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Purpose To study sub-basal corneal nerve alterations in patients with acute Acanthamoeba keratitis (AK) and fungal keratitis (FK), using laser in vivo confocal microscopy (IVCM). Methods A retrospective analysis of IVCM (Heidelberg Retina Tomograph 3/Rostock Cornea Module) images of 10 AK corneas and 4 FK corneas was performed, and the results compared with those of 10 normal and 12 acute herpetic keratitis (HK) corneas. Sub-basal corneal nerves were analyzed with respect to total number of nerves, main nerve trunks, branching pattern and total length of nerves per image, as well as tortuosity. For each variable, results for three frames were averaged and analyzed using analysis of variance. Results Total corneal nerve length was significantly ( P <0.0001) reduced in patients with AK (193.4±124.5  μ m) and FK (268.6±257.4  μ m) when compared with normal controls (3811.84±911.4  μ m). Total nerve counts in patients with AK (3.9±1.2) and FK (3.6±3.2) were significantly ( P <0.0001) decreased in comparison with normal controls (24.7±5.5). The number of main nerve trunks and nerve branching was found to be significantly lower in AK and FK corneas, when compared with controls. There was a statistically significant decrease in the above parameters when compared with HK controls. Conclusions The sub-basal corneal nerve plexus is significantly diminished in eyes with AK and FK, as demonstrated by IVCM. These results are more profound than previously reported findings of a diminished nerve plexus in HK.

PURPOSE: To evaluate the visualization and depth of the demarcation line with anterior segment optical coherence tomography (AS-OCT) after iontophoresis-assisted transepithelial corneal collagen cross-linking (CXL). METHODS: This prospective, consecutive, single center, non-randomized clinical study involved 15 eyes of 12 patients with keratoconus who underwent an AS-OCT scan (Spectralis; Heidelberg Engineering, Inc., Carlsbad, CA) to search for a demarcation line and its depth at 1 month after iontophoresis-assisted transepithelial CXL. AS-OCT scan measurements were performed by two independent examiners. RESULTS: No intraoperative or postoperative complications were observed. Kappa coefficient estimation for operator agreement in demarcation line visualization (whether it was visualized) was 70.6%. The corneal stromal demarcation line was identified in 9 eyes (60%) by both examiners. Mean depth of the corneal stromal demarcation line was 246.67 ± 50.72 No intraoperative or postoperative complications were observed. Kappa coefficient estimation for operator agreement in demarcation line visualization (whether it was visualized) was 70.6%. The corneal stromal demarcation line was identified in 9 eyes (60%) by both examiners. Mean depth of the corneal stromal demarcation line was 246.67 ± 50.72 µ m (range: 183 to 339 µ m) for the first examiner and 241.89 ± 62.52 µ m (range: 163 to 358 µ m) for the second examiner. There were no statistically significant differences for the measurements of the paired comparisons between the two examiners ( P = .61). The Pearson correlation coefficient between the measurements was 0.910. CONCLUSIONS: Iontophoresis-assisted transepithelial CXL creates a demarcation line that can be visualized with AS-OCT, which seems less easily distinguishable and shallower than in conventional CXL. However, its depth and visualization seems to be more similar to conventional CXL than transepithelial CXL. [[ J Refract Surg . 2015;31(1):36–40.]

Sodium hyaluronate (SH) is used in patients with dry eye. We evaluated the efficacy and safety of SH and carboxymethylcellulose (CMC) in the treatment of dry eye syndrome with superficial keratitis. A total of 22 patients with moderate dry eye and superficial keratitis were enrolled in a prospective, randomised, masked-observer, parallel-group, single-centre study. Patients were randomly assigned to a 0.18% SH or 1% CMC solution for a 2-month period. In addition to the commonly assessed parameters in patients with dry eye (among others symptoms and corneal staining with fluorescein), flow cytometry analysis of CD44, HLA DR expressions in impression cytology was investigated as a potential efficacy parameter. Both treatments improved the symptoms and ocular surface and were well tolerated. SH significantly (p<0.05) decreased CD44 values compared with CMC. Comfort was significantly (P<0.05) better in the SH group than that in the CMC group throughout the study. Recovery in keratitis (type, extent and depth) and symptoms were faster in the SH group than in the CMC group. Blurred vision was reported by patients in the CMC group only. SH was well tolerated and tended to show a faster efficacy than did the CMC-based formulation in patients with moderate dry eye and superficial keratitis. SH could therefore advantageously be prescribed from the early stages of dry eye disease. This study also showed that flow cytometry in impression cytology specimens is a reliable tool for exploring the ocular surface at the epithelial level and that CD44, in addition to HLA DR, could be an interesting endpoint for future trials in dry eye syndrome with products based on SH.

This report describes the case of a 28-year-old woman, who presented with a two-week history of severe ocular pain and photophobia in her right eye. She was a soft contact lens wearer with no history of ocular trauma or systemic illness. Ophthalmic examination revealed conjunctival hyperemia, epithelial irregularities, and a developing ring-shaped stromal infiltrate. In vivo confocal microscopy demonstrated double-walled hyperreflective cysts, and culture followed by PCR and sequencing confirmed the presence of Acanthamoeba T4 genotype. Despite intensive treatment with topical polyhexamethylene biguanide, chlorhexidine, propamidine, and voriconazole, as well as oral miltefosine, the infection progressed, leading to stromal necrosis. The patient underwent two therapeutic penetrating keratoplasties; however, the disease continued to advance, eventually resulting in phthisis bulbi and permanent vision loss. This case highlights the potential for aggressive, clinically refractory Acanthamoeba keratitis caused by the T4 genotype, emphasizing the importance of early diagnosis, vigilant monitoring, and timely surgical intervention in resistant cases.

Infectious keratitis refers to a group of corneal disorders in which corneal tissues suffer inflammation and damage caused by pathogenic infections. Among these disorders, fungal keratitis (FK) and acanthamoeba keratitis (AK) are particularly severe and can cause permanent blindness if not diagnosed early and accurately. In Vivo Confocal Microscopy (IVCM) allows for imaging of different corneal layers and provides an important tool for an early and accurate diagnosis. In this paper, we introduce the IVCM-Keratitis dataset, which comprises of a total of 4001 sample images of AK and FK, as well as non-specific keratitis (NSK) and healthy corneas classes. We use this dataset to develop multiple deep-learning models based on Convolutional Neural Networks (CNNs) to provide automated assistance in enhancing the diagnostic accuracy of confocal microscopy in infectious keratitis. Densenet161 had the best performance among these models, with an accuracy, precision, recall, and F1 score of 93.55%, 92.52%, 94.77%, and 96.93%, respectively. Our study highlights the potential of deep learning models to provide automated diagnostic assistance for infectious keratitis via confocal microscopy images, particularly in the early detection of AK and FK. The proposed model can provide valuable support to both experienced and inexperienced eye-care practitioners in confocal microscopy image analysis, by suggesting the most likely diagnosis. We further demonstrate that these models can highlight the areas of infection in the IVCM images and explain the reasons behind their diagnosis by utilizing saliency maps, a technique used in eXplainable Artificial Intelligence (XAI) to interpret these models.

Chronic inflammation is associated with a variety of pathological conditions in epithelial tissues, including cancer, metaplasia and aberrant wound healing. In relation to this, a significant body of evidence suggests that aberration of epithelial stem and progenitor cell function is a contributing factor in inflammation-related disease, although the underlying cellular and molecular mechanisms remain to be fully elucidated. In this study, we have delineated the effect of chronic inflammation on epithelial stem/progenitor cells using the corneal epithelium as a model tissue. Using a combination of mouse genetics, pharmacological approaches and in vitro assays, we demonstrate that chronic inflammation elicits aberrant mechanotransduction in the regenerating corneal epithelium. As a consequence, a YAP–TAZ/β-catenin cascade is triggered, resulting in the induction of epidermal differentiation on the ocular surface. Collectively, the results of this study demonstrate that chronic inflammation and mechanotransduction are linked and act to elicit pathological responses in regenerating epithelia. Nowell et al.  report that chronic inflammation of the corneal epithelium activates β-catenin signalling through YAP/TAZ-dependent mechanotransduction, leading to epidermal differentiation on the ocular surface and corneal squamous cell metaplasia.

Fungal keratitis caused by Candida albicans (CA) is a common, disabling eye disease with a complex immune response system, affecting diagnosis, treatment, and prognosis. The specific regulatory roles and interactions of IL-36γ and pigment epithelium-derived factor (PEDF) in this disease remain largely unclarified. Additionally, the influence of miR-204-5p on the expression and anti-inflammatory functions of IL-36γ and PEDF in CA keratitis is insufficiently explored. Therefore, research focused on understanding the disease’s pathogenesis and immune regulation. Human corneal epithelial cells treated with heat-killed CA showed anti-inflammatory responses from IL36γ and PEDF, confirmed via western blot, PCR, and ELISA. Transfection of small interfering RNA and recombinant protein granules showed PEDF exerts immunoprotected regulatory mechanisms by inhibiting NF-κB via PPARγ. Analysis of multiple miRNA target gene prediction databases and literature revealed that miR-204-5p is differentially expressed in fungal keratitis. PCR and dual luciferase reporter assays confirmed that miR-204-5p directly binds to PEDF mRNA, negatively regulating IL36γ and PEDF expression. Consequently, both PEDF and IL-36 γ exhibit anti-inflammatory effects in CA keratitis. PEDF may inhibit the NF-κB signaling pathway through the PPAR γ pathway. In addition, miR-204-5p inhibits the mRNA expression of IL-36 γ and PEDF, exacerbating inflammation. This provides a theoretical basis for new methods and drug targets for the prevention and treatment of CA keratitis, and promotes the clinical application of IL-36 γ/PEDF.

In vivo confocal microscopy (IVCM) offers a non-invasive, rapid method for diagnosing Acanthamoeba keratitis (AK) by detecting cysts or trophozoites in the initial clinic visit images. In this retrospective observational study, we reviewed HRT3 IVCM images from patients presenting to Manchester Royal Eye Hospital with clinically- suspected AK for IVCM morphological features (IVCM-MF) of both Acanthamoeba and corneal cells. Twenty-seven patients were included in the study: median age 29 years (range 16–71 years), female gender (59%; n = 16/27) and contact lens wear as the main risk factor. Median symptom duration before the initial ophthalmologist visit was 9 days (range 2 to 42 days). IVCM had a higher detection rate for AK in 85% of patients (n = 23/27), with culture positivity in only 74% (n = 20/27; 17 of whom were also IVCM-positive). Acanthamoeba IVCM-MF included: bright spots (87%, n = 20/23), double-walled cysts (56%, n = 13/23), signet-ring (22%, n = 5/23) and trophozoites (30%, n = 7/23). Bright spots and double-walled cysts coalesced in lines/clusters in 1 patient. Corneal epithelial cells had a “koilocyte” appearance in 64% (n = 14/22). Microtubules connecting adjacent keratocytes were visible in 52% (n = 12/23), particularly associated with A. polyphaga ulcers (p = 0.02). These IVCM features observed in corneal epithelial cells and keratocytes may represent potential imaging biomarkers for AK diagnosis and warrant further investigation to validate their diagnostic utility. By demonstrating IVCM’s superior diagnostic performance, providing rapid and accurate diagnostics, this study advocates for its inclusion in standard diagnostic workflows for AK, paving the way for future advancements in clinical practice.

Infectious keratitis is a life-hindering disease that has been one of the leading causes of blindness worldwide. The current study aimed to test a combination of levofloxacin and ibuprofen for treating Staphylococcus aureus-associated keratitis, with special emphasis on the potential antimicrobial and antibiofilm activities of the non-steroidal anti-inflammatory drug (NSAID) moiety. keratitis was induced in male Sprague Dawley rats by abrasion in the right eye after topical anesthesia, then the wounded eyes were inoculated with a 10 µl aliquot containing Staphylococcus aureus . Rats were divided into five groups: control, infected keratitis rats, infected keratitis rats treated with 0.5% levofloxacin, infected keratitis rats treated with 0.3% ibuprofen, and infected keratitis rats treated with 0.5% levofloxacin + 0.3% ibuprofen. Treatments were given as eye drops for two weeks. Then, the corneal tissues were isolated for investigations. The molecular study showed that, among the four groups, rats treated with combined eye therapy of 0.5% levofloxacin + 0.3% ibuprofen had the lowest expression levels of inflammatory mediators, metalloproteinases, corneal angiogenesis, and the proapoptotic BCL2-associated X (Bax). Histological investigation confirmed the transcriptional changes, with the rats that received combined eye therapy showing the best therapeutic outcomes.

A highly contagious infection caused by human adenovirus species D (HAdV-D), epidemic keratoconjunctivitis (EKC) results in corneal subepithelial infiltration (SEI) by leukocytes, the hallmark of the infection. To date, the pathogenesis of corneal SEI formation in EKC is unresolved. HMGB1 (high-mobility group box 1 protein) is an alarmin expressed in response to infection and a marker of sepsis. Earlier studies using a different adenovirus species, HAdV-C, showed retention of HMGB1 in the infected cell nucleus by adenovirus protein VII, enabling immune evasion. Here, using HAdV-D we show cell-specific HMGB1 secretion by infected cells, and provide an HAdV-D specific mechanism for SEI formation in EKC. HMGB1 was secreted only upon infection of human corneal epithelial cells, not from other cell types, and only upon infection by HAdV-D types associated with EKC. Acetylated HMGB1 translocation from the nucleus to the cytoplasm, then to the extracellular milieu, was tightly controlled by CRM1 and LAMP1, respectively. Primary stromal cells when stimulated by rHMGB1 expressed proinflammatory chemokines. In a novel 3D culture system in tune with the architecture of the cornea, HMGB1 released by infected corneal epithelial cells induced leukocytic infiltrates either directly and/or indirectly via stimulated stromal cells, which together explains SEI formation in EKC.