Efficacy and Safety of the Modified Cretan Protocol in Patients with Post-LASIK Ectasia

Objectives: To investigate the clinical efficacy and safety of the modified Cretan protocol in patients with post-laser in situ keratomileusis ectasia (PLE). Materials and Methods: In this retrospective study, 26 eyes of 16 patients with PLE were treated with the modified Cretan protocol (combined transepithelial phototherapeutic keratectomy and accelerated corneal collagen cross-linking). Visual, refractive, tomographic, and aberrometric outcomes and point spread function (PSF) were recorded preoperatively and at 6, 12, and 24 months after treatment. Results: Both uncorrected and best corrected visual acuity were stable at 24 months postoperatively compared to baseline (from 0.89±0.36 to 0.79±0.33 logarithm of the minimum angle of resolution [LogMAR] and 0.31±0.25 to 0.24±0.19 LogMAR, respectively, p>0.05 for all values). The mean K1, K2, Kmean, thinnest corneal thickness, and spherical aberration at baseline were 45.76±5.75 diopters (D), 48.62±6.17 D, 47.13±5.89 D, 433.16±56.86 µm, and -0.21±0.63 µm respectively. These values were reduced to 42.86±6.34 D, 45.92±6.74 D, 44.21±6.4 D, 391.07±54.76 µm, and -0.51±0.58 µm at 24 months postoperatively (p<0.001, p=0.002, p<0.001, p=0.001, and p=0.02, respectively). The mean spherical equivalent, manifest cylinder, Kmax, central corneal thickness, other corneal aberrations (root mean square, trefoil, coma, quatrefoil, astigmatism), and PSF remained stable (p>0.05 for all variables), while anterior and posterior elevation were significantly improved at 24 months postoperatively (p<0.001 and p=0.02, respectively). No surgical complications occurred during the 24-month follow-up. Conclusion: The modified Cretan protocol is a safe and effective treatment option for PLE patients that provides visual stabilization and significant improvement in topographic parameters during the 24-month follow-up. Further studies are needed to support our results.

Corneal collagen cross-linking in patients with keratoconus from the Dresden protocol to customized solutions: theoretical basis.

Keratoconus is an ectatic condition characterized by gradual corneal thinning, corneal protrusion, progressive irregular astigmatism, corneal fibrosis, and visual impairment. The therapeutic options regarding improvement of visual function include glasses or soft contact lenses correction for initial stages, gas-permeable rigid contact lenses, scleral lenses, implantation of intrastromal corneal ring or corneal transplants for most advanced stages. In keratoconus cases showing disease progression corneal collagen crosslinking (CXL) has been proven to be an effective, minimally invasive and safe procedure. CXL consists of a photochemical reaction of corneal collagen by riboflavin stimulation with ultraviolet A radiation, resulting in stromal crosslinks formation. The aim of this review is to carry out an examination of CXL methods based on theoretical basis and mathematical models, from the original Dresden protocol to the most recent developments in the technique, reporting the changes proposed in the last 15y and examining the advantages and disadvantages of the various treatment protocols. Finally, the limits of non-standardized methods and the perspectives offered by a customization of the treatment are highlighted.

Keratometric Outcomes after Simultaneous versus Sequential Intracorneal Ring Segment Implantation with Femtosecond Laser and Corneal Collagen Crosslinking in Egyptian Patients with Keratoconus and Ectasia.

Background: Keratoconus (KC) is degenerative corneal disorder, with central and paracentral thinning and corneal ectasia. For KC progressive cases, primary treatment included corneal collagen cross linking (CXL) to stabilize coning and intracorneal rings segment (ICRS) to correct visual acuity. Aim: The aim of the study is to assess efficacy and safety of ICRS and CXL on one session (Simultaneous) or two sessions (sequential) with maximum of 1 month apart. Patients and Methods: This Prospective Intervention Comparative research made at Armed forces hospital, Cairo, Egypt from January 2017 to December 2019. Forty patients (60 eyes) with mild to moderate KC were enrolled. Patients sorted into Simultaneous group includes 21 patients (30 eyes) undergo two procedures (ICRS then CXL) at the same session and Sequential group included 19 patients (30 eyes) undergo ICRS then CXL on two sessions with month apart. Patients followed up at end of 1st, 3rd, and 6th months. Assessment included changes in corrected corneal surface irregularities as minimum keratometric 1 (K1), maximum keratometric readings (K2), and mean keratometric (Km) readings. Results: Improvement of K1, K2, and Km in Simulations and Sequential groups achieved at end of 1st-, 3rd-, and 6th-month postoperative versus preoperative. Maximum improvement in Simulations and Sequential groups in K1 achieved at end of 6th and 1st months, in K2 at end of 3rd and 6th months and in Km at end of 1st and 3rd months. Conclusions: Combined ICRS and CXL act safely in one or two sessions and there are no statistically significant variations between results on both methods in keratometric readings.

Refractive surgical correction and treatment of keratoconus.

Keratoconus is an ectatic corneal disorder that causes severe vision loss. Surgical options allow us to correct, partially or totally, the induced refractive error. Intracorneal ring segments (ICRS) implantation represents a minimally invasive surgical option that improves visual acuity, with a high success rate and a low overall complication rate. Corneal allogenic ICRS consists of ring segments derived from allogenic eye bank-processed donor corneas. Selective topography-guided transepithelial photorefractive or phototherapeutic keratectomy combined with CXL is another way in selected cases to improve spectacles corrected distance visual acuity. The microphotoablative remodeling of the central corneal profile is generally planned by optimizing the optical zones and minimizing tissue consumption. Phakic intraocular lens (PIOL) implant is considered in patients with stable disease and acceptable anatomical requirements. The two types of pIOLs, depending on their implantation inside the eye, are anterior chamber-pIOLs, which fixate to the anterior surface of the iris by using a polymethomethacrolate claw at the two haptics, and posterior chamber-pIOLs. In patients with both cataracts and keratoconus, the correct IOL power is difficult to obtain due to the irregular corneal shape and K values. Toric IOL is recommended, but carefully judging the topography and the possible need of subsequent keratoplasties.

Corneal stromal lenticule-combined accelerated transepithelial corneal collagen cross-linking for severe keratoconus / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the clinical efficacy of corneal stromal lenticule-combined accelerated transepithelial corneal collagen cross-linking(SC-A-TE-CXL)in the treatment of severe keratoconus.METHODS: Prospective before-after self-control study. A total of 10 cases(14 eyes)of severe keratoconus with the thinnest corneal thickness(including epithelium)less than 400 μm were collected from March 2019 to July 2022 at the ophthalmology department of Affiliated Eye Hospital of Nanjing Medical University. Among them, 8 males(12 eyes)and 2 females(2 eyes)were treated with SC-A-TE-CXL. Corneal curvature, uncorrected visual acuity(UCVA), best corrected visual acuity(BCVA), the thinnest corneal thickness(TCT), central corneal thickness(CCT), non-contact intraocular pressure, endothelial cell density(ECD)and anterior or posterior elevations at the thinnest point before surgery and at 1, 3, 6 and 12 mo postoperatively were observed and recorded, as well as corneal cross-linking depth at 1 mo postoperatively.RESULTS: UCVA and BCVA at 1, 3, 6, and 12 mo after SC-A-TE-CXL were higher than those preoperatively, but there were no differences(F=0.793, P=0.535; F=0.783, P=0.542). K1, K2, Km and Kmax decreased at each time point postoperatively compared with those preoperatively, but there were no differences(F=0.627, P=0.574; F=1.264, P=0.296; F=0.727, P=0.520; F=1.115, P=0.359). Anterior and posterior elevations at the thinnest point both decreased compared with those preoperatively, but the differences were not statistically significant(F=1.046, P=0.359; F=1.164, P=0.337). The non-contact intraocular pressure at each time point postoperatively was higher than that preoperatively, but the differences were not statistically significant(F=0.814, P=0.522). There were no differences in CCT and TCT at any time points of the follow-ups compared with those preoperatively(F=0.931, P=0.453; F=0.782, P=0.542). There was no difference in ECD at 12 mo postoperatively versus preoperative value(t=1.266, P=0.228). At 1 mo postoperatively, anterior segment optical coherence tomography(AS-OCT)exhibited an increase of density in the anterior stroma, and there was a demarcation line with an average depth of 124.07±25.13 μm.CONCLUSION: SC-A-TE-CXL can be considered as a surgical treatment for severe keratoconus, which can delay the progression of severe keratoconus with high safety. However, the long-term efficacy of this treatment requires further observation.

Intraocular pressure after combined photorefractive keratectomy and corneal collagen cross-linking for keratoconus.

PURPOSE: The purpose of this prospective study was to evaluate the effect of combined photorefractive keratectomy (PRK) and corneal collagen cross-linking (CXL) on intraocular pressure (IOP) in patients with keratoconus (KC). METHODS: We included 64 eyes of 34 patients (19 males and 15 females; age: 19-40y) with stages 1-2 keratoconus which had undergone combined wavefront-optimized photorefractive keratectomy and corneal collagen cross linking. Two other groups of patients were added as controls: the PRK group including 110 eyes of 57 patients (23 males and 34 females; age: 18-44y) which had undergone wavefront-optimized photorefractive keratectomy for myopic refractive errors, and the CXL group including 36 eyes of 23 patients (14 males and 9 females; age: 12-38y) with keratoconus, not filling the inclusion criteria for combined PRK and CXL, which had undergone corneal collagen cross-linking. IOP was recorded preoperatively and postoperatively at 3, 6 and 12 months follow-up visits. RESULTS: Preoperative IOP in both CXL (12.1 ± 2.53 mmHg) and PRK + CXL (13.2 ± 2.50 mmHg) groups was significantly lower than PRK group (15.8 ± 3.10 mmHg) (F = 30.505, p < 0.001). At 3 months postoperatively, IOP showed no statistically significant difference between the three studied groups (F = 1.821, p = 0.164). At 6 months postoperatively, IOP in the CXL group (14.6 ± 2.64 mmHg) was significantly higher than both PRK (13.4 ± 2.27 mmHg) and PRK + CXL (13.3 ± 2.62 mmHg) groups (F = 3.721, p = 0.026). At 12 months postoperatively, IOP in the CXL group (14.3 ± 2.69 mmHg) was significantly higher than the PRK group (13.2 ± 2.23 mmHg) and was higher than PRK + CXL group (13.3 ± 2.59 mmHg) although not statistically significant (F = 3.393, p = 0.035). Regarding the percent of change from preoperative IOP, a statistically significant difference between the three studied groups was detected at 3, 6 and 12 months postoperatively (H = 117.459, 109.303, 122.694 respectively, p < 0.001). The median percent of change from preoperative IOP in the PRK group was -16.7%, -15%, and -16.7%, in the CXL group was + 14.3%, + 19.4%, and + 19.1%, while in PRK + CXL group was 0% at 3, 6 and 12 months postoperatively. (Post-hoc power analysis 75%). CONCLUSIONS: Combined PRK and CXL in patients with KC shows no significant effect on IOP, in contrast to either procedure performed separately.

Paediatric cornea crosslinking current strategies: A review.

Background: In the general population, 1 in 2000 people has keratoconus. Indians and other people from Southeast Asia have a higher incidence of keratoconus. Children with keratoconus typically present earlier in life and with a more severe disease. Rubbing the eyes has been identified as a risk factor. Children have a higher incidence and a faster rate of keratoconus progression. Visual rehabilitation in children with keratoconus is challenging. They have a low compliance with contact lens use. Many of these children require penetrating keratoplasty at an early age. Therefore, stopping the progression of keratoconus in children is of paramount importance. Main text: Compared to treatment, keratoconus progression prophylaxis is not only preferable, but also easier. Corneal collagen cross-linking has been shown to be safe and effective in stopping its progression in children. The Dresden protocol, which involves central corneal deepithelization (7-9 â€‹mm), saturation of the stroma with riboflavin (0.25%), and 30 â€‹min UV-A exposure, has proven to be the most successful. Two significant disadvantages of the typical Dresden regimen are the prolonged operating time and the significant post-operative pain. Accelerated-CXL (9 â€‹mW/cm2 x 10 â€‹min) has been studied to reduce operative time and has been shown to be equally effective in some studies. Compared to accelerated CXL or traditional CXL, epi-off procedures, transepithelial treatment without the need for de-epithelialization and without postoperative discomfort, have been shown to be safer but less effective. Corneal crosslinking should only be performed after treating children with active vernal keratoconjunctivitis. Corneal opacity, chronic corneal edema, sterile infiltrates, and microbial keratitis have been reported after cross-linking of corneal collagen. Conclusions: The "Dresden protocol", also known as the conventional corneal cross-linking approach, should be used to halt the progression of keratoconus in young patients. However, if the procedure needs to be completed more rapidly, accelerated corneal crosslinking may be considered. Transepithelial corneal cross-linking has been proven to be less effective at stabilizing keratoconus, although being more safer.

Safety and Efficacy of Corneal Cross-Linking in Patients Affected by Keratoconus: Long-Term Results.

The present study evaluated the effectiveness and safety of corneal collagen cross-linking (CXL). A total of 886 eyes with progressive keratoconus were enrolled in a retrospective cohort study in a tertiary care university hospital. CXL was performed using a standard epithelium-off Dresden protocol. Visual outcomes, maximum keratometry (Kmax), demarcation line measurements, and complications were recorded. Visual outcomes and keratometric data were analyzed in a subgroup comprising 610 eyes. Uncorrected distance visual acuity (UDVA) improved from 0.49 ± 0.38 LogMAR to 0.47 ± 0.39 LogMAR (p = 0.03, n = 610) three years after the procedure, while corrected distance visual acuity (CDVA) improved from 0.15 ± 0.14 LogMAR to 0.14 ± 0.15 LogMAR (p = 0.007, n = 610). A significant reduction of Kmax from 56.28 ± 6.10 to 54.98 ± 6.19 (p < 0.001, n = 610) was observed three years after CXL. In five eyes (0.82%, 5/610) keratoconus progression continued after CXL. Three eyes were retreated successfully with documented refractive and topographic stability after five years. In the 35 eyes that completed 10 years of follow-up, mean visual acuity and topographic parameters remained stable. In conclusion, CXL is a safe and effective treatment for avoiding keratoconus progression. Long-term data are encouraging, supporting a high safety profile for this procedure.

[Analysis of the results of modified personalized topographically and tomographically oriented technique of ultraviolet corneal collagen crosslinking]. / Analiz rezul'tatov modifitsirovannoi personalizirovannoi topograficheski i tomograficheski orientirovannoi metodiki ul'trafioletovogo krosslinkinga rogovichnogo kollagena.

PURPOSE: The study aims to develop a modified personalized topographically and tomographically oriented technique of ultraviolet corneal collagen cross-linking (UVCXL) to affect the area of the cornea with weakest biomechanical properties as determined by mathematical modeling. MATERIAL AND METHODS: Modeling of the biomechanics of keratoconic cornea under conditions of external diagnostic action was done using COMSOL Multiphysics® software. Finite-element analysis procured 3D images of stress/deformation distribution pattern throughout the cornea. Matching these 3D images with primary topographic and tomographic Pentacam AXL maps and Corvis ST findings allowed determining localization and dimensions of impaired regions of the cornea. The acquired data helped develop the modified corneal collagen cross-linking technique, which was applied in the treatment of 36 persons (36 eyes) with degrees I and II keratoconus. RESULTS: Uncorrected and best-corrected visual acuity (UCVA and BCVA logMAR) in all patients after modified UVCXL increased after the follow-up period lasting 6-12 months by 0.2±0.19 (23%) and 0.1±0.14 (29%) (p<0.05), respectively, in comparison with preoperative values. Maximum keratometry (Kmax) decreased by 1.35±1.63% (3%; p<0.05) in all cases at 6-12 months follow-up. Improvement of corneal biomechanical strength was determined by statistically significant increase in corneal stiffness index (SP-A1) and corneal stress-strain index (SSI) measured with Pentacam AXL and Corvis ST at 6-12 months follow-up by 15.1±5.04 (18%) and 0.21±0.20 (23%) (p<0.05), respectively. Effectiveness of the developed UVCXL technique is also confirmed by the appearance of a characteristic morphological marker - «demarcation line¼ at the cross-linking site in keratoconus projection at the depth of 240±10.2 µm. CONCLUSION: The developed personalized topographically and tomographically oriented UVCXL technique provides an evident stabilizing effect on the cornea in the form of an increase in its biomechanical strength, improvement of clinical, functional indicators and safety of keratoconus treatment.

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

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

The Keratectasia Volume (KEV) in Corneal Topography to Evaluate the Effect of Corneal Collagen Cross-linking in Pediatric Keratoconus.

The study aimed to evaluate the keratectasia volume (KEV) before and after corneal cross-linking (CXL) in pediatric patients. This study included 40 eyes of 25 pediatric patients (10-19 years) undergoing standard CXL. The support vector machine (SVM) algorithm was applied to transform mass pixels in corneal topography into a three-dimensioned model to calculate the KEV. The KEV, Kmax, K1, K2, Kave, keratectasia area (KEA), and thinnest corneal thickness (TCT) were determined before CXL and at 3, 6, and 12 months after surgery. The correlation between KEV and other parameters (Kmax, TCT, max decentration, eccentricity, and so on) was calculated. The KEV was 4.75 ± 0.74 preoperatively and 4.43 ± 1.22 postoperatively at last follow-up (p < 0.002). There was strong positive correlation between the KEV and Kmax (r = 0.806, p < 0.0005). The preoperat ive KEV was 4.32 ± 0.69 in mild to moderate keratoconus (Kmax < 58D) and 5.27 ± 0.37 in advanced keratoconus (Kmax > 58D) (p < 0.0005, t-test). Postoperative KEV and K readings remained stable at the early stage, and the KEV showed a more drastic decreasing trend than Kmax at sixth month. Statistical significance was found in the KEV between preoperative and 6 months after surgery (p < 0.0005), but not in Kmax and other parameters. In 83.3% (15 eyes out of 18 eyes) of the eyes, the preoperative KEV was greater than 4.6 in patients with significant flattening after CXL. Compared with K readings, the KEV can be regarded as a more sensitive index to evaluate the postoperative morphological changes after CXL in pediatric patients.

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.

Corneal epithelial remodeling following stromal lenticule addition keratoplasty combined with corneal collagen cross-linking for the treatment of keratoconus / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe the epithelial remodeling of femtosecond laser-assisted stromal lenticule addition keratoplasty combined with corneal collagen cross-linking(SLAK-CXL)in patients with progressive keratoconus, investigate the remodeling rules of corneal epithelial and influencing factors, and provide clinical data for further refractive correction.METHODS: Retrospective and observational study. A total of 28 keratoconus patients(29 eyes)who received SLAK-CXL from September 2020 to October 2021 were included. Preoperative and postoperative visual acuity, intraocular pressure(IOP), diopter, keratometry and corneal epithelial thickness(CET)were recorded. The trend of CET change was observed. The factors affecting CET were analyzed according to the thickness and depth of the lenticule.RESULTS: Flattest meridian keratometry(Kf)and steepest meridian keratometry(Ks)at 1mo postoperatively were significantly larger than those preoperatively(P&#x003C;0.05). The thinnest corneal thickness(TCT)at 1, 2, 6mo and 1a postoperatively were significantly larger than preoperative(P&#x003C;0.05). The CET changed with time, with the central CET showing a larger variation tendency. The CET of superior, superior nasal, nasal, superior temporal in paracentral area were thinned, the CET of superior, temporal, superior temporal in midperipheral area were thinned, while the CET of superior nasal was thickened in peripheral area at 1, 2, 6mo and 1a postoperatively. The variation of CET was not correlated with the thickness or depth of lenticule at 1a postoperatively(P&#x003E;0.05).CONCLUSIONS: It is firstly found that the corneal morphology has changed after SLAK-CXL. CET decreases and then increases and then decreases again. At 1a postoperatively, the CET of the central and paracentral areas is thinner, while the CET of the midperipheral and peripheral areas is thicker. The degree of epithelial remodeling is not correlated with lenticule thickness or depth.

Characteristics of corneal stromal demarcation line after different cross-linking methods in keratoconus and its influence on the cross-linking effect / 中华实验眼科杂志

Objective:To compare the characteristics of corneal stromal demarcation line after different surgical methods of riboflavin/ultraviolet A corneal collagen cross-linking (CXL) in early keratoconus, and analyze the influence of the demarcation line on the cross-linking effect.Methods:A non-randomized controlled clinical study was conducted.Sixty-nine eyes of 69 patients treated with riboflavin/ultraviolet A CXL in the Eye Hospital of Shandong First Medical University from May 2019 to February 2021 were included.According to the cross-linking methods, the patients were divided into epithelium-on treatment group (21 eyes) and epithelium-off treatment group (48 eyes). There were 25 eyes in 5.4 J energy group and 44 eyes in 7.2 J energy group.The morphology and changes of corneal stromal cross-linking reaction (corneal stromal demarcation line) were observed at 2 weeks, 1, 3 and 4 months after operation.Changes in the thinnest corneal thickness (TCT), uncorrected visual acuity (UCVA, LogMAR), best corrected visual acuity (BCVA, LogMAR) and corneal maximum curvature (Kmax) were recorded.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Eye Hospital of Shandong First Medical University (No.2019.05). Written informed consent was obtained from each subject.Results:Of the 69 eyes after operation, 44 eyes (63.77%) had demarcation lines, and 25 eyes (36.23%) had no demarcation lines.The occurrence rate of demarcation lines in the epithelium-on treatment group was 79.17%(38/48), which was significantly higher than 28.57%(6/21) in the epithelium-off treatment group ( χ2=16.186, P<0.01). The occurrence rate of demarcation line in 5.4 J energy group was 72.00%(18/25), and the 7.2 J energy group was 56.80%(25/44), with no significant difference ( χ2=1.565, P=0.302). Slit lamp microscopy and anterior segment-optical coherence tomography showed that the demarcation line appeared at 1-2 weeks after operation, gradually converged and strengthened after 1 month, turned diffuse, blurred and faded by degrees after 2-3 months, and basically disappeared after 4 months.The depth of the demarcation line reached 141-423 μm, with an average depth of (263.44±84.22)μm.Scanning laser confocal microscopy showed that corneal stromal cells were activated and light reflection was enhanced after CXL.Collagen fibers extended vertically and horizontally, crisscrossed, and were in a reticular arrangement.The TCT decreased from preoperative (458.69±38.28)μm to (443.86±36.54)μm at 4 months after operation, showing a statistically significant difference ( t=6.705, P<0.001). There was no significant difference in the TCT reduction between groups with and without demarcation lines ( t=1.684, P=0.100). At 4 months postoperatively, the UCVA of all eyes increased from preoperative 0.74±0.37 to 0.69±0.38, and the difference was statistically significant ( t=2.109, P=0.039). There was no significant difference in BCVA between before and after operation ( t=1.006, P=0.319). There was no significant difference in change of UCVA and BCVA between groups with and without demarcation lines ( t=0.065, P=0.949; t=0.346, P=0.730). There was no significant difference in Kmax in all patients between before and after operation ( t=0.050, P=0.950). There was no significant difference in the Kmax change between groups with and without demarcation lines ( t=-0.739, P=0.464). The change in TCT in the epithelium-off treatment group was significantly greater than that in the epithelium-on treatment group ( t=2.815, P=0.008). There was no significant difference in UCVA, BCVA and Kmax changes between epithelium-on and epithelium-off treatment groups (all at P>0.05). There was no obvious corneal scarring, infectious keratitis, corneal endothelial decompensation or other complications. Conclusions:The demarcation line after CXL may be a sign of the depth of cross-linking reaction, which is more prone to occur after the epithelium-off operation method.Both the epithelium-on and epithelium-off operation methods have similar therapeutic effects.Demarcation line after different cross-linking methods has no significant influence on the cross-linking effect in keratoconus.

A Comparison Between Cross-Linking Protocols in Patients With Progressive Keratoconus: A Review.

Keratoconus (KC) is a noninflammatory cornea disease leading to progressive thinning, causing it to change from its normal dome shape to a cone shape. One of the novel treatments of KC is corneal collagen cross-linking (CXL). Due to its importance, many studies have been conducted to compare corneal cross-linking protocols; this review article aims to discuss corneal cross-linking and compare its different treatment options, including Dresden, accelerated, and customized protocols in patients with progressive KC and their respective long-term outcomes. A search was performed in PubMed and Google Scholar with no language, dates, or study type restriction. Most of the results showed almost no difference between protocols over traditional cross-linking. However, published data are limited, long-term outcomes of novel age groups remain unclear, and further studies are needed.

Evaluation of a Post-Operative Therapy Protocol after Epithelium-Off Corneal Cross-Linking in Patients Affected by Keratoconus.

A large retrospective study evaluated the safety of a post-operative therapy protocol after epithelium-off corneal collagen cross-linking (CXL). In total, 1703 eyes of the 1190 patients with progressive keratoconus were enrolled in a retrospective cohort study in a tertiary care university hospital. CXL was performed using a standardized technique (Dresden protocol: 0.1% riboflavin solution containing dextran 20% for 30 min during the soaking phase followed by 30-min ultraviolet A irradiation (3 mW/cm2)). Postoperatively, a bandage contact lens was applied, and therapy included a topical fluoroquinolone antibiotic until the epithelium healed, followed by topical fluorometholone treatment for three weeks. Post-operative complications were recorded and analyzed. No cases of infectious keratitis occurred, whereas peripheral sterile infiltrates were observed in 1.17% of cases. Trace haze was typically present but did not have an impact on visual acuity. In fifteen cases (0.88%), visually significant anterior stromal opacity developed. Mild signs of dry eye were observed in 22 eyes (1.29%). The present study demonstrates that a post-operative treatment protocol including fluoroquinolone antibiotics and a BCL in the first phase until complete epithelial healing, followed by a three-week period of topical steroid treatment is safe and not associated with the development of microbial keratitis.

Photoactivated Chromophore Corneal Collagen Cross-Linking for Infectious Keratitis (PACK-CXL)-A Comprehensive Review of Diagnostic and Prognostic Factors Involved in Therapeutic Indications and Contraindications.

Infectious keratitis is a severe infection of the eye, which requires urgent care in order to prevent permanent complications. Typical cases are usually diagnosed clinically, whereas severe cases also require additional tools, such as direct microscopy, corneal cultures, molecular techniques, or ophthalmic imaging. The initial treatment is empirical, based on the suspected etiology, and is later adjusted as needed. It ranges from topical administration of active substances to oral drugs, or to complex surgeries in advanced situations. A novel alternative is represented by Photoactivated Chromophore Corneal Collagen Cross-Linking (PACK-CXL), which is widely known as a minimally invasive therapy for corneal degenerations. The purpose of this review is to identify the main diagnostic and prognostic factors which further outline the indications and contraindications of PACK-CXL in infectious keratitis. Given the predominantly positive outcomes in the medical literature, we ponder whether this is a promising treatment modality, which should be further evaluated in a systematic, evidence-based manner in order to develop a clear treatment protocol for successful future results, especially in carefully selected cases.

Combined corneal wavefront-guided transepithelial photorefractive keratectomy and accelerated corneal collagen cross-linking following intracorneal ring segment implantation in management of moderate keratoconus.

PURPOSE: Keratoconus (KC) leads to gradual progressive loss of vision in young and adult patients. For the purpose of visual rehabilitation and for hindering KC progression in patients, we designed this study. The main aim of this study is to help the KC patients to improve and stabilize their vision. METHODS: This prospective consecutive uncontrolled study includes 36 eyes of 36 patients with moderate degree of KC. All patients underwent combined wavefront-guided transepithelial photorefractive keratectomy (TPRK) and accelerated corneal collagen cross-linking (ACXL) after intracorneal ring segment (ICRS) implantation. Different measures will be evaluated at baseline, after ICRS implantation, and at one, 3, 6, and 12 months after combined (TPRK and ACXL). These measurements are uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), corneal indices based on Scheimpflug tomography, and higher-order aberrations (HOAs) based on (Sirius, Schwind) tomography. RESULTS: There were significant improvements in logMAR (UDVA and CDVA) and reduction in sphere, manifest cylinder, MRSE, maximal keratometry, and mean keratometry after ICRS implantation in the first stage. After TPRK and ACXL as the second stage, there were significant improvements in visual acuity of both logMAR UDVA and CDVA. Reduction in refractive outcomes, including MRSE, sphere, and manifest cylinder. All corneal indices including steep, flat, mean, and maximal keratometries had been decreased. Furthermore, there were significant improvements in the final root mean square, HOAs, and coma aberrations from baseline. CONCLUSION: In moderate KC, triple therapy of ICRS implantation followed by combined TPRK and ACXL appears to be a safe and effective approach. This approach provides an improvement in visual acuity, refraction, corneal indices, and HOAs. These improvements were maintained for 1 year postoperatively. It also halts KC progression.

[Changes in precorneal tear film and ocular surface in keratoconic patients after corneal collagen cross-linking]. / Izmenenie sostoyaniya prerogovichnoi sleznoi plenki i glaznoi poverkhnosti posle krosslinkinga rogovichnogo kollagena pri keratokonuse.

The article reviews the current available data on the signs and symptoms of dry eye syndrome (DES) in patients with keratoconus (KC), describes the clinical features of DES in KC patients and the morphological features of this type of keratectasia that lead to manifestations of the «dry eye¼, and highlights the risk factors, consequences of therapeutic measures, concomitant ophthalmological and general somatic diseases that contribute to the development of DES in KC.

Ovalbumin-Induced Allergic Inflammation Diminishes Cross-Linked Collagen Structures in an Experimental Rabbit Model of Corneal Cross-Linking.

Background: Allergic conjunctivitis (AC) is one of the reported potential risk factors of progression in keratoconus patients after corneal cross-linking surgery; however, the causal relationship is still inconclusive. Recent studies have indicated that various inflammatory cytokines play a vital role in the development of primary keratoconus. It is still unclear whether these inflammatory mediators also trigger CXL failures. This study aimed to investigate the impact of AC on the rabbit corneas after trans-epithelial corneal cross-linking (TCXL). Methods: A total of six rabbits were kept untreated as the normal control (NC) group. A total of 18 rabbits were treated by TCXL and divided into three groups (six in each group), namely, no treatment (TCXL group); induction of AC (TCXL + AC group); and induction of AC plus topical prednisolone acetate (TCXL + AC + PA group), according to additional treatment. AC was induced by topical application of ovalbumin after intraperitoneal pre-sensitization with ovalbumin. Rabbits were evaluated by slit lamp, in vivo laser scanning confocal microscopy, anterior segment optical coherence tomography, and measurement of corneal biomechanics. The cornea specimens were collected for the transmission electron microscope, the collagenase I digestion test, and PCR assay for TNF-α, IL-6, IL-1ß, matrix metalloproteinase 9 (MMP-9), lysyl oxidase (LOX), and tissue inhibitor of metalloproteinases 1 (TIMP-1) on the day (D) 28. Results: On D28, the TNF-α, IL-6, IL-1ß, MMP-9, and LOX levels were significantly increased while the TIMP-1 was decreased in the TCXL + AC group when compared with the TCXL and TCXL + AC + PA groups. In vivo confocal microscopy revealed that at a depth of 150-210 µm, a trabecular patterned hyperdense structure surrounded by elongated needle-like processes could be observed in the TCXL and TCXL + AC + PA groups, but hardly seen in the TCXL + AC group. The demarcation lines were indistinct and blurred in the TCXL + AC group. An electron microscope demonstrated less interlacing fibril lamellae and higher interfibrillar spacing in the TCXL + AC group. The stability of corneal biomechanics and resistance to collagenase were decreased in the TCXL + AC group. Conclusion: The corneal microstructures induced by TCXL and biomechanical stability were diminished in rabbits with AC but could be maintained by topical anti-inflammatory treatment. Our results supported the causal relationship between altered cytokine profiles and corneal microstructure after primary corneal cross-linking.