Comparative Evaluation of Anterior Segment Optical Coherence Tomography Findings Following Accelerated Corneal Crosslinking Protocols Using Different Riboflavin Formulations and Soaking Durations.

PURPOSE: To comparatively evaluate the influence of different riboflavin formulations and soaking durations on the anterior segment optical coherence tomography (AS-OCT) findings following accelerated corneal crosslinking (ACXL) at 9 mW/cm2 for in progressive keratoconus. METHODS: In this prospective study, consecutive patients with progressive keratoconus were randomized into 4 groups. Group 1: hydroxypropyl methylcellulose (HPMC)-based riboflavin for 10 min; Group 2: HPMC-based riboflavin for 20 min; Group 3: dextran-based riboflavin (0.1%) for 30 min. Riboflavin soaking was followed by ultraviolet-A irradiation at 9 mW/cm2 for 10 min in all three groups. Group 4 underwent conventional CXL (CCXL) using Dresden protocol. The AS-OCT features of the crosslinked cornea were evaluated at postoperative month 1 and correlated to the clinical outcomes at postoperative month 12. RESULTS: The study enrolled 26 eyes of 26 patients in each group. In groups 1 and 2, the AS-OCT findings were similar (p > .05) and the demarcation lines depth (DLD) were deep as obtained following CCXL. The DLD was significantly shallower in group 3 compared to the other groups (p < .01). There were no between-group differences in regards to the visual, refractive, keratometric, and tomographic outcomes at postoperative month 12. No significant endothelial cell loss or any other clinically significant adverse event was encountered in any patient's eye at 12 months follow-up. CONCLUSION: Although structural variations were noted in the crosslinked cornea, DLDs observed following ACXL (9 mW/cm2) using HPMC-based solution for 10 or 20 min were similar to those observed following CCXL. Whereas, ACXL (9 mW/cm2) using dextran-based solution for 30 min resulted in the shallowest DLD. Despite these remodeling differences, the visual, refractive and tomographic outcomes of all groups were comparable at postoperative 1-year follow-up. Studies with a greater number of patients and longer follow-ups are required to establish any relation between AS-OCT characteristics of crosslinked cornea and ACXL efficacy.

A comparison of conventional and accelerated corneal crosslinking: corneal epithelial remodeling and in vivo confocal microscopy analysis.

PURPOSE: To evaluate the effect of conventional and accelerated corneal crosslinking (CXL) on visual acuity, corneal topography, corneal epithelial thickness, and subbasal nerve morphology in progressive keratoconus patients. METHODS: In this prospective and randomized study, twenty eyes of 20 patients were treated with conventional CXL (3 mW/cm2, 30 min, C-CXL) and 19 eyes of 19 patients were treated with accelerated CXL (9 mW/cm2, 10 min, A-CXL). The spherical equivalent, uncorrected visual acuity, best-corrected visual acuity, keratometric measurements, demarcation line measurement and epithelial thickness mapping analyses, and subbasal nerve morphology with in vivo confocal microscopy (IVCCM) were evaluated at baseline and at postoperative months 1, 3 and 6. RESULTS: At postoperative 6 months, a significant improvement was observed in all keratometric values in both treatment groups (p < 0.05). All epithelial thickness indices, except central, temporal, and inferotemporal thickness, were reduced at 1 month postoperatively in both treatment groups. The epithelial map uniformity indices (standard deviation and difference between min-max thickness) were significantly lower than the baseline values at all time points after CXL in both treatment groups (p < 0.001). Compared with the preoperative values, there was a significant decrease in all IVCCM parameters at 1 month postoperatively (p < 0.05). At 6 months postoperatively, corneal nerve fiber density and corneal nerve branch density recovered to preoperative values in the A-CXL group, whereas corneal nerve regeneration was not complete in the C-CXL group. CONCLUSION: Both conventional and accelerated CXL treatments appear to be effective in halting the progression of KC. Corneal epithelial irregularity slightly improves after CXL. The regeneration of subbasal nerves is faster after A-CXL treatment.

Accelerated corneal cross-linking (18mW/cm2 for 5 min) with HPMC-riboflavin in progressive keratoconus - 5 years follow-up.

PURPOSE: To evaluate long-term results of accelerated corneal cross-linking (ACXL) in patients with progressive keratoconus, seventy-four eyes of 53 patients with progressive keratoconus (documented Kmax progression > 1D/a) who underwent ACXL (18mW/cm2 for 5 min) were included in a retrospective observational clinical study. The investigation focused on tomographic and keratometric parameters, refractive data, and visual outcomes at 5 years follow-ups. METHODS: Corrected distance visual acuity (CDVA), slit lamp, and Pentacam® examinations were conducted, including assessments of thinnest corneal point (TP), minimum radius (Rmin), corneal astigmatism, and maximum anterior keratometry (Kmax). These examinations were performed two weeks before the surgery and, on average, 56 months after the surgery. In a subgroup of 24 eyes, Pentacam® examination data from an intermediate visit at 12 months until the final visit was evaluated to confirm continuous stability. The ACXL protocol included corneal abrasion, hydroxypropylmethylcellulose (HPMC)-riboflavin eye drops administered every 5 min for a total duration of 30 min, and irradiation with 18mW/cm2 for 5 min using riboflavin eye drops applied every minute during the irradiation process. Intraoperatively, minimal corneal pachymetry of > 400 µm was ensured in every patient. RESULTS: After 56 months, all values exhibited statistically significant changes (paired t-test; CDVA p = 0.002; Kmax p < 0.001; Rmin p < 0.001; astigmatism p = 0.03; TP p < 0.001). In the subgroup analysis of 24 eyes, which included tomographical and keratometric parameters, no statistically significant changes were observed during the last 12 months of observation (paired t-test; Kmax p = 0.72; Rmin p = 0.67; astigmatism p = 0.72). Treatment failure was strictly defined as an increase in Kmax (> 1D) during the 5-year follow-up and was observed in only 3 eyes (4%). CONCLUSIONS: ACXL is an effective and safe treatment for patients with progressive keratoconus. Our results demonstrate improvements in functional and tomographical outcomes even after high-energy ACXL (18mW/cm2 for 5 min) over a long-term period of 56 months. Our analysis indicates stable conditions in previously progressive keratoconus, particularly during the final year of the observation period. The treatment failure rate was 4%.

Analysis of the outcomes of three different cross-linking protocols for treatment of paediatric keratoconus: A multicentre randomized controlled trial.

PURPOSE: To analyse long-term outcomes of standard cross-linking (SCXL), accelerated cross-linking (ACXL) and transepithelial cross-linking (TCXL) in the treatment of progressive paediatric keratoconus regarding stability, safety and efficacy. METHODS: This prospective multicentre randomized controlled trial included 97 eyes of 97 paediatric patients with stages I-III ABCD keratoconus grading system, who were randomized into three groups; SCXL group (control group, n = 32; 3 mW/cm2 × 30 min/5.4 J/cm2 ), ACXL (n = 33; 18 mW/cm2 × 5 min/5.4 J/cm2 ) and TCXL (n = 32; 18 mW/cm2 × 5 min/5.4 J/cm2 ). Subjective refraction, uncorrected and corrected visual acuity, keratometry and pachymetry measurements using corneal topography were recorded preoperatively and 1, 2 and 3 years postoperatively. RESULTS: SCXL group exhibited significant successive improvements in the mean visual, refractive and keratometric parameters throughout the entire postoperative 3 years while ACXL group exhibited significant improvements in visual and keratometric parameters in the first postoperative year that remained stable in second and third postoperative years. TCXL group exhibited significant progressive deterioration in all mean parameters compared to SCXL and ACXL (p < 0.0001). Both SCXL and ACXL revealed final 100% success rate with good stability while TCXL revealed final 22% failure rate with keratoconus progression (p < 0.0001). CONCLUSION: SCXL and ACXL were comparable in halting keratoconus progression and achieved good stability and safety; however, SCXL was more efficient than ACXL as it yielded greater significant postoperative mean visual, refractive and keratometric improvements achieving smoother corneal remodelling. Both SCXL and ACXL were much superior to TCXL. SCXL is the best CXL treatment option for paediatric keratoconus while ACXL is a good and effective alternative.

Efficacy, Safety, and Outcomes following Accelerated and Iontophoresis Corneal Crosslinking in Progressive Keratoconus.

PURPOSE: To investigate the outcomes of accelerated (A-CXL) and iontophoresis (I-CXL) corneal crosslinking in a large retrospective cohort with progressive keratoconus. METHODS: This retrospective observational cohort study included consecutive patients treated by A-CXL (9 mW/5.4 J/cm2) or I-CXL with a minimal follow-up of 12 months. Visual acuity, manifest refraction, topography, specular microscopy, and corneal optical coherence tomography (OCT) were evaluated at baseline and at the last visit. Progression was defined as an increase in the maximum topographic keratometry (Kmax) of 1D. RESULTS: 302 eyes of 241 patients with a mean age of 25.2 ± 7.5 years were included from 2012 to 2019: 231 and 71 eyes in the A-CXL and I-CXL groups, respectively. The mean follow-up was 27.2 ± 13.2 months (maximum: 85.7 months). Preoperatively, the mean Kmax was 51.8 ± 4.0D, with no differences between groups. Mean topographic measurements and spherical equivalent remained stable during the follow-up. At the last visit, CXL failure was reported in 60 eyes (19.9%): 40 (14.7%) versus 20 (28.2%) in A-CXL versus I-CXL, respectively, p = 0.005. The likelihood of progression after CXL was significantly higher following I-CXL: RR = 1.62, CI95 = [1.02 to 2.59], p = 0.04. Demarcation line presence at 1 month was positively correlated with higher efficacy of CXL, p = 0.03. No endothelial damage was reported, especially in 51 thin corneas (range = 342-399 µm). CONCLUSIONS: A-CXL seems more effective than I-CXL in stabilizing keratoconus; this is to be taken into account when a therapeutic indication is posed according to the aggressiveness of the keratoconus.

Network meta-analysis comparing efficacy and safety of different protocols of corneal cross-linking for the treatment of progressive keratoconus.

PURPOSE: This study aimed to determine the preferred protocol of corneal collagen cross-linking (CXL) in the treatment of progressive keratoconus. METHODS: Relevant studies were retrieved in PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL). Maximum keratometry value (Kmax), best spectacle-corrected visual acuity (BSCVA), manifest refraction spherical equivalent (MRSE), and endothelial cell density (ECD) were evaluated in network meta-analysis. RESULTS: Eight randomized controlled trials (RCTs) were included. Low-level evidence suggested that aCXL with 30mW/cm2 for 3 min (aCXL-3) might be the best protocol for reducing BSCVA (65.22%) but worst protocol for reducing MRSE (51.53%). aCXL with 18mW/cm2 for 5 min (aCXL-5) might be the best protocol for reducing Kmax (39.58%) and MRSE (77.85%) but might be the worst for preserving ECD (50.98%). aCXL with 9mW/cm2 for 10 min (aCXL-10) might be the best protocol for preserving ECD (31.53%). CONCLUSION: Overall, three protocols of aCXL are comparable in therapeutic efficacy and safety for treating progressive keratoconus. Despite no direct data comparing the efficacy of each technique according to different patients' profiles, it is reasonable to state that aCXL-5 may be the best for patients at early-stage to reduce Kmax and MRSE, aCXL-3 may be the best for patients at mid-stage to improve BSCVA, and aCXL-10 may be the best for patients at late-stage to preserve DEC.

Subjective and objective evaluation of corneal haze after accelerated corneal crosslinking for corneal ectasias.

PURPOSE: To evaluate the relationship between subjective (slit lamp examination [SLE]) and objective (densitometry) measurements of corneal haze after accelerated corneal crosslinking (aCXL), assess the relationship between densitometry and corrected distance visual acuity (CDVA), and determine the effect of baseline characteristics on densitometry after aCXL in eyes with progressive keratoconus and other ectasias. SETTING: Kensington Eye Institute and Bochner Eye Institute, Toronto, Canada. DESIGN: Retrospective analysis of a prospective interventional cohort study. METHODS: Scheimpflug-derived corneal densitometry, CDVA, maximum keratometry (Kmax ), and central corneal thickness were measured preoperatively and up to 1 year after aCXL, and post-operative haze was estimated with SLE (n = 483 eyes). A random effect model was used to examine the relationship between post-operative subjective haze with SLE and densitometry. Linear mixed models were used to examine the relationship between densitometry, pre-operative baseline characteristics, and CDVA. RESULTS: There was a significant association between subjective haze with SLE and densitometry (p < 0.001). There was a significant relationship between CDVA and densitometry: for every 10 GSUs of increased densitometry in the 0-2 mm zone, CDVA worsened by approximately half a Snellen line (p < 0.001). Age and pre-operative Kmax were significant predictors of densitometry. For every 10 years of age, densitometry increased by 0.68 GSUs (95% CI [0.27 to 1.07], p < 0.001). For every 10 D of increased preoperative Kmax , densitometry increased by 0.69 GSUs (95% CI [0.41 to 0.98], p < 0.001). CONCLUSIONS: Subjective haze after aCXL estimated with SLE, is significantly associated with densitometry. Increased densitometry after aCXL is associated with a reduction in CDVA.

Transepithelial Enhanced Fluence Pulsed Light M Accelerated Crosslinking for Early Progressive Keratoconus with Chemically Enhanced Riboflavin Solutions and Air Room Oxygen.

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.

Comparison of accelerated corneal cross-linking for progressive keratoconus in pediatric and adult age groups: One-year results.

BACKGROUND: To compare one-year results of accelerated cross-linking (ACXL) treatment for progressive keratoconus in pediatric and adult age groups. METHODS: The records of patients who had undergone the ACXL procedure (9mV/cm2, 10min) for progressive keratoconus were evaluated retrospectively. The patients were divided into 2 groups, with the pediatric group aged 17years or less and the adult group aged 18years or more, for the statistical analysis. Pre- and 12-month post- ACXL best-corrected visual acuity (BCVA), maximum keratometry (Kmax), sim K1, sim K2, corneal thickness at the thinnest point (thCT), and corneal astigmatism (CA) values of the patient groups were recorded. RESULTS: Thirty-two right eyes of 32 patients were included in the pediatric group, and 32 right eyes of 32 patients were included in the adult group. A significant improvement in BCVA and a significant decrease in thCT values were present in both groups 12months after the surgery compared to the preoperative period. The decrease in Kmax, sim K1 and sim K2 values compared to the preoperative period was significant in the adult group. When the two groups were compared after 12months, only the simK1 value was significantly lower in the adult group, and there was no significant difference between the other measurements. CONCLUSIONS: There is a slight tendency toward more flattening in the adult group 12months after ACXL treatment, but this is not statistically significant.

Comparative Results Between "Epi-Off" Accelerated and "Epi-Off" Standard Corneal Collagen Crosslinking-UVA in Progressive Keratoconus - 7 Years of Follow-Up.

PURPOSE: The purpose of the present study was to assess the long-term efficiency and safety of the "epi-off" accelerated CXL (9 mW/cm2 for 10 minutes) in comparison to the standard "epi-off" CXL (3 mW/cm2 for 30 minutes) in terms of topographical and keratometric parameters, refractive data and visual outcomes at 7 years of follow-up, in progressive keratoconus. MATERIAL AND METHOD: A retrospective and comparative study was performed. A total of 183 eyes from 183 patients with documented progressive keratoconus were included in the study. The patients were divided in two groups: 93 eyes from 93 patients underwent "epi-off" standard cross-linking technique (3 mW/cm2 for 30 minutes) (S-CXL group) and 90 eyes from 90 patients underwent accelerated "epi-off" corneal CXL technique (9 mW/cm2 for 10 minutes) (A-CXL group). RESULTS: Improvements in uncorrected distance visual acuity (UDVA) were statistically significant compared to baseline values in both groups at each time-point visit (p=0.0421 at 1 year, p=0.0411 at 7 years for A-CXL and p=0.0375 at 1 year, p=0.0389 at 7 years for S-CXL). At 7 years there was a statistically significant increase in CDVA (p=0.039 in the A-CXL group and p=0.0343 in the S-CXL group at 7 years). Statistically significant reduction was noticed in Ksteep (p=0.0411 in A-CXL group and p=0.0224 in S-CXL group), Kflat (p=0.0198 in A-CXL group and p=0.008 in S-CXL group), K mean (p=0.0106 in A-CXL group and p=0.0193 in S-CXL group) and Kmax (p=0.0413 in A-CXL group and p=0.054 in S-CXL group) at 7 years, compared to baseline values, in both groups, but without any statistically difference between the two procedures, at all time-point visits (p>0.05). CONCLUSION: The long-term outcomes of "epi-off" accelerated corneal collagen crosslinking-UVA (9 mW/cm2 for 10 minutes) are similar to standard "epi-off" corneal collagen crosslinking procedure in the treatment of progressive keratoconus.

Safety of accelerated corneal collagen cross-linking in keratoconus patients on the basis of macular segmentation.

PURPOSE: To investigate the safety of accelerated corneal collagen cross-linking (A-CXL) in patients with keratoconus on the basis of thickness analysis measurements of retinal layers and retinal morphology. STUDY DESIGN: This was a retrospective and comparative study. METHODS: The study included 64 eyes of 32 patients with keratoconus disease. One eye of the patients underwent A-CXL for progressive keratoconus (CXL group) and the fellow eye was followed due to the absence of progression. Patients with at least 1-year follow-up after A-CXL were included. Keratometry, pachymetry and corrected-distance visual acuity (CDVA) levels of the patients were compared. The segmentation analysis of the individual retinal layers of the eyes with (CXL group) and without CXL (no CXL group) was compared with spectral domain-optical coherence tomography automatic segmentation program at baseline and at the last follow-up. The thickness of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer and retina pigment epithelium layer in the central 1-mm subfield defined by the ETDRS was analyzed. RESULTS: The mean age of keratoconus patients was 23.9 ± 5.4 years, patients were more likely to be male (21/11, 65.6%), and the mean follow-up duration was 13.9 ± 1.5 months. When keratometry, pachymetry and CDVA levels were compared, only a significant difference was found between CDVA at the last follow-up (0.21 vs. 0.11 LogMAR). No significant difference was observed in neither retinal morphology nor segmentation of individual retinal layers at baseline and at the final evaluation (P > 0.05). CONCLUSIONS: It has been observed that the A-CXL protocol did not cause a significant change in both retinal layer thickness and macular morphology.

Long term results of accelerated 9 mW corneal crosslinking for early progressive keratoconus: the Siena Eye-Cross Study 2.

PURPOSE: To assess clinical results of the 9 mW/5.4 J/cm2 accelerated crosslinking (ACXL) in the treatment of progressive keratoconus (KC) over a span of 5 years. METHODS: The prospective open non-randomized interventional study (Siena Eye-Cross Study 2) included 156 eyes of 112 patients with early progressive KC undergoing the Epi-Off 9 mW/5.4 J/cm2 ACXL at the Siena Crosslinking Centre, Italy. The mean age was 18.05 ± 5.6 years. The 20-min treatments were performed using the New KXL I (Avedro, Waltham, USA), 10 min of 0.1% HPMC Riboflavin soaking (VibeX Rapid, Avedro, Waltham, USA) and 10 min of continuous-light UV-A irradiation. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), Kmax, coma, minimum corneal thickness (MCT), surface asymmetry index (SAI), endothelial cell count (ECC) were measured, and corneal OCT performed. RESULTS: UDVA and CDVA improved significantly at the 3rd (P = 0.028), Δ + 0.17 Snellen lines and 6th postoperative month, respectively (P < 0.001), Δ + 0.23 Snellen lines. Kmax improved at the 6th postoperative month (P = 0.03), Δ - 1.49 diopters from the baseline value. Also, coma aberration value improved significantly (P = 0.004). A mild temporary haze was recorded in 14.77% of patients without affecting visual acuity and without persistent complications. Corneal OCT revealed a mean demarcation line depth at 332.6 ± 33.6 µm. CONCLUSION: The 5-year results of Epi-Off 9 mW/5.4 J/cm2 ACXL demonstrated statistically significant improvements in UCVA and CDVA, corneal curvature and corneal higher-order aberrations which confers a long-term stability for progressive ectasia. Based on the results of the Siena Eye-Cross Study 2, the 9 mW/5.4 J/cm2 ACXL is a candidate to be  the natural evolution of Epi-Off CXL treatment for the management of early progressive corneal ectasia, and thus optimize clinic workflow.

Chemically-Boosted Corneal Cross-Linking for the Treatment of Keratoconus through a Riboflavin 0.25% Optimized Solution with High Superoxide Anion Release.

The purpose of this study was to evaluate the effectiveness and safety of a novel buffered riboflavin solution approved for corneal cross-linking (CXL) in progressive keratoconus and secondary corneal ectasia. Following the in vivo preclinical study performed on New Zealand rabbits comparing the novel 0.25% riboflavin solution (Safecross®) containing 1% hydroxypropyl methylcellulose (HPMC) with a 0.1% riboflavin solution containing 0.10% EDTA, accelerated epithelium-off CXL was performed on 10 patients (10 eyes treated, with the contralateral eye used as control) through UV-A at a power setting of 9 mW/cm2 with a total dose of 5.4 J/cm2. Re-epithelialization was evaluated in the postoperative 7 days by fluorescein dye test at biomicroscopy; endothelial cell count and morphology (ECD) were analyzed by specular microscopy at the 1st and 6th month of follow-up and demarcation line depth (DLD) measured by anterior segment optical coherence tomography (AS-OCT) one month after the treatment. We observed complete re-epithelization in all eyes between 72 and 96 h after surgery (88 h on average). ECD and morphology remained unchanged in all eyes. DLD was detected at a mean depth of 362 ± 50 µm, 20% over solutions with equivalent dosage. SafeCross® riboflavin solution chemically-boosted corneal cross-linking seems to optimize CXL oxidative reaction by higher superoxide anion release, improving DLD by a factor of 20%, without adverse events for corneal endothelium.

[Safety and efficiency of epithelium-off accelerated corneal cross-linking for progressive keratoconus in pediatric patients]. / Efficacité et tolérance du cross-linking cornéen épithélium-off accéléré dans le traitement du kératocône évolutif de l'enfant.

In adults, the management of keratoconus has evolved in recent years to achieve a well-codified treatment algorithm. The technique of cross-linking (CXL) has allowed us to stabilize the progression of keratoconus and has been largely developed. It is very effective, with few postoperative complications. Currently, there is no specific keratoconus management protocol for children. As we already know that keratoconus usually evolves more rapidly in children, we might consider whether a stabilizing treatment should be proposed as first-line therapy at the time of diagnosis. We carried out a retrospective study including patients less than 18 years of age with keratoconus who consulted the ophthalmology department at Edouard Herriot hospital in Lyon between 2013 and 2017. The main study parameter was whether or not CXL was performed. The other parameters were gender, age, ethnicity, eye rubbing, presence or absence of atopic disease, maximum keratometry (Kmax), minimal pachymetry, best corrected visual acuity (BCVA) and spherical equivalent. Forty-eight eyes of 34 patients were included. We found that two-thirds of the patients were Caucasian boys. Half of the patients had allergies, and over 60% of patients rubbed their eyes regularly. Only six percent of patients had a family history of keratoconus. The mean age of the patients was 14 (7-18) years at the time of diagnosis. Thirty-four eyes of 22 patients underwent CXL, for a total of 71% of our cohort. No postoperative complications occurred. After CXL, there was no significant difference in minimum pachymetry (455.6±37.25µm vs. 453.45±42.6µm after treatment (P=0.71)) or Kmax (50.23±7.17D vs. 50.99±7.01D after treatment (P=0.058)). There was a significant improvement in BCVA (from 0.30±0.3LogMar to 0.17±0.17LogMar after CXL (P=0.024)) and spherical equivalent (-1.91±2.1D to -2.54±1.89D after treatment (P=0.009)). The mean duration of follow-up was 32.2 months (12-59). CXL shows long-term disease stabilization in children with keratoconus. Nevertheless, this technique is indicated only for progressive keratoconus. Early diagnosis and management are essential in this population where the disease is rapidly changing. Treatment of atopy and performance of corneal topography when a child has irregular astigmatism should become automatic for early detection of this disease.

Comparison of Different Methods of Corneal Collagen Crosslinking: A Systematic Review.

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.

Refractive surgery with simultaneous collagen cross-linking for borderline corneas - A review of different techniques, their protocols and clinical outcomes.

Simultaneous corneal cross-linking (CXL) has been proposed as an adjunct therapy to corneal refractive procedures to prevent future ectasia, especially when performed in borderline corneas. This review analyses the currently available literature (minimum follow-up 6 months) on corneal refractive surgery and simultaneous CXL (PRK Xtra, LASIK Xtra, and SMILE Xtra) to evaluate the overall results including the safety, efficacy, and potential complications associated with these procedures. A comprehensive literature search of various electronic databases (PubMed, PubMed Central, Cochrane database, and MEDLINE) was performed up to 20th May 2020. Four relevant studies were found for PRK Xtra, 12 for LASIK Xtra, and 3 for SMILE Xtra. The total number of eyes included in this review was 1,512: 294 for PRK Xtra, 221 for PRK-only, 446 eyes for LASIK Xtra, 398 eyes for LASIK-only, 91 for SMILE Xtra and 62 for SMILE-only. Current literature suggests that refractive surgery and simultaneous CXL is generally safe and delivers comparable results in terms of visual and refractive outcomes than refractive surgery alone. However, there is no consensus on a standard cross-linking protocol, and complications such as diffuse lamellar keratitis, central toxic keratopathy, and corneal ectasia following Xtra procedures have been reported. It is therefore suggested that surgeons exercise caution in case-selection and counsel their patients regarding the potential risks and benefits with Xtra procedures. Also, further studies are required to standardize the UV-A irradiation protocols and to evaluate the long-term effect on safety, refractive predictability, and stability of these procedures.

Accelerated and Standard Corneal Cross-Linking Protocols in Patients with Down Syndrome: A Non-inferiority Contralateral Randomized Trial.

INTRODUCTION: To compare the results of an accelerated corneal cross-linking (CXL) protocol (9 mW/cm2, 10 min) with the standard CXL protocol (3 mW/cm2, 30 min) in patients with Down syndrome (DS) who have keratoconus (KC). METHODS: Twenty-seven 10- to 20-year-old patients with DS who had bilateral progressive KC were enrolled in a contralateral randomized trial and completed 2 years of follow-up examinations. Fellow eyes were randomly allocated to the accelerated CXL group or the standard CXL group. The main outcome measure was change in maximum keratometry (Kmax) centered on the steepest point (zonal Kmax - 3 mm) with a non-inferiority margin of 1.0 diopter (D). Vision and refraction tests, ophthalmic examinations, and corneal tomography were performed at baseline and at 6, 12, and 24 months after CXL. Failure was defined as an increase of ≥ 1.0 D in zonal Kmax - 3 mm within a 12-month period. RESULTS: The mean age (± standard deviation) of the patients was 15.71 ± 2.40 years. The within-group change in zonal Kmax - 3 mm was not significant after 2 years in either group, and within-group zonal Kmax - 3 mm remained stable. At 2 years after CXL, the mean change in the zonal Kmax - 3 mm was - 0.02 ± 0.81 D and - 0.31 ± 0.86 D in the accelerated CXL and standard CXL groups, respectively (P = 0.088). At 1 year of follow-up, three patients in the accelerated CXL group showed treatment failure (mean change in zonal Kmax - 3 mm + 2.12 ± 0.11 D); no patients in the standard CXL group showed treatment failure. At 2 years of follow-up, these three patients showed a decrease of - 0.43 ± 0.18 D in zonal Kmax - 3 mm from a baseline value of 55.11 ± 0.32 D. The 2-year trends of the inferior-superior asymmetry and vertical coma were statistically significantly different between the two groups, with the accelerated CXL protocol showing superiority in patients with higher baseline values. CONCLUSION: In young patients with Down syndrome, the accelerated CXL protocol was able to halt disease progression and may be an alternative for the standard CXL protocol. In advanced KC, the efficacy of the accelerated approach was delayed and appeared later in the follow-up. In asymmetric cornea, the accelerated CXL resulted in centralization of the corneal cone. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20100706004333N3.

Comparative 2-year outcomes of conventional and accelerated corneal collagen crosslinking in progressive keratoconus.

AIM: To compare the safety and efficacy of conventional versus accelerated (9 mW/cm2) corneal collagen crosslinking (CXL) in progressive keratoconus at the 2-year follow-up. METHODS: In this prospective study, consecutive progressive keratoconus patients were randomized to receive either conventional CXL (CCXL) or accelerated CXL (ACXL; using hydroxypropyl methylcellulose-assisted riboflavin imbibition for 10min at 9 mW/cm2). Visual, refractive, keratometric, topographic, and aberrometric outcomes and stromal demarcation line depth (DLD) measurements were compared at the end of a 2-year follow-up. RESULTS: Thirty-two eyes from 32 patients in the CCXL and 27 eyes from 27 patients in the ACXL groups completed 2-year follow-up. At 2y post-CXL, both uncorrected and corrected visual acuities improved significantly in both groups. The improvements in keratometric readings, flattening rate (flattening of the maximum keratometry more than 1 D), 3 topographic indices, and vertical coma were significantly better in the CCXL group compared to the ACXL group (P<0.05). The DLD as measured by anterior segment optical coherence tomography or in vivo confocal microscopy was better detectable and significantly deeper in the CCXL group compared to the ACXL group. The deeper DLD was found to be significantly correlated with improvements in the mean keratometry measurements. Progression was noted in 11.1% of eyes in the ACXL group, whereas progression was not observed in any patient eye in the CCXL group. CONCLUSION: In this prospective randomized study, ACXL is less effective in halting the progression of keratoconus at a 2-year follow-up compared to CCXL.

Long-term results of accelerated and conventional corneal cross-linking.

PURPOSE: The aim of this study is to compare the long-term follow-up outcomes of traditional and accelerated corneal cross-linking (CXL) for keratoconus. METHODS: This retrospective comparative cohort study included patients with keratoconus who underwent corneal cross-linking (CXL) between August 2008 and December 2016. Patients treated before August 2013 underwent the traditional Dresden protocol, and those treated subsequently received the accelerated protocol, i.e., 0.1% riboflavin soaking for 10 min, followed by pulsed UV-A irradiation at 30 mW/cm2 for 8 min, and a total irradiation power of 7.2 J/cm2. The primary outcome was the success rate in halting the disease progression. The postoperative changes in visual acuity, keratometry readings, endothelial cell count and complications following accelerated CXL and conventional CXL were compared. RESULTS: This study evaluated 113 eyes over a mean follow-up period of 37.61 ± 16.34 months. It was found that 89.6% and 95.7% of the eyes were successfully treated with the traditional and accelerated protocols, respectively (p = 0.239). The corrected-distance visual acuity improved in both groups, but it was significantly better following the accelerated protocol (p = 0.037). Traditional protocol group had more postoperative complications than the accelerated group (8.9% versus 2%), although not reaching statistically significant difference (p = 0.142). There were no significant differences in the topographic (p = 0.122) and refractive (p = 0.570) outcomes. CONCLUSION: Accelerated CXL and conventional CXL are both safe and effective, and the long-term follow-up showed that the accelerated protocol was similar to the standard one in terms of halting keratoconus and achieving visual outcomes. Because of its potential benefits, the accelerated protocol may be considered for the treatment of progressive keratoconus.

Efficacy of pulsed-light accelerated crosslinking in the treatment of progressive keratoconus: Two-year results.

PURPOSE: The aim of this study was to evaluate the 2-year results of epithelium-off pulsed-light accelerated corneal collagen crosslinking treatment in progressive keratoconus using 30 mW/cm2 ultraviolet A light for 6 min with a total dose of 5.4 J/cm2. METHODS: A total of 30 eyes of 22 patients with documented progressive keratoconus and treated with epithelium-off pulsed-light accelerated corneal collagen crosslinking using the KXL® crosslinking device (Avedro Inc, Waltham, MA, USA) were included in this retrospective study. Corneal tomographic measurements and best spectacle-corrected visual acuity were compared using analysis of variance with repeated measurements between the baseline visit (before the corneal collagen crosslinking treatment), and the sixth month, first, and second year visits. RESULTS: Flat keratometry (K1), steep keratometry (K2), and mean keratometry (Km) decreased significantly at sixth month, first, and second years (p < 0.001, p = 0.001, and p < 0.001, respectively). Maximum keratometry (Kmax) decreased from 55.40 ± 4.90 D at baseline to 54.82 ± 4.68 D, 54.80 ± 5.12 D, and 54.65 ± 5.36 D at sixth month, first year, and second year, respectively (p = 0.007). The best spectacle-corrected visual acuity improved from 0.34 ± 0.24 logMAR at baseline to 0.25 ± 0.16 logMAR, 0.22 ± 0.15 logMAR, and 0.17 ± 0.13 logMAR at sixth month, first year, and second year, respectively (p < 0.001). At the second year visit, best spectacle-corrected visual acuity remained stable (no lines lost) with respect to the baseline in 8 eyes and increased 1 or more lines in 22 eyes. CONCLUSION: Pulsed-light accelerated corneal collagen crosslinking using 30 mW/cm2 ultraviolet A light for 6 min with a total dose of 5.4 J/cm2 is an effective treatment modality in cases with progressive keratoconus-it stops progression at 2 years also regresses some of the cases.