Crosslinking with UV-A and riboflavin in progressive keratoconus: From laboratory to clinical practice - Developments over 25 years.

Changes in the biomechanical and biochemical properties of the human cornea play an important role in the pathogenesis of ectatic diseases. A number of conditions in primarily acquired (keratoconus or pellucid marginal degeneration) or secondarily induced (iatrogenic keratectasia after refractive laser surgeries) ectatic disorders lead to decreased biomechanical stability. Corneal collagen cross-linking (CXL) represents a technique to slow or even halt the progression of ectatic pathologies. In this procedure, riboflavin is applied in combination with ultraviolet A radiation. This interaction induces the production of reactive oxygen species, which leads to the formation of additional covalent bonds between collagen molecules and subsequent biomechanical corneal strengthening. This procedure is so far the only method that partially interferes etiopathogenetically in the treatment of ectatic diseases that slows or stops the process of corneal destabilization, otherwise leading to the need for corneal transplantation. Besides, CXL process increases markedly resistance of collagenous matrix against digesting enzymes supporting its use in the treatment of corneal ulcers. Since the discovery of this therapeutic procedure and the first laboratory experiments, which confirmed the validity of this method, and the first clinical studies that proved the effectiveness and safety of the technique, it has been spread and adopted worldwide, even with further modifications. Making use of the Bunsen-Roscoe photochemical law it was possible to shorten the duration of this procedure in accelerated CXL and thus improve the clinical workflow and patient compliance while maintaining the efficacy and safety of the procedure. The indication spectrum of CXL can be further expanded by combining it with other vision-enhancing procedures such as individualized topographically-guided excimer ablation. Complementing both techniques will allow a patient with a biomechanically stable cornea to regularize it and improve visual acuity without the need for tissue transplantation, leading to a long-term improvement in quality of life.

Corneal cross-linking for treatment of keratoconus relapse in post-keratoplasty eyes.

PURPOSE: Keratoconus relapse after penetrating keratoplasty is a rare condition that may result in severe visual deterioration and corneal graft thinning. Therefore, treatment to stabilize the cornea should be considered. The purpose of this study was to evaluate the safety and efficacy of Corneal Cross-Linking (CXL) in eyes with relapse of keratoconus after penetrating keratoplasty for keratoconus. MATERIALS AND METHODS: A retrospective review of eyes that developed keratoconus relapse following a penetrating keratoplasty and treated with CXL. The main outcome measures were change in maximal keratometry (Kmax), best-corrected distance visual acuity (BCVA), thinnest corneal thickness (TCT) and central corneal thickness (CCT), and complications. RESULTS: We identified 10 consecutive eyes of 9 patients. Preoperative median BCVA before the CXL and 1 year after the CXL procedure remained stable (p = 0.68). The median (IQR) of Kmax improved from 63.2 (24.9) D before the CXL procedure to 62.2 (27.1) D at 1 year postoperatively (P = 0.028). Median TCT and CCT also remained with no significant change 1 year after CXL. No complications were noted following the procedure. CONCLUSION: CXL in eyes with keratoconus relapse after keratoplasty is a safe and effective procedure enabling not only visual stabilization but also might bring keratometry improvement. Routine follow-up after keratoplasty should be performed for early detection of keratoconus relapse and CXL is timely advised when such a relapse is documented.

Analysis of riboflavin/ultraviolet a corneal cross-linking by molecular spectroscopy.

Corneal cross-linking (CXL) with riboflavin and ultraviolet A light is a therapeutic procedure to restore the mechanical stability of corneal tissue. The treatment method is applied to pathological tissue, such as keratoconus and induces the formation of new cross-links. At present, the molecular mechanisms of induced cross-linking are still not known exactly. In this study, we investigated molecular alterations within porcine cornea tissue after treatment with riboflavin and ultraviolet A light by surface enhanced Raman spectroscopy (SERS). For that purpose, after CXL treatment a thin silver layer was vapor-deposited onto cornea flaps. To explore molecular alterations induced by the photochemical process hierarchical cluster analysis (HCA) was used. The detailed analysis of SERS spectra reveals that there is no general change in collagen secondary structure while modifications on amino acid side chains are the most dominant outcome. The formation of secondary and aromatic amine groups as well as methylene and carbonyl groups were observed. Even though successful cross-linking could not be registered in all treated samples, Raman signals of newly formed chemical groups are already present in riboflavin only treated corneas.

Corneal Crosslinking With Riboflavin and UVA Light in Progressive Keratoconus: Fifteen-Year Results.

PURPOSE: To analyze the 15-year results of corneal crosslinking (CXL) in progressive keratoconus. DESIGN: Retrospective follow-up analysis of interventional study patients. METHODS: This study included keratoconic eyes with progressive disease treated from 2001 to 2006 at the Department of Ophthalmology, Carl Gustav Carus University Hospital, TU Dresden, Germany. CXL was performed by applying riboflavin and ultraviolet A (UVA) light according to a standard protocol. The best-corrected distance visual acuity (BCVA), slitlamp examination, and corneal topography as well as corneal thickness values were recorded preoperatively and 15 years after the treatment. RESULTS: A total of 42 eyes received a complete follow-up of 15 years. The mean age of the patients at baseline was 26.9 (95% CI: 25.0-28.8) years. The maximum keratometry was 61.6 (95% CI: 58.2 - 64.9) diopters (D) preoperatively and 55.1 (95% CI: 51.6-58.4) D postoperatively; the decrease was statistically significant (P < .001). The mean keratometry value changed from 50.3 (95% CI: 48.3-52.4) D to 47.5 (95% CI: 45.3-49.4) D (P < 0.001). Furthermore, the thinnest corneal thickness decreased statistically significantly by 40 (95% CI: 24-56) µm (P < .001). The BCVA improved statistically significantly from 0.4 to 0.2 logMAR after the treatment. Retreatment was needed in 14% of cases. Mild scarring of the superficial stromal corneal layers was observed in 36% of the eyes, and in 67% of them visual acuity was stable or even improved. CONCLUSIONS: The CXL procedure proved to be an effective method in the treatment of keratoconic eyes in the progressive stage of the disease, and achieved long-term stabilization without the occurrence of serious complications or side effects.

Evaluation of Biomechanical Changes After Accelerated Cross-Linking in Progressive Keratoconus: A Prospective Follow-Up Study.

PURPOSE: The aim of this study was to analyze the biomechanical effect of accelerated corneal cross-linking (9*10) in progressive keratoconus (KC) in comparison to untreated fellow eyes using Scheimpflug-based tonometry (Corvis ST, CVS). METHODS: Forty-three eyes of 43 patients with KC showed progressive KC and were treated using accelerated corneal cross-linking. Twenty-five untreated fellow eyes were used as the control group. All eyes were examined biomechanically (CVS) and tomographically (Pentacam) at baseline, after 1-month, 6-month, and 12-month follow-up. Statistical analysis was performed using a linear mixed model. A logistic regression was performed to attribute the effects of changes in each parameter to treatment status (treated or untreated). RESULTS: Maximum keratometry values decreased statistically significantly at 12 months by -1.1 D (95 confidence interval: -2.0 to -0.1, P = 0.025) compared with baseline. Thinnest corneal thickness decreased significantly after 1 month ( P < 0.001) and recovered to baseline after 12 months ( P = 0.752). In the corneal cross-linking (CXL) group, biomechanical changes were observed by an increased bIOP, a shorter A2 time, and a lower integrated radius after 1 month (all P < 0.05). No biomechanical and tomographical changes were observed in the control group (all P > 0.05). Logistic regression pointed out that treated eyes can be separated from untreated eyes by differences in bIOP, corneal thickness, A1 velocity, integrated radius, and Kc mean at 1, 6, and 12 months. CONCLUSIONS: The alterations in biomechanical parameters indicated a corneal stiffening effect after CXL treatment, which was mostly detectable 1 month after treatment, although corneal thickness was reduced. The logistic regression model showed an adequate separation between CXL-treated and untreated eyes.

Repeatability of corneal deformation response parameters by dynamic ultra-high-speed Scheimpflug imaging before and after corneal crosslinking.

PURPOSE: To evaluate the repeatability of deformation corneal response (DCR) parameters before and after corneal crosslinking (CXL) compared with their untreated fellow eyes (uFEs). SETTING: University Hospital Carl Gustav Carus, Dresden, Germany; IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. DESIGN: Multicenter, interventional reliability analysis. METHODS: 53 eyes of 53 patients with keratoconus who received CXL treatment after the disease progression (CXL group) were included. Patients were measured 3 times using a dynamic Scheimpflug analyzer to determine repeatability before and 1 month after CXL treatment. The uFEs were measured in the same way (uFE group). Reliability of DCR parameters was assessed by a coefficient of repeatability, coefficient of variation, and intraclass correlation coefficient (ICC). RESULTS: The repeatability of DCR parameters did not change after CXL compared with the preoperative values for all investigated DCR parameters ( P > .05). In the uFE group, no statistically significant shift was observed regarding the repeatability ( P > .05). An ICC greater than 0.75 was achieved in both groups for almost all parameters. Concerning the biomechanical stiffening induced by CXL, integrated inverse radius and stress-strain index were found to be statistically significantly decreased and increased ( P < .001), respectively, both indicating stiffening. No changes were observed for the uFE group. CONCLUSIONS: The study demonstrated highly repeatable measurements of the dynamic Scheimpflug analyzer before and after CXL. The improvement of certain DCR parameters after CXL confirmed the capability of the device to detect the stiffening effect.

Evaluation of Corneal Biomechanical Indices in Distinguishing Between Normal, Very Asymmetric, and Bilateral Keratoconic Eyes.

PURPOSE: To evaluate the ability of biomechanical indices provided by the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments) and dynamic Scheimpflug analyzer (Corvis ST; Oculus Optikgeräte GmbH) to distinguish between normal eyes and eyes with very asymmetric ectasia (VAE) and mild and moderate keratoconus. METHODS: This prospective, observational, and monocentric study included normal eyes (defined as keratoconus percentage index < 60, Belin/Ambrósio total deviation value [BAD-D] < 1.6, inferior-superior keratometry [I-S value] < 1.45 and maximum keratometry [Kmax] < 47) and eyes with clinical bilateral keratoconus (mild and moderate) and VAE (defined as unilateral keratoconus, where one eye showed a clinical keratoconus and the fellow eye was topographically normal [VAE-NT] or topographically and tomographically normal [VAE-NTT]). All eyes were measured by the Pentacam (Oculus Optikgeräte GmbH), ORA, and Corvis ST. Receiver operating characteristic curve analysis was performed to test the diagnostic ability. RESULTS: Fifty-eight normal eyes and 238 ectatic eyes were included. The highest area under the curve (AUC) was provided by the Corvis Biomechanical Index (CBI) with an AUC of 0.979, followed by ORA corneal resistance factor (0.865), and corneal hysteresis (0.824) separating normal eyes from all ectatic subgroups. The AUC of the CBI was statistically significantly higher than all other parameters (DeLong test, P < .001). A sensitivity of 100% and 70.9%, respectively, and a specificity of 93.1% was found to distinguish normal eyes from VAE-NT and VAE-NTT using a cut-off value of 0.2. CONCLUSIONS: The assessment of biomechanical properties is an additional important method to evaluate corneal ectasia independent of its stage. The CBI provides further information for ectasia screening in cases where corneal topography and tomography are clinically not suspicious by using a cutoff of 0.2. [J Refract Surg. 2022;38(6):364-372.].

Comparison of corneal tomography using a novel swept-source optical coherence tomographer and rotating Scheimpflug system in normal and keratoconus eyes: repeatability and agreement analysis.

BACKGROUND: To determine the repeatability and agreement using corneal tomography of a swept-source optical coherence tomographer (SS-OCT) compared to a rotating Scheimpflug camera (RSC) in normal eyes and keratoconus (KC) eyes. METHODS: This prospective repeatability analysis was performed at the Department of Ophthalmology of University Hospital Carl Gustav Carus, Dresden, Germany. Forty-three normal and 57 KC eyes were enrolled in the study. Three consecutive measurements were performed by the same operator on each device. Corneal parameters of anterior and posterior corneal surface, such as simulated keratometry (SimK), as well as central and thinnest corneal thickness were evaluated. Repeatability and agreement were assessed by using the coefficient of repeatability and Bland-Altman analysis. RESULTS: The repeatability of anterior corneal parameters was comparable between RSC and SS-OCT in normal eyes (repeatability < 0.5 D). Repeatability was increased in mild and moderate KC for all parameters using both devices. In moderate KC, repeatability of Kmax was 1.33 D and 0.78 D for RSC and SS-OCT, respectively. Repeatability of posterior corneal parameters was consistently better for SS-OCT. Significant offsets and wide ranges of limits of agreement were found between the devices for SimK and corneal thickness values. CONCLUSIONS: SS-OCT showed highly repeatable measurements of anterior and posterior corneal parameters in normal and KC eyes. Compared to RSC, the SS-OCT had a better repeatability of anterior corneal parameters in mild and moderate KC as well as posterior corneal parameters in all groups. Both devices should not be used interchangeably in the diagnostic process of patients. Trial registration NCT04251143 at Clinicaltrials.gov, registered on 12 March 2018, https://clinicaltrials.gov/ct2/show/NCT04251143?cond=Keratoconus&cntry=DE&city=Dresden&draw=2&rank=1.

Statistical Evaluation of Correlated Measurement Data in Longitudinal Setting Based on Bilateral Corneal Cross-Linking.

PURPOSE: In ophthalmology, data from both eyes of a person are frequently included in the statistical evaluation. This violates the requirement of data independence for classical statistical tests (e.g. t-Test or analysis of variance (ANOVA)) because it is correlated data. Linear mixed models (LMM) were used as a possibility to include the data of both eyes in the statistical evaluation. METHODS: The LMM is available for a variety of statistical software such as SPSS or R. The application was applied to a retrospective longitudinal analysis of an accelerated corneal cross-linking (ACXL (9*10)) treatment in progressive keratoconus (KC) with a follow-up period of 36 months. Forty eyes of 20 patients were included, whereas sequential bilateral CXL treatment was performed within 12 months. LMM and ANOVA for repeated measurements were used for statistical evaluation of topographical and tomographical data measured by Pentacam (Oculus, Wetzlar, Germany). RESULTS: Both eyes were classified into a worse and better eye concerning corneal topography. Visual acuity, keratometric values and minimal corneal thickness were statistically significant between them at baseline (p < 0.05). A significant correlation between worse and better eye was shown (p < 0.05). Therefore, analyzing the data at each follow-up visit using ANOVA partially led to an overestimation of the statistical effect that could be avoided by using LMM. After 36 months, ACXL has significantly improved BCVA and flattened the cornea. CONCLUSION: The evaluation of data of both eyes without considering their correlation using classical statistical tests leads to an overestimation of the statistical effect, which can be avoided by using the LMM.

Corneal Biomechanics Differences Between Chinese and Caucasian Healthy Subjects.

Purpose: The aim of this study was to evaluate the difference between Caucasian and Chinese healthy subjects with regards to Corvis ST dynamic corneal response parameters (DCRs). Methods: Two thousand eight hundred and eighty-nine healthy Caucasian and Chinese subjects were included in this multicenter retrospective study. Subsequently, Chinese eyes were matched to Caucasians by age, intraocular pressure (IOP), and Corneal Thickness (CCT) using a case-control matching algorithm. The DCRs assessed were Deformation Amplitude (DA) Applanation 1 velocity (A1v), integrated radius (1/R), deformation amplitude ratio (DAratio), stiffness parameter at applanation 1 (SPA1), ARTh (Ambrósio's Relational Thickness to the horizontal profile), and the novel Stress Strain Index (SSI). Results: After age-, CCT-, and IOP- matching, 503 Chinese were assigned to 452 Caucasians participants. Statistical analysis showed a statistical significant difference between Chinese and Caucasian Healthy subjects in the values of SPA1 (p = 0.008), Arth (p = 0.008), and SSI (p < 0.001). Conversely, DA, A1v, DAratio, and 1/R were not significantly different between the two ethnical groups (p > 0.05). Conclusion: We found significant differences in the values of the DCRs provided by the Corvis ST between Chinese and Caucasian healthy subjects.

Agreement and repeatability of corneal tomography in healthy eyes using a new swept-source OCT, a rotating Scheimpflug camera, and a dual Scheimpflug-Placido system.

PURPOSE: To investigate the accordance and repeatability of tomographic parameters measured by a new swept-source optical coherence tomographer (SS-OCT, ANTERION), a rotating Scheimpflug camera (RSC, Pentacam), and a dual Scheimpflug-Placido system (DSP, Galilei G6). SETTING: Department of Ophthalmology of University of Hospital Carl Gustav Carus, Dresden, Germany. DESIGN: Prospective reliability analysis. METHODS: Normal tomography was ensured by bilaterally evaluating appropriated parameters using RSC. All subjects received 3 consecutive measurements on each device by the same operator and in the uniform order RSC, SS-OCT, and DSP. Anterior (ACP) and posterior (PCP) corneal parameters such as flat and steep keratometry and corneal thickness were analyzed. Repeatability was assessed by using a coefficient of repeatability (CoR) and a coefficient of variation. Agreement between RSC and SS-OCT and between RSC and DSP were shown by Bland-Altman plots. RESULTS: This study included 30 randomly selected eyes of 30 healthy participants. CoR of ACP did not exceed 0.5 diopters. There were no statistically significant differences in repeatability of ACP obtained from the 3 devices (P > .05). For PCP and corneal thickness, there was statistically significant higher repeatability mostly found for SS-OCT as opposed to RSC and DSP (P < .05). For a wide range of analyzed parameters, there were large limits of agreement (95% LoA) found between the devices. CONCLUSIONS: The SS-OCT showed highly repeatable measurements in healthy subjects regarding anterior, posterior, and corneal thickness parameters. Repeatability of ACP did not differ between the devices. A mostly wide range of 95% LoA prevents interchangeability between the devices.

[Principles of corneal cross-linking : Presentation based on the development of the various treatment protocols]. / Grundlagen des kornealen Crosslinking : Dargestellt anhand der Entwicklung der verschiedenen Behandlungsprotokolle.

BACKGROUND: Corneal cross-linking (CXL) is used to treat corneal ectatic diseases. The aim is to improve the reduced consolidation of the cornea in order to halt further corneal protrusion and therefore subsequent deterioration of the optical imaging proportions. MATERIAL AND METHODS: In this article the principles of corneal cross-linking based on riboflavin and UV light are presented including recent research results. Furthermore, the most important treatment protocols including standard CXL (S-CXL), accelerated CXL (A-CXL), transepithelial CXL (TE-CXL) and the approach of the CXL procedure for thin corneas are explained. RESULTS: The CXL method depends on four major components, the riboflavin solution, oxygen, UV light and the availability of cross-linking sites on the collagen tissue. According to the present state of knowledge, the photochemical process of the CXL method induces covalent bonds between the fibrils and proteoglycans and thus stabilizes the collagen fibers, resulting in corneal consolidation. In addition to the S­CXL, which has proven its effectiveness and safety in a large number of studies, there are other treatment protocols that have been developed based on the Bunsen-Roscoe law of reciprocity. The A­CXL protocol has the advantage of having a shorter irradiation time but it seems to be less effective than the S­CXL protocol concerning the increase in corneal stiffness. The use of TE-CXL has so far not yet gained acceptance in the clinical practice. CONCLUSION: The CXL procedures primarily aim to stabilize the cornea. In the future, in addition to stabilization of the cornea, simultaneous improvement of visual acuity will be the main focus.

Risk Factors for Progression of Keratoconus and Failure Rate After Corneal Cross-linking.

PURPOSE: To assess the occurrence of risk factors for progression of keratoconus and failure rate after corneal cross-linking (CXL) in patients with progressive keratoconus. METHODS: This retrospective study observed 230 eyes of 173 patients with a minimum follow-up of 36 months after CXL. A total of 185 eyes underwent CXL once (80%) (control) and 45 (20%) underwent this treatment more than once (Re-CXL-group). Subgroup analysis included standard CXL with the Dresden protocol (S-CXL group, n = 120) and accelerated CXL with a reduced radiation time of 10 minutes and a higher radiation power of 9 mW/cm2 (A-CXL group, n = 110). Risk factors of interest were age, maximum keratometry (Kmax), minimum corneal thickness (MCT), sex, and atopy (including allergic bronchial asthma, food allergy, allergic rhinitis, and neurodermatitis). RESULTS: Follow-up for the control group was 76.0 ± 33.2 months. Re-CXL was performed after 46.2 ± 34.1 months overall and after 62.6 ± 41.9 months in the S-CXL subgroup and 29.2 ± 19.2 months in the A-CXL subgroup (P = .02). Kaplan-Meier analysis revealed a cumulative prediction rate of success after CXL of 92.5% (S-CXL) and 86.4% (A-CXL) after 36 months (P = .103). A high preoperative Kmax value (odds ratio = 1.056, P = .003 and odds ratio = 1.067, P = .028) in both subgroups and the presence of neurodermatitis combined with other atopic diseases in the A-CXL group (odds ratio = 11.662, P = .003) were significant risk factors for new progression of keratoconus after CXL. CONCLUSIONS: Risk factors for progression of keratoconus after CXL are both high preoperative Kmax values and the presence of neurodermatitis combined with other atopic diseases. Patients with severe atopy should receive the S-CXL procedure. [J Refract Surg. 2021;37(12):816-823.].

Development of a classification system based on corneal biomechanical properties using artificial intelligence predicting keratoconus severity.

BACKGROUND: To investigate machine-learning (ML) algorithms to differentiate corneal biomechanical properties between different topographical stages of keratoconus (KC) by dynamic Scheimpflug tonometry (CST, Corvis ST, Oculus, Wetzlar, Germany). In the following, ML models were used to predict the severity in a training and validation dataset. METHODS: Three hundred and eighteen keratoconic and one hundred sixteen healthy eyes were included in this monocentric and cross-sectional pilot study. Dynamic corneal response (DCR) and corneal thickness related (pachymetric) parameters from CST were chosen by appropriated selection techniques to develop a ML algorithm. The stage of KC was determined by the topographical keratoconus classification system (TKC, Pentacam, Oculus). Patients who were classified as TKC 1, TKC 2 and TKC 3 were assigned to subgroup mild, moderate, and advanced KC. If patients were classified as TKC 1-2, TKC 2-3 or TKC 3-4, they were assigned to subgroups according to the normative range of further corneal indices (index of surface variance, keratoconus index and minimum radius). Patients classified as TKC 4 were not included in this study due to the limited amount of cases. Linear discriminant analysis (LDA) and random forest (RF) algorithms were used to develop the classification models. Data were divided into training (70% of cases) and validation (30% of cases) datasets. RESULTS: LDA model predicted healthy, mild, moderate, and advanced KC eyes with a sensitivity (Sn)/specificity (Sp) of 82%/97%, 73%/81%, 62%/83% and 68%/95% from a validation dataset, respectively. For the RF model, a Sn/Sp of 91%/94%, 80%/90%, 63%/87%, 72%/95% could be reached for predicting healthy, mild, moderate, and advanced KC eyes, respectively. The overall accuracy of LDA and RF was 71% and 78%, respectively. The accuracy for KC detection including all subgroups of KC severity was 93% in both models. CONCLUSION: The RF model showed good accuracy in predicting healthy eyes and various stages of KC. The accuracy was superior with respect to the LDA model. The clinical importance of the models is that the standalone dynamic Scheimpflug tonometry is able to predict the severity of KC without having the keratometric data. TRIAL REGISTRATION: NCT04251143 at Clinicaltrials.gov, registered at 12 March 2018 (Retrospectively registered).

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.

Comparison of waveform-derived corneal stiffness and stress-strain extensometry-derived corneal stiffness using different cross-linking irradiances: an experimental study with air-puff applanation of ex vivo porcine eyes.

PURPOSE: To assess corneal stiffening of standard (S-CXL) and accelerated (A-CXL) cross-linking protocols by dynamic corneal response parameters and corneal bending stiffness (Kc[mean/linear]) derived from Corvis (CVS) Scheimpflug-based tonometry. These investigations were validated by corneal tensile stiffness (K[ts]), derived from stress-strain extensometry in ex vivo porcine eyes. METHODS: Seventy-two fresh-enucleated and de-epithelized porcine eyes were soaked in 0.1% riboflavin solution including 10% dextran for 10 min. The eyes were separated into four groups: controls (n = 18), S-CXL (intensity in mW/cm2*time in min; 3*30) (n = 18), A-CXL (9*10) (n = 18), and A-CXL (18*5) (n = 18), respectively. CXL was performed using CCL Vario. CVS measurements were performed on all eyes. Subsequently, corneal strips were extracted by a double-bladed scalpel and used for stress-strain measurements. K[ts] was calculated from a force-displacement curve. Mean corneal stiffness (Kc[mean]) and constant corneal stiffness (Kc[linear]) were calculated from raw CVS data. RESULTS: In CVS, biomechanical effects of cross-linking were shown to have a significantly decreased deflection amplitude as well as integrated radius, an increased IOP, and SP A1 (P < 0.05). Kc[mean]/Kc[linear] were significantly increased after CXL (P < 0.05). In the range from 2 to 6% strain, K[ts] was significantly higher in S-CXL (3*30) compared to A-CXL (9*10), A-CXL (18*5), and controls (P < 0.05). At 8% to 10% strain, all protocols induced a higher stiffness than controls (P < 0.05). CONCLUSION: Several CVS parameters and Kc[mean] as well as Kc[linear] verify corneal stiffening effect after CXL on porcine eyes. S-CXL seems to have a higher tendency of stiffening than A-CXL protocols have, which was demonstrated by Scheimpflug-based tonometry and stress-strain extensometry.

[Scedosporium apiospermum-a rare pathogen of keratomycosis]. / Scedosporium apiospermum ­ Seltener Erreger einer mykotischen Keratitis.

This article presents the case of a 44-year-old contact lens wearer who presented with acute keratitis resistant to antibacterial treatment in the right eye. The anterior segment of the eye showed circular conjunctival hyperemia, a corneal white cell infiltrate with radiating margins and a central corneal erosion. Microbiological investigation of a corneal scraping revealed growth of Scedosporium apiospermum. Intensive antimycotic treatment and several corneal collagen crosslinking procedures were performed; however, because of rapidly evolving necrotizing ulcerative keratitis, a keratoplasty à chaud was carried out.

Repeatability and reproducibility of corneal deformation response parameters of dynamic ultra-high-speed Scheimpflug imaging in keratoconus.

PURPOSE: To assess the repeatability and reproducibility of dynamic corneal response (DCR) parameters obtained by ultra-high-speed Scheimpflug imaging (Corvis ST); in keratoconic patients. SETTING: Clinics in Germany, Italy, and Brazil. DESIGN: Prospective, observational study. METHODS: Patients were examined 3 times using 2 different dynamic Scheimpflug analyzers (Corvis ST) to obtain repeatability and reproducibility. The reliability of intraocular pressure (IOP), biomechanically corrected IOP (bIOP), pachymetry, and DCR parameters were assessed by the coefficient of repeatability, coefficient of variation (CoV), intraclass correlation coefficient (ICC), and within-subject standard deviation (sw). RESULTS: Ninety-eight eyes from 98 KC patients were included. The sw of the IOP and bIOP did not exceed 1.1 mm Hg. A CoV less than 10% was found in all DCR parameters and had a good to excellent accordance regarding the ICC. The Corvis Biomechanical Index showed an excellent repeatability and interdevice reproducibility of 0.918 and 0.827, respectively. Also, the tomographic biomechanical index showed an excellent repeatability of 3 Corvis ST and Pentacam measurements (ICC = 0.997). With regard to keratoconic severity, a significant increase in the CoV was found between mild and moderate stages compared with the advanced stage. Nevertheless, it did not exceed 10% of the CoV in severe keratoconic eyes. CONCLUSION: Corvis ST measurements in keratoconic eyes were highly repeatable and reproducible.

Intraocular Pressure Measurement Using Ocular Response Analyzer, Dynamic Contour Tonometer, and Scheimpflug Analyzer Corvis ST.

PURPOSE: To compare intraocular pressure (IOP) measurements with Goldmann applanation tonometry (GAT), ocular response analyzer (ORA), dynamic contour tonometer (DCT), and Corvis ST (CST) in healthy subjects. METHODS: In a prospective, observational study, IOP measurements with GAT (GAT-IOPc), ORA (IOPcc), DCT (DCT-IOP), and CST (bIOP) were performed and analyzed in 94 healthy subjects. RESULTS: Mean age of the participants was 45.6 ± 17.2 years (range 18 to 81 years). Mean GAT-IOPc was 12.9 ± 2.4 mmHg, mean DCT-IOP was 16.1 ± 2.6 mmHg, and mean IOPcc was 15.6 ± 3.3 mmHg. DCT-IOP and IOPcc were significantly higher than GAT-IOPc (P < 0.001). Mean bIOP was 13.5 ± 2.4 mmHg that was slightly higher but not significantly different from GAT-IOPc (P=0.146). Correlation analysis of IOP values and central corneal thickness (CCT) revealed a negative correlation between GAT-IOPc and CCT (r = -0.347; P=0.001). However, IOPcc, DCT-IOP, and bIOP showed no significant correlation to CCT. Only bIOP revealed a weak but significant age dependency (r = 0.321, P=0.002). CONCLUSION: All tonometry devices showed a good agreement of biomechanical corrected IOP values with GAT-IOPc. As no influence of CCT on IOPcc, DCT-IOP, and bIOP was detectable, the used correction algorithms appear to be appropriate in these tonometers in the clinical setting. The highest agreement was found between GAT-IOPc and bIOP. However, bIOP weakly correlated with participants' age. Further studies are needed to elucidate the role of bIOP for IOP measurement.

Assessment of corneal biomechanical parameters in healthy and keratoconic eyes using dynamic bidirectional applanation device and dynamic Scheimpflug analyzer.

PURPOSE: To investigate corneal biomechanical parameters in healthy and keratoconic eyes using the Ocular Response Analyzer dynamic bidirectional applanation device (ORA) and the Corvis ST dynamic Scheimpflug analyzer (CST). SETTING: Department of Ophthalmology, Carl Gustav Carus University Hospital Dresden, Germany. DESIGN: Prospective, monocentric, case-control study. METHODS: Corneal biomechanical parameters were obtained in 60 eyes of 60 healthy participants (Group I) and 60 eyes of 60 keratoconus patients (Group II) with different grades of severity using the ORA and the CST. Participants were matched by age (Group I: 38.3 years ± 12.8 [SD], Group II: 37.3 ± 11.2 years) and intraocular pressure (Group I: 13.7 ± 1.7 mm Hg, Group II: 13.6 ± 1.5 mm Hg). RESULTS: For the ORA, the receiver operating characteristic curve analysis showed an area under the curve (AUC) of 0.950 for the keratoconus score, a sensitivity of 87% and a specificity of 93%. The AUC for the corneal resistant factor and corneal hysteresis was 0.930 and 0.868 with a sensitivity of 87% and a specificity of 87%, and sensitivity of 80% and a specificity of 80%, respectively. For the CST, the corneal biomechanical index showed the highest AUC (0.977) with a sensitivity of 97% and a specificity of 98%. The AUC of integrated radius (0.974; 90% sensitivity, 93% specificity) was followed by maximum inverse radius (0.962; 92% sensitivity, 93% specificity). Most parameters were able to discriminate healthy eyes from different keratoconus stages and early stages of keratoconus from moderate stages. CONCLUSION: Both devices allowed for good differentiation between healthy eyes and keratoconic eyes and between different severity grades of keratoconus. Several parameters of ORA and CST revealed high sensitivity and specificity values for keratoconus detection.