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.

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.

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 the propensity of corneal cross-linking (CXL) in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (epi-off; 25 eyes) and epithelium-on (epi-on; 25 eyes) CXL protocols using UV-A medical device incorporating theranostic software module. The device used controlled UV-A light both for performing CXL and for estimating the corneal riboflavin concentration (riboflavin score) and assessing treatment effect (theranostic score) in real time. A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epi-off and epi-on protocols respectively. All eyes underwent 9 minutes 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 correctly classify eyes and positively predict a Kmax flattening at 1 year after CXL. Other outcome measures were the change of Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction, and central corneal thickness one year after CXL. RESULTS: Accuracy and precision of the combined use of theranostic imaging biomarkers in predicting eyes that had more than 0.1 diopter (D) 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, -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 LogMAR (IQR: -0.3, 0.0 LogMAR; P < 0.001 and IQR: -0.2, 0.0 LogMAR; P < 0.001 respectively). There were no significant changes in endothelial cell density (P = 0.33) and central corneal thickness (P = 0.07) 1 year postoperatively. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epi-off and epi-on CXL protocols. The concentration of riboflavin and its UV-A light mediated photo-activation in the cornea are the primary factors determining CXL treatment efficacy.

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.

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.

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.

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.

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.

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%.

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.

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.

The impact of interrupted corneal collagen crosslinking (CXL) treatment.

PURPOSE: To evaluate progression of keratoconus in patients where CXL treatment was interrupted due to insufficient swelling of the cornea. METHODS: A retrospective review was conducted of all patients with keratoconus diagnosis who underwent CXL at the Department of Ophthalmology, Örebro University Hospital (USÖ) during the years 2010-2017. In total 377 eyes of 280 patients were screened for inclusion. In 17 eyes (15 patients), the treatment was interrupted due to insufficient swelling of the cornea. Patient journals were reviewed and keratometry examinations were analysed for long-term progression. RESULTS: Eleven eyes (nine patients) were included in the study. Five eyes showed no signs of progression after the interrupted CXL treatment. In one eye progression continued, however, first after a period of a number of years, indicating a delayed course of clinical progression. CONCLUSION: This study indicates that debridement of the corneal epithelium and riboflavin administration without intense UVA radiation may slow or arrest the progression of keratoconus, likely due to photosensitisation from ambient light.

Evaluation of a new portable corneal topography system for self-measurement using smartphones: a pilot study.

PURPOSE: Herein, we propose the use of the "KeraVio Ring", which is a portable, selfie-based, smartphone-attached corneal topography system that is based on the Placido ring videokeratoscope. The goal of this study was to evaluate and compare corneal parameters between KeraVio Ring and conventional corneal tomography images. METHODS: We designed the KeraVio Ring as a device comprising 3D-printed LED rings for generating Placido rings that can be attached to a smartphone. Two LED rings are attached to a cone-shaped device, and both corneas are illuminated. Selfies were taken using the KeraVio Ring attached to the smartphone without assistance from any of the examiners. Captured Placido rings on the cornea were analysed by intelligent software to calculate corneal parameters. Patients with normal, keratoconus, or LASIK-treated eyes were included. Anterior segment optical coherence tomography (AS-OCT) was also performed for each subject. RESULTS: We found highly significant correlations between the steepest and flattest keratometry, corneal astigmatism, and vector components obtained with the KeraVio Ring and AS-OCT. In subjects with normal, keratoconus, and LASIK-treated eyes, the mean difference in corneal astigmatism between the two devices was -0.8 ± 1.4 diopters (D) (95% limits of agreement (LoA), -3.6 to 2.0), -1.8 ± 3.7 D (95% LoA, -9.1 to 5.5), and -1.5 ± 1.3 D (95% LoA, -4.0 to 1.1), respectively. CONCLUSIONS: The experimental results showed that the corneal parameters obtained by the KeraVio Ring were correlated with those obtained with AS-OCT. The KeraVio Ring has the potential to address an unmet need by providing a tool for portable selfie-based corneal topography.

Quantitative evaluation of morphological and functional changes in meibomian glands and lipid layer thickness in patients with and without keratoconus.

PURPOSE: To quantitatively evaluate the morphological parameters of meibomian glands (MGs) and lipid layer thickness (LLT) in patients with keratoconus (KC). METHODS: In this prospective, cross-sectional study, 164 eyes of 164 keratoconus patients and 64 eyes of 64 age-matched control subjects were included. An advanced automatic MG analyzer was used to quantitatively measure the morphological and functional parameters of MGs. Morphological and functional parameters of MGs, LLT, and other ocular surface parameters were compared between the control and KC groups. RESULTS: The mean meibomian gland diameter, length, square, and gland area ratio (GA) were all significantly decreased in the KC group (all P < 0.05), while no significant difference was observed in the gland tortuosity index (TI) and gland signal index (SI) between the KC and control groups (all P > 0.05). There was no significant difference in the number of total and incomplete blinking among patients with different stages of keratoconus (all P > 0.05). The gland diameter, square, and TI were all negatively associated with KC severity (all P < 0.05), while no significant difference was observed among all stages of KC in gland length, GA, and SI (all P > 0.05). Moreover, the LLTs were positively correlated with the gland diameter, square, GA, and TI and negatively correlated with anterior corneal curvature or KC severity (all P < 0.05). CONCLUSIONS: Atrophic morphological changes in the meibomian glands were closely correlated with the severity of keratoconus. Gland diameter may be a sensitive functional morphology metric of meibomian glands in patients with keratoconus.

Biomechanical changes following corneal crosslinking in keratoconus patients.

PURPOSE: To evaluate the biomechanical and tomographic outcomes of keratoconus patients up to four years after corneal crosslinking (CXL). METHODS: In this longitudinal retrospective-prospective single-center case series, the preoperative tomographic and biomechanical results from 200 keratoconus eyes of 161 patients undergoing CXL were compared to follow-up examinations at three-months, six-months, one-year, two-years, three-years, and four-years after CXL. Primary outcomes included the Corvis Biomechanical Factor (CBiF) and five biomechanical response parameters obtained from the Corvis ST. Tomographically, the Belin-Ambrósio deviation index (BAD-D) and the maximal keratometry (Kmax) measured by the Pentacam were analyzed. Additionally, Corvis E-staging, the thinnest corneal thickness (TCT), and the best-corrected visual acuity (BCVA) were obtained. Primary outcomes were compared using a paired t-test. RESULTS: The CBiF decreased significantly at the six-month (p < 0.001) and one-year (p < 0.001) follow-ups when compared to preoperative values. E-staging behaved accordingly to the CBiF. Within the two- to four-year follow-ups, the biomechanical outcomes showed no significant differences when compared to preoperative. Tomographically, the BAD-D increased significantly during the first year after CXL with a maximum at six-months (p < 0.001), while Kmax decreased significantly (p < 0.001) and continuously up to four years after CXL. The TCT was lower at all postoperative follow-up visits compared to preoperative, and the BCVA improved. CONCLUSION: In the first year after CXL, there was a temporary progression in both the biomechanical CBiF and E-staging, as well as in the tomographic analysis. CXL contributes to the stabilization of both the tomographic and biomechanical properties of the cornea up to four years postoperatively.

Comparison of different corneal imaging modalities using artificial intelligence for diagnosis of keratoconus: a systematic review and meta-analysis.

PURPOSE: This review was designed to compare different corneal imaging modalities using artificial intelligence (AI) for the diagnosis of keratoconus (KCN), subclinical KCN (SKCN), and forme fruste KCN (FFKCN). METHODS: A comprehensive systematic search was conducted in scientific databases, including Web of Science, PubMed, Scopus, and Google Scholar based on the PRISMA statement. Two independent reviewers assessed all potential publications on AI and KCN up to March 2022. The Critical Appraisal Skills Program (CASP) 11-item checklist was used to evaluate the validity of the studies. Eligible articles were categorized into three groups (KCN, SKCN, and FFKCN) and included in the meta-analysis. The pooled estimate of accuracy (PEA) was calculated for all selected articles. RESULTS: The initial search yielded 575 relevant publications, of which 36 met the CASP quality criteria and were included in the analysis. Qualitative assessment showed that Scheimpflug and Placido combined with biomechanical and wavefront evaluations improved KCN detection (PEA, 99.2, and 99.0, respectively). The Scheimpflug system (92.25 PEA, 95% CI, 94.76-97.51) and a combination of Scheimpflug and Placido (96.44 PEA, 95% CI, 93.13-98.19) had the highest diagnostic accuracy for the detection of SKCN and FFKCN, respectively. The meta-analysis outcomes showed no significant difference between the CASP score and accuracy of the publications (all P > 0.05). CONCLUSIONS: Simultaneous Scheimpflug and Placido corneal imaging methods provide high diagnostic accuracy for early detection of keratoconus. The use of AI models improves the discrimination of keratoconic eyes from normal corneas.