Multi-dataset identification of innovative feature genes and molecular mechanisms in keratoconus.

This study aimed to identify feature genes and explore the molecular mechanisms of keratoconus (KC). We downloaded data files from NCBI GEO public database. The Limma package was used for differential expression analysis of gene profiles. Lasso regression was used to identify the feature genes. The CIBERSORT algorithm was used to infer the proportion of immune-infiltrating cells and analyse the correlation between gene expression levels and immune cells. Related transcription factors and miRNAs of key genes were predicted using the Cistrome DB and Mircode databases. Analysis of expression differences in disease genes was based on the GeneCards database. The CMap was used to analyse targeted therapeutic drugs. IHC was performed to verify the expression levels of ATOH7 and MYRF in corneas. Exactly 593 upregulated and 473 downregulated genes were identified. Lasso regression analysis identified ATOH7, DBNDD1, RNF217-AS1, ARL11, MYRF and SNORA74B as feature genes for KC. All key genes were correlated with immune infiltration and the levels of activated memory CD4+ T cells and plasma cells were significantly increased. miRNA, IRF and STAT families were correlated to feature genes. The expression levels of key genes were significantly correlated to KC-related genes. Entinostat, ochratoxin-a, diphencyprone and GSK-3-inhibitor-II were predicted as potential KC medications. The expression of MYRF was significantly higher in the KC samples, contrary to the expression of ATOH7. KC is related to both immune infiltration and genetic factors. MYRF and ATOH7 were newly identified and verified feature genes of KC.

Static magnetic field effects on the secondary structure and elasticity of collagen molecules; a possible biophysical approach to treat keratoconus.

Type I collagen is among the major extracellular proteins that play a significant role in the maintenance of the cornea's structural integrity and is essential in cell adhesion, differentiation, growth, and integrity. Here, we investigated the effect of 300 mT Static Magnetic Field (300 mT SMF) on the structure and molecular properties of acid-solubilized collagens (ASC) isolated from the rat tail tendon. The SMF effects at molecular and atomic levels were investigated by various biophysical approaches like Circular Dichroism Spectropolarimetery (CD), Fourier Transform Infrared Spectroscopy (FTIR), Zetasizer light Scattering, and Rheological assay. Exposure of isolated type I collagen to 300 mT SMF retained its triple helix. The elasticity of collagen molecules and the keratoconus (KCN) cornea treated with SMF decreased significantly after 5 min and slightly after 10, 15, and 20 min of treatments. The exposure to 300 mT SMF shifted the Amid I bond random coil to antiparallel wave number from 1647 to 1631 cm-1. The pH of the 300 mT SMF treated collagen solution increased by about 25 %. The treatment of the KCN corneas with 300 mT SMF decreased their elasticity significantly. The promising results of the effects of 300 mT SMF on the collagen molecules and KCN cornea propose a novel biophysical approach capable of manipulating the collagen's elasticity, surface charges, electrostatic interactions, cross binding, network formation and fine structure. Therefore, SMF treatment may be considered as a novel non-invasive, direct, non-chemical and fast therapeutic and manipulative means to treat KCN cornea where the deviated physico-chemical status of collagen molecules cause deformation.

Subclinical Keratoconus Detection and Characterization Using Motion-Tracking Brillouin Microscopy.

PURPOSE: To characterize focal biomechanical alterations in subclinical keratoconus (SKC) using motion-tracking (MT) Brillouin microscopy and evaluate the ability of MT Brillouin metrics to differentiate eyes with SKC from normal control eyes. DESIGN: Prospective cross-sectional study. PARTICIPANTS: Thirty eyes from 30 patients were evaluated, including 15 eyes from 15 bilaterally normal patients and 15 eyes with SKC from 15 patients. METHODS: All patients underwent Scheimpflug tomography and MT Brillouin microscopy using a custom-built device. Mean and minimum MT Brillouin values within the anterior plateau region and anterior 150 µm were generated. Scheimpflug metrics evaluated included inferior-superior (IS) value, maximum keratometry (Kmax), thinnest corneal thickness, asymmetry indices, Belin/Ambrosio display total deviation, and Ambrosio relational thickness. Receiver operating characteristic (ROC) curves were generated for all Scheimpflug and MT Brillouin metrics evaluated to determine the area under the ROC curve (AUC), sensitivity, and specificity for each variable. MAIN OUTCOME MEASURES: Discriminative performance based on AUC, sensitivity, and specificity. RESULTS: No significant differences were found between groups for age, sex, manifest refraction spherical equivalent, corrected distance visual acuity, Kmax, or KISA% index. Among Scheimpflug metrics, significant differences were found between groups for thinnest corneal thickness (556 µm vs. 522 µm; P < 0.001), IS value (0.29 diopter [D] vs. 1.05 D; P < 0.001), index of vertical asymmetry (IVA; 0.10 vs. 0.19; P < 0.001), and keratoconus index (1.01 vs. 1.05; P < 0.001), and no significant differences were found for any other Scheimpflug metric. Among MT Brillouin metrics, clear differences were found between control eyes and eyes with SKC for mean plateau (5.71 GHz vs. 5.68 GHz; P < 0.0001), minimum plateau (5.69 GHz vs. 5.65 GHz; P < 0.0001), mean anterior 150 µm (5.72 GHz vs. 5.68 GHz; P < 0.0001), and minimum anterior 150 µm (5.70 GHz vs. 5.66 GHz; P < 0.001). All MT Brillouin plateau and anterior 150 µm mean and minimum metrics fully differentiated groups (AUC, 1.0 for each), whereas the best performing Scheimpflug metrics were keratoconus index (AUC, 0.91), IS value (AUC, 0.89), and IVA (AUC, 0.88). CONCLUSIONS: Motion-tracking Brillouin microscopy metrics effectively characterize focal corneal biomechanical alterations in eyes with SKC and clearly differentiated these eyes from control eyes, including eyes that were not differentiated accurately using Scheimpflug metrics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial.

PURPOSE: To validate the ability of theranostic imaging biomarkers in assessing corneal cross-linking (CXL) efficacy in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (ClinicalTrails.gov identifier, NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (25 eyes) and epithelium-on (25 eyes) CXL protocols using an ultraviolet A (UV-A) medical device with theranostic software. The device controlled UV-A light both for performing CXL and assessing the corneal riboflavin concentration (riboflavin score) and treatment effect (theranostic score). A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epithelium-off and epithelium-on protocols, respectively. All eyes underwent 9 minutes of UV-A irradiance at 10 mW/cm2. MAIN OUTCOME MEASURES: The primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to classify eyes correctly and predict a Kmax flattening at 1 year after CXL. Other outcome measures included change in Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction and central corneal thickness 1 year after CXL. RESULTS: Accuracy and precision of the theranostic imaging biomarkers in predicting eyes that had >0.1 diopter (D) of Kmax flattening at 1 year were 91% and 95%, respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR, -2.11 to -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 logarithm of the minimum angle of resolution (logMAR; IQR, -0.3 to 0.0 logMAR [P < 0.001] and -0.2 to 0.0 logMAR [P < 0.001], respectively). No significant changes in endothelial cell density (P = 0.33) or central corneal thickness (P = 0.07) were noted 1 year after surgery. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epithelium-off and epithelium-on CXL protocols. Concentration of riboflavin and its UV-A light mediated photoactivation in the cornea are the primary factors determining CXL efficacy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Trends and Sociodemographic Patterns in Keratoconus Management 2015-2020: An American Academy of Ophthalmology IRIS® Registry Analysis.

PURPOSE: Investigate trends in keratoconus (KCN) treatment patterns and diagnosis age from 2015 to 2020 and evaluate sociodemographic associations with the treatment approach. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients with a new KCN diagnosis from 2015 to 2020 were identified in the Academy IRIS® Registry (Intelligent Research in Sight). METHODS: Associations between sociodemographic factors and treatment were evaluated using multivariable logistic regression. MAIN OUTCOME MEASURES: Outcomes included percentages and rates of each treatment (collagen crosslinking [CXL], keratoplasty, or no procedure) from 2015 to 2020, age at diagnosis during this period, and sociodemographic factors associated with treatment type. RESULTS: A total of 66 199 patients with a new diagnosis of KCN were identified. The percentage of patients undergoing CXL increased from 0.05% in 2015 to 29.5% in 2020 (P = 0.008). The average age (standard deviation) of KCN patients decreased from 44.1 (±16.9) years in 2015 to 39.2 (±16.9) years in 2020 (P < 0.001). In multivariable analyses comparing CXL versus no procedure and keratoplasty versus no procedure, patients undergoing CXL tended to be younger with the odds of having CXL decreasing with increasing age, for example, comparing CXL and no procedure patients, using ages 0-20 years as reference, the odds ratio (OR) (95% confidence interval [CI]) decreased from 0.62 (0.57-0.67; P < 0.0001) for patients aged 21-40 years to 0.03 (0.02-0.04; P < 0.0001) for patients aged > 60 years. Men were more likely than women to have CXL (OR, 1.31; 95% CI, 1.23-1.40; P < 0.0001) and keratoplasty (OR, 1.30; 95% CI, 1.19-1.42; P < 0.0001). Black patients were less likely than White patients to have CXL (OR, 0.70; 95% CI, 0.63-0.77; P < 0.0001) and more likely to have keratoplasty (OR, 2.24; 95% CI, 2.01-2.50; P < 0.0001). Likewise, Hispanic patients had higher odds of CXL (OR, 1.12; 95% CI, 1.00-1.24; P < 0.05) and keratoplasty (OR, 1.29; 95% CI, 1.12-1.50; P < 0.001) compared with non-Hispanic patients. Collagen crosslinking and keratoplasty also varied by region and insurance status. CONCLUSIONS: A significant increase in use of CXL was noted from 2015 to 2020. Sociodemographic differences in treatment among KCN patients may reflect differences in access, use, or care patterns, and future studies should aim to identify strategies to improve access for all patients. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Advanced Corneal Imaging in Keratoconus: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the published literature on the diagnostic capabilities of the newest generation of corneal imaging devices for the identification of keratoconus. METHODS: Corneal imaging devices studied included tomographic platforms (Scheimpflug photography, OCT) and functional biomechanical devices (imaging an air impulse on the cornea). A literature search in the PubMed database for English language studies was last conducted in February 2023. The search yielded 469 citations, which were reviewed in abstract form. Of these, 147 were relevant to the assessment objectives and underwent full-text review. Forty-five articles met the criteria for inclusion and were assigned a level of evidence rating by the panel methodologist. Twenty-six articles were rated level II, and 19 articles were rated level III. There were no level I evidence studies of corneal imaging for the diagnosis of keratoconus found in the literature. To provide a common cross-study outcome measure, diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were extracted. (A perfect diagnostic test that identifies all cases properly has an AUC of 1.0.) RESULTS: For the detection of keratoconus, sensitivities for all devices and parameters (e.g., anterior or posterior corneal curvature, corneal thickness) ranged from 65% to 100%. The majority of studies and parameters had sensitivities greater than 90%. The AUCs ranged from 0.82 to 1.00, with the majority greater than 0.90. Combined indices that integrated multiple parameters had an AUC in the mid-0.90 range. Keratoconus suspect detection performance was lower with AUCs ranging from 0.66 to 0.99, but most devices and parameters had sensitivities less than 90%. CONCLUSIONS: Modern corneal imaging devices provide improved characterization of the cornea and are accurate in detecting keratoconus with high AUCs ranging from 0.82 to 1.00. The detection of keratoconus suspects is less accurate with AUCs ranging from 0.66 to 0.99. Parameters based on single anatomic locations had a wide range of AUCs. Studies with combined indices using more data and parameters consistently reported high AUCs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Circular RNA expression profile identifies potential circulating biomarkers for keratoconus.

Early diagnosis is important for improving the outcomes of keratoconus (KC). Stable expression and a closed-loop structure of circular RNAs (circRNAs) make them ideal for the diagnosis and treatment of diseases. However, the expression pattern and potential function of circRNAs in KC is not studied yet. Hence, this study explored the circRNA expression profile of KC corneas through transcriptome sequencing and circRNA expression profile analysis. The diagnostic potential of blood circRNAs for KC was explored by analysing the circRNAs' expression levels of fifty paired blood samples from patients with KC and normal controls. The results showed that 107 significantly upregulated and 145 significantly downregulated circRNAs (|fold change| ≥ 2.0, p-value <0.05) were identified in KC tissues. Eight top differently expressed circRNAs were further validated in more cornea samples. Among them, five circRNAs expressed in peripheral blood, and four circRNAs (circ_0006156, circ_0006117, circ_0000284 and circ_0001801) showed significant downregulation in KC patients' peripheral blood too. The blood circ_0000284 expression levels of early, moderate, and advanced KC patients both were significantly lower than the controls. The blood circ_0006117 expression levels present a positive correlation with corrected distance visual acuity values, and a negative correlation with back elevation values of KC eyes. Notably, the expression levels of these circRNAs distinguished KC patients from their healthy counterparts, with the area under the curve (AUC) of circ_0000284, circ_0001801, and circ_0006117 being 0.7306, 0.6871 and 0.6701, respectively. Further, the AUC value for five circRNAs under the logistic regression model was 0.8203, indicating that they can function as effective biomarkers for the KC diagnostics. In conclusion, the expression of circRNAs showed a relationship with KC, with four significantly differentially expressed circRNAs demonstrating potential as biomarkers for the disease.

Revisiting rabbit models for keratoconus: A long-term study on collagenase-induced disease progression.

Keratoconus (KC) is a degenerative disorder resulting from the degradation of the stromal collagen fibril network in the cornea, leading to its thinning and conical deformation. Various studies have established animal models of KC by using the collagenase type II enzyme to gain a better understanding of the pathogenesis, however, long-term monitoring or follow-up of the models have not been reported so far. This study evaluates the long-term stability of collagenase type II-induced KC in a rabbit model. Six New Zealand rabbits were divided into 4 study groups with 3 eyes per group. The groups were control (group 1), 0.5% proparacaine + 5 min collagenase treatment on day 0 and day 30 (group 2), 0.5% proparacaine + 10 min collagenase treatment on day 0 (group 3) and, mechanical debridement + 2 min collagenase treatment on day 0 (group 4). Inflammation was observed in group 4 till week 10. Significant decrease in the central corneal thickness was observed in group 3 by week 4 (p < 0.001) however, the thickness was regained in the subsequent follow-ups in all the groups. Keratography results showed no changes in Km values but an increased astigmatic power in all groups. Scanning electron microscopy images revealed thinner collagen fibrils arranged in a mesh-like pattern above the uniform layer of the collagen lamellae in the central part of the treated corneas. Similarly, histological staining revealed loosely packed stromal fibrils in the anterior portion of the cornea which corroborates with the immunofluorescent staining results. This study revealed the remodeling of the corneal structure by eight weeks of collagenase treatment. Consequently, the possibility of creating a rabbit keratoconus model induced by collagenase may warrant further consideration.

CYR61/CCN1: A novel mediator of redox response in corneal stromal cells of keratoconus.

Keratoconus (KC) is a progressive, multifactorial and ectatic corneal disorder that characterized by steepening thinning of the cornea. It was previously demonstrated that oxidative stress has a strong link with KC progression. However, the molecular mechanism underlying oxidative stress response in KC remains unclear. Hence, the present study analyzed the heterogeneity of response of corneal stromal cells (CSCs) to oxidative stress in order to further illustrate how oxidative shape the pathophysiology of KC. Single-cell transcriptomics analysis revealed that CSCs demonstrated significant higher oxidative stress score in the KC group compared to the Ctrl group. The expression of oxidative markers verified by experiments illustrated elevated oxidative stress levels and insufficient antioxidant levels in CSCs of KC. In further single-cell transcriptomics analysis, we identified CYR61 to distinguish different subgroups of CSCs responding to oxidative stress. The cornea stroma cells in KC could be differentiated into CYR61high cells and CYR61low cells. Of note, the CYR61high cells showed lower score in collagen production process and higher score in collagen catabolic process. Further experiments illustrated that CYR61 was elevated in KC and associated with collagen production.

Whole-exome sequencing screening for candidate genes and variants associated with primary sporadic keratoconus in Chinese patients.

The pathogenesis of keratoconus (KC) is complex, and genetic factors play an important role. The purpose of this study was to screen and analyse candidate genes and variants in Chinese patients with primary sporadic KC. Whole-exome sequencing (WES) was performed to identify candidate genes and variants in 105 unrelated Chinese patients with primary sporadic KC. Through a series of screening processes, 54 candidate variants in 26 KC candidate genes were identified in 53 KC patients (53/105, 50.5%). These 54 candidate variants included 10 previously identified variants in 9 KC candidate genes and 44 novel variants in 20 KC candidate genes. The previously identified variants occurred in 25.7% (27/105) of patients. Of these, 4 variants (COL6A5, c.5014T > G; CAST, c.1814G > A; ZNF469, c.946G > A; and MPDZ, c.3836A > G) were identified for the first time in Chinese KC patients. The novel variants occurred in 33.3% (35/105) of patients. Of the 26 screened KC candidate genes, 11 KC candidate genes (CAT, COL12A1, FLG, HKDC1, HSPG2, PLOD1, ITGA2, TFAP2B, USH2A, WNT10A, and COL6A5) were found to be potentially pathogenic in Chinese KC patients for the first time. Gene Ontology (GO) biological process (BP) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the 26 KC candidate genes using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The results showed that the KC candidate genes were significantly enriched in biological processes such as collagen fibril organization and extracellular matrix (ECM) organization and in ECM-receptor interaction and protein digestion and absorption pathways. The results further expand the spectrum of KC candidate variants and provide a basis for further KC gene studies.

Trio-based whole-exome sequencing of 200 Chinese patients with keratoconus.

Keratoconus (KC) is a complex corneal disorder with a well-recognized genetic component. In this study, we aimed to expand the genetic spectrum of 200 Chinese patients with keratoconus and their unaffected parents. Trio-based whole-exome sequencing was performed in 200 patients with sporadic keratoconus and their unaffected parents. The variants identified in candidate genes for keratoconus were analyzed using multiple bioinformatics tools. Finally, we identified 7 variants in 5 candidate genes for keratoconus in 5 patients. The c.T464C variant in the IMPDH1 gene was defined as likely pathogenic according to the guidelines of the American College of Medical Genetics and Genomics, and the remaining variants in candidate genes (TRANK1, SLC4A11, CERKL, IFT172) were defined as uncertain significance. Our results expand the genetic spectrum in KC, highlight the genetic heterogeneity of this disease and provide important clues for future functional validation.

Impact of a 50bp insertion/deletion polymorphism of the superoxide dismutase-1 on oxidative stress status and risk of keratoconus.

Keratoconus (KC) is characterized by the predominant primary ectatic disease, affecting the cornea, necessitating corneal transplants in some cases. While some loci associated with KC risk have been identified, the understanding of the disease remains limited. Superoxide dismutase (SOD) enzymes play a crucial role in countering the reactive oxygen species and providing protection against oxidative stress (OS). Accordingly, the objective of this study was to investigate a potential association of a 50 nucleotide base pairs (bp) insertion/deletion (I/D) within the SOD1 promoter, and the located 1684 bp upstream of the SOD1 ATG, with KC in the Iranian population. Additionally, an assessment was conducted on SOD activity and the total antioxidant capacity (TAC), as determined by the ferric reducing-antioxidant power assay, along with malondialdehyde (MDA) levels. In this case-control study, genomic DNA was extracted from the blood cells of KC (n = 402) and healthy (n = 331) individuals. The genotype of this gene was determined using the PCR technique. Furthermore, the amount of SOD enzyme activity and the MDA and TAC levels were measured in the serum of the study groups. The (I/I) genotype was present in 84.23%, the (I/D) genotype in 15.06%, and the (D/D) genotype in 0.69% of both groups. A statistically significant relationship was seen between different genotypes and TAC, MDA, and SOD1 activity indices (P < 0.05). Individuals with the D/D genotype exhibited a decrease in total antioxidant capacity, an increase in the amount of MDA, and a decrease in SOD1 enzyme activity (P < 0.05). Moreover, the logistic regression analysis of KC development indicated that elevated levels of MDA increased the risk of KC incidence in the patient group compared to the healthy group, while a higher activity of SOD1 and greater values of TAC decreased the KC risk. The removal of the 50 bp fragment reduced SOD1 activity and elevated OS levels, thereby impacting the oxidant-antioxidant balance. This could potentially play a significant role in individuals afflicted by KC.

The Chinese keratoconus (CKC) cohort study.

The Chinese keratoconus (CKC) cohort study is a population-based longitudinal prospective cohort study in the Chinese population involving a clinical database and biobanks. This ongoing study focuses on the prevention of KC progression and is the first to involve the effect of gene‒environment interactions on KC progression. The CKC cohort is hospital-based and dynamic and was established in Zhengzhou, China; KC patients (n = 1114) from a large geographical area were enrolled from January 2019 to June 2023, with a mean age of 22.23 years (6‒57 years). Demographic details, socioeconomic characteristics, lifestyle, disease history, surgical history, family history, and visual and social function data are being collected using questionnaires. General physical examination, eye examination, biological specimen collection, and first-degree relative data were collected and analyzed in the present study. The primary focus of the present study was placed on gene, environment and the effect of gene‒environment interactions on KC progression. The follow-up of the CKC cohort study is expected to include data collection at 3 months, 6 months, and 1 year after the initial examination and then at the annual follow-up examinations. The first follow-up of the CKC cohort study was recorded. A total of 918 patients completed the follow-up by June 1, 2023, with a response rate of 82.40%. Aside from the younger age of patients who were followed up, no significant differences were found between patients who were followed up and patients who were not.

Corneal biomechanics in early diagnosis of keratoconus using artificial intelligence.

Keratoconus is a blinding eye disease that affects activities of daily living; therefore, early diagnosis is crucial. Great efforts have been made toward an early diagnosis of keratoconus. Recent studies have shown that corneal biomechanics is associated with the occurrence and progression of keratoconus. Hence, detecting changes in corneal biomechanics may provide a novel strategy for early diagnosis. However, an early keratoconus diagnosis remains challenging due to the subtle and localized nature of its lesions. Artificial intelligence has been used to help address this problem. Herein, we reviewed the literature regarding three aspects of keratoconus (keratoconus, early keratoconus, and keratoconus grading) based on corneal biomechanical properties using artificial intelligence. Furthermore, we summarized the current research progress, limitations, and possible prospects.

Accuracy of intraocular lens power formulas in eyes with keratoconus: Multi-center study in Japan.

PURPOSE: To assess the accuracy of intraocular lens (IOL) power formulas, namely, SRK/T, Haigis, Barrett Universal II, Barrett True-K for keratoconus, Kane formula, and Kane formula for keratoconus, for cataract with keratoconus in Japanese eyes. SETTING: Five surgical sites in Japan. DESIGN: A retrospective case series. METHODS: Eyes with keratoconus undergoing cataract surgery were included. Postoperative refraction was compared with the prediction by the formulas. Visual acuity, manifest spherical equivalent, prediction error (PE), and mean absolute errors (MAEs) were determined 1 month postoperatively. The PE within 0.50 diopter (D), 1.00 D, and 2.00 D were compared between IOL formulas. Subgroup analysis based on the steepest keratometry (stage 1, ≤ 48 D; stage 2, > 48 D and ≤ 53 D; and stage 3, > 53 D) was performed. The relationship between PE and preoperative biometric data were assessed. RESULTS: Fifty eyes were included. The MAE of the Barrett True-K for keratoconus, Kane keratoconus, and Kane formulas were significantly lower than that of Haigis. A statistically significant difference in the prediction accuracy within ± 0.50 D was found between Kane keratoconus and Haigis. The prediction accuracy of the Barrett True-K for keratoconus, SRK/T, and Kane within ± 1.00 D was statistically significant compared with that of Haigis. In stage 3, the Barrett True-K for keratoconus had a significantly lower MAE than SRK/T and Haigis. CONCLUSION: Keratoconus-specific formulas were more accurate than existing formulas in Japanese eyes. The Barrett True-K formula for keratoconus had higher prediction accuracy in severe keratoconus.

Comparison of corneal measurements in keratoconus eyes with two swept-source-optical coherence tomography devices and a Scheimpflug device.

PURPOSE: To assess the feasibility and reliability of biometric measurements taken with the Eyestar 900 device in keratoconus eyes in comparison with those taken with the Pentacam HR and IOLMaster 700. METHODS: Seventy-five eyes of 75 patients with keratoconus were included. The central corneal thickness (CCT), thinnest point of corneal thickness (TCT), axial length (AL), flat (K1) and steep (K2) anterior and posterior (Kp1, Kp2) keratometry, maximal keratometry (KMax) and anterior chamber depth (ACD) were compared between the Eyestar 900, Pentacam HR and IOLMaster 700. Reliability parameters such as the coefficient of variation (CoV) and intraclass correlation coefficient (ICC) were calculated. Pearson's r was determined to assess the correlation between devices. RESULTS: A high repeatability (CoV < 1%) and intraclass correlation (ICC > 0.9) was found for all devices, led by AL, TCT, K1 and K2 (CoV 0.01-0.36%; ICC 0.994-1.00). The largest correlation between devices was found for AL (Eyestar vs. IOLMaster, r = 1.0), K1 (Eyestar vs. IOLMaster, r = 0.997) and ACD (Eyestar vs. IOLMaster, r = 0.995; Pentacam vs. IOLMaster, r = 0.987; Eyestar vs. Pentacam, r = 0.983), but there were significant differences in measured values between devices (p < 0.001), whereas the correlation was only slightly lower (r = 0.947 to 0.994) for KMax, CCT, TCT, K2, Kp1 and Kp2. CONCLUSION: Keratometric and axial length measurements with the Eyestar 900 were feasible and revealed a high repeatability and a good correlation to the other devices in eyes with keratoconus.

Repeatability and agreement of two ocular biometers with single and dual Scheimpflug cameras in keratoconus eyes.

BACKGROUND: To evaluate the repeatability and agreement of two different ocular biometers and Scheimpflug devices in keratoconus eyes. METHODS: This prospective, comparative trial took place at the University hospital, Goethe University, Frankfurt am Main, Germany. We included eyes with keratoconus, one eye per patient, randomly selected. Measurements were taken with Galilei G6 (Ziemer, Switzerland) and Pentacam AXL (Oculus, Germany), three consecutive measurements each. Repeatability and agreement were evaluated for simulated keratometry (simK), astigmatism (simA), maximum keratometry (KMax) and its axis, total keratometry (TCP), axial length (AL), anterior chamber depth (ACD), and thinnest pachymetry (TCT). RESULTS: Both devices showed an excellent repeatability with intra class correlation (ICC) of > 0.97 for all parameters. The 95% limits of repeatability (LoR95%) and agreement (LoA95%) were narrow for all parameters. The Galilei G6 had a narrower LoAR95% for TCT (2.1 µm vs. 4.6 µm), but a wider LoR95% for KMax (0.52D vs. 1.18D). No relevant difference was found for the other parameters. Agreement between the devices was good to moderate, especially for simK and TCP. CONCLUSIONS: Both devices show excellent repeatability with narrow LoR95% and high ICC for all parameters. The only relevant difference was found for KMax and TCT in favor of Pentacam AXL and Galilei G6, respectively. Agreement was good to moderate, and most parameters should not be considered interchangeable.

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

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

Enhanced morphological assessment based on interocular asymmetry analysis for keratoconus detection.

PURPOSE: To clarify the interocular asymmetry of corneal morphological descriptors and evaluate its discriminant ability of keratoconus (KC). METHODS: This retrospective study recruited 344 normal participants and 290 KC patients, randomized to training and validation datasets. Interocular correlation and agreement were evaluated on 44 corneal morphological descriptors derived from Schiempflug tomography. Logistic regression models were constructed using binocular data and of which diagnostic performance was evaluated using the area under receiver operating characteristics curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Interocular agreement of corneal descriptors is better in the normal than in KC except for dimensions of cornea and anterior chamber. The interocular asymmetry increases along with the severity of KC. Interocular asymmetry in maximum anterior keratometry, mean anterior keratometry and higher-order aberrations of anterior surface show high AUC above 0.950. Binocular logistic regression index reaches an AUC of 0.963 with high specificity (95.2%) and brings gain to monocular parameters in distinguishing the normal eyes from KC (NRI = 0.080 (0.042 ~ 0.118), P < 0.001) and IDI = 0.071 (0.049 ~ 0.092), P < 0.001). Interocular asymmetry benefits even more in subclinical keratoconus (SKC) detection reflected by NRI (0.4784 (0.2703-0.6865), P < 0.001) and IDI (0.2680 (0.1495-0.3866), P < 0.001) measures. CONCLUSION: Interocular asymmetry is a well-characterized feature of KC and related to the severity. It is feasible to apply the interocular asymmetry in diagnosis of KC and SKC as a replenishment of monocular parameters and in progression tracking.

Ocular manifestations of obstructive sleep apnea: a systematic review and meta-analysis.

BACKGROUND: The association of obstructive sleep apnea (OSA) with development of eye diseases is unclear. This current systematic review and meta-analysis attempts to summarize and analyze associations between OSA and ocular disorders in the literature. METHODS: PubMed, EMBASE, Google Scholar, Web Of Science, and Scopus databases were searched from 1901 to July 2022 in accordance with the Preferred Reporting in Systematic Review & Meta-Analysis (PRISMA). Our primary outcome assessed the association between OSA and the odds of developing floppy eyelid syndrome (FES), glaucoma, non-arteritic anterior ischemic optic neuropathy (NAION), retinal vein occlusion (RVO), keratoconus (KC), idiopathic intracranial hypertension (IIH), age-related macular degeneration (AMD), and central serous chorioretinopathy (CSR) through odds ratio calculated at the 95% confidence interval. RESULTS: Forty-nine studies were included for systematic review and meta-analysis. The pooled OR estimate was highest for NAION [3.98 (95% CI 2.38, 6.66)], followed by FES [3.68 (95% CI 2.18, 6.20)], RVO [2.71(95% CI 1.83, 4.00)], CSR [2.28 (95% CI 0.65, 7.97)], KC [1.87 (95% CI 1.16, 2.99)], glaucoma [1.49 (95% CI 1.16, 1.91)], IIH [1.29 (95% CI 0.33, 5.01)], and AMD [0.92 [95% CI 0.24, 3.58] All observed associations were significant (p < 0.001) aside from IIH and AMD. CONCLUSION: OSA is significantly associated with NAION, FES, RVO, CSR, KC, and glaucoma. Clinicians should be informed of these associations so early recognition, diagnosis, and treatment of eye disorders can be addressed in at-risk groups, and early referral to ophthalmic services is made to prevent vision disturbances. Similarly, ophthalmologists seeing patients with any of these conditions should consider screening and referring patients for assessment of possible OSA.