Perspectives on the incidence of Acanthamoeba Keratitis: A Systematic Review and Meta-Analysis.

TOPIC: To provide an overview on the incidence of Acanthamoeba Keratitis (AK). CLINICAL RELEVANCE: Although being a major and sight-threatening cause of infectious keratitis in the population, a comprehensive assessment of the incidence of this condition is lacking. METHODS: Incidence of AK was computed as the number of AK eyes, per healthcare center, per year (annualized-center-incidence, or ACI). Two meta-analytical ratios were also calculated: a) the ratio of AK eyes to the count of non-viral microbial keratitis (MK) eyes; b) the ratio of AK eyes to the overall population (i.e., the total number of subjects of a nation or region, as indicated by the authors in each study). Center was defined as the healthcare facility (e.g., Hospital, Private Practice, Clinic) where the study took place. Actual and projected estimates of the number of AK eyes in years were calculated multiplying the ratio of AK to the total population and the corresponding present and projected population estimates (age range: 15 to 70), sourced from the United Nations (UN) Population Prospects. RESULTS: Overall, 105 articles were included, published between 1987 and 2022. The total number of eyes identified was 91,951, with 5,660 affected by AK and 86,291 by non-viral MK. The median ACI was 1.9 new AK eyes per healthcare center per year (95%CI of the median: 1.5 to 2.6), with no statistically significant differences observed among continents. The ratio of AK eyes to the total number of MK eyes was 1.52% (95%CI: 1.02% to 2.24%), while the ratio of AK in relation to the entire population was estimated at 0.0002% (95%CI: 0.0001 to 0.0006), or 2.34 eyes per 1,000,000 subjects (95%CI: 0.98 to 5.55 per 1.000.000 subjects). The projected increase in the numbers of AK eyes indicates a rise of +18.5% (15,356 AK eyes) in 2053 and +25.5% (16,253 AK eyes) in 2073, compared to the baseline of 2023 (12,954 AK eyes) CONCLUSION: AK emerged as a relatively low-incident disorder, and no significant differences in terms of its incidence were found among different continents.

Enhancing Rose Bengal penetration in ex vivo human corneas using iontophoresis.

Aim: Rose Bengal photodynamic antimicrobial therapy (RB-PDAT) has poor corneal penetration, limiting its efficacy against acanthamoeba keratitis (AK). Iontophoresis enhances corneal permeation of charged molecules, piquing interest in its effects on RB in ex vivo human corneas. Methods: Five donor whole globes each underwent iontophoresis with RB, soaking in RB, or were soaked in normal saline (controls). RB penetration and corneal thickness was assessed using confocal microscopy. Results: Iontophoresis increased RB penetration compared with soaking (177 ± 9.5 µm vs. 100 ± 5.7 µm, p < 0.001), with no significant differences in corneal thickness between groups (460 ± 87 µm vs. 407 ± 69 µm, p = 0.432). Conclusion: Iontophoresis significantly improves RB penetration and its use in PDAT could offer a novel therapy for acanthamoeba keratitis. Further studies are needed to validate clinical efficacy.

The study aimed to improve a new treatment for eye infections known as photodynamic antimicrobial therapy. It investigated whether the use of electricity through a technique called iontophoresis could help a chemical called Rose Bengal go deeper into the eye in order to target more severe infections. The iontophoresis machine was custom built, with patient-contacting components 3D printed. The experiments were performed using donated human eye tissue and found that iontophoresis significantly improved the penetration depth of Rose Bengal as compared with the current technique of only soaking the eye in Rose Bengal.

Design and Biocompatibility of a Novel, Flexible Artificial Cornea.

Purpose: We sought to introduce the materials, design, and biocompatibility of a flexible and suturable artificial corneal device. Methods: Single-piece, fully synthetic, optic-skirt design devices were made from compact perfluoroalkoxy alkane. The skirt and the optic wall surfaces were lined with a porous tissue ingrowth material using expanded polytetrafluoroethylene. Full-thickness macroapertures around the skirt perimeter were placed to facilitate nutrition of the recipient cornea. Material properties including the skirt's modulus of elasticity and bending stiffness, optic light transmission, wetting behavior, topical drug penetrance, and degradation profile were evaluated. Results: The final prototype suitable for human use has a transparent optic with a diameter of 4.60 mm anteriorly, 4.28 mm posteriorly, and a skirt outer diameter of 6.8 mm. The biomechanical and optical properties of the device closely align with the native human cornea with an average normalized device skirt-bending stiffness of 4.7 kPa·mm4 and light transmission in the visible spectrum ranging between 92% and 96%. No optical damage was seen in the 36 devices tested in fouling experiments. No significant difference was observed in topical drug penetrance into the anterior chamber of the device implanted eye compared with the naïve rabbit eye. Conclusions: The flexibility and biocompatibility of our artificial cornea device may offer enhanced tissue integration and decreased inflammation, leading to improved retention compared with rigid keratoprosthesis designs. Translational Relevance: We have developed a fully synthetic, flexible, suturable, optic-skirt design prototype artificial cornea that is ready to be tested in early human feasibility studies.

Creating realistic anterior segment optical coherence tomography images using generative adversarial networks.

AIMS: To develop a generative adversarial network (GAN) capable of generating realistic high-resolution anterior segment optical coherence tomography (AS-OCT) images. METHODS: This study included 142 628 AS-OCT B-scans from the American University of Beirut Medical Center. The Style and WAvelet based GAN architecture was trained to generate realistic AS-OCT images and was evaluated through the Fréchet Inception Distance (FID) Score and a blinded assessment by three refractive surgeons who were asked to distinguish between real and generated images. To assess the suitability of the generated images for machine learning tasks, a convolutional neural network (CNN) was trained using a dataset of real and generated images over a classification task. The generated AS-OCT images were then upsampled using an enhanced super-resolution GAN (ESRGAN) to achieve high resolution. RESULTS: The generated images exhibited visual and quantitative similarity to real AS-OCT images. Quantitative similarity assessed using FID scored an average of 6.32. Surgeons scored 51.7% in identifying real versus generated images which was not significantly better than chance (p value >0.3). The CNN accuracy improved from 78% to 100% when synthetic images were added to the dataset. The ESRGAN upsampled images were objectively more realistic and accurate compared with traditional upsampling techniques by scoring a lower Learned Perceptual Image Patch Similarity of 0.0905 compared with 0.4244 of bicubic interpolation. CONCLUSIONS: This study successfully developed and leveraged GANs capable of generating high-definition synthetic AS-OCT images that are realistic and suitable for machine learning and image analysis tasks.

Clinical Features and Treatment Outcomes of Carbapenem-Resistant Pseudomonas aeruginosa Keratitis.

Importance: Evaluation of the microbiological diagnostic profile of multidrug-resistant Pseudomonas aeruginosa keratitis and potential management with rose bengal-photodynamic antimicrobial therapy (RB-PDAT) is important. Objective: To document the disease progression of carbapenemase-resistant P aeruginosa keratitis after an artificial tear contamination outbreak. Design, Setting, and Participants: This retrospective observation case series included 9 patients 40 years or older who presented at Bascom Palmer Eye Institute and had positive test results for multidrug-resistant P aeruginosa keratitis between January 1, 2022, and October 31, 2023. Main Outcomes and Measures: Evaluation of type III secretion phenotype, carbapenemase-resistance genes blaGES and blaVIM susceptibility to antibiotics, and in vitro and in vivo outcomes of RB-PDAT against multidrug-resistant P aeruginosa keratitis. Results: Among the 9 patients included in the analysis (5 women and 4 men; mean [SD] age, 73.4 [14.0] years), all samples tested positive for exoU and carbapenemase-resistant blaVIM and blaGES genes. Additionally, isolates were resistant to carbapenems as indicated by minimum inhibitory concentration testing. In vitro efficacy of RB-PDAT indicated its potential application for treating recalcitrant cases. These cases highlight the rapid progression and challenging management of multidrug-resistant P aeruginosa. Two patients were treated with RB-PDAT as an adjuvant to antibiotic therapy and had improved visual outcomes. Conclusions and Relevance: This case series highlights the concerning progression in resistance and virulence of P aeruginosa and emphasizes the need to explore alternative therapies like RB-PDAT that have broad coverage and no known antibiotic resistance. The findings support further investigation into the potential effects of RB-PDAT for other multidrug-resistant microbes.

Variations in irradiation energy and rose bengal concentration for photodynamic antimicrobial therapy of fungal keratitis isolates.

The purpose is to assess the efficacy of rose bengal photodynamic antimicrobial therapy (PDAT) using different irradiation energy levels and photosensitizer concentrations for the inhibition of fungal keratitis isolates. Seven different fungi (Aspergillus fumigatus, Candida albicans, Curvularia lunata, Fusarium keratoplasticum, Fusarium solani, Paecilomyces variotii, and Pseudallescheria boydii) were isolated from patients with confirmed infectious keratitis. Experiments were performed in triplicate with suspensions of each fungus exposed to different PDAT parameters including a control, green light exposure of 5.4 J/cm2, 2.7 J/cm2 (continuous and pulsed), and 1.8 J/cm2 and rose bengal concentrations of 0.1%, 0.05%, and 0.01%. Plates were photographed 72 h after experimentation, and analysis was performed to assess fungal growth inhibition. PDAT using 5.4 J/cm2 of irradiation and 0.1% rose bengal completely inhibited growth of five of the seven fungal species. Candida albicans and Fusarium keratoplasticum were the most susceptible organisms, with growth inhibited with the lowest fluence and minimum rose bengal concentration. Fusarium solani, Pseudallescheria boydii, and Paecilomyces variotii were inhibited by lower light exposures and photosensitizer concentrations. Aspergillus fumigatus and Curvularia lunata were not inhibited by any PDAT parameters tested. Continuous and pulsed irradiation using 2.7 J/cm2 produced similar results. Rose bengal PDAT successfully inhibits the in vitro growth of five fungi known to cause infectious keratitis. Differences in growth inhibition of the various fungi to multiple PDAT parameters suggest that susceptibilities to PDAT are unique among fungal species. These findings support modifying PDAT parameters based on the infectious etiology.

Automatic Classification of Slit-Lamp Photographs by Imaging Illumination.

PURPOSE: The aim of this study was to facilitate deep learning systems in image annotations for diagnosing keratitis type by developing an automated algorithm to classify slit-lamp photographs (SLPs) based on illumination technique. METHODS: SLPs were collected from patients with corneal ulcer at Kellogg Eye Center, Bascom Palmer Eye Institute, and Aravind Eye Care Systems. Illumination techniques were slit beam, diffuse white light, diffuse blue light with fluorescein, and sclerotic scatter (ScS). Images were manually labeled for illumination and randomly split into training, validation, and testing data sets (70%:15%:15%). Classification algorithms including MobileNetV2, ResNet50, LeNet, AlexNet, multilayer perceptron, and k-nearest neighborhood were trained to distinguish 4 type of illumination techniques. The algorithm performances on the test data set were evaluated with 95% confidence intervals (CIs) for accuracy, F1 score, and area under the receiver operator characteristics curve (AUC-ROC), overall and by class (one-vs-rest). RESULTS: A total of 12,132 images from 409 patients were analyzed, including 41.8% (n = 5069) slit-beam photographs, 21.2% (2571) diffuse white light, 19.5% (2364) diffuse blue light, and 17.5% (2128) ScS. MobileNetV2 achieved the highest overall F1 score of 97.95% (CI, 97.94%-97.97%), AUC-ROC of 99.83% (99.72%-99.9%), and accuracy of 98.98% (98.97%-98.98%). The F1 scores for slit beam, diffuse white light, diffuse blue light, and ScS were 97.82% (97.80%-97.84%), 96.62% (96.58%-96.66%), 99.88% (99.87%-99.89%), and 97.59% (97.55%-97.62%), respectively. Slit beam and ScS were the 2 most frequently misclassified illumination. CONCLUSIONS: MobileNetV2 accurately labeled illumination of SLPs using a large data set of corneal images. Effective, automatic classification of SLPs is key to integrating deep learning systems for clinical decision support into practice workflows.

Infectious and Noninfectious Corneal Ulcers in Ocular Graft-Versus-Host Disease: Epidemiology, Clinical Characteristics, and Outcomes.

PURPOSE: To evaluate the incidence, clinical characteristics, microbiological profile, and therapeutic outcomes of corneal ulcers in individuals with chronic ocular graft-vs-host disease (coGVHD). DESIGN: Retrospective clinical cohort study. METHODS: Review of individuals diagnosed with coGVHD following hematopoietic stem cell transplantation (HSCT) who were seen at the Bascom Palmer Eye Institute between May 2010 and November 2021. Baseline demographics, clinical characteristics, microbiological profile, risk factors for corneal ulceration, and treatment outcomes were collected. Etiology was deemed infectious in individuals with a positive culture or appropriate clinical scenario (presence of stromal infiltrate or hypopyon); otherwise, ulcers were presumed to be noninfectious. Treatment success was defined as reepithelialization with infiltrate resolution, and treatment failure as progression to corneal perforation or keratoplasty. Kaplan-Meier survival analysis estimated the incidence of ulceration. Cox regression analyses examined demographic and risk factors. Infectious and noninfectious ulcer groups were compared using 2-way independent t tests, 1-way analysis of variances, and χ2 tests, as appropriate. RESULTS: 173 individuals were included (53.7±14.4 years old; 59.0% male). Thirty-three individuals developed an ulcer 74.5±54.3 months after HSCT, with estimated 5- and 10-year incidences of 14% and 30%, respectively. Twenty-two (66.6%) ulcers were deemed infectious (15 microbiologically confirmed, 7 clinically) and 11 (33.3%) were deemed noninfectious. Risk factors for corneal ulceration included Black race (hazards ratio [HR] 2.89, 95% CI 1.30-6.42, P < .01), previous ocular surgery (HR 9.16, 95% CI 3.86-21.72, P < .01), eyelid margin abnormalities (HR 3.44, 95% CI 1.69-6.99, P < .01), and topical steroid use (HR 2.74, 95% CI 1.33-5.62, P < .01). Conversely, contact lens use reduced the risk of corneal ulceration (HR 0.29, 95% CI 0.13-0.66, P < .01). Infectious ulcers had a significantly higher frequency of treatment failure than noninfectious ulcers (57.1% vs 20.0%, P = .04). CONCLUSION: Corneal ulceration is a potential complication of coGVHD, with several clinical features identified as risk factors. Infectious ulcers had worse outcomes than noninfectious ulcers.

A patient with concurrent Axenfeld-Rieger and Stickler syndromes verified by molecular genetics.

Purpose: To report a case of Axenfeld-Rieger and Stickler Syndrome in a pediatric patient. Observations: A 3-month-old male was referred to the glaucoma clinic after he was noted to have elevated intraocular pressures in both eyes. His family history was notable for infantile glaucoma on his maternal side and retinal detachment on his paternal side. He was found to have anterior segment dysgenesis with iris strands, iridocorneal adhesions, and corectopia, as well as veil-like vitreous in both eyes. He required trabeculotomy, goniotomy, and multiple Baerveldt glaucoma implants in both eyes to achieve intraocular pressure control. Furthermore, the patient later developed macula-involving retinal detachments in both eyes, requiring pars plana vitrectomy with silicone oil tamponade. Genetic analysis confirmed heterozygous pathogenic variants in both the FOXC1 and COL2A1 genes, leading to the concurrent diagnoses of Axenfeld-Rieger and Stickler syndromes. Conclusions and importance: This is a rare case of a patient with concurrent Axenfeld-Rieger and Stickler syndromes. The severity of pathology in both the anterior and posterior segments required a collaborative multidisciplinary approach. In the diagnostic evaluation of congenital eye diseases, if there is strong family history of atypical findings for a given diagnosis, concurrent syndromes should be considered and ruled out. A comprehensive eye genetics panel may be a useful tool in these cases.

Twelve-Month Clinical and Histopathological Performance of a Novel Synthetic Cornea Device in Rabbit Model.

Purpose: To report the biological stability and postoperative outcomes of a second-generation, single-piece, flexible synthetic cornea in a rabbit model. Methods: Device materials and design were amended to enhance biointegration. Optic skirt design devices were made from compact perfluoroalkoxy alkane with porous expanded polytetrafluoroethylene ingrowth surface overlying the skirt and optic wall. Sixteen devices were implanted into intrastromal pocket in rabbit eyes. Rabbits were randomly assigned to 6- and 12-month follow-up cohorts (n = 8 in each) postoperatively. Monthly examinations and optical coherence tomography assessed cornea-device integration, iridocorneal angle, optic nerve, and retina. Results: There were no intraoperative complications. All devices were in situ at exit, with clear optics. No retroprosthetic membrane, glaucoma, cataract formation, or retinal detachment was observed. Two rabbits in the 6-month group had mild, focal anterior lamella thinning without retraction adjacent to the optic near tight sutures. Three postoperative complications occurred in the 12-month group. One rabbit diagnosed with endophthalmitis was euthanized on day 228. Mild sterile focal retraction of anterior lamella occurred in two rabbits, which were terminated on days 225 and 315. Light microscopic examination of enucleated globes demonstrated fibroplasia with new collagen deposition into the porous scaffold without significant inflammation, encapsulation, or granuloma formation. Conclusions: Clinical evaluations, imaging, and histopathological findings indicate favorable outcomes of this synthetic corneal device in a rabbit model. Early feasibility studies in humans are being planned. Translational Relevance: Favorable 12-month results of the device in rabbits demonstrate vision-restoring potential in corneally blind individuals at high risk of failure with donor keratoplasty.

Efficacy of Plasma Rich in Growth Factors (PRGF) in Stage 1 Neurotrophic Keratitis.

Background/Aims: Neurotrophic keratitis (NK) is a neurodegenerative disease that can lead to corneal hypoesthesia, decreased tear production, and epitheliopathy. Based on the severity of ocular surface damage, NK is classified into 3 stages. Stage 1 NK is characterized by superficial punctate keratopathy, tear film instability, and reduced corneal sensation. The therapeutic efficacy of PRGF eye drops for NK stages 2 and 3 has been previously reported. In this study, we evaluated the efficacy and safety of autologous PRGF eye drops in improving corneal sensitivity and other ocular surface clinical signs in patients with stage 1 NK. Methods: Retrospective chart review. Results: 26 eyes of 15 stage 1 NK patients (seven males, eight females), aged 76.3 ± 12.1 years, were included in the study. The mean treatment duration was 2 ± 1.8 months. With PRGF treatment, corneal sensitivity increased from 2.8 to 4.5 cm in 53.8% (14/26) (p < 0.01), TBUT increased from 3.6 to 5.0 s in 69.2% (18/26) (p < 0.01), and Schirmer score increased from 13.7 to 16.8 mm in 80.7% (21/26) of treated eyes (p < 0.01). Similarly, an improvement in corneal staining (punctate epithelial erosions) and MMP-9 levels was seen in 80.7% (n = 21) and 65.4% (n = 17) of treated eyes, respectively. BCVA improvement was seen in 26.9% of treated eyes (n = 7). Conclusions: This study demonstrates the effective role of PRGF therapy in recovering corneal sensation and tear film function and in the healing of corneal erosions in stage 1 NK patients.