Collagen cross-linking beyond corneal ectasia: A comprehensive review.

The history of corneal cross-linking (CXL) dates back to 2003 when some German scientists investigated possible treatments to harden the corneal structure to increase its resistance in ectatic corneal diseases. Nowadays, CXL is considered the most effective therapy in ectatic corneal diseases due to its proven efficacy in hardening the cornea, thus halting the development of the disease. Since 2003, CXL applications have dramatically expanded and have been implemented in several other areas such as infectious keratitis, corneal edema, and before performing keratoplasty for various purposes. Moreover, several irradiation patterns are being studied to correct refractive errors, taking into account the corneal refractive changes that occur after the procedure. Currently, scleral cross-linking is also being investigated as a potential therapy in cases of progressive myopia and glaucoma. In this article, we provide a comprehensive overview of the available applications of cross-linking in nonectatic ocular conditions and highlight the possible future indications of this procedure.

Topical tacrolimus in high-risk corneal transplants.

PURPOSE: The purpose of this study was to assess the use of topical tacrolimus ointment in preventing rejection in high-risk corneal grafts, when added to the standard immunosuppressive regimen. METHODS: We conducted an observational, retrospective study using clinical data of high-risk patients subjected to penetrating keratoplasty, who were treated with topical tacrolimus ointment 0.2 mg/g twice a day plus topical dexamethasone 0.1 mg/ml 6 id and compared it with a similar control group treated with topical dexamethasone 0.1 mg/ml 6 id alone. High-risk status was attributed to patients with previous ipsilateral corneal graft failure, two or more quadrants with corneal neovascularization or an infectious or inflammatory corneal disease. RESULTS: We analysed 53 patients in the trial group versus 53 patients in the control group, with similar age, baseline diagnosis and risk factors, and median follow-up times of 30 and and 24 months, respectively. Survival analysis showed a higher graft survival rate at all follow-up periods for patients treated with topical tacrolimus (p < 0.01). No adverse reactions were reported. DISCUSSION: This study shows that topical tacrolimus ointment increases the survival rate of the graft if added to the previous topical steroid regimen in high-risk patients. CONCLUSION: Topical tacrolimus is safe and effective in prolonging graft survival in high-risk patients.

The role of the JAK/STAT3 signaling pathway in acquired corneal diseases.

Acquired corneal diseases such as dry eye disease (DED), keratitis and corneal alkali burns are significant contributors to vision impairment worldwide, and more effective and innovative therapies are urgently needed. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway plays an indispensable role in cell metabolism, inflammation and the immune response. Studies have shown that regulators of this pathway are extensively expressed in the cornea, inducing significant activation of JAK/STAT3 signaling in specific acquired corneal diseases. The activation of JAK/STAT3 signaling contributes to various pathophysiological processes in the cornea, including inflammation, neovascularization, fibrosis, and wound healing. In the context of DED, the hypertonic environment activates JAK/STAT3 signaling to stimulate corneal inflammation. Inflammation and injury progression in infectious keratitis can also be modulated by JAK/STAT3 signaling. Furthermore, JAK/STAT3 signaling is involved in every stage of corneal repair after alkali burns, including acute inflammation, angiogenesis and fibrosis. Treatments modulating JAK/STAT3 signaling have shown promising results in attenuating corneal damage, indicating its potential as a novel therapeutic target. Thus, this review emphasizes the multiple roles of the JAK/STAT3 signaling pathway in common acquired corneal disorders and summarizes the current achievements of JAK/STAT3-targeting therapy to provide new insights into future applications.

Animal Models in Eye Research: Focus on Corneal Pathologies.

The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on laboratory animals are essential to ensure the safety of therapeutic products directly applied or injected into the eye to treat ocular diseases before eventually proceeding to clinical trials. Among these tissues, the cornea has unique homeostatic and regenerative mechanisms for maintaining transparency and refraction of external light, which are essential for vision. However, being the outermost tissue of the eye and directly exposed to the external environment, the cornea is particularly susceptible to injury and diseases. This review highlights the evidence for selecting appropriate animals to better understand and treat corneal diseases, which rank as the fifth leading cause of blindness worldwide. The development of reliable and human-relevant animal models is, therefore, a valuable research tool for understanding and translating fundamental mechanistic findings, as well as for assessing therapeutic potential in humans. First, this review emphasizes the unique characteristics of animal models used in ocular research. Subsequently, it discusses current animal models associated with human corneal pathologies, their utility in understanding ocular disease mechanisms, and their role as translational models for patients.

Netarsudil in the management of refractory pediatric glaucoma.

We performed a retrospective review of patients with refractory pediatric glaucoma who were started on netarsudil at the Wilmer Eye Institute. We found minimally sustained IOP lowering over a 6-month period in 29 eyes of 23 patients. Our results suggest that although netarsudil is an alternative medication in the management of pediatric glaucoma, its efficacy may be limited in refractory pediatric glaucoma patients. In addition, careful cornea examination is required to evaluate for signs of corneal decompensation, especially in patient with preexisting cornea disease.

rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

Corneal squamous neoplasia: masquerades and management outcomes at a rural eyecare centre.

The authors describe two cases of corneal ocular surface squamous neoplasia (OSSN), presenting at our rural eyecare centre, which were initially misdiagnosed as viral epithelial keratitis and corneal pannus with focal limbal stem cell deficiency. Both the cases were refractory to initial treatment and corneal OSSN was suspected. Anterior segment-optical coherence tomography (AS-OCT) revealed a thickened, hyper-reflective epithelium with abrupt transition and an underlying cleavage plane, features typical of OSSN. Topical 1% 5-fluorouracil (5-FU) therapy was initiated and in two cycles (first case) to three cycles (second case), complete resolution was noted both clinically and on AS-OCT, with no significant side effects. Both patients are currently free of tumour at the 2-month follow-up period. The authors report the rare, atypical presentations of corneal OSSN, discuss the masquerades and highlight the role of primary topical 5-FU in managing corneal OSSN in limited resource settings.

Corticosteroid-Antibiotic Interactions in Bacteria that Cause Corneal Infection.

Purpose: Although a comprehensive knowledge of antibiotic/corticosteroid combinations is essential for the appropriate treatment of eye infections, the impact of their co-administration has not been well studied to date. A systematic pharmacodynamic/pharmacokinetic study to determine the effects of cotreatment with various antibiotics and corticosteroids was conducted. Methods: Four bacterial strains, seven antibiotics, and four corticosteroids were used in the analyses. Drug interactions were evaluated by considering antibacterial effects with a checkerboard assay and intracellular concentrations in human corneal epithelial cells. Results: The drug combinations that showed the most stable effects against Pseudomonas aeruginosa was levofloxacin-prednisolone. Stable combinations against the three types of Gram-positive bacteria were neomycin-prednisolone, ofloxacin-dexamethasone, ofloxacin-prednisolone, and polymyxin-dexamethasone. The cellular concentrations were changed for the gatifloxacin-fluorometholone, moxifloxacin-fluorometholone, tobramycin-dexamethasone, and tobramycin-prednisolone combinations. Conclusions: Loteprednol and fluorometholone reduced the antibacterial effects of all of the tested antibiotics in this study. Dexamethasone and prednisolone showed various effects in this regard, depending on the co-administered antibiotic. Prior knowledge of specific antibiotic/corticosteroid interactions provides valuable information to clinical practitioners by combining data on the antibacterial and intracellular uptake effects of their co-administration. Translational Relevance: When using antibiotics and corticosteroids, drug combinations can be selected by referring to the results of this study.

The mTOR signalling in corneal diseases: A recent update.

Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as antibiotics, steroids, and surgical interventions, have numerous disadvantages and challenges. Thus, there is an urgent need for more effective therapies. Although the pathogenesis of corneal diseases is not fully understood, it is known that injury caused by various stresses and postinjury healing, such as epithelial renewal, inflammation, stromal fibrosis, and neovascularization, are highly involved. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, metabolism, and the immune response. Recent studies have revealed that activation of mTOR signalling extensively contributes to the pathogenesis of various corneal diseases, and inhibition of mTOR with rapamycin achieves promising outcomes, supporting the potential of mTOR as a therapeutic target. In this review, we detail the function of mTOR in corneal diseases and how these characteristics contribute to disease treatment using mTOR-targeted drugs.

[Modern possibilities of pathogenetically oriented therapy for dry eye syndrome]. / Sovremennye vozmozhnosti patogeneticheski orientirovannoi terapii sindroma «sukhogo glaza¼.

In recent years, anti-inflammatory therapy has become a significant part of the complex approach to treatment of patients with dry eye syndrome (DES), with cyclosporine preparations becoming increasingly important in the structure of the therapy. Taking into account the immunosuppressive effect of cyclosporine A, which is realized through hindering the activation of T-lymphocytes in the tissues of the ocular surface, its topical application in DES has a pronounced pathogenetic focus. Numerous clinical studies have shown that instillations of cyclosporine into the conjunctival cavity contribute to an increase in total tear production, as well as recovery of the density of goblet cells in the conjunctiva of DES patients. The positive effect of cyclosporine A instillations has been convincingly demonstrated in the complex therapy of patients with vernal and atopic corneal conjunctivitis, Thygeson's superficial punctate keratitis, autoimmune keratitis, meibomian gland dysfunction, etc. However, one significant problem associated with cyclosporine A instillations is the irritating effect of the drug. That prompted the development of a drug that is safe and tolerable during instillations into the conjunctival cavity - preservative-free 0.1% cyclosporine A labelled Ikervis (Santen, Japan). The drug carrier is artificial tear Cationorm (Santen), which has an advantage of stabilizing the tear film and protecting the ocular surface from the irritating effect of cyclosporine. According to numerous clinical studies, Ikervis instillations can improve the effectiveness of complex therapy in patients with DES (especially secondary to Sjögren syndrome, Stevens-Johnson syndrome, graft-versus-host disease), with allergic diseases of the cornea and conjunctiva (spring, atopic corneal conjunctivitis), with corneal transplant disease, and other similar conditions. The high efficacy and safety of Ikervis constitute the reason to recommend it for wide clinical use.

Efectividad de la insulina tópica en el tratamiento de patologías de la superficie corneal / Effectiveness of topical insulin for the treatment of surface corneal pathologies

El propósito es identificar a través de una revisión sistemática de la literatura, la evidencia actual frente a la eficacia del tratamiento de la insulina tópica en patologías de la superficie ocular. Se implementó una búsqueda de literatura en bases de datos de indexación médica Medline (Pubmed), Embase y Web Of Science a través de palabras claves como «insulin» AND «córnea» OR «corneal» OR «dry eye» artículos publicados en inglés o español en los últimos once años (2011-2022). Se identificaron nueve artículos con 180 participantes provenientes de Estados Unidos, España, Irlanda, Canadá, Portugal y Malasia, con defectos epiteliales persistentes refractarios y secundarios a vitrectomía, cuya extensión de la lesión fue de 3,75 mm2 hasta 65,47 mm2. La preparación fue disuelta con lágrimas artificiales y la concentración de insulina fue desde 1 UI/ml hasta 100 UI/ml. En todos los casos la resolución del cuadro clínico fue completa con un tiempo de curación desde 2,5 días hasta 60,9 días siendo este último un caso secundario a una quemadura por cáusticos de difícil control. La insulina tópica ha sido efectiva para el tratamiento de defectos epiteliales persistentes; la de acción intermedia y en bajas concentraciones demostró menor tiempo de resolución, en úlceras neurotróficas y secundarias a vitrectomías (AU)

The purpose is to identify, through a systematic literature review, the current evidence regarding the effectiveness of topical insulin treatment in ocular surface pathologies. A literature search was implemented in Medline (Pubmed), Embase and Web Of Science medical indexing databases by using keywords such as “insulin” AND “cornea” OR “corneal” OR “dry eye” in published papers in English or Spanish within the last eleven years (2011-2022). Nine papers were identified with 180 participants from the United States, Spain, Ireland, Canada, Portugal and Malaysia, with persistent refractory epithelial defects and secondary to vitrectomy, whose extension of the lesion was from 3.75 mm2 to 65.47 mm2. The preparation was dissolved with artificial tears and the insulin concentration ranged from 1 IU/ml to 100 IU/ml. In all cases, the resolution of the clinical picture was complete with a healing time from 2.5 days to 60.9 days, the latter being a secondary case to a difficult-to-control caustic burn. Topical insulin has been effective for the treatment of persistent epithelial defects. The intermediate action and low concentrations showed a shorter resolution time in neurotrophic ulcers and induced during vitreoretinal surgery (AU)

Refractory Keratolimbal Allograft Rejection in Autoimmune Polyglandular Syndrome-Associated Keratopathy Treated With Intravenous Immunoglobulin.

PURPOSE: The aim of this study was to describe the use of intravenous immunoglobulin (IVIG) in the management of a 20-year-old woman with autoimmune polyglandular syndrome-associated keratopathy who developed acute transplant rejection after keratolimbal allograft (KLAL) surgery. CASE: Nine weeks after KLAL surgery, a 20-year-old woman with autoimmune polyglandular syndrome-related limbal stem cell deficiency presented with graft injection, hemorrhage, and an epithelial rejection line. This was concerning for acute rejection in the setting of triple-agent systemic immunosuppression (albeit nonadherence at times). There was initial reversal of the rejection process with a sub-Tenon's injection of triamcinolone, frequent topical corticosteroids, increase in oral prednisone, and optimization of systemic immunosuppression medications; however, recurrence of the epithelial rejection line and symptoms were noted whenever the prednisone dose was tapered. This was accompanied by ocular surface decompensation (late staining, neovascularization, and persistent epithelial defects). She was found to have weakly positive HLA Class 1 antibodies. The patient was treated with a pulsed corticosteroid infusion and 2 monthly IVIG infusions. This led to resolution of the acute rejection. However, there was a subsequent rejection episode 4 months later after tapering the prednisone. Monthly IVIG for 6 more months led to final resolution with successful prednisone tapering and no further rejection. CONCLUSIONS: Treatment with prolonged IVIG showed better improvement in a case of acute rejection refractory to traditional treatments, especially in the setting of HLA antibodies. The case demonstrates that close follow-up with a corneal specialist and collaboration with a transplant specialist is important to monitor for postoperative KLAL rejection.

Therapeutic non-ectasia applications of cornea cross-linking.

Corneal cross-linking is a photopolymerization technique traditionally used to strengthen corneal tissue. Corneal cross-linking utilizes riboflavin (vitamin B2) as a photosensitizer and ultraviolet-A light (UVA) to create strong covalent bonds within the corneal stroma, increasing tissue stiffness. Multiple studies have demonstrated corneal cross-linking's effectiveness in treating corneal ectasia, a progressive, degenerative, and non-inflammatory thinning disorder, as quantified by key tomographic, refractive, and visual parameters. Since its introduction two decades ago, corneal cross-linking has surpassed its original application in halting corneal ectatic disease and its application has expanded into several other areas. Corneal cross-linking also possesses antibacterial, antienzymolytic and antioedematous properties, and has since become a tool in treating microbial keratitis, correcting refractive error, preventing iatrogenic ectasia, stabilising bullous keratopathy and controlling post keratoplasty ametropia. This review provides an overview of the current evidence base for the therapeutic non-ectasia applications of cornea cross-linking and looks at future developments in the field.

From bench to clinic: Emerging therapies for corneal scarring.

Corneal diseases are one of the leading causes of moderate-to-severe visual impairment and blindness worldwide, after glaucoma, cataract, and retinal disease in overall importance. Given its tendency to affect people at a younger age than other blinding conditions such as cataract and glaucoma, corneal scarring poses a huge burden both on the individuals and society. Furthermore, corneal scarring and fibrosis disproportionately affects people in poorer and remote areas, making it a significant ophthalmic public health problem. Traditional medical strategies, such as topical corticosteroids, are not effective in preventing fibrosis or scars. Corneal transplantation, the only effective sight-restoring treatment for corneal scars, is curbed by challenges including a severe shortage of tissue, graft rejection, secondary conditions, cultural barriers, the lack of well-trained surgeons, operating rooms, and well-equipped infrastructures. Thanks to tremendous research efforts, emerging therapeutic options including gene therapy, protein therapy, cell therapy and novel molecules are in development to prevent the progression of corneal scarring and compliment the surgical options currently available for treating established corneal scars in clinics. In this article, we summarise the most relevant preclinical and clinical studies on emerging therapies for corneal scarring in recent years, showing how these approaches may prevent scarring in its early development.

Case Report: A Rare Fungal Keratitis Caused by Plectosphaerella Cucumerina.

PURPOSE: To report a rare case of fungal keratitis caused by Plectosphaerella cucumerina. METHODS: This study retrospectively reviewed the medical records of a case of fungal keratitis. RESULTS: Silt-lamp biomicroscopy revealed corneal infiltration and epithelial defects. Anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM) were performed to assist in the diagnosis and evaluate corneal conditions. The isolate was identified as Plectosphaerella cucumerina by MALDI-TOF mass spectrometry. The patient was treated with topical 5% pimaricin and oral voriconazole for 1 month and recovered. CONCLUSION: Fungal keratitis caused by Plectosphaerella cucumerina is rare. AS-OCT and IVCM can help locate the lesion and diagnose fungal keratitis. Furthermore, MALDI-TOF mass spectrometry showed potential prospects in the identification of filamentous fungi. Plectosphaerella cucumerina rarely infects humans and is sensitive to antifungal agents such as pimaricin and voriconazole.

Prospective, Randomized, Multicenter, Double-Masked, Clinical Trial of Corneal Cross-Linking for Boston Keratoprosthesis Carrier Tissue.

PURPOSE: To assess whether cross-linking the carrier donor cornea of the Boston Keratoprosthesis (BKPro) improves retention of the device in participants at high risk for keratolysis. DESIGN: Prospective, double-masked, randomized clinical trial. METHODS: In this multicenter study, 68 adult participants who were scheduled for BKPro implantation were enrolled. Masked participants were randomized to receive either a cross-linked (CXL) or non-cross-linked (non-CXL) donor corneal carrier. The Kaplan-Meier event-free survival was determined by the product-limit method and compared by the log-rank test to examine whether survival curves were different between the CXL and non-CXL groups. The primary outcome of the study was time from surgery to BKPro removal. The secondary endpoint was 12-month retention rate. RESULTS: A total of 68 participants were enrolled and randomized 1:1 to each group. The average age at the time of surgery was 62 (range = 24-89) years, and 42 participants (62%) were male. The overall BKPro retention rate was 70% during a mean follow-up time of 93 (range = 6-201) weeks. Twenty BKPros were removed, 10 in the CXL group and 10 in the non-CXL group, with 18 requiring removal because of sterile keratolysis. There was no difference in the time to removal between the groups during the study (P = .910). At 12 months, there was no significant difference in the retention rate in the CXL group (94%) vs the non-CXL group (82%, P = .150). CONCLUSIONS: In this prospective study, cross-linking of the carrier cornea prior to BKPro implantation did not reduce the incidence of sterile keratolysis or increase device retention among participants at high risk for retention failure.

Acremonium keratitis: Risk factors, clinical characteristics, management, and outcome in 65 cases.

Purpose: To study the risk factors, clinical presentation, management options, and outcomes in cases of culture-proven Acremonium keratitis. Methods: Medical and microbiology records of culture-proven Acremonium keratitis from Jan 2007 to Dec 2019 at a tertiary eye care center were reviewed. Details of clinical findings on each visit and operating notes were reviewed from the medical records. All cases were subjected to corneal scraping at the first visit for microbiological investigation consisting of direct smear examination and culture. Topical natamycin 5% was the mainstay of medical treatment. Surgical treatment was considered for nonresponding patients. Results: During the 13-year study period, 65 cases of culture-proven Acremonium keratitis were identified out of 1605 cases of fungal keratitis. Trauma was the most common predisposing factor in 32 cases (49.2%). The average area of the corneal stromal infiltrate was 24.8 mm2 at the initial presentation. Hypopyon at the time of presentation was evident in 28 (43.1%) cases. Staphylococcus spp. was the most common (n = 22, 33.8%) organism coexistent with Acremonium. Direct microscopy of corneal scraping was positive for fungal filaments in 57/65 (87.6%) cases. Medical management alone was given in 44 patients (67.6%). Age (>50 years) and treatment delay (>15 days) were found to be independent risk factors for the poor final visual outcome (VA <20/60). Conclusion: When treated early, Acremonium keratitis responds well to medical therapy with currently available topical antifungals. However, advanced and nonresponding cases require surgical intervention for resolution of the infection.

Reversible Corneal Decompensation Caused by a Topical Dorzolamide/Timolol Fixed Combination After Descemet Stripping Automated Endothelial Keratoplasty.

PURPOSE: The purpose of this study was to report a case of acute corneal endothelial decompensation caused by a topical dorzolamide/timolol fixed combination (DTFC) after Descemet stripping automated endothelial keratoplasty. METHODS: A 75-year-old woman who was referred to our hospital with a chief complaint of visual disturbance in the right eye after cataract surgery. Anterior segment optical coherence tomography identified an extensive defect in Descemet membrane. The patient subsequently underwent uneventful Descemet stripping automated endothelial keratoplasty surgery for persistent corneal edema. Two weeks after surgery, she had been prescribed topical DTFC twice daily to control elevated intraocular pressure. On the day she started using the eye drops, the patient noticed an acute deterioration of visual acuity. Severe corneal edema was detected at follow-up 5 days later. RESULTS: The topical DTFC was stopped immediately. Thereafter, the corneal edema improved gradually, and there was a reduction in corneal thickness. CONCLUSIONS: Topical DTFC should be used with caution after corneal endothelial transplantation because of the possibility of iatrogenic corneal endothelial dysfunction.