Corneal haze and visual outcome after collagen crosslinking for keratoconus: A comparison between total epithelium off and partial epithelial removal methods.
ABSTRACT: Keratoconus is an asymmetric, bilateral, progressive noninflammatory ectasia of the cornea that affects approximately 1 in 2000 of the general population. This may cause a significant negative impact on quality of life. Corneal collagen crosslinking (CXL) is one of the recently introduced methods that have been used to decrease the progression of keratoconus, in particular, as well as other corneal-thinning processes.A total of 44 keratoconic eyes of 22 patients were enrolled in this randomized prospective study, after obtaining informed consent. In the first group, the corneal epithelium were totally removed and in the second group, the central 3 mm of epithelium was kept intact and partial removal was performed. After collagen crosslinking in both groups, comprehensive ophthalmologic examination was performed on all patients before and 6 months after the surgery. This article is registered at www.clinicaltrial.gov with registration number NCT01809977.The difference between the two groups was not statistically significant regarding postoperative corneal haziness, refraction, and visual acuity (P > 0.05). However, comparison of pre- and postoperative parameters within each group revealed that total removal of the cornea has resulted in significant improvement of K-max (P value: 0.01) and Q-value (P value: 0.009); while eyes in partial removal group had better improvement of corrected vision (P value: 0.006). Both methods had significant and similar increase in optical corneal density (P < 0.0001).In our study, keeping the central corneal epithelium intact was not beneficial for decreasing corneal haziness, however, this method caused better improvement in corrected vision. Total epithelium off technique resulted in better improvement of K-max and Q-value.
Project description:Corneal collagen crosslinking with riboflavin photosensitization and ultraviolet irradiation is a novel approach to limiting the progression of keratoconus in patients by increasing the elastic modulus of the degenerate cornea. Beneficial reductions in corneal steepness and aberrations after crosslinking also frequently occur. In a previous study, we described a computational modeling approach to simulating topographic progression in keratoconus and regression of disease with corneal collagen crosslinking. In the current study, this model has been expanded and applied to the inverse problem of estimating longitudinal time-dependent changes in the corneal elastic modulus after crosslinking using in vivo measurements from 16 human eyes. Topography measured before crosslinking was used to construct a patient-specific finite element model with assumed hyperelastic properties. Then the properties of the cornea were altered using an inverse optimization method to minimize the difference between the model-predicted and in vivo corneal shape after crosslinking. Effects of assumptions regarding sclera-to-cornea elastic modulus ratio and spatial attenuation of treatment effect due to ultraviolet beam characteristics on the predicted change in elastic modulus were also investigated. Corneal property changes computed by inverse finite element analysis provided excellent geometric agreement with clinical topography measurements in patient eyes post-crosslinking. Over all post-treatment time points, the estimated increase in corneal elastic modulus was 110.8 ± 48.1%, and slightly less stiffening was required to produce the same amount of corneal topographic regression of disease when the sclera-to-cornea modulus ratio was increased. Including the effect of beam attenuation resulted in greater estimates of stiffening in the anterior cornea. Corneal shape responses to crosslinking varied considerably and emphasize the importance of a patient-specific approach.
Project description:Purpose:To present the case of a patient that underwent corneal crosslinking for progressive keratoconus and 18 months later revealed clinically significant corneal stromal haze. Observations:A 20-year-old male presented with progressive visual loss OU for the past few years. His corrected distance visual acuity (CDVA) OD was 20/30 (-2.75 -1.75 @55) and OS 20/30 (-0.50 -1.75@110). Corneal topography revealed keratoconus OU and the patient underwent corneal crosslinking according to the Dresden Protocol. The postoperative regimen included combined tobramycin and dexamethasone qid along with lubrication until epithelium healed and then fluorometholone qid with weekly tapering. At 3 months postoperatively, his topography was stable and his corrected distance visual acuity (CDVA) was 20/25 OU. On slit lamp examination, only clinically insignificant stromal haze was observed. At 18 months postoperatively, the patient reported vision deterioration. On examination his CDVA was 20/25 in right eye, and 20/40 in his left eye. Deep stromal haze was revealed in his central cornea, more dense in his left eye. Corneal topography was stable and the CDVA loss was attributed to the notable deep stromal haze. The patient was treated with dexamethasone qid with biweekly tapering. 18 months after corneal crosslinking, the patient demonstrated clinically significant stromal haze, most prominent OS. He was treated with dexamethasone qid. One month later his CDVA OS gradually improved to 20/25, and stromal haze was still noted but less dense. Conclusions and importance:Late-onset deep corneal haze is a possible complication of corneal crosslinking in keratoconic patients.
Project description:Keratoconus is a thinning corneal dystrophy that begins in the early teenage years and ultimately requires cornea transplantation to restore vision. Here we conducted a highly sensitive mass spectrometric analysis of the epithelium and the stroma from keratoconus and normal donor corneas. We identified a total of 932 and 1157 proteins in the consolidated data of the epithelium and stroma, respectively. Technical replicates showed strong correlations (?0.88) in levels of all common proteins, indicating very low technical variations in the data. Analysis of the most increased (?1.5 fold) and decreased (?0.8 fold) proteins in the keratoconus corneal epithelial protein extracts identified proteins related to dermal diseases, inflammation, epithelial stratification and mesenchymal changes. Increased proteins included keratins 6A, 16 and vimentin, while the iron transporter lactotransferrin was decreased. The keratoconus stromal proteome suggests endoplasmic reticular stress, oxidative stress and widespread decreases in many extracellular matrix proteoglycan core proteins, lumican and keratocan, collagen types I, III, V and XII. Marked increase in apoptosis and endocytosis-related proteins suggest degenerative changes in keratocytes, the resident cells of the stroma. This is the most comprehensive proteome analysis of the cornea that highlights similarities of keratoconus with other neurodegenerative diseases.This study provides, to our knowledge, the most comprehensive proteomic analysis of the vision threatening disease keratoconus, which affects a significant portion of the US and global populations. Using iTRAQ and LC/MS/MS, we have identified significant changes in the human corneal epithelium and stromal proteome that correlate to in vivo clinical findings. The protein changes identified will lead to molecular insights into disease pathogenesis and provide candidate genes for genetic studies of keratoconus.
Project description:Keratoconus (KC) is a corneal dystrophy characterized by progressive ectasia that leads to severe visual impairment and remains one of the leading indications for corneal transplantation. The etiology is believed to be multifactorial and alterations have been documented in the biomechanical, biochemical and ultrastructural characteristics of the cornea. While the exact site of disease origin is still debated, changes in the corneal epithelium are believed to occur even before the disease is clinically manifested. In this study we investigate the possible role of ?-catenin as mechanotransducer in KC corneal epithelium. The sheets of corneal epithelium removed from keratoconic eyes when they underwent collagen crosslinking as a therapeutic procedure were used for this study. The healthy corneal epithelium of patients undergoing Laser Refractive Surgery for the correction of their refractive error, served as controls. Immunoblotting and tissue immunofluorescence studies were performed on KC epithelium to analyse the expression and localization of ?-catenin, E-cadherin, ZO1, ?-catenin, Cyclin D1, ?-actinin, RhoA, and Rac123. Co-immunoprecipitation of ?-catenin followed by mass spectrometry of KC epithelium was performed to identify its interacting partners. This was further validated by using epithelial tissues grown on scaffolds of different stiffness. Histology data reported breaks in the Bowman's layer in KC patients. We hypothesize that these breaks expose the epithelium to the keratoconic corneal stroma, which, is known to have a decreased elastic modulus and that ?-catenin acts as a mechanotransducer that induces structural changes such as loss of polarity (Syntaxin3) and barrier function (ZO1) through membrane delocalization. The results of our study strongly suggest that ?-catenin could be a putative mechanotransducer in KC epithelium, thus supporting our hypothesis.
Project description:<h4>Background</h4>The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients aged 10-16?years. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written before the end of the patient follow-up, while the outcome of the trial is still unknown.<h4>Design and methods</h4>KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. Keratoconus is a disorder of the shape of the cornea in which the normally round dome-shaped clear front window of the eye (cornea) thins progressively leading to a cone-like bulge. This impairs the ability of the eye to focus properly, causing reduced vision which requires spectacle or contact lens wear or, in a minority of patients, eventually corneal replacement by a transplant for best vision. The primary outcome measure is the between-group difference in K<sub>2</sub> at 18?months adjusted for K<sub>2</sub> at baseline examination. K<sub>2</sub> is the value of the steepest corneal meridian as measured on Pentacam topography. Secondary outcomes are keratoconus progression, time to keratoconus progression, visual acuity, refraction, apical corneal thickness and adverse events. Patient-reported effects will be explored by questionnaires. We describe in detail the statistical aspects of KERALINK: the outcome measures, the sample size calculation, general analysis principles, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses.<h4>Discussion</h4>The KERALINK statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in May 2020 when follow-up for the trial is completed.<h4>Trial registration</h4>EudraCT, 2016-001460-11. Registered on 19 May 2016.
Project description:Corneal transparency is maintained by the corneal endothelium through its pump and barrier function. Severe corneal endothelial damage results in dysregulation of water flow and eventually causes corneal haziness and deterioration of visual function. In 2013, we initiated clinical research of cell-based therapy for treating corneal decompensation. In that study, we removed an 8-mm diameter section of damaged corneal endothelium without removing Descemet's membrane (the basement membrane of the corneal endothelium) and then injected cultured human corneal endothelial cells (CECs) into the anterior chamber. However, Descemet's membrane exhibits clinically abnormal structural features [i.e., multiple collagenous excrescences (guttae) and thickening] in patients with Fuchs endothelial corneal dystrophy (FECD) and the advanced cornea guttae adversely affects the quality of vision, even in patients without corneal edema. The turnover time of cornea guttae is also not certain. Therefore, we used a rabbit model to evaluate the feasibility of Descemet's membrane removal in the optical zone only, by performing a small 4-mm diameter descemetorhexis prior to CEC injection. We showed that the corneal endothelium is regenerated both on the corneal stroma (the area of Descemet's membrane removal) and on the intact peripheral Descemet's membrane, based on the expression of function-related markers and the restoration of corneal transparency. Recovery of the corneal transparency and central corneal thickness was delayed in areas of Descemet's membrane removal, but the cell density of the regenerated corneal endothelium and the thickness of the central corneal did not differ between the areas with and without residual Descemet's membrane at 14 days after CEC injection. Here, we demonstrate that removal of a pathological Descemet's membrane by a small descemetorhexis is a feasible procedure for use in combination with cell-based therapy. The current strategy might be beneficial for improving visual quality after CEC injection as a treatment for FECD.
Project description:PURPOSE:To report a case of bilateral and repetitive corneal perforations after corneal cross-linking (CXL) for keratoconus in a woman harboring potentially pathogenic variants in the ZNF469 gene and to characterize the keratoconus phenotype in this woman and her daughter who shared the same ZNF469 mutations. METHODS:Clinical characterization of the proband and her daughter followed by sequencing of the genes associated with brittle cornea syndrome, ZNF469 and PRDM5, in both individuals. RESULTS:An Ashkenazi Jewish woman in her sixth decade presented with diffuse corneal thinning and progressive steepening consistent with keratoconus. After CXL, epithelium-off in the first eye and epithelium-on in the second, she developed spontaneous corneal perforations in each eye. Her daughter in her fourth decade demonstrated a similar pattern of diffuse corneal thinning and progressive corneal steepening but did not undergo CXL and did not develop corneal perforation. Screening of the ZNF469 and PRDM5 genes revealed 3 missense ZNF469 variants (c.2035G>A, c.10244G>C, and c.11119A>G) in cis arrangement on 1 allele of ZNF469 in both proband and her daughter. Although the 3 variants share low (<0.01) global minor allele frequencies, each has significantly higher minor allele frequencies (0.01-0.03) in the Ashkenazi Jewish population, leading to uncertainty regarding a pathogenic role for the identified variants. CONCLUSIONS:CXL may be associated with the development of corneal perforation in particular at-risk individuals with keratoconus. Identifying clinical and genetic risk factors, including screening of ZNF469 and PRDM5, may be useful in the prevention of significant complications after CXL.
Project description:INTRODUCTION:The primary purpose of crosslinking is to halt the progression of ectasia. We retrospectively assessed the condition of keratoconus patients who were followed-up at least twice after the initial examination to evaluate keratoconus progression, to identify definitive factors to predict a later need for corneal crosslinking (CXL). METHODS:The medical charts of 158 eyes of 158 keratoconus patients (112 males and 46 females; mean age, 27.8 ± 11.7 years), who were followed up at the Department of Ophthalmology, Keio University School of Medicine at least twice after the initial examination to evaluate keratoconus progression were retrospectively reviewed. Best-spectacle corrected visual acuity, intraocular pressure, steepest corneal axis on the anterior float (Ks), thinnest corneal thickness according to Pentacam® HR, and corneal endothelial cell density were assessed. Gender, age, onset age of keratoconus, history of atopic dermatitis, and Pentacam® indices were also recorded. CXL was performed when the eye showed significant keratoconus progression, an increase in the steepest keratometric value, or an increase in the spherical equivalent or cylinder power of the manifest refraction by more than 1.0 D versus the respective values 2 years prior. Predictor variables and the requirement for CXL were analyzed using logistic regression. RESULTS:Fifty-eight eyes required CXL treatment. The best predictor of the requirement for CXL was patient age, followed by the Pentacam® Rmin (the minimum sagittal curvature evaluated by Pentacam®) value. The incidence of CXL was 86.4% in the < 20 years age group, with an Rmin of ? 5.73 mm, whereas 10.8% in the ? 27 years age group with an Rmin > 5.73 mm underwent treatment. CONCLUSIONS:An age of < 20 years and an Rmin value of ? 5.73 mm predicted keratoconus progression and the requirement for CXL treatment in the near future.
Project description:To characterize corneal structural changes in keratoconus using a new morphogeometric approach and to evaluate its potential diagnostic ability.Comparative study including 464 eyes of 464 patients (age, 16 and 72 years) divided into two groups: control group (143 healthy eyes) and keratoconus group (321 keratoconus eyes). Topographic information (Sirius, CSO, Italy) was processed with SolidWorks v2012 and a solid model representing the geometry of each cornea was generated. The following parameters were defined: anterior (Aant) and posterior (Apost) corneal surface areas, area of the cornea within the sagittal plane passing through the Z axis and the apex (Aapexant, Aapexpost) and minimum thickness points (Amctant, Amctpost) of the anterior and posterior corneal surfaces, and average distance from the Z axis to the apex (Dapexant, Dapexpost) and minimum thickness points (Dmctant, Dmctpost) of both corneal surfaces.Significant differences among control and keratoconus group were found in Aapexant, Aapexpost, Amctant, Amctpost, Dapexant, Dapexpost (all p<0.001), Apost (p = 0.014), and Dmctpost (p = 0.035). Significant correlations in keratoconus group were found between Aant and Apost (r = 0.836), Amctant and Amctpost (r = 0.983), and Dmctant and Dmctpost (r = 0.954, all p<0.001). A logistic regression analysis revealed that the detection of keratoconus grade I (Amsler Krumeich) was related to Apost, Atot, Aapexant, Amctant, Amctpost, Dapexpost, Dmctant and Dmctpost (Hosmer-Lemeshow: p>0.05, R2 Nagelkerke: 0.926). The overall percentage of cases correctly classified by the model was 97.30%.Our morphogeometric approach based on the analysis of the cornea as a solid is useful for the characterization and detection of keratoconus.
Project description:PURPOSE: To evaluate the prevalence and associated factors of steep cornea/keratoconus in the adult Chinese population. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years (range: 50-93 years). A detailed ophthalmic examination was performed including optical low-coherence reflectometry. Steep cornea/keratoconus were defined as an anterior corneal refractive power exceeding 48 diopters. RESULTS: Mean refractive power of the cornea was 43.16±1.45 diopters (range: 36.51 to 48.46 diopters; flattest meridian) and 43.98±1.52 diopters (range: 37.00 to 52.88 diopters; steepest meridian). A steep cornea/keratoconus defined as corneal refractive power of ≥48 diopters and ≥49 diopters was detected in 27 subjects (prevalence rate: 0.9±0.2%) and 6 (0.2± 0.1%) subjects, respectively. Presence of steep cornea/keratoconus was associated with shorter axial length (P<0.001), smaller interpupillary distance (P = 0.038), lower best corrected visual acuity (P = 0.021), higher cylindrical refractive error (P<0.001) and more myopic refractive error (P<0.001). It was not significantly associated with gender, body height, psychic depression, cognitive function, blood concentrations of glucose, lipids, creatinine and C-reactive protein, blood pressure and quality of life score, nor with intraocular pressure, dry eye feeling, and lens thickness. CONCLUSIONS: A steep cornea/keratoconus defined as corneal refractive power of 48+ diopters has a prevalence of 0.9±0.2% among Chinese aged 50 years and above. Its prevalence was significantly associated with the ocular parameters of shorter axial length, smaller interpupillary distance, higher cylindrical and myopic refractive error and lower best corrected visual acuity, however, with none of the systemic parameters tested.