epithelial debridement performed to facilitate the entry of riboflavin drug. Riboflavin, a key molecule in CXL protocol, is a sparsely permeable hydrophilic drug in corneal tissues. The present study has employed cell penetrating peptide (CPP), Tat 2 , to enhance the penetration of riboflavin molecule, and thereby improve currently followed CXL protocol. This study demonstrates approximately two-fold enhanced uptake of CPP riboflavin conjugate, Tat 2 riboflavin-5′Phosphate (RiTe conjugate), both in vitro and in vivo. Two different CXL protocols (Epi ON and Epi OFF) have been introduced and implemented in rabbit corneas using RiTe conjugate in the present study. The standard and RiTe conjugate mediated CXL procedures exhibited an equivalent extent of crosslinking in both the methods. Reduced keratocyte loss and no endothelial damage in RiTe conjugate mediated CXL further ascertains the safety of the proposed CXL protocols. Therefore, RiTe conjugate mediated CXL protocols present as potential alternatives to the standard keratoconus treatment in providing equally effective, less invasive and patient compliant treatment modality. [ABSTRACT FROM AUTHOR]

Keratoconus is a progressive noninflammatory ectatic disease of the cornea with onset at puberty in most cases. Both genetic and nongenetic or environmental factors have been implicated. Keratoconus has been associated with numerous genetic systemic disorders. many keratoconus-associated syndromes have a high incidence of eczema and atopy, such as Down syndrome, hyper-IgE syndrome, ichthyosis, and oculodentodigital syndrome, Turner syndrome (conjunctival lymphangiectasia), autographism and Mulvihill-Smith syndrome. In each of these syndromes associated with atopy and eczema, associations are known to include both keratoconus and eye rubbing. Keratocyte density, possibly from IL-1-induced apoptosis, is reduced in keratoconus and can be demonstrated as well with eye rubbing and with contact lens wear. A recently developed treatment for keratoconus is corneal collagen crosslinking (CXL). In CXL, stromal fibers are photopolymerized by the combined action of a photosensitizing substance (riboflavin or vitamin B2) and ultraviolet rays A. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the long-term visual, refractive, tomographic, and aberrometric outcomes of corneal collagen crosslinking (CXL) with or without hypoosmolar riboflavin solution in the treatment of progressive keratoconus patients with thin corneas. Methods: Charts of consecutive progressive keratoconus patients with thinnest corneal thickness less than 470 µm who underwent corneal collagen CXL with or without hypoosmolar riboflavin solution and using a standardized protocol for treatment and examinations were analyzed retrospectively. The indication for hypoosmolar riboflavin use was a central corneal thickness less than 400 µm as measured by ultrasound pachymetry after epithelial debridement and before exposure to ultraviolet A (UVA) light. Uncorrected distance visual acuity (UDVA), best spectacle-corrected distance visual acuity (CDVA), manifest refraction, slit lamp biomicroscopy, corneal tomography, corneal aberrometry, and endothelial cell counts were evaluated at baseline and yearly at all postoperative follow-up examinations until month 36. The outcomes of corneal CXL procedure performed using hypoosmolar riboflavin were compared to those performed using the standard procedure. Results: Twenty-three eyes (19 patients) were treated using hypoosmolar riboflavin application, and 30 eyes (28 patients) were treated using the standard procedure. Compared to baseline, the mean UDVA, CDVA, and keratometric readings improved statistically significantly in both groups at postoperative year 3, without any statistically significant between-group differences. Progression was not observed in any patient eye in either group. No significant endothelial cell loss and no sight threating complication were observed in any patient eye. Conclusion: At 3 years follow-up, the safety and efficacy of CXL using hypoosmolar riboflavin solution seems to be similar to that of standard CXL in progressive keratoconic eyes with thin corneas. The visual, refractive, keratometric, tomographic and aberrometric outcomes of the two procedures were comparable, as well. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the clinical outcomes and assess preoperative characteristics that may predict outcomes in keratoconus 1 year after accelerated transepithelial corneal cross-linking (ATE-CXL).Methods: This prospective study included 93 eyes of 84 consecutive keratoconus patients with 1-year follow-up after ATE-CXL. Preoperative characteristics included corneal astigmatism, anterior chamber depth, anterior chamber volume, radius of curvature, posterior elevation, central corneal thickness (CCT), thinnest corneal thickness, steepest meridian keratometry, flattest meridian keratometry, and the maximum keratometry (Kmax). Data were obtained preoperatively and at 1, 3, 6, and 12 months postoperatively. The patient eyes were grouped into 3 subgroups according to CCT and Kmax values to observe the changes of keratoconus progression.Results: All patients were successfully operated without complications at any follow-up time point. Mean changes of Kmax from baseline at 6 and 12 months were - 0.60 ± 2.21 D (P = 0.011) and - 0.36 ± 1.58 D (P = 0.030), respectively. Eyes with a thinner CCT and higher Kmax values exhibited a tendency for topographic flattening of ≥1.0 D (P = 0.003; P = 0.003). In the subgroup comparison, the Kmax values decreased significantly at 6 and 12 months after ATE-CXL in the group with CCT ≤ 450 μm (P = 0.018 and P = 0.045); the Kmax values of the group with Kmax > 65.0 D decreased significantly at 6 months postoperatively (P = 0.025).Conclusion: ATE-CXL is a safe and effective treatment for keratoconus patients. Patients with thinner CCT and higher Kmax values are more likely to benefit from ATE-CXL. [ABSTRACT FROM AUTHOR]

Purpose: To monitor the changes in the ABCD grading system during a one-year follow-up after a corneal cross-linking (CXL) procedure.Methods: This prospective study included 30 eyes of 25 patients with keratoconus, who received the CXL treatment. The patients with a history of ocular trauma or surgery and other corneal pathology were excluded from the study. The patients were examined at the baseline visit and followed up at 3, 6, and 12 months after the CXL. All the patients underwent a standard CXL procedure with visual acuity and Scheimpflug tomography testing at each visit. The corneal parameters and ABCD grading were monitored throughout the follow-up period.Results: There were no significant changes of parameter A and anterior radius curvature (ARC) in the ABCD grading system. Parameters B and D showed progression postoperatively, with an improvement of parameter D on the final visit. Parameter C showed a statistically significant increase at all three post-CXL visits, but a constant gradual decrease in the value over time.Conclusion: The ABCD grading system can be very useful in monitoring the progression of keratoconus (KC), but it can also help in monitoring the efficacy of corneal cross-linking. The anterior surface parameters in the ABCD grading system did not show progression in the post-CXL period, and parameters C and D showed improvement and stability a year after the procedure. [ABSTRACT FROM AUTHOR]

Purpose: To find the intraocular lens (IOL) power calculation changes before and after isotonic collagen cross-linking (CXL) in keratoconus patients.Methods: : Thirty-five eyes of 25 patients who underwent isotonic CXL were included. The cases included conventional CXL (n = 16), accelerated CXL (n = 7), contact lens-assisted CXL (CACXL) (n = 9), accelerated CACXL (n = 3). All underwent ocular biometry (IOL master), corneal topography (Orbscan II), and simulated keratometry (Orbscan II) preoperatively and 1-year post CXL. Change in best-corrected visual acuity (BCVA), axial length (AL), simulated keratometry (Sim K), anterior chamber depth (ACD), and IOL power were analyzed in the overall data and then grouped based on flattening (Group A) and no flattening (Group B) of Sim K value post CXL procedure.Results: For the overall data, there was no significant change in IOL power (P = 0.05) at the end of 1 year, BCVA showed a significant increase (P < 0.01), and Sim K reading showed a statistically significant flattening (P = 0.001); ACD and AL showed insignificant change. In intergroup comparison, there was no statistically significant change in IOL power. However, in Group A, a significant change in BCVA and Sim K values was observed. In both groups (Group A and Group B), IOL power was found to be negatively correlated with AL and Sim K values.Conclusion: Isotonic CXL did not affect IOL power calculation at the end of 1 year. However, significant change in BCVA and sim K reading was noted. [ABSTRACT FROM AUTHOR]

Purpose: Early diagnosis of keratoconus (KCN) and corneal collagen cross-linking can ensure that best-corrected visual acuity is preserved. We report the sequence of events leading to the diagnosis of KCN, as well as its impact on quality of life.Methods: This survey-based study included patients diagnosed with KCN for the first time at our center. Their corneal tomography was analyzed, and they were provided with a proforma and the NEI-VFQ-25 questionnaire and were asked to answer the given set of questions.Results: The study included 328 eyes of 164 patients. At the time of diagnosis, 112 (68.3%) patients were not aware of a disease called "keratoconus." VKC was present in 56 patients, and 92 patients were not aware of the need to avoid eye rubbing. In total, 101 patients gave a history of sleeping more often on the side with worse KCN. The preferred primary point of contact was an optometrist for 45.1% of patients; 51.2% of patients reported never having visited an ophthalmologist. Sixty-four (39%) patients were advised a screening test to rule out KCN before presenting to our center; 42 (71.8%) of these patients did not get it done. Vision-targeted score showed a significant negative correlation with grade of KCN (r value: -0.471) and positive correlation (r value: 0.534) with LogMAR vision.Conclusion: KCN is a disease of the young and severely affects the quality of life. Improving awareness of the general public, ensuring timely referral by optometrists, and keeping a high index of suspicion is emphasized. [ABSTRACT FROM AUTHOR]

Background: Keratoconus is a condition characterized by biomechanical instability of cornea presenting in a progressive asymmetry and bilateral way. Corneal collagen crosslinking with riboflavin and UVA is a technique that has influenced the treatment of Keratoconus by arresting the progression. Aims and Objectives: The aim of the study was to assess the short-term efficacy and safety of collagen cross-linking in Keratoconus. Materials and Methods: This prospective, nonrandomized, interventional case study was conducted at Aravind Eye hospital and PGI, Puducherry from June 2012 to April 2013. Statistical analysis was done using repeated measures ANOVA and Bonferonn's using IBM SPSS Inc. 20.Version. Results: A total of 30 patients were enrolled in this study and standard cross linking procedure was done. It was found that UCVA, BSCVA both improved about 40%. Spherical Equivalent reduced by 0.7 D, cylinder reduced by 0.8 D and total astigmatism decreased by about 0.4 D. Steepest K value reduced by 2 D, Irregularity and astigmatism at 3 and 5 mm also changed significantly (P<0.05). Conclusion: Collagen cross-linking arrests the progression of Keratoconus. It seems to improve the UCVA and BCVA and it is a safe and effective procedure. [ABSTRACT FROM AUTHOR]

Purpose: To compare the visual acuity, topographic and the biomicroscopic features in patients who had accelerated corneal crosslinking (CXL) by using hydroxypropyl methylcellulose-based (HPMC) or dextran-based riboflavin solutions. Materials and Methods: In this study, 62 eyes with progressive keratoconus were included. Accelerated CXL has been performed to all patients. Riboflavin with dextran (0.1% Riboflavin, 20% dextran) (n: 33) or HPMC (0.1% Riboflavin, 1.1% HPMC) (n: 29) were used as photosensitizer in CXL procedure. Visual acuity, topographic measurements and biomicroscopic features were compared between 2 groups in 12 months of follow-up. Results: Totally 62 eyes (34 right and 28 left) of 62 patients (25 female, 37 male) with a mean age of 24.37±6.93 years were included. Although best corrected visual acuity (0.29 ±0.16 vs 0.28±0.16; p= 0.89) and uncorrected visual acuity (0.62 ±0.34 vs 0.48±0.29; p=0.08) were both better in dextran free riboflavin group at 12th month of follow-up, the differences between 2 groups were not statistically significant. There was not any statistically significant difference between groups regarding any of the topographic findings. The biomicroscopic findings were also very similar in first, sixth and 12th months of follow-up in both groups. Corneal haze was the most common finding in the 1st month of follow up in all cases. Conclusions: Accelerated CXL procedures performed by using riboflavin with dextran or HPMC represent similar affects in corneal parameters during the 12 months of follow-up period. Larger studies with longer follow-up periods are warranted to define the differences and similarities of these 2 photosensitizers. [ABSTRACT FROM AUTHOR]

Introduction: Keratoconus (KC) is the most common corneal ectatic disorder with a prevalence of about 1 in 2,000 people. KC is a progressive, non-inflammatory, almost bilateral and asymmetric of corneal. Corneal collagen cross-linking (CXL) with riboflavin and ultraviolet- A (UVA) is a new technique of mechanical stability of the cornea and prevention of keratoconus progression. Purpose: Determining the relationship between changes in corneal density before and after collagen cross-linking surgery in patients with keratoconus Materials and Methods This prospective study was performed on 45 eyes of 23 patients with keratoconus undergoing corneal collagen cross-linking treatment at Imam Khomeini Hospital in Ahvaz in 2019. Corneal densitometry (CD) and pachymetry were measured using Pentacam before CXL and at 3, 6 and 12 months after CXL. Also, all of the patients were evaluated in terms of best corrected visual acuity (BCVA), during follow-up. Results: In this study, 23 people including 12 men (54.2%) and 11 women (45.8%) with a mean age of 25.2 ± 4.64 years in the age range of 18-34 years participated. The mean value of corneal density in total layer over the annular diameters 0-2 mm was 19.10±5.58, 22.31±5.64, 24.28±6.37 and 20.89±5.73 for before, 3 months, 6 months and 12 months after CXL, respectively (P = 0.001). The mean value of corneal density in ant layer over the annular diameters 0-2 mm was 22.38±8.38, 27.46±9.63, 28.07±11.28 and 24.53±9.21for before, 3 months, 6 months and 12 months after CXL, respectively (P = 0.001). The mean value of corneal pachymetry in thinnest location was 426.2±34.7 µm, 412.5±42.6 µm, 419.2±37.3 µm and 428.3±36.9 µm for before, 3 months, 6 months and 12 months after CXL, respectively (P = 0.392). The pre-CXL value of BCVA was significantly lower than the post-CXL values in 12 months (0.10 ± 0.19, 0.15 ± 0.10 and 0.019 ± 0.15, respectively, P<0.0001). In general, Densitometry values increases and corneal thinnest location decreses during the 3-6 months after CXL and then return to baseline preoperative values in 12 months. There was a significant improvement in best corrected visual acuity (BCVA) before and 12 months after surgery (P<0.0001). Conclusions: CXL can increase corneal densitometry and decrease corneal thinnest location during the postoperative 6 months period. Densitometric values and corneal thickness return to baseline preoperative values to a large extent during 6-12 months postoperatively. The patient's BCVA increased over 12 months but no correlation was observed between this increase and densitometric changes. [ABSTRACT FROM AUTHOR]

The aim of this study was to formulate the thermoreversible gel containing riboflavin and dexamethasone to treat keratoconus. Gel was prepared by the cold method by mixing the poloxamer 407 as a thermosensitive polymer and HPMC as viscosity enhancing agent. The formulation was evaluated for pH, clarity, isotonicity, visual appearance. Also, gelation temperature, drug content, ex vivo permeation study, bioadhesive strength, hemolytic toxicity, rheological properties have also been evaluated. All results for this formulation were found to be in an acceptable range. Bioadhesive strength increased with HPMC concentration. The pH of the formulation was found to be 6.1 to 6.51. The gelation temperature was found to be in the range 30–38°C. F5 formulation showed maximum drug release of 99.77% and 98.8% for riboflavin and dexamethasone, respectively, within 8 h. Hemolytic study revealed no change in the shape or surface of blood cells. In vitro keratoconus model was developed in mice using keratoconus and corneal fibroblast cells. The results revealed the that increased thickness of cell lines. The formulated gel played important role in the increasing thickness of cells. Further, the overall study demonstrates the safe and effective use of riboflavin and dexamethasone in the treatment of keratoconus. [ABSTRACT FROM AUTHOR]

Corneal cross-linking (CXL) using riboflavin and ultraviolet A (UVA) light has become a useful treatment option for not only corneal ectasias, such as keratoconus, but also a number of other corneal diseases. Riboflavin is a photoactivated chromophore that plays an integral role in facilitating collagen crosslinking. Modifications to its formulation and administration have been proposed to overcome shortcomings of the original epithelium-off Dresden CXL protocol and increase its applicability across various clinical scenarios. Hypoosmolar riboflavin formulations have been used to artificially thicken thin corneas prior to cross-linking to mitigate safety concerns regarding the corneal endothelium, whereas hyperosmolar formulations have been used to reduce corneal oedema when treating bullous keratopathy. Transepithelial protocols incorporate supplementary topical medications such as tetracaine, benzalkonium chloride, ethylenediaminetetraacetic acid and trometamol to disrupt the corneal epithelium and improve corneal penetration of riboflavin. Further assistive techniques include use of iontophoresis and other wearable adjuncts to facilitate epithelium-on riboflavin administration. Recent advances include, Photoactivated Chromophore for Keratitis-Corneal Cross-linking (PACK-CXL) for treatment of infectious keratitis, customised protocols (CurV) utilising riboflavin coupled with customised UVA shapes to induce targeted stiffening have further induced interest in the field. This review aims to examine the latest advances in riboflavin and UVA administration, and their efficacy and safety in treating a range of corneal diseases. With such diverse riboflavin delivery options, CXL is well primed to complement the armamentarium of therapeutic options available for the treatment of a variety of corneal diseases. [ABSTRACT FROM AUTHOR]

Introduction: Epithelium-off cross-linking (epi-off CXL) has long been established as the gold standard treatment for progressive keratoconus. Several protocols for epithelium-on (epi-on) CXL have been proposed to help reduce post-operative pain and facilitate visual recovery, but there is no epi-on treatment approach that is currently approved in the United States. The hydrophilic and macromolecular characteristics of conventional epi-off riboflavin formulations may create clinical challenges for absorption through an intact epithelium. This study investigates the clinical efficacy of a dextran-free hypotonic riboflavin ophthalmic solution (Photrexa, Glaukos, Burlington, MA, USA), approved for epi-off CXL, in a novel epi-on CXL protocol. Methods: Twenty-five eyes of 17 patients were treated in this prospective, single-arm study using a hypotonic riboflavin formulation without dextran and low irradiance UVA (3mW/cm2) for epi-on CXL. Visual acuity, as well as refractive and keratometry outcomes, were observed over 12 months. Results: At 12 months, Kmax was stable with no clinically or statistically significant change from a mean pre-op of 55.4D to 55.9D (p=0.13). Uncorrected and best corrected logMAR visual acuity significantly improved from 0.77 to 0.62 and from 0.17 to 0.12, respectively. There were no significant adverse safety events. Conclusion: Patients who underwent epi-on CXL with dextran-free hypotonic riboflavin demonstrated improvements in uncorrected and best corrected visual acuity with stable keratometry at 12 months post-operatively. The efficacy is consistent with other epi-on studies to date but remains lower than standard epi-off CXL. New technologies, including supplemental oxygen and transepithelial riboflavin ophthalmic solutions, are currently under clinical evaluation and may offer a path forward for epi-on CXL in the USA. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to test a method for estimating corneal rigidity before and after cross-linking (CXL) using a Schiøtz tonometer.Methods: The study was performed in the Kyiv City Clinical Ophthalmological Hospital "Eye Microsurgical Center", Ukraine. This was a prospective, consecutive, randomized, masked, case-by-case, clinical study. Corneal rigidity, indicated by the gradient (G) between lg applied weight and corresponding lg scale reading during Schiøtz tonometry, were obtained by increasing (A-mode) then reducing (D-mode) weights by two operators [A] in keratoconus, post-CXL and control subjects for estimation of (i) interoperator and (ii) intersessional errors, (iii) intergroup differences; [B] before and after CXL. Central corneal thickness CCT was measured by scanning slit pachymetry. ANOVA, t tests, linear regression were the statistical tools used.Results: Average interoperator difference (ΔG) was -0.120 (SD = ±0.294, 95%CI = -0.175 to -0.066). A significant correlation between ΔG and the mean of each pair of G values was found (r = -0.196, n = 112, P = 0.038). Intersessional differences in mean G values were insignificant (P > 0.05). There was a significant correlation between G at first session (X1) and difference between sessions (ΔG) [Operator 1, ΔG = 0.598x1-0.461, r = 0.601, n = 27, P = 0.009]. Significant intergroup differences in G were found (Operator 1, one-way ANOVA, F = 4.489, P = 0.014). The difference (Δ) between the pre-(X2) and post-CXL treatment G values was significantly associated with the pre-CXL treatment value (Operator 1, Δ = 1.970x2-1.622, r = 0.642, n = 18, P = <.001). G values were correlated with CCT in keratoconus and post-CXL.Conclusion: Corneal rigidity (G) estimated using the Schiøtz tonometer can be useful for detecting changes after CXL. However, G values are linked to CCT, can vary from time-to-time and the procedure is operator dependent. [ABSTRACT FROM AUTHOR]

Purpose: To compare the safety and efficacy of 0.1% riboflavin in two different solutions which is used in corneal collagen crosslinking (CXL) for the treatment of keratoconus. Methods: This was a prospective, randomized, comparison study which included 100 eyes of 61 patients with progressive keratoconus who underwent CXL with riboflavin 0.1% solution as a photosensitizer, using the standard Dresden protocol of using 3mW/cm2 UV-A irradiation for 30 minutes which corresponds to a total energy of 5.4 J/cm2. The recruited patients were divided into 2 groups ie, Flavin Group and Peschke-D group by computer generated randomization. Postoperative examinations were conducted on 1 day, 1 month, 3 months, 6 months and 12 months after the crosslinking. Results: For both groups, the mean manifest spherical equivalent (SE), astigmatism, best corrected distance visual acuity, keratometry values, thinnest pachymetry values, demarcation line depth and endothelial cell density preoperatively and at postoperative 12 months were comparable with no statistically significant differences. At 12 months postoperatively, 62% of eyes in the Flavin group, and 68% of eyes in the Peschke-D group had postoperative manifest SE of within ± 1.00 D. During UV-A exposure, the cornea in the Flavin group showed intraoperative thinning of 112 microns (27%) as compared with a thinning of 108.12 microns (26.5%) observed in the Peschke group (p=1.67) from the initial pachymetry readings. No eye in either group had any immediate or long-term postop vision threatening complications such as infectious keratitis, corneal melt, non-resolving corneal oedema or endothelial decompensation. Conclusion: Both riboflavin solutions were equally safe and effective in the management of progressive keratoconus, and resulted in similar changes in terms of mean manifest spherical equivalent (SE), astigmatism, best corrected distance visual acuity, keratometry values, thinnest pachymetry values, demarcation line depth and endothelial cell density at the end of 12 months postoperatively. Trial Registration Number: Ctri/2019/11/021841 (Www.ctri.nic.in). [ABSTRACT FROM AUTHOR]

[Display omitted] Corneal cross-linking has been described as an effective treatment to slow the progression of keratoconus. The standard protocol entails corneal epithelial removal to allow the diffusion of riboflavin into the stroma. Although, de-epithelization can generate risks or complications that transepithelial cross-linking tries to solve or avoid. Different formulations were developed after verifying that hydroxypropyl-β-cyclodextrin (HPβCD) and sulfobuthylether-β-cyclodextrin (SBEβCD) in a 20% concentration, increased the solubility of practically insoluble in water drugs such as riboflavin from 0.12 mg/mL to 0.35 mg/mL and 0.29 mg/mL respectively. These values were higher when chitosan and arginine were added to the formulation, showing solubility of 0.78 mg/mL when HPβCD concentration was not modified. Ex vivo corneal permeability was measured after having kept in contact bovine corneas with intact epithelium for 5 h with the 0.1 mg/mL riboflavin solution, the formulations developed and a reproduced nanoemulsion from another work. Riboflavin's permeability was increased when cyclodextrins, chitosan, and arginine were part of the formulations, compared to the control drug solution. The best permeability coefficient was reached when riboflavin was combined with 40% (w/v) HPβCD, 0.5% (w/w) arginine, and 0.5% (w/w) chitosan. After having carried out toxicity studies as bovine corneal opacity and permeability (BCOP) and Heńs Egg Test - Chorioallantoic Membrane Test (HET-CAM) it was verified that both, the active ingredients and the excipients of the different formulations were not harmful without generating irritation, loss of transparency or corneal permeability alterations. The results show the great potential of the ocular developed solution for their use in transepithelial cross-linking for keratoconus treatment. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the effect of riboflavin UV-A illumination on mRNA and protein expression of healthy (HCFs) and keratoconus human corneal fibroblasts (KC-HCFs), concerning the inflammatory markers NF-κB, iNOS, IL-6, and collagen 1 and 5 (Col 1/Col 5). Methods: Keratocytes were isolated from healthy (n = 3) and keratoconus (KC) corneas (n = 3) and were cultivated in basal medium with 5% fetal calf serum, which resulted in their transformation into human corneal fibroblasts (HCFs/KC-HCFs). Cells underwent 0.1% riboflavin UV-A illumination for 250 s (CXL). NF-κB, iNOS, IL-6, Col 1, and Col 5 expression was investigated by qPCR and Western blot analysis. IL-6 concentration of the cell culture supernatant and cell lysate was determined by ELISA. Results: In untreated KC-HCFs, NF-κB (p = 0.0002), iNOS (p = 0.0019), Col 1 (p = 0.0286), and Col 5 (p = 0.0054) mRNA expression was higher and IL-6 expression was lower (p = 0.0057), than in healthy controls. In HCFs, CXL led to an increased NF-κB (p = 0.0286) and IL-6 (p = 0.0057) mRNA expression. The IL-6 concentration in the cell culture supernatant was increased in HCFs (p = 0.0485) and KC-HCFs (p = 0.0485) after CXL. CXL increased intracellular IL-6 concentration only in KC-HCFs (p = 0.0357). In the HCF group (p = 0.0286), an increased Col 1 mRNA expression after CXL could be observed. Conclusion: Our study confirmed altered gene expression in untreated KC-HCFs compared to untreated HCFs. Riboflavin UV-A illumination affected gene expression only in HCFs. Increased IL-6 concentration in the cell culture supernatant and cell lysate indicate a secondary inflammatory response of HCFs and KC-HCFs to riboflavin UV-A illumination. [ABSTRACT FROM AUTHOR]

Purpose: To review the scientific literature on the comparison of the efficacy of different corneal collagen crosslinking (CXL) protocols for the treatment of progressive keratoconus. Methods: Systematic review of randomized clinical trials (RCTs) on CXL outcomes. A search was carried out using the Cochrane Library, PubMed, EMBASE, Web of Science, Ovid MEDLINE, and Scopus databases. Internal validity was analyzed by applying the filter CASPe (Critical Appraisal Skills Program Spain). Results: The search yielded 1151 articles, and among these, 14 articles met the inclusion and exclusion criteria defined. Conventional (S) crosslinking (CXL) provided better topographic outcomes than transepithelial (TE) CXL, and S-CXL had a better therapeutic effect of corneal flattening than accelerated (A) CXL. The corneal thinning after CXL was lower with hypotonic riboflavin than with riboflavin-dextran. While one study demonstrated a better therapeutic effect of corneal flattening with S-CXL than with A-CXL, another study showed similar results between both techniques. No correlation was found between the depth of the demarcation line and topographic changes, which was not a direct measure of treatment effectiveness. Quality analysis of the literature reviewed yielded a mean score of 8.64, indicating that the RCTs evaluated had an overall acceptable quality. Conclusions: Good-quality RCTs comparing CXL techniques have been conducted, and most of them suggest that epi-off CXL can be considered the standard treatment for progressive keratoconus. TE-CXL and iontophoresis-assisted CXL are mainly indicated in patients with a risk of corneal scarring and patients with pain intolerance, respectively. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate effects of sodium iodide (NaI) on riboflavin concentration in corneal stroma before and during ultraviolet A (UVA) light exposure using a novel transepithelial corneal collagen crosslinking (CXL) procedure (EpiSmart CXL system, CXL Ophthalmics, Encinitas CA). Methods: Riboflavin solutions with NaI (Ribostat, CXL Ophthalmics, Encinitas CA) and without NaI were used for CXL in rabbits using EpiSmart. A pilot study determined sufficient riboflavin loading time. Four rabbits were dosed and monitored. Riboflavin fluorescence intensity was assessed from masked slit-lamp photos. A 12 min loading time was selected. Sixteen additional rabbits received the two formulae in contralateral eyes for CXL. Riboflavin uptake was assessed at 0, 10, 15, 20, 25, and 30 min of UVA exposure using a scale for riboflavin fluorescence previously validated against stromal concentration. Post sacrifice, corneal stromal samples were analyzed for concentrations of riboflavin and riboflavin 5ʹ-phosphate. Results: Eyes dosed with NaI riboflavin had higher riboflavin grades compared to eyes dosed with the NaI-free riboflavin formulation immediately after riboflavin loading and persisting throughout UVA exposure, with significantly higher (P < 0.01 to < 0.05) riboflavin grades from 15 through 25 min of UVA exposure. Riboflavin grades decreased more slowly in eyes dosed with NaI riboflavin through 25 minutes of UVA exposure. Minor conjunctival irritation was noted with or without NaI. Conclusion: The addition of NaI to riboflavin solution is associated with increased riboflavin concentration in corneal stroma throughout a clinically relevant time course of UVA exposure. This effect may be a combination of enhanced epithelial penetration and reduced riboflavin photodegradation and should enhance intrastromal crosslinking. [ABSTRACT FROM AUTHOR]

The past two decades have witnessed an unprecedented evolution in the management of keratoconus that demands a holistic approach comprising of inhibiting the ectatic progression as well as visual rehabilitation. The advent of corneal cross-linking (CXL) in the late 1990s resulted in long-term stabilization of the ectatic cornea along with limited reduction in corneal steepening and regularization of corneal curvature. However, CXL as a standalone procedure does not suffice in rehabilitating the functional vision especially in patients who are unwilling or intolerant towards contact lenses. The concept of "CXL plus" was proposed which incorporates adjunctive use of refractive procedures with CXL in order to overcome the optical inefficiency due to corneal irregularity, decrease the irregular astigmatism, correct the residual refractive error and improve functional visual outcome in keratoconus. Several refractive procedures such as conductive keratoplasty (CK), photorefractive keratectomy (PRK), transepithelial phototherapeutic keratectomy (t-PTK), intrastromal corneal ring segments (ICRS) implantation, phakic intraocular lens (PIOL) implantation and multiple other techniques have been combined with CXL to optimize and enhance the CXL outcome. This review aimed to summarize the different protocols of CXL plus, provide guidelines for selection of the optimum CXL plus technique and aid in decision-making for the comprehensive management of cases with primary keratoconus in addition to discussing the future and scope for innovations in the existing treatment protocols. [ABSTRACT FROM AUTHOR]

Background: Keratoconus is a frequent, familiar, bilateral, non inflammatory, and gradually progressive corneal ectasia, which leads to corneal protrusion, irregular astigmatism, and decrease vision. Currently, the corneal cross-linking (CXL) treatment could attain vision improvement. Aim: To investigate the topographic, refractive, and clinical-out-comes after six months CXL in gradually progressing keratoconic eyes. Patients & Methods: A follow-up, randomized, controlled-trial study was used. In this study, 30eyes with progressive-keratoconus (PK) were recruited in the study. Cross-linking was done and achieved by a solution of 0.1% riboflavin mixture with 20% dextran for 15minutes before and during 30minutes time-period of ultraviolet A (UV-A) irradiation (3Mw\cm2). The obtained data were analysed using IBM SPSS software. Results: Statistically significant improvements were noticed in Sim k (at 6months), Kmin (at 6months), spherical power (at 6momths), cylinder power (at 6momths), spherical equivalent [SE] (at 6months), uncorrected visual acuity (UCVA) (at 6months) and best corrected visual acuity [BCVA] (at 6months) in trial group (15patients) when compared with the controls. Conclusions: At 6months, hopeful, promising improvements were reported in Kmax, UCVA, and BCVA. So, long term studies are requested to survey the efficiency of CXL as well as the safety of the repeated procedures. [ABSTRACT FROM AUTHOR]

Purpose: To compare the corneal densitometry changes after transepithelial pulsed (t-ACXL), epithelium-off continuous (c-ACXL) and epithelium-off pulsed (p-ACXL), accelerated corneal crosslinking for patients with progressive keratoconus.Methods: Prospective, interventional case series at a university hospital tertiary referral center. Forty eyes received t-ACXL, 40 eyes received c-ACXL, and 40 eyes received p-ACXL. Corneal tomography, densitometry and visual acuity were evaluated preoperatively and at 1, 3, 6, 12 and 24 months postoperatively.Results: Total densitometry values of the total layer over the annular diameters 0-12 mm expressed in grayscale units (GSU) showed no significant change after t-ACXL and p-ACXL but increased significantly after c-ACXL at 1 month (16.76 ± 2.38, P value < 0.01) and 3 months (16.12 ± 2.22, P value 0.04), returning to baseline levels at month 6 (14.97 ± 2.13, P value 0.99) and remained stable until final follow-up. At 1 month, the mean change in total densitometry value of the t-ACXL group (-0.53 ± 2.08) was significantly lower than the p-ACXL (0.70 ± 1.96 P value 0.04) and c-ACXL (1.97 ± 2.65 P value < 0.01). There was no statistical difference in the mean change in total densitometry between the three groups from 6 to 24 months. In the c-ACXL group, a higher degree of CXL-induced corneal haze at 1 month was observed in patients with steeper preoperative keratometry readings and in individuals where a greater flattening effect was achieved at 24 months.Conclusions: Continuous epithelium-off accelerated cornea crosslinking appears to induce more corneal haze than pulsed epithelium-off and transepithelial pulsed cornea crosslinking in the early postoperative period. Differences resolve by six-months. [ABSTRACT FROM AUTHOR]

Keratoconus is a common and progressive eye disease characterized by thinning and tapering of the cornea. This degenerative eye disease is currently treated in the clinic with an interventional technique ("epi-off") that can cause serious side effects as a result of the surgical procedure. The aim of this project is to design innovative formulations for the development of a riboflavin-containing medicinal product to develop a non-invasive ("epi-on") keratoconus treatment as an alternative to current treatment modalities. Nanostructured lipid carriers (NLCs) were successfully loaded with either riboflavin base of riboflavin-5-phosphate sodium and designed with either Stearylamine (positive charge) or Trancutol P (permeation enhancer). In vitro characterization studies, cytotoxicity and permeability studies were performed. Selected formulations and commercial preparations were applied and compared in ex-vivo corneal drug accumulation and transition studies. Furthermore, in vivo studies were performed to assess drug accumulation in the rat cornea and the corneal stability after NLC treatment was investigated via a biomechanical study on isolated rabbit corneas. Both in vitro and ex-vivo as well as in vivo data showed that from the prepared NLC formulations, the most effective formulation was riboflavin-5-phosphate sodium containing NLC with Transcutol P as permeation enhancer. It possessed the highest drug loading content, low accumulation in the cornea but high permeability through the cornea as well as the highest functional performance in corneal crosslinking. Topical application of riboflavin-5-phosphate sodium loaded NLC systems designed with permeation enhancer Transcutol P may act as a potential alternative for non-invasive keratoconus treatments. Unlabelled Image • Riboflavin salt showed higher nanoparticle drug loading than riboflavin base. • Riboflavin salt leads to higher corneal drug transport than riboflavin base. • Transcutol p (permeation enhancer) increased the effectiveness of riboflavin salt. • Stearylamine (cationic agent) increased the effectiveness of riboflavin base. • Riboflavin containing NLCs can significantly improve corneal crosslinking. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to report refractive, topographic, and tomographic outcomes of 2-years corneal collagen cross-linking in patients with progressive keratoconus. Materials and Method: This prospective study was conducted on76 eyes of 40 patients with progressive keratoconus and a corneal thickness of at least 400μm. After the baseline examination, cross-linking was performed using riboflavin 0.1% and ultraviolet irradiation (370 nm, 3 mW/cm2) for 30 min. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), manifest refraction spherical equivalent (MRSE), cylinder, keratometric readings, and corneal thickness were evaluated at baseline, 6, 12, and 24 months after corneal collagen cross-linking. Results: Results showed that at a 24-month follow-up, mean BSCVA, and UCVA had significant improvements. Changes in MRSE and cylinder were not significant during the two years of follow-up. At a 2-years follow-up, the mean values of minimum keratometry, maximum keratometry, and average keratometry decreased significantly to0.75, 0.97, and 0.52 D, respectively, compared to their baseline values. Anterior best fit sphere (BFS) also had significant difference at 24-month follow-up compared to base line evaluation. The central corneal thickness decreased significantly up to38 μ after 2 years. Conclusion: Corneal collagen cross-linking is an effective treatment to stop the progression of keratoconusas shown by reduced keratometry and improved vision. [ABSTRACT FROM AUTHOR]

Purpose: Corneal collagen crosslinking (CXL) through an intact epithelium (epi-on) at high irradiance could potentially improve patient comfort, visual recovery, and clinical workflow compared to conventional epi-off CXL. However, intact epithelium limits stromal delivery of the oxygen, photosensitizer, and ultraviolet-A (UV-A) radiation needed to drive CXL. This ex vivo study evaluated three different epi-on CXL protocols compared to positive and negative controls, specifically focusing on the impact of supplemental oxygen. Endpoints included stromal oxygen levels, stiffness of crosslinked tissue, and acute flattening of whole eyes. Materials & Methods: Ex vivo porcine eyes were held in a custom environmental chamber. Intrastromal oxygen levels were continuously measured before, during, and after UV illumination by a fiberoptic probe inserted into a laser-cut flap. Accelerated, high irradiance, epi-on CXL protocols using riboflavin formulated with benzalkonium chloride (BAC) were studied, with and without supplemental oxygen. These were compared to an alternate, low irradiance, epi-on protocol using riboflavin formulated with sodium iodide. Both negative (no CXL) and positive (epi-off modified Dresden protocol) controls were performed. Post-CXL elastic modulus was measured using extensiometry and anterior tangential curvature was measured using a Scheimpflug tomographer. Results: Protocols including supplemental oxygen resulted in an approximately 5-fold increase in stromal oxygen levels prior to CXL. During epi-on, high-irradiance UV-A delivery under hyperoxic conditions, an aerobic state was maintained. Conversely, under normoxic conditions, stromal oxygen rapidly depleted to 0-5% for all other protocols. The combination of supplemental oxygen, BAC formulation, and high-irradiance UV-A resulted in the largest biomechanical changes and most pronounced flattening effects of the three epi-on protocols. Conclusions: Ex vivo analysis of stromal oxygen levels, corneal stiffness, and acute anterior curvature change indicates that simultaneous optimization of the oxygen environment, riboflavin formulation, and UV-A protocol can significantly increase the effects of corneal collagen crosslinking. [ABSTRACT FROM AUTHOR]

Purpose: To assess corneal concentration of riboflavin in two different corneal crosslinking protocols performed by a novel image-guided therapeutic (or "theranostic") UV-A device. Methods: Ten human eye bank donor tissues were used in this work. The tissues underwent corneal cross-linking according to the conventional treatment protocol (n = 5; 30 min of stromal soaking followed by 30 min of 3 mW/cm2 UV-A irradiance) and the iontophoresis-assisted transepithelial protocol (n = 5; soaking for 5 min at 1 mA/min and 9 min of 10 mW/cm2 UV-A irradiance) using a theranostic UV-A device (Vision Engineering Italy srl, Italy). The device provided real time assessment of riboflavin concentration by hyperspectral image analysis of the cornea. A 0.1% riboflavin hypotonic solution (Ricrolin+, Sooft Italia Spa, Italy) was used in all cases. Results: Manual application of hypotonic riboflavin for 30 min into the stroma achieved greater corneal riboflavin concentration (425 ± 77 μg/cm3) than transepithelial delivery of riboflavin by corneal iontophoresis (195 ± 35 μg/cm3; P = 0.001). In both UV-A irradiation protocols, corneal riboflavin concentration decreased exponentially with a constant energy rate of 2.3 ± 0.5 J/cm2 and 1.8 ± 0.3 J/cm2 respectively. At the end of treatment, the average corneal concentration of riboflavin decreased by ≥ 85%, with values of 54 ± 29 μg/cm3 and 31 ± 9 μg/cm3 (P = 0.11), respectively. Conclusion: Manual application of riboflavin onto the stroma achieved almost 50% greater concentration of riboflavin than transepithelial delivery by corneal iontophoresis. The theranostic UV-A device provided a novel approach to estimate corneal concentration of riboflavin non-invasively during treatment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the corneal epithelial thickness profiles in patients with a confirmed diagnosis of stable and progressive keratoconus.Setting: Studio Italiano di Oftalmologia, Rome, Italy.Design: Observational study.Methods: 86 patients with either stable (n = 52) or progressive (n = 34) keratoconus and 182 healthy controls were enrolled in the study. Disease progression was confirmed by repeated corneal topographies over 1 year follow-up before inclusion in the study. All subjects had full corneal and epithelial thickness mapping taken by spectral domain optical coherence tomography (SD-OCT). The full corneal mapping was investigated by evaluating the central corneal thickness, the thinnest point, the superonasal-inferotemporal thickness difference and the minimum-median thickness difference. The epithelial mapping was investigated by assessing the 2 mm central thickness, the inferior paracentral (2-5 mm) thickness, and the minimum-maximum thickness difference.Results: No significant differences in full corneal mapping were found between stable and progressive keratoconic eyes. Of note, the inferior paracentral region of the corneal epithelium was significantly thinner in progressive (50 ± 3 μm) than stable (53 ± 4 μm) keratoconus (P < 0.001).Conclusions: The SD-OCT corneal epithelial mapping was valuable for detecting local thickness changes in eyes with keratoconus. Monitoring the corneal epithelial changes across the inferior area in patients with keratoconus could be worthy for assessing disease progression. [ABSTRACT FROM AUTHOR]

Members of the ASCRS Cornea Clinical Committee performed a review of the current literature on the corneal crosslinking (CXL) procedure for treating corneal ectasia. The members explored the data on the techniques currently in use and under investigation, including their advantages, safety profiles, risks, and cost analyses, compared with data on corneal transplantation. They concluded that CXL limits the progression of keratoconus, thus reducing the need for transplantation. They also found that compared with permitting the disease to progress naturally, CXL techniques carry significant and long-term cost and safety benefits, primarily by reducing the need for corneal transplantation. Studies of various CXL techniques (eg, epithelium-on treatment, changes in ultraviolet light parameters, riboflavin composition) continue with the ultimate goal of improving the procedure's safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: Corneal collagen cross-linking (CXL) has been used as a treatment option in patients with either keratoconus or iatrogenic corneal ectasia after LASIK. The purpose of corneal cross-linking is to stabilize the corneal stroma and to delay the progression of these two pathologic entities. Objective: The aim of this study is to compare the corneal hysteresis before and after corneal collagen cross-linking using riboflavin and ultraviolet-A light by the epithelial-off technique for treatment of keratoconus. Patients and methods: This study is a single-centre prospective interventional study. It was conducted between April 2018 to December 2018 and included 30 eyes of 18 patients with a mean age 27.08 years (range from 17- 30). They were 12 female eyes and 18 male eyes; all underwent corneal collagen cross-linking using riboflavin and ultraviolet-A light at Kobry El Kobba Military Specialized Eye Hospital. Results: All patients were evaluated preoperatively for their uncorrected corrected visual acuity (UCVA), best corrected visual acuity (BCVA), k-reading, spherical equivalent and pachymetry (using Pentacam), and corneal biomechanical properties (using ocular response analyzer (ORA). The mean age was 27.08±7.86 years, and postoperative follow up was at 1 and 4 months. The mean CH was 7.93±1.79 mmHg preoperatively, 8.27±1.22 mmHg at 1 month, 8.99±1.24 mmHg at 4 months, which show a statistically significant increase in the mean CH pre- and postoperatively, while CRF the other parameter, show a highly statistically significant decrease pre- and postoperatively. Conclusion: CXL is a promising new treatment modality for keratoconus patients and may affect corneal biomechanics. [ABSTRACT FROM AUTHOR]

Introduction: The demarcation line (DL) observed since the pioneering crosslink (CLX) protocol at the posterior edge of the cross-linked stroma has been universally accepted as a therapeutic milestone of treatment. Numerous laboratory and clinical CXL studies demonstrate that a deeper DL is associated with a higher amount and saturation level of crosslinks, a more pronounced stiffening effect, and a more durable ectasia stability. Areas covered: A critical revision of laboratory, clinical, and analytical studies on the DL depth supports the significance of the DL as an evaluator of the performance of CLX procedures in terms of biomechanical efficacy and safety avoiding extensive experiments. A mechanical approach based on experimental data shows that the DL depth obtained with different CXL protocols relates with an asymptotic non-linear increasing function to the modified biomechanical corneal stiffness (elastic modulus). Expert opinion: The strong connection between the depth of the DL and the increase of the biomechanical efficacy can be explained by means of UV cross-linking chemical investigations demonstrating that only a limited amount of free reactive collagen residues is involved in the short-wave UV-mediated CXL. Thus, the CXL density can rise only up to an upper boundary value, i.e. the saturation value. [ABSTRACT FROM AUTHOR]

Corneal collagen cross-linking is advance technique use ultraviolet A with riboflavin (vitamin B2) to increase corneal stiffness. The aim of this study to evaluate visual outcome, keratometric reading and corneal topographic outcomes after corneal collagen cross-linking in a progressive keratoconus. A prospective study was conducted from March 2016 to March 2017, 44 eyes with progressive keratoconus were treated by photosensitizer and ultraviolet-A. Preoperative examination included uncorrected and best corrected visual acuity, slit lamp examination of the cornea and corneal topography. A soft bandaging contact lens was putting after complete the procedure. On the fifth day, we removing the contact lens and postoperative follow up was done every month for six months. Forty four eyes included in this study, 56.8% were male and 43.2% were female, age group was 15-30 years. After six months follow-up there were 17eyes exhibited improvement of uncorrected visual acuity by one line while 15 cases exhibited improvement by two or more line. Three eyes (6.8%) lost two or more lines of UCVA. In the majority of the cases (63.6%) keratometric reading was stable. This study revealed improvement in the visual results of the corneal collagen cross-linking and confirmed the safety and effectiveness of this procedure. [ABSTRACT FROM AUTHOR]

Purpose: Contact lens‐assisted corneal cross‐linking (CACXL) has been proposed for the cross‐linking treatment in thin corneas. The aim of this study was to assess the biomechanical efficacy of this treatment. Methods: Post‐mortem porcine eyes were treated with standard cross‐linking and with cross‐linking placing a contact lens soaked with isoosmolar riboflavin solution on the debrided cornea with or without an adherent precorneal riboflavin film of up to 100 μm thickness. Three soft contact lenses (Air Optix Aqua, SofLens and Galifa) with different degrees of hydrophilic properties were tested. After cross‐linking with a surface UVA irradiance of 3 mW/cm² for 30 min (fluence 5.4 J/cm²), a 400 μm deep anterior corneal flap was created using a lamellar rotating microkeratome. Biomechanical stress–strain measurements and thermal shrinkage tests were performed. Results: In the Air Optix Aqua group (30% hydration) without riboflavin film, Young′s modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was 92.4% respectively 86.35% of the standard CXL value. In the SofLens group (59% hydration) without riboflavin film, Young′s modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was 67.04% respectively 65.28% of the standard CXL value. In the Galifa group (72% hydration) without riboflavin film, Young′s modulus and stress at 8% strain were increased significantly versus untreated controls and the effect was about 68.48% respectively 75.52% of the standard CXL value. In all samples with a precorneal riboflavin film under the contact lens, there was no significant biomechanical effect compared to the untreated controls. Similarly, in the hydrothermal experiments at 70°C, there was a typical mushroom pattern with increased resistance to thermal shrinkage in the anterior stroma after standard CXL, a markedly reduced mushroom effect using a riboflavin‐soaked contact lens only and no effect with the use of a riboflavin‐soaked contact lens plus a precorneal riboflavin film. Conclusion: The biomechanical effect of CACXL in porcine corneas is about one‐third less than after standard CXL. The efficacy of CACXL might be improved by reducing or omitting the riboflavin film on the contact lens. Further risk assessment studies are necessary. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Microemulsions are potential ophthalmic delivery vehicle. • Microemulsions can transfer riboflavin through intact eye epithelium into the stroma. • Omega-3-loaded microemulsion formulations relieve dry eye syndrome. • Microemulsions are a basis for convenient aqueous formulation of omega-3 fatty acids. Abstract Microemulsions are widely studied as potential ocular drug delivery vehicles. In the present study we show the versatility of possible use microemulsions as ocular delivery vehicle. The ME is loaded with a hydrophilic drug, riboflavin phosphate (RFP) and a lipophilic, docosahexaenoic acid in triglyceride form (TG-DHA), each separately. These drugs treat keratoconus and dry eye syndrome, respectively. The advantage of using ME loaded with RFP is in overcoming eye epithelium debridement during collagen cross-linking therapy for treatment of keratoconus. ME loaded with lipophilic TG-DHA provides convenient dosage in liquid aqueous form of administration of highly lipophilic TG-DHA, which is known as a protective molecule in dry eye syndrome. The capability of RFP-loaded MEs was demonstrated in terms of improvement of biomechanical strength of the rabbit cornea, as a result of successful penetration of RFP through the intact epithelium. TG-DHA-loaded microemulsion applied topically onto an eye with induced dry eye syndrome showed the significant relief of the dry eye condition. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this study was to measure collagen fiber crimping (CFC) using nonlinear optical imaging of second harmonic generated (SHG) signals to determine the effects of UVA-riboflavin induced corneal collagen crosslinking (UVA CXL) on collagen structure. Two groups, four rabbits each, were treated in the right eye with standard UVA CXL. In vivo confocal microscopy was performed at 1, 2, and 4 weeks after treatment for the first group and up to three months for the second group to measure epithelial/stromal thickness and corneal haze during recovery. Rabbits were sacrificed at one and three months, respectively, and their corneas fixed under pressure. Regions of crosslinking were identified by the presence of collagen autofluorescence (CAF) and then collagen structure was imaged using SHG microscopy. The degree of CFC was determined by measuring the percentage difference between the length of the collagen fiber and the linear distance traveled. CFC was measured in the central anterior and posterior CXL region, the peripheral non-crosslinked region in the same cornea, and the central cornea of the non-crosslinked contralateral eye. No change in corneal thickness was detected after one month, however the stromal thickness surpassed its original baseline thickness at three months by 25.9 μm. Corneal haze peaked at one month and then began to clear. Increased CAF was detected in all CXL corneas, localized to the anterior stroma and extending to 42.4 ± 3.4% and 47.7 ± 7.6% of the corneal thickness at one and three months. There was a significant (P < 0.05) reduction in CFC in the CAF region in all eyes averaging 1.007 ± 0.006 and 1.009 ± 0.005 in one and three month samples compared to 1.017 ± 0.04 and 1.016 ± 0.06 for controls. These results indicate that there is a significant reduction in collagen crimping following UVA CXL of approximately 1%. One possible explanation for this loss of crimping could be shortening of the collagen fibers over the CXL region. Highlights • Corneal thickness remained consistent over time, and corneal haze was shown to peak at one month and then decrease. • CAF showed no decrease between one and three months, indicating persistent mechanical stiffening over time. • Collagen fiber crimping measurements revealed a straighter area of fibers within the crosslinked region, found using CAF. • Cellular staining showed migration of keratocytes into the crosslinked region from the periphery. [ABSTRACT FROM AUTHOR]

Purpose. To present safety, efficacy, and early results of a new combinational treatment for early corneal ectasia with hyperopic refractive error aimed to reinstate emmetropia and stabilize cornea. Method. This is a retrospective case series. All surgeries were performed at the Beirut Eye Specialist Hospital, Lebanon. Surgical procedure consisted of (1) lifting flap (post-LASIK ectasia)/creation of corneal flap (keratoconus), (2) application of excimer laser ablation to correct refractive error, (3) loose repositioning of flap, (4) under-the-flap irrigation with riboflavin 0.1% dextran solution, and (5) application of UVA light. Results. A total of 7 eyes (4 patients; mean age 24.25 years; all male) were included. 2 patients had early keratoconus, and 2 patients had early post-LASIK ectasia. Pretreatment vs. last postoperative follow-up visit (mean 11.25 months; range 6–15 months) UDVA (logMAR), spherical equivalent (SE) (D), astigmatism (D), and central pachymetry (µm) were 0.35 ± 0.18 vs. 0.05 ± 0.07, p=0.017; −0.81 ± 0.67 vs. −0.46 ± 0.57, p=0.078; 2.46 ± 0.53 vs. 0.68 ± 0.28, p=0.018; and 547 ± 58 vs. 536 ± 49, p=0.07, respectively. In all eyes, BCVA was 0.1 logMAR or better before and after treatment. No eye showed a decrease in BCVA. Two eyes of one patient had an epithelial ingrowth, which was removed in one case. Follow-up results showed no major complications and no progression of corneal ectasia. Conclusion. Early results showed that under-the-flap CXL with excimer laser correction is an effective treatment for early hyperopic keratectasia, with the advantage of rapid recovery, postoperative corneal stability, and no epithelial healing complications. The procedure seems to bear a risk for postoperative epithelial growth into the flap interface. [ABSTRACT FROM AUTHOR]

Abstract The UVA/riboflavin collagen crosslinking (CXL) is one of the treatment procedure for stopping the progression of keratoconus. The inclusion criterion for this procedure is a minimum corneal thickness of 400 μm, which is not often met in patients with advanced keratoconus. Preoperatively swelling thin corneas was shown to stabilize the keratectasia without any postoperative endothelial damage. Recently, we have shown that swelling porcine corneas prior to the CXL treatment had no significant effect on the resulting improvement in their tensile properties. In the present study, we extended this previous study and characterized the stiffening effects of CXL on anterior and posterior flaps as a function of their hydration. A DSAEK system was used to excise 10 mm corneal flaps from 80 porcine corneas. Individual flaps were crosslinked at different initial hydration levels by using riboflavin solutions composed of different dextran concentrations; the thickness was taken as a measure of flap hydration. A DMA machine was used to measure the tensile properties either immediately after the CXL treatment or after the thickness (hydration) of the crosslinked samples was brought down to a specific value. The average thickness of anterior groups was 670 μm, 540 μm, and 410 μm, and the average thickness of posterior groups was 845 μm, 650 μm, and 440 μm. It was found that although CXL significantly increased the tensile properties of all anterior groups, it had an insignificant effect on the stiffness of posterior flaps. Furthermore, except for the posterior flaps in 845 μm and 650 μm thickness groups, decreasing the hydration significantly increased the tensile modulus (p < 0.05). Finally, the anterior flaps that were crosslinked at higher hydration, i.e. swollen before CXL, showed significantly less amount of stiffening in comparison with those crosslinked at lower hydration when the tensile property measurement was done at similar hydration (p < 0.05). Highlights • Characterizing corneal inhomogeneous through-thickness tensile properties. • Measuring the stress-strain response of anterior and posterior flaps under tension. • Determining the interrelation of hydration and collagen crosslinking treatment. [ABSTRACT FROM AUTHOR]