SMAD4-Dependent Signaling Pathway Involves in the Pathogenesis of TGFBR2-Related CE-like Phenotype.

(1) Background: Our previous data indicated that disturbance of the Transforming Growth Factor beta (TGFB) signaling pathway via its Type-2 Receptor (TGFBR2) can cause a Corneal Ectasia (CE)-like phenotype. The purpose of this study is to elucidate whether the SMAD4-dependent signaling pathway is involved in the TGFBR2-related CE-like pathogenesis. (2) Methods: Smad4 was designed to be conditionally knocked out from keratocytes. Novel triple transgenic mice, KerartTA; Tet-O-Cre; Smad4flox/flox (Smad4kera-cko), were administered with doxycycline (Dox). Optical Coherence Tomography (OCT) was performed to examine Central Corneal Thickness (CCT), Corneal Radius, Anterior Chamber and CE-like phenotype and compared to the littermate Control group (Smad4Ctrl). (3) Results: The OCT revealed normal cornea in the Smad4Ctrl and a CE-like phenotype in the Smad4kera-cko cornea, in which the overall CCT in Smad4kera-cko was thinner than that of Smad4Ctrl at P42 (n = 6, p < 0.0001) and showed no significant difference when compared to that in Tgfbr2kera-cko. Furthermore, the measurements of the Anterior Chamber and Corneal Radius indicated a substantial ectatic cornea in the Smad4kera-cko compared to Smad4Ctrl. The H&E staining of Smad4kera-cko mimics the finding in the Tgfbr2kera-cko. The positive immunostaining of cornea-specific marker K12 indicating the cell fate of cornea epithelium remained unchanged in Smad4kera-cko and the Proliferating Cell Nuclear Antigen (PCNA) immunostaining further indicated an enhanced proliferation in the Smad4kera-cko. Both immunostainings recapitulated the finding in Tgfbr2kera-cko. The Masson's Trichrome staining revealed decreased collagen formation in the corneal stroma from both Smad4kera-cko and Tgfbr2kera-cko. The collagen type 1 (Col1a1) immunostaining further confirmed the reduction in collagen type 1 formation in Smad4kera-cko. (4) Conclusions: The aforementioned phenotypes in the Smad4kera-cko strain indicated that the SMAD4-dependent signaling pathway is involved in the pathogenesis of the CE-like phenotype observed in Tgfbr2kera-cko.

[Severe Conjunctival and Corneal Epithelial Dysplasia: A Case Series]. / Schwere konjunktivale und korneale epitheliale Dysplasie: eine Fallserie.

BACKGROUND/OBJECTIVES: Ocular surface squamous neoplasia (OSSN) are among the most frequent non-pigmented malignancies of the ocular surface. They have a wide range of histological characteristics - ranging from mild epithelial dysplasia to invasive carcinoma of the squamous cells of the cornea. They may be restricted to the conjunctiva or also involve the cornea. As there are no leading symptoms in the early stages, diagnosis may be very delayed in patients who do not receive regular ophthalmological treatment. The present case series describes clinical and histological data on OSSN and includes clinical and histological data on OSSN, including possible clinical presentations, important risk factors, special histological and cytological features and therapeutic options. METHODS: Retrospective case series of patients with histologically confirmed severe epithelial dysplasia of the conjunctiva and cornea consistent with OSSN who presented to the Department of Ophthalmology in Basel University Hospital. The analysis covered demographic data, symptoms, diagnostic testing (photo documentation, brush biopsy), treatment and cytological and/or histological material and findings. RESULTS: We report on five patients aged between 41 and 92 years at the time of diagnosis. The histological findings in all patients included severe epithelial dysplasia, but with a heterogenous clinical presentation. In all cases, the lesion started in the conjunctiva, but traversed the limbus and extended to the cornea. The primary treatment was always surgical removal. In one patient, this had to be repeated several times due to recurrent metaplasia and was complemented by subsequent mitomycin C therapy. The clinical outcome ranged between total restitution of the original state to inevitable enucleation. CONCLUSION: The clinical presentation of OSSN is highly heterogenous, so that the initial diagnosis is difficult. There are no official guidelines for treatment, so that the treatment of choice varied between clinics. Regular ophthalmological follow-ups are recommended, even after complete surgical excision. Possible relevant concomitant diseases and risk factors must be identified before therapy.

Associations between corneal curvature and other anterior segment biometrics in young myopic adults.

To investigate the associations between corneal curvature (CC) and other anterior segment biometrics in young myopic adults. In this retrospective multi-center study, 7893 young myopic adults were included. CC and other anterior segment biometrics were measured by Scheimpflug imaging (Pentacam). CC was defined as SimK at central 3 mm area, and other anterior segment biometrics included white-to-white corneal diameter (WTW), central corneal thickness (CCT), corneal volume (CV) at 3 mm, 5 mm, and 7 mm area, anterior corneal astigmatism (ACA), posterior corneal astigmatism (PCA), anterior corneal eccentricity (ACE) and asphericity (ACAP), posterior corneal eccentricity (PCE) and asphericity (PCAP), anterior chamber depth (ACD), and anterior chamber volume (ACV). Univariate regression analyses were used to assess the associations between CC and other anterior segment biometrics, and multivariate regression analyses were further performed to adjusted for age, gender and spherical equivalent. CC was higher in patients of female gender and higher myopia (all P < 0.05). Eyes in higher CC quartiles had lower WTW, thinner CCT, lower CV at 3 mm and 5 mm, lower ACD, and lower ACV (all P < 0.001), but had larger ACA, larger PCA, less PCE and less PCAP (all P < 0.001), compared to eyes in lower CC quartiles. The trends of CV at 7 mm, ACE and ACAP were inconsistent in different CC quartiles. After adjusting for age, gender and spherical equivalent with multivariate linear regression, CC was positively correlated to CV at 7 mm (ßs = 0.069), ACA (ßs = 0.194), PCA (ßs = 0.187), ACE (ßs = 0.072), PCAP (ßs = 0.087), and ACD (ßs = 0.027) (all P < 0.05), but was negatively correlated to WTW (ßs = - 0.432), CCT (ßs = - 0.087), CV-3 mm (ßs = - 0.066), ACAP (ßs = - 0.043), PCE (ßs = - 0.062), and ACV (ßs = - 0.188) (all P < 0.05). CC was associated with most of the other anterior segment biometrics in young myopic adults. These associations are important for better understanding of the interactions between different anterior segment structures in young myopic patients, and are also useful for the exploration of the pathogenesis of myopia.

Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy.

Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is rapidly increasing. Most patients with a long-term history of DM present with some degree of keratopathy (DK). Despite its high incidence, the underlying inflammatory mechanism of DK has not been elucidated yet. For further insights into the underlying immunopathologic processes, we utilized streptozotocin-induced mice to model type 1 DM (T1D) and B6.Cg-Lepob/J mice to model type 2 DM (T2D). We evaluated the animals for the development of clinical manifestations of DK. Four weeks post-induction, the total frequencies of corneal CD45+CD11b+Ly-6G- myeloid cells, with enhanced gene and protein expression levels for the proinflammatory cytokines TNF-α and IL-1ß, were higher in both T1D and T2D animals. Additionally, the frequencies of myeloid cells/mm2 in the sub-basal neural plexus (SBNP) were significantly higher in T1D and T2D compared to non-diabetic mice. DK clinical manifestations were observed four weeks post-induction, including significantly lower tear production, corneal sensitivity, and epitheliopathy. Nerve density in the SBNP and intraepithelial terminal endings per 40x field were lower in both models compared to the normal controls. The findings of this study indicate that DM alters the immune quiescent state of the cornea during disease onset, which may be associated with the progressive development of the clinical manifestations of DK.

Allogeneic limbo-deep anterior lamellar keratoplasty (Limbo-DALK)-A novel surgical technique in corneal stromal disease and limbal stem cell deficiency.

PURPOSE: To describe a novel corneal surgical technique combining Deep Anterior Lamellar Keratoplasty (DALK) with grafting of allogeneic limbus (Limbo-DALK) for the treatment of eyes with corneal stromal pathology and limbal stem cell deficiency (LSCD). METHODS: Clinical records of six Limbo-DALKs performed in five patients diagnosed with LSCD and corneal stromal pathology requiring keratoplasty were retrospectively reviewed. All patients were diagnosed with LSCD due to various pathologies including thermal and chemical burns, congenital aniridia or chronic inflammatory ocular surface disease. Parameters analysed included demographics, diagnoses, clinical history, thickness measurements using anterior segment OCT, visual acuity, and epithelial status. Regular follow-up visits were scheduled at 6 weeks as well as 3, 6, 9, and 12 and 18 months postoperatively. Main outcome measures were time to graft epithelialisation and the occurrence of corneal endothelial decompensation. RESULTS: Two grafts showed complete epithelial closure at 2 days, two at 14 days. In one eye, complete epithelial closure was not achieved after the first Limbo-DALK, but was achieved one month after the second Limbo-DALK. No endothelial decompensation occurred except in one patient with silicone oil associated keratopathy. Endothelial graft rejection was not observed in any of the grafts. CONCLUSION: Based on the data from this pilot series, limbo-DALK appears to be a viable surgical approach for eyes with severe LSCD and corneal stromal pathology, suitable for emergency situations (e.g. corneal ulceration with impending corneal perforation), while minimising the risk of corneal endothelial decompensation.

Evaluation of biophysical alterations in the epithelial and endothelial layer of patients with Bullous Keratopathy.

The cornea is a fundamental ocular tissue for the sense of sight. Thanks to it, the refraction of two-thirds of light manages to participate in the visual process and protect against mechanical damage. Because it is transparent, avascular, and innervated, the cornea comprises five main layers: Epithelium, Bowman's layer, stroma, Descemet's membrane, and endothelium. Each layer plays a key role in the functionality and maintenance of ocular tissue, providing unique ultrastructural and biomechanical properties. Bullous Keratopathy (BK) is an endothelial dysfunction that leads to corneal edema, loss of visual acuity, epithelial blisters, and severe pain, among other symptoms. The corneal layers are subject to changes in their biophysical properties promoted by Keratopathy. In this context, the Atomic Force Microscopy (AFM) technique in air was used to investigate the anterior epithelial surface and the posterior endothelial surface, healthy and with BK, using a triangular silicone tip with a nominal spring constant of 0.4 N/m. Six human corneas (n = 6) samples were used for each analyzed group. Roughness data, calculated by third-order polynomial adjustment, adhesion, and Young's modulus, were obtained to serve as a comparison and identification of morphological and biomechanical changes possibly associated with the pathology, such as craters and in the epithelial layer and exposure of a fibrotic layer due to loss of the endothelial cell wall. Endothelial cell membrane area and volume data were calculated, obtaining a relevant comparison between the control and patient. Such results may provide new data on the physical properties of the ocular tissue to understand the physiology of the cornea when it has pathology.

Comparative evaluation of corneal and limbal epithelial thickness in brachycephalic dogs with and without corneal diseases using spectral domain optical coherence tomography.

OBJECTIVE: To evaluate alterations in epithelial thickness during corneal degeneration, corneal pigmentation, and additional features observed through spectral-domain optical coherence tomography (SD-OCT) in brachycephalic dogs. ANIMALS AND PROCEDURES: The study used 55 eyes from 49 brachycephalic dogs that underwent OCT-containing ophthalmic examinations. The examined eyes were classified into corneal degeneration, corneal pigmentation, and normal groups according to corneal lesions. For each eye, corneal epithelial thickness (CET) in the central cornea and maximum limbal epithelial thickness (maxLET) in 4 quadrants of limbus (superior, inferior, nasal, and temporal) were measured from OCT images. Additional abnormal findings on OCT images, including irregular epithelium, subepithelial hyperreflectivity, and conjunctivochalasis, were also recorded. RESULTS: The corneal degeneration group had significantly thinner nasal and temporal maxLETs than that of the normal group (p < .001). In the central corneal OCT image of the corneal degeneration group, an irregular epithelium was observed in 70.6% and subepithelial hyperreflectivity in 82.4%, both of which were significantly higher than the normal group (p < .001). In a comparative analysis, the nasal, temporal, and inferior maxLETs were significantly thinner in the corneal pigmentation group than those in the normal group (p < .001, p < .001, and p = .01, respectively). CONCLUSIONS: Morphological changes in the limbal epithelium were observed in dogs with corneal degeneration and corneal pigmentation. LET reduction could be associated with their pathogenesis and would be valuable as an additional parameter for corneal diseases.

The potential benefits of polyphenols for corneal diseases.

The cornea functions as the primary barrier of the ocular surface, regulating temperature and humidity while providing protection against oxidative stress, harmful stimuli and pathogenic microorganisms. Corneal diseases can affect the biomechanical and optical properties of the eye, resulting in visual impairment or even blindness. Due to their diverse origins and potent biological activities, plant secondary metabolites known as polyphenols offer potential advantages for treating corneal diseases owing to their anti-inflammatory, antioxidant, and antibacterial properties. Various polyphenols and their derivatives have demonstrated diverse mechanisms of action in vitro and in vivo, exhibiting efficacy against a range of corneal diseases including repair of tissue damage, treatment of keratitis, inhibition of neovascularization, alleviation of dry eye syndrome, among others. Therefore, this article presents a concise overview of corneal and related diseases, along with an update on the research progress of natural polyphenols in safeguarding corneal health. A more comprehensive understanding of natural polyphenols provides a novel perspective for secure treatment of corneal diseases.

Corneal grafting.

Corneal grafting is performed approximately 650 times a year in Denmark. A summary of these procedures is given in this review. Fuchs' endothelial dystrophy and pseudophakic bullous keratopathy are frequent indications for transplantation. Previously, penetrating keratoplasty was the technique of choice but is nowadays mainly used for combined stromal and endothelial pathology. Instead, techniques specifically replacing diseased layers are more common. The Danish Cornea Bank is the only center in Denmark which undertakes preparation and distribution of tissue. The operative procedures are performed at Aarhus University Hospital or Rigshospitalet Glostrup.

Insights into mustard gas keratopathy- characterizing corneal layer-specific changes in mice exposed to nitrogen mustard.

Exposure to mustard agents, such as sulfur mustard (SM) and nitrogen mustard (NM), often results in ocular surface damage. This can lead to the emergence of various corneal disorders that are collectively referred to as mustard gas keratopathy (MGK). In this study, we aimed to develop a mouse model of MGK by using ocular NM exposure, and describe the subsequent structural changes analyzed across the different layers of the cornea. A 3 µL solution of 0.25 mg/mL or 5 mg/mL NM was applied to the center of the cornea via a 2-mm filter paper for 5 min. Mice were evaluated prior to and after exposure on days 1, 3, 7, 14, and 28 for 4 weeks using slit lamp examination with fluorescein staining. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) tracked changes in the epithelium, stroma, and endothelium of the cornea. Histologic evaluation was used to examine corneal cross-sections collected at the completion of follow-up. Following exposure, mice experienced central corneal epithelial erosion and thinning, accompanied by a decreased number of nerve branches in the subbasal plexus and increased activated keratocytes in the stroma in both dosages. The epithelium was recovered by day 3 in the low dose group, followed by exacerbated punctuate erosions alongside persistent corneal edema that arose and continued onward to four weeks post-exposure. The high dose group showed persistent epitheliopathy throughout the study. The endothelial cell density was reduced, more prominent in the high dose group, early after NM exposure, which persisted until the end of follow-up, along with increased polymegethism and pleomorphism. Microstructural changes in the central cornea at 4 weeks post-exposure included dysmorphic basal epithelial cells and reduced epithelial thickness, and in the limbal cornea included decreased cellular layers. We present a mouse model of MGK using NM that successfully replicates ocular injury caused by SM in humans who have been exposed to mustard gas.

Development and validation of a reliable rabbit model of limbal stem cell deficiency by mechanical debridement using an ophthalmic burr.

A simple and reproducible method is necessary to generate reliable animal models of limbal stem cell deficiency (LSCD) for assessing the safety and efficacy of new therapeutic modalities. This study aimed to develop and validate a rabbit model of LSCD through mechanical injury. The corneal and limbal epithelium of New Zealand White rabbits (n = 18) were mechanically debrided using an ophthalmic burr (Algerbrush II) with a 1.0-mm rotating head after 360° conjunctival peritomy. The debrided eyes were serially evaluated for changes in corneal opacity, neo-vascularization, epithelial defect and corneal thickness using clinical photography, slit lamp imaging, fluorescein staining, and anterior segment optical coherence tomography scanning (AS-OCT). Following this, an assessment of histopathology and phenotypic marker expression of the excised corneas was conducted. The experimental eyes were grouped as mild (n = 4), moderate (n = 10), and severe (n = 4) based on the grade of LSCD. The moderate group exhibited abnormal epithelium, cellular infiltration in the stroma, and vascularization in the central, peripheral, and limbal regions of the cornea. The severe group demonstrated central epithelial edema, peripheral epithelial thinning with sparse goblet cell population, extensive cellular infiltration in the stroma, and dense vascularization in the limbal region of the cornea. A significant decrease in the expression of K12 and p63 (p < 0.0001) was observed, indicating the loss of corneal epithelium and limbal epithelial stem cells in the LSCD cornea. This study demonstrates that the Alger brush-induced mechanical debridement model provides a reliable model of LSCD with comprehensive clinic-pathological features and that is well suited for evaluating novel therapeutic and regenerative approaches.

Transforming growth factor beta receptor 2 (Tgfbr2) deficiency in keratocytes results in corneal ectasia.

PURPOSE: We hypothesized that Transforming growth factor beta receptor 2 (Tgfbr2) deletion in keratocyte (Tgfbr2kera-cko), the corneal stroma cell, can result in corneal thinning and generate a potential model for Cornea Ectasia (CE). METHODS: Corneal thickness of Tgfbr2kera-cko and Tgfbr2Ctrl was examined with Optical Coherence Tomography (OCT) at post-natal (P) days 42 and 70, respectively. Histological H&E staining, transmission electron micrograph (TEM), and immunofluorescence staining (IFS) were harnessed to examine corneal cell morphology, proliferation, differentiation, and collagen fibrils. RESULTS: Slit-Lamp revealed that corneas were transparent in both Tgfbr2kera-cko and Tgfbr2Ctrl, however, Tgfbr2kera-cko cornea was 33.5% and 42.9% thinner as compared with those of Tgfbr2Ctrl at P42 and P70, respectively. H&E and semithin section staining with toluidine blue-O confirmed that Tgfbr2kera-cko cornea has a thinner stroma. In contrast, the epithelium in Tgfbr2kera-cko was substantially thicker. The cell proliferation marker Ki67 expression level increased ∼9% in Tgfbr2kera-cko corneal epithelium as compared with that in Tgfbr2Ctrl, however, the Krt14 and Krt12 expression pattern was not obviously changed in Tgfbr2kera-cko corneal epithelium. It was noticed that Col1a1 expression was substantially reduced in Tgfbr2kera-cko as compared with that in Tgfbr2Ctrl. TEM showed that keratocytes were unhealthy and stromal collagen fibril density was significantly reduced in Tgfbr2kera-cko as compared with that in Tgfbr2Ctrl cornea. Moreover, mechanical eye-rubbing on Tgfbr2kera-cko resulted in corneal hydrops and edema. CONCLUSION: Tgfbr2 in keratocytes is indispensable for the corneal stroma at postnatal homeostasis. The cornea phenotype manifested in these Tgfbr2kera-cko mice resembles corneal ectasia disease in humans.

Rare case of corneal keloid following radial keratotomy for myopia.

An adult male in his 50s presented with complaints of glare and gradual, painless, progressive diminution of vision in the right eye (RE). Visual acuity in RE was noted to be 2/60, and slit lamp biomicroscopy revealed a pearly grey-white elevated corneal opacity measuring 4 mm × 3 mm, obscuring the visual axis. There was no history of ocular trauma or infection. The patient had undergone bilateral radial keratotomy for myopia correction 25 years ago. Anterior segment optical coherence tomography imaging demonstrated increased corneal thickness of 1080 µm at the site of lesion and the height of the epicorneal mass was noted to be 493 µm. The patient underwent fibrin glue-aided anterior lamellar keratoplasty. Histopathological examination of the excised host tissue confirmed the diagnosis of corneal keloid.

A Mouse Model for Corneal Neovascularization by Alkali Burn.

Corneal neovascularization (CoNV), a pathological form of angiogenesis, involves the growth of blood and lymph vessels into the avascular cornea from the limbus and adversely affects transparency and vision. Alkali burn is one of the most common forms of ocular trauma that leads to CoNV. In this protocol, CoNV is experimentally induced using sodium hydroxide solution in a controlled manner to ensure reproducibility. The alkali burn model is useful for understanding the pathology of CoNV and can be extended to study angiogenesis in general because of the avascularity, transparency, and accessibility of the cornea. In this work, CoNV was analyzed by direct examination under a dissecting microscope and by immunostaining flat-mount corneas using anti-CD31 mAb. Lymphangiogenesis was detected on flat-mount corneas by immunostaining using anti-LYVE-1 mAb. Corneal edema was visualized and quantified using optical coherence tomography (OCT). In summary, this model will help to advance existing neovascularization assays and discover new treatment strategies for pathologic ocular and extraocular angiogenesis.

Safety and efficacy of topical interferon alpha 2B and mitomycin C for localized conjunctival intraepithelial neoplasia: long-term report of their pharmacological safety and efficacy.

PURPOSE: Ocular surface squamous neoplasia (OSSN) comprises a wide spectrum of squamous tumors, from which corneal/conjunctival intraepithelial neoplasia (CIN) is the most common one. The classic treatment is complete excision, but recurrence rates are high. Antineoplastic drugs such as mitomycin C (MMC) and interferon alpha 2b (IFNα2b) have been used as adjuvants or as primary treatment. To evaluate the efficacy and safety of topical IFNα2b and MMC in patients with CIN, a phase IIb double-blind clinical trial was performed. METHODS: Patients diagnosed with localized CIN were evaluated by slit lamp and impression cytology and were randomly given MMC 0.04% or INF2b (1 million IU/mL) 4 times daily until neoplasia resolution. Time of resolution and frequency of adverse effects were analyzed to determine the pharmacological efficacy and safety of both medications. RESULTS: Seventeen patients were included. Nine patients were treated with MMC and 8 with IFNα2b. All patients responded to treatment. The resolution time in days was 59.11 ± 24.02 in patients treated with MMC and 143.50 ± 47.181 in those treated with IFNα2b (p < 0.001). In the MMC group, one recurrence was reported (11%). There were no recurrences at 2 years of follow-up in the IFNα2b group. Regarding adverse effects, one or more mild adverse reaction occurred in 77% of patients managed with MMC and in 50% of patients managed with IFNα2b (p > 0.05). No serious adverse effects were reported. CONCLUSIONS: Topical chemotherapy with MMC and IFNα2b demonstrate pharmacological safety and efficacy. Therefore, these drugs could be considered as primary therapies for localized CIN .

Cellular senescence implication in mustard keratopathy.

Mustard agents are vesicants that were used in warfare multiple times. They are potent alkylating agents that activate cellular pathways of apoptosis, increase oxidative stress, and induce inflammation. Eyes are particularly susceptible to mustard exposure with a wide range of ocular surface damage. Three main categories of mustard-related eye injuries are acute, chronic, and delayed-onset manifestations. Mustard keratopathy (MK) is a known complication characterized by corneal opacification, ulceration, thinning, and neovascularization that can lead to severe vision loss and discomfort. Recently, a few reports demonstrated the role of senescence induction as a new pathological mechanism in mustard-related injuries that could affect wound healing. We ran the first murine model of delayed-onset MK and nitrogen mustard-induced senescence, evaluating the pathological signs of senescence in the cornea using beta-galactosidase staining. Our results suggest that nitrogen mustard exposure causes senescence in the corneal cells, which could be the underlying mechanism for chronic and late-onset ocular surface damage. We also found a significant correlation between the percentage of positive beta-galactosidase staining and the degree of fibrosis in the cornea. This provides valuable insight into the possible role of anti-senescence drugs in the near future for accelerating corneal healing and restricting fibrosis in patients with mustard keratopathy.

Evidence of Contact Lenses for Vision Rehabilitation in Corneal Diseases: A Review.

OBJECTIVES: To evaluate the efficacy and safety of contact lenses (CL) as a therapeutic option for patients affected by a corneal disease and to determinate which is the best lens modality for each disease. METHODS: A literature review using PubMed was performed. All relevant articles published during the last 15 years have been included. RESULTS: Various studies point to CL as the best therapeutic option for some corneal diseases and even as an alternative to surgery in some cases. After fitting, patients show an improvement in their functional vision and quality of life, in some cases being able to drive or work again. CONCLUSIONS: There is a lack of scientific evidence to determine which lens modality is suitable for each corneal pathology. Currently, according to this review, the reason for choosing between the different options depends on the severity of symptoms, and it is worth mentioning that scleral lenses seem to be the best option in advanced stages of disease. However, the expertise of professionals is also an important factor at the time of choosing a particular CL modality. Standardized criteria are still necessary for correct selection of lens modality for a correct management of the disease.

ROCK inhibitors in ophthalmology: A critical review of the existing clinical evidence.

Rho kinase (ROCK) inhibitors have emerged as a key therapeutic class of interest in ophthalmology over the last decade. Promising in vitro studies laid the foundations for the development of novel therapeutic agents that target the ROCK signalling pathway in ocular disease, with subsequent clinical trials supporting their use. Corneal endothelial disease, glaucoma, and vitreoretinal disease are the major pathologies in which ROCK inhibitors have been investigated to date. Ripasudil and netarsudil represent the current leaders in this pharmaceutical group, having been extensively validated and approved for use in glaucoma in some countries. Less substantial evidence exists for fasudil in ophthalmic use. ROCK inhibitors are also increasingly used in cultured endothelial cell grafting and as an adjunct to aid in endothelial cell migration and replication in Descemet's stripping procedures or Descemet's membrane injuries. This review has synthesised both established and emerging research to provide a practical guide to prescribing in this drug class. Drug efficacies, side effect profiles, and the demographic and clinical characteristics of appropriate drug candidates are discussed.

Presence of pseudo-Kayser-Fleischer rings in patients without Wilson disease: a prospective cohort study.

BACKGROUND AND AIMS: Kayser-Fleischer (KF) rings are due to copper deposition in Descemet membrane of the cornea in Wilson disease. Pseudo-KF ring (PKF), seen in patients with high bilirubin, is often misinterpreted as KF rings. These are bilirubin deposits in posterior corneal stroma. The aim of the study was to prospectively evaluate the presence of KF and PKF rings in Wilson disease and non-Wilsonian liver disease with serum bilirubin >5 mg/dL. METHODS: All patients referred from the hepatology unit with serum bilirubin >5 mg/dL were assessed by slit-lamp examination (SLE) and anterior segment optical coherence tomography at baseline, 3 months, and 6 months for differences in corneal deposits between KF and PKF rings. All other clinical, laboratory, radiological, genetic, and tissue diagnoses by liver biopsy were done as required to confirm the cause of liver disease. RESULTS: Among the 750 patients examined, corneal deposits were present in 13%, KF rings as granular deposits in 31.7%, and PKF as a posterior stromal hue in 68.3% of cases. PKF rings showed regression in 60%, disappearance in 36.6% at 3 months, and in 100% of cases at 6 months. KF ring showed regression in 10.7% and 8.3% until 6 months. Anterior segment optical coherence tomography identified KF ring as a hyperintense line on Descemet membrane in an additional 9.7% of patients compared with a scattered hyperintense hue in PKF rings. CONCLUSIONS: The presence of PKF rings in patients with jaundice is not uncommon and should be differentiated from true KF rings. Serial monitoring is essential to look for resolution, and anterior segment optical coherence tomography may be additionally helpful.

Genetic analysis of allogenic donor cells after successful allo-limbal epithelial transplantation in simple and cultivated limbal epithelial transplantation procedures.

This non-comparative cohort study investigated long-term donor cell survival after allogenic simple/cultivated limbal epithelial transplantations (allo-SLET/allo-CLET, respectively) by genetic analysis. Transplanted corneal epithelial cells, which underwent impression cytology and/or corneal-button biopsy, were examined for personal identities of autosomal short-tandem repeats; the percentages of donor cells were calculated based on matching recipient or donor buccal-DNA references. Twelve patients were included; 4 underwent allo-CLET, 8 underwent allo-SLET. Eight patients (67%) had total limbal stem cell deficiency (LSCD). Genetic analysis was performed postoperatively (mean, 55.3 months). Donor cells were detected in 4 of 12 patients (25%), all of whom underwent allo-SLET; 1 patient had a donor genotype and 3 patients had a mixed donor/recipient genotype. The longest time of donor cell detection was 30 months. Seven patients (58%) used systemic immunosuppressives at the time of genetic analysis (mean use, 22.5 months). Allogenic donor cells survived in both procedures for the long term postoperatively, which encourages the long-term use of systemic immunosuppressives. Donor cells may not be the only factor in graft survival, in that most successful cases had a recipient profile. Their presence for a specific time may promote niches for the patients' own cells to repopulate, especially for partial LSCD.