Mimickers of anterior uveitis, scleritis and misdiagnoses- tips and tricks for the cornea specialist.

BACKGROUND: Anterior uveitis, inflammation of the anterior chamber and related structures, is a cohort of diseases that can present to almost any general or sub-specialty Ophthalmology practice. Its features classically involve anterior chamber cell and flare. Below the surface of these two signs exist a panoply of diagnoses. BODY: The purpose of this review is to provide a general framework for diagnoses of anterior uveitis that are often missed as well as non-uveitic pathologies that often mimic anterior uveitis. Diagnostic deviation in either direction can have vision-threatening and rarely life-threatening consequences for patients. Using a comprehensive literature review we have collected a broad spectrum of etiologies of anterior uveitis that are easily missed and non-uveitic pathologies that can masquerade as anterior uveitis. CONCLUSIONS: We present a focused review on specific misdiagnosed anterior uveitis pathologies and some of the conditions that can masquerade as anterior uveitis and scleritis.

Demographic Characteristics, Clinical Presentations, and Risk Factors Impacting Visual Outcomes in Peripheral Ulcerative Keratitis.

PURPOSE: To assess the demographic characteristics, ophthalmic and systemic presentations, and risk factors impacting the outcomes in patients diagnosed with peripheral ulcerative keratitis (PUK). METHODS: This retrospective study includes patients diagnosed with PUK at a tertiary care center over 13 years. A descriptive analysis of the demographics, clinical history, and presentation was performed. A reverse risk analysis was performed to assess the PUK resolution in patients with underlying autoimmune and non-autoimmune etiologies. Finally, we evaluated the correlation between treatment duration and final best corrected visual acuity (BCVA) and continuous and categorical variables. RESULTS: A total of 58 eyes of 51 patients with a mean age of 59.67 ± 13.41 years diagnosed with PUK were included in the study; 58.82% were female. The resolution duration was significantly shorter in patients with autoimmune etiologies (vs. non-autoimmune etiologies, P = 0.028) and female patients (vs. male patients, P = 0.008). The BCVA worsened in patients with non-autoimmune etiologies after treatment (P = 0.17). Despite worse BCVA at presentation in patients with underlying autoimmune etiologies, significantly better final vision outcomes were observed (P = 0.04). Linear regression analysis showed that longer treatment duration (P = 0.001; R2 = 0.1704) and worse vision (P = 0.002; R2 = 0.1502) at presentation were the primary risk factors of poor vision outcomes. Similarly, the treatment duration was significantly longer in male compared with female patients (P < 0.001; R2 = 0.2027). CONCLUSIONS: The clinical outcomes in PUK with underlying autoimmune disorders were observed to be better than non-autoimmune etiologies, which may be attributed to the early detection of the PUK-related changes and aggressive medical management. A delayed diagnosis of PUK leads to poor vision outcomes.

Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions.

PURPOSE: The aim of this study was to investigate the association between cytosine-thymine-guanine trinucleotide repeat (TNR) expansion in TCF4 and the clinical phenotypes of corneal densitometry or anterior segment morphology in Fuchs endothelial corneal dystrophy. METHODS: This retrospective cross-sectional study included 150 eyes from 75 Japanese consecutive patients with Fuchs endothelial corneal dystrophy. Cytosine-thymine-guanine repeat expansion of leukocyte-derived genomic DNA was analyzed through fragment analysis using polymerase chain reaction and triplet repeat primed polymerase chain reaction. Scheimpflug-based densitometry and anterior segment optical coherence tomography were applied. Corneal densitometry, and corneal and anterior segment morphology parameters were compared between patients with and without TNR expansion of 50 or more (expansion and nonexpansion groups, respectively) using a mixed model. RESULTS: The average age of the patients was 66.8 ± 13.0 years, and the modified Krachmer grading scale was 1, 2, 3, 4, 5, and 6 for 7, 32, 28, 51, 6, and 18 eyes, respectively. Sixteen patients (21%) exhibited ≥50 TNR expansion. No significant differences in sex, age, history of keratoplasty, modified Krachmer grade, and corneal densitometry in either diameter or depth were observed between the 2 groups. No significant differences in anterior segment morphology, including the anterior chamber depth and anterior chamber angle width parameters, were observed using a univariate mixed model, except for central corneal thickness (P = 0.047). However, according to the multivariate mixed model, repeat expansion was not significantly associated with central corneal thickness (P = 0.27). CONCLUSIONS: No significant differences in clinical phenotypes were found between Japanese patients having Fuchs endothelial corneal dystrophy with and without TNR expansion.

Good manufacturing practice production of human corneal limbus-derived stromal stem cells and in vitro quality screening for therapeutic inhibition of corneal scarring.

BACKGROUND: Mesenchymal stem cells in the adult corneal stroma (named corneal stromal stem cells, CSSCs) inhibit corneal inflammation and scarring and restore corneal clarity in pre-clinical corneal injury models. This cell therapy could alleviate the heavy reliance on donor materials for corneal transplantation to treat corneal opacities. Herein, we established Good Manufacturing Practice (GMP) protocols for CSSC isolation, propagation, and cryostorage, and developed in vitro quality control (QC) metric for in vivo anti-scarring potency of CSSCs in treating corneal opacities. METHODS: A total of 24 donor corneal rims with informed consent were used-18 were processed for the GMP optimization of CSSC culture and QC assay development, while CSSCs from the remaining 6 were raised under GMP-optimized conditions and used for QC validation. The cell viability, growth, substrate adhesion, stem cell phenotypes, and differentiation into stromal keratocytes were assayed by monitoring the electric impedance changes using xCELLigence real-time cell analyzer, quantitative PCR, and immunofluorescence. CSSC's conditioned media were tested for the anti-inflammatory activity using an osteoclastogenesis assay with mouse macrophage RAW264.7 cells. In vivo scar inhibitory outcomes were verified using a mouse model of anterior stromal injury caused by mechanical ablation using an Algerbrush burring. RESULTS: By comparatively assessing various GMP-compliant reagents with the corresponding non-GMP research-grade chemicals used in the laboratory-based protocols, we finalized GMP protocols covering donor limbal stromal tissue processing, enzymatic digestion, primary CSSC culture, and cryopreservation. In establishing the in vitro QC metric, two parameters-stemness stability of ABCG2 and nestin and anti-inflammatory ability (rate of inflammation)-were factored into a novel formula to calculate a Scarring Index (SI) for each CSSC batch. Correlating with the in vivo scar inhibitory outcomes, the CSSC batches with SI < 10 had a predicted 50% scar reduction potency, whereas cells with SI > 10 were ineffective to inhibit scarring. CONCLUSIONS: We established a full GMP-compliant protocol for donor CSSC cultivation, which is essential toward clinical-grade cell manufacturing. A novel in vitro QC-in vivo potency correlation was developed to predict the anti-scarring efficacy of donor CSSCs in treating corneal opacities. This method is applicable to other cell-based therapies and pharmacological treatments.

Corneal Biomechanical Properties to Predict Prognosis of Abnormal Tomographic Corneas: A Prospective Cohort Study.

PURPOSE: To analyze the corneal biomechanical properties in patients with abnormal corneal tomography (ACT) and predict their stability using the biomechanical stability index (BSI). DESIGN: Prospective cohort study. METHODS: Setting: Multicenter study. STUDY POPULATION: This study included 385 eyes of 278 patients with stable ACT (n = 70), subclinical keratoconus (SKC, n = 65), keratoconus (n = 65), normal controls (NL, n = 142). Forty-three eyes with first-visit ACT were included in a separate cohort (follow-up ACT group). OBSERVATION PROCEDURE: Tomographical and biomechanical parameters (Pentacam and Corvis ST) were recorded. MAIN OUTCOME MEASURES: Nonparametric tests were used for comparison. Logistic regression was employed to introduce BSI to separate stable ACT and SKC accurately. An independent dataset of 43 first-visit ACT eyes was followed up for 1 year to validate BSI's accuracy and positive and negative predictive values (PPV, NPV). RESULTS: The tomographical and biomechanical parameters in patients with Stable ACT remained stable over the follow-up period (12.73 ± 2.57 months, P > .05). Stable ACT had 12/14 biomechanical parameters different (P < .05) from SKC but not different from NL (P > .05). With a cut-off value of 0.585, BSI demonstrated the strongest ability to distinguish between stable ACT and SKC (area under the receiver operating characteristic curve = 0.991), with 93.85% sensitivity and 97.14% specificity. During the 1-year follow-up of 43 eyes (follow-up ACT group), 30 remained stable. The accuracy, PPV, and NPV of the BSI were 95.35%, 100%, and 93.75%, respectively. CONCLUSIONS: Biomechanical properties of patients with stable abnormal tomography corneas were stronger than SKC and close to normal corneas, which may explain the reason for tomographic stability. The BSI may be useful for predicting disease progression in patients with ACT and the possible management of corneal cross-linking at the first visit.

Prevalence and Economic Burden of Keratoconus in the United States.

PURPOSE: To assess the prevalence and economic burden of keratoconus in the United States. DESIGN: Retrospective cohort study. METHODS: Patients enrolled in Medicaid and Children's Health Insurance Program (CHIP) who were diagnosed with keratoconus between 2016 and 2019 were included. The data reported to the Centers for Disease Control and Prevention (CDC) Vision and Eye Health Surveillance System (VEHSS) were analyzed. The crude prevalence rates (national and statewise) were obtained from the database and extrapolated to estimate the keratoconus case count in the United States. The keratoconus prevalence was compared between male and female individuals using the Mann-Whitney test, whereas Brown-Forsythe 1-way analysis of variance was used to compare prevalence between age and racial groups. The Dunnett T3 multiple comparison test was used for intergroup comparison. Finally, the economic burden of keratoconus was assessed by inflation-adjusted direct costs to patients and total cases in the country. RESULTS: In the cohort of 69,502,000 patients enrolled for Medicaid and CHIP, the national prevalence of keratoconus was computed to be 0.04% in 2019 and had increased from 0.03% in 2016. The highest prevalence of keratoconus was observed in patients 18 to 39 years of age, followed by patients 40 to 64 years of age; comparable prevalence rates were observed in these age groups in the Black population. The prevalence was moderately higher in female compared to male individuals; however, significantly higher keratoconus prevalence was observed in Black female individuals compared to male individuals. A significantly high prevalence of keratoconus was observed in the Black population, followed by Hispanic population. In 2019, the average inflation-adjusted lifetime cost of keratoconus treatment was USD 28,766.69, with a cumulative economic burden of USD 3.8 billion. CONCLUSIONS: In the United States, keratoconus is most prevalent in individuals 18 to 39 years of age. The keratoconus prevalence is higher in the Black population, specifically female individuals, and the diagnosis is often delayed in these patients.

Infectious Keratitis After Keratoplasty in the United States: Analysis of a National Medicare Claims Data Set.

PURPOSE: The aim of this study was to assess the incidence, trends, and risk factors of infectious keratitis (IK) and subsequent repeat keratoplasty after penetrating keratoplasty (PK) and endothelial keratoplasty (EK). METHODS: Using a retrospective cohort study design, IK cases within 6 months of keratoplasty were identified using billing codes among 100% Medicare beneficiaries aged 65 years and older who underwent either PK or EK between 2011 and 2020. Multivariable logistic regression models were used to evaluate factors associated with postkeratoplasty IK. RESULTS: We identified 115,588 keratoplasties, of which 20.0% (n = 23,144) were PK and 80.0% (n = 92,444) were EK. IK developed within 6 months with a rate of 3.32% (n = 769) post-PK and 0.72% (n = 666) post-EK. Overall rates of IK decreased from 16.05 to 9.61 per 1000 keratoplasties between 2011 and 2020 ( P < 0.001). The median interval between keratoplasty and diagnosis of IK was 73 days (interquartile range: 29-114 days) for PK and 74 days (interquartile range: 38-116 days) for EK. After IK, 22.9% (n = 176) and 23.8% (n = 159) eyes underwent repeat keratoplasty within 1 year for PK and EK, respectively. The occurrence of IK after PK was associated with age 85 years and older [odds ratio (OR): 1.38; 95% confidence interval (CI): 1.13-1.68] relative to patients aged 65 to 74 years. The occurrence of IK after EK was also associated with age 85 years and older (OR: 1.44; 95% CI: 1.14-1.82) relative to patients aged 65 to 74 years. CONCLUSIONS: IK was 4 times more common after PK than EK and the complication was associated with older age. Our findings may help corneal surgeons in counseling patients at higher risk and guiding their postoperative care.

Localized Corneal Biomechanical Alteration Detected In Early Keratoconus Based on Corneal Deformation Using Artificial Intelligence.

PURPOSE: This study aimed to develop a novel method to diagnose early keratoconus by detecting localized corneal biomechanical changes based on dynamic deformation videos using machine learning. DESIGN: Diagnostic research study. METHODS: We included 917 corneal videos from the Tianjin Eye Hospital (Tianjin, China) and Shanxi Eye Hospital (Xi'an, China) from February 6, 2015, to August 25, 2022. Scheimpflug technology was used to obtain dynamic deformation videos under forced puffs of air. Fourteen new pixel-level biomechanical parameters were calculated based on a spline curve equation fitting by 115,200-pixel points from the corneal contour extracted from videos to characterize localized biomechanics. An ensemble learning model was developed, external validation was performed, and the diagnostic performance was compared with that of existing clinical diagnostic indices. The performance of the developed machine learning model was evaluated using precision, recall, F1 score, and the area under the receiver operating characteristic curve. RESULTS: The ensemble learning model successfully diagnosed early keratoconus (area under the curve = 0.9997) with 95.73% precision, 95.61% recall, and 95.50% F1 score in the sample set (n=802). External validation on an independent dataset (n=115) achieved 91.38% precision, 92.11% recall, and 91.18% F1 score. Diagnostic accuracy was significantly better than that of existing clinical diagnostic indices (from 86.28% to 93.36%, all P <0.01). CONCLUSIONS: Localized corneal biomechanical changes detected using dynamic deformation videos combined with machine learning algorithms were useful for diagnosing early keratoconus. Focusing on localized biomechanical changes may guide ophthalmologists, aiding the timely diagnosis of early keratoconus and benefiting the patient's vision.

A rise in the frequency of lasR mutant Pseudomonas aeruginosa among keratitis isolates between 1993 and 2021.

Introduction: Pseudomonas aeruginosa causes vision threatening keratitis. The LasR transcription factor regulates virulence factors in response to the quorum sensing molecule N-3-oxo-dodecanoyl-L-homoserine lactone. P. aeruginosa isolates with lasR mutations are characterized by an iridescent high sheen phenotype caused by a build-up of 2-heptyl-4-quinolone. A previous study demonstrated 22% (n=101) of P. aeruginosa keratitis isolates from India between 2010 and 2016 were sheen positive lasR mutants, and the sheen phenotype correlated with worse clinical outcomes for patients. In this study, a longitudinal collection of P. aeruginosa keratitis isolates from Eastern North America were screened for lasR mutations by the sheen phenotype and sequencing of the lasR gene. Methods: Keratitis isolates (n=399) were classified by sheen phenotype. The lasR gene was cloned from a subset of isolates, sequenced, and tested for loss of function or dominant-negative status based on an azocasein protease assay. A retrospective chart review compared outcomes of keratitis patients infected by sheen positive and negative isolates. Results: A significant increase in sheen positive isolates was observed between 1993 and 2021. Extracellular protease activity was reduced among the sheen positive isolates and a defined lasR mutant. Cloned lasR alleles from the sheen positive isolates were loss of function or dominant negative and differed in sequence from previously reported ocular lasR mutant alleles. Retrospective analysis of patient information suggested significantly better visual outcomes for patients infected by sheen positive isolates. Discussion: These results indicate an increase in lasR mutations among keratitis isolates in the United States and suggest that endemic lasR mutants can cause keratitis.

Prevalence and Economic Burden of Fuchs Endothelial Corneal Dystrophy in the Medicare Population in the United States.

PURPOSE: The aim of this study was to assess the prevalence and economic burden of Fuchs endothelial corneal dystrophy (FECD) in patients older than 65 years in the United States. METHODS: A retrospective analysis of the Medicare data reported to the Vision and Eye Health Surveillance System including patients diagnosed with FECD between 2014 and 2019 was performed. The crude prevalence rate of FECD was assessed and extrapolated to estimate the total case burden in the United States. The prevalence data were further compared between men and women and different racial groups. In addition, the economic burden was computed using inflation-adjusted direct costs of treatment to patients. RESULTS: The Medicare database included 25,432,700 patients older than 65 years. The national prevalence of FECD in this population cohort was calculated to be 1.12% in 2019. In 2019, FECD case burden in Medicare patients older than 65 years was 284,846 and total estimated FECD case count in the country in this age group was 591,226. FECD prevalence was significantly higher in women as compared to men during the 6-year period evaluated in this study. The intergroup comparison revealed that FECD prevalence in the White population was significantly higher than all other racial groups (P < 0.0001). The total inflation-adjusted economic burden of FECD in the United States in 2019 was USD 291.648 million and has increased from USD 243.998 million over the 6-year study period. CONCLUSIONS: The estimated prevalence of FECD in the individuals older than 65 years is 1.12% in the United States. FECD prevalence is significantly higher in women and White population compared with other ethnicities.

Rate of fractional change in corneal tomography parameters in keratoconus using a combination of predictive parameters.

BACKGROUND: To compare the rate of fractional change for multiple corneal tomographic factors in progressive keratoconus (KC). METHODS: In this retrospective case series, 40 eyes (40 patients) with progressive KC (increase in central keratometry of 1.00 D or maximum keratometry of 1.50 D on two visits at least six months apart) were included. Cases with previous history of ocular surgery, poor scans, corneal scars, severe dry eyes, post-excimer ectasia, pellucid marginal degeneration were excluded. Medical records, corneal tomography and anterior corneal wavefront (8 mm) (Scheimpflug tomography, Pentacam, Oculus, Germany) were analyzed. Rate of fractional change (Rx = (x1 - x0)/(|x0|tm)); where, x1 = value at follow-up, x0 = value at initial visit and tm = time in months, was measured. RESULTS: The mean age of the patients was 30.0 ± 8.4 years. The mean follow-up duration was 8.9 ± 4.2 months. Coma (0.076 ± 1.4) had the largest rate of fractional change (P = 1.7 × 10-14, Kruskal-Wallis test). The rate of fractional change was higher for aberrometric parameters (anterior corneal higher-order aberrations root mean square and anterior coma) compared to pachymetric and keratometric parameters (P values ranging from 1.4 × 10-4 to 7.4 × 10-10, Mann-Whitney test, effect size ranging from 0.4-0.7). The rate of fractional change was comparable between pachymetric and keratometric factors (P > 0.05 for all comparisons, Mann-Whitney test). CONCLUSIONS: Anterior corneal wavefront, especially anterior coma, were noted to have higher rate of fractional change compared to single point keratometric and pachymetric indices in progressive KC. This information can be used for decision-making when monitoring patients with KC.

Rise in frequency of lasR mutant Pseudomonas aeruginosa among keratitis isolates between 1993 and 2021.

Pseudomonas aeruginosa causes severe vision threatening keratitis. LasR is a transcription factor that regulates virulence associated genes in response to the quorum sensing molecule N-3-oxo-dodecanoyl-L-homoserine lactone. P. aeruginosa isolates with lasR mutations are characterized by an iridescent high sheen phenotype caused by a build-up of 2-heptyl-4-quinolone. A previous study indicated a high proportion (22 out of 101) of P. aeruginosa keratitis isolates from India between 2010 and 2016 were sheen positive and had mutations in the lasR gene, and the sheen phenotype correlated with worse clinical outcomes for patients. In this study, a longitudinal collection of P. aeruginosa keratitis isolates from Eastern North America were screened for lasR mutations by the sheen phenotype and sequencing of the lasR gene. A significant increase in the frequency of isolates with the sheen positive phenotype was observed in isolates between 1993 and 2021. Extracellular protease activity was lower among the sheen positive isolates and a defined lasR mutant. Cloned lasR alleles from the sheen positive isolates were loss of function or dominant negative and differed in sequence from previously reported ocular lasR mutant alleles. Insertion elements were present in a subset of independent isolates and may represent an endemic source from some of the isolates. Retrospective analysis of patient information suggested significantly better visual outcomes for patients with infected by sheen positive isolates. Together, these results indicate an increasing trend towards lasR mutations among keratitis isolates at a tertiary eye care hospital in the United States.