Deep-learning based analysis of in-vivo confocal microscopy images of the subbasal corneal nerve plexus' inferior whorl in patients with neuropathic corneal pain and dry eye disease.

PURPOSE: To evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images. METHODS: Subbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density. RESULTS: 160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001). CONCLUSIONS: Deep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP.

Lessons Learned From Ocular Graft versus Host Disease: An Ocular Surface Inflammatory Disease of Known Time of Onset.

ABSTRACT: The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.

Strategic combination of cultivated oral mucosal epithelial transplantation and postoperative limbal-rigid contact lens-wear for end-stage ocular surface disease: a retrospective cohort study.

PURPOSE: To provide the long-term outcome of patients with end-stage severe ocular surface disease (OSD) consecutively treated with cultivated oral mucosal epithelial transplantation (COMET) followed by limbal-rigid contact lens (CL)-wear therapy. DESIGN: Retrospective cohort. METHODS: In 23 eyes of 18 patients with severe OSD who underwent COMET surgery between 2002 and 2019 and who were followed with limbal-rigid CL-wear therapy for at least 1 year postoperative, patient demographics, best-corrected visual acuity (BCVA, logMAR), Ocular Surface Grading Scores (OSGS), surgical indication and adverse events were reviewed. Primary and secondary outcomes were BCVA and OSGS changes at baseline and final examination, respectively. RESULTS: This study involved 16 patients with Stevens-Johnson syndrome and 2 patients with mucous membrane pemphigoid (mean age: 59±15 years). The indications for COMET were as follows: corneal reconstruction for vision improvement (10 eyes (43.5%)), corneal reconstruction for persistent epithelial defect (4 eyes (17.4%)) and conjunctival (fornix) reconstruction for symblepharon release (9 eyes (39.1%)). The mean duration of CL-wear postsurgery was 6.4±3.9 years (range: 1.4 to 13.3 years). The mean BCVA at baseline and at final follow-up was logMAR 1.9±0.5 and 1.3±0.7, respectively (p<0.05). Compared with those at baseline, the OSGSs for symblepharon and upper and lower fornix shortening showed significant improvement at each follow-up time point post treatment initiation. No serious intraoperative or postoperative adverse events were observed. CONCLUSION: In patients afflicted with severe OSD, COMET combined with limbal-rigid CL-wear therapy postsurgery was found effective for vision improvement and ocular surface stabilisation.

Delayed presentation of surgically induced scleral necrosis after I-BRITE procedure treated with immunosuppressive therapy.

Surgically induced scleral necrosis (SISN) is an uncommon complication of ocular procedures. Cosmetic eye-whitening surgery involves conjunctival and Tenon's capsule dissection, cautery, and mitomycin C application. We report the case of a 36-year-old white woman referred to our clinic for severe pain, scleral inflammation, and necrosis in both eyes 9 years after I-BRITE, an elective eye-whitening procedure. An extensive workup yielded negative results. The patient improved with aggressive lubrication and topical and high-dose systemic prednisone (60 mg), with recurrence upon steroid tapering. Concomitant weekly methotrexate was added, resulting in inflammatory control and allowing discontinuance of topical and oral steroids.

Differences in gene regulation by TLR3 and IPS-1 signaling in murine corneal epithelial cells.

Toll-like receptor 3 (TLR3) and interferon-beta promoter stimulator-1 (IPS-1) are associated with antiviral responses to double-stranded RNA viruses and contribute to innate immunity. We previously reported that conjunctival epithelial cell (CEC) TLR3 and IPS-1 pathways respond to the common ligand polyinosinic:polycytidylic acid (polyI:C) to regulate different gene expression patterns as well as CD11c + cell migration in murine-model corneas. However, the differences in the functions and the roles of TLR3 and IPS-1 remain unclear. In this study, we investigated the differences of TLR3 or IPS-1-induced gene expression in corneal epithelial cells (CECs) in response to polyI:C stimulation using cultured murine primary CECs (mPCECs) derived from TLR3 and IPS-1 knockout mice via comprehensive analysis. The genes associated with viral responses were upregulated in the wild-type mice mPCECs after polyI:C stimulation. Among these genes, Neurl3, Irg1, and LIPG were dominantly regulated by TLR3, while interleukin (IL)-6 and IL-15 were dominantly regulated by IPS-1. CCL5, CXCL10, OAS2, Slfn4, TRIM30α, and Gbp9 were complementarily regulated by both TLR3 and IPS-1. Our findings suggest that CECs may contribute to immune responses and that TLR3 and IPS-1 possibly have different functions in the corneal innate immune response.

Long-term outcome of cultivated oral mucosal epithelial transplantation for fornix reconstruction in chronic cicatrising diseases.

BACKGROUND/AIMS: To investigate the long-term outcomes of cultivated oral mucosal epithelial transplantation (COMET) for fornix reconstruction in eyes with chronic cicatrising disease. METHODS: This retrospective cohort study involved 16 eyes of 15 patients who underwent COMET for symblepharon release and fornix reconstruction between June 2002 and December 2008. The mean postoperative follow-up period was 102.1±46.0 months (range: 32-183 months). The treated cicatrising disorders included ocular cicatricial pemphigoid (OCP, five eyes), thermal/chemical injury (three eyes) and other chronic diseases (seven eyes; including recurrent pterygium (two eyes), Stevens-Johnson syndrome (one eye) and graft-versus-host disease (one eye)). Ocular-surface appearance was evaluated before surgery, at 1, 4, 12 and 24 weeks postoperative, and then annually based on the previously reported scoring system. Main outcome measures included overall and disease-specific fornix-reconstruction success probabilities analysed by the Kaplan-Meier survival curve. Symblepharon/fornix-shortening recurrence at 24 weeks postoperative, and its relationship to long-term surgical success was also examined. RESULTS: At 5 years postoperative, the mean±SD overall fornix-reconstruction success probability was 79.6%±10.7%, and success probability for thermal/chemical injury and OCP was 100% and 53.3%±24.8%, respectively (p=0.53, log-rank test). The 3-year success probability was significantly higher in the no-disease-recurrence group at 24 weeks postoperative (13 eyes) than in the disease-recurrence group (three eyes) (100% and 33.3%±27.2%, respectively) (p=0.0073, log-rank test). CONCLUSION: COMET was found to be safe and effective for symblepharon release and long-term fornix reconstruction in eyes with chronic cicatrisation. Although the 5-year success probability differed depend on the underlying disease, ocular-surface appearance at 24 weeks postoperative is a factor for predicting long-term outcome.

Oral Mucosal Epithelial Transplantation and Limbal-Rigid Contact Lens: A Therapeutic Modality for the Treatment of Severe Ocular Surface Disorders.

Stevens-Johnson syndrome, ocular cicatricial pemphigoid, and severe thermal or chemical injury are considered severe ocular surface disorders (OSDs) because they affect the entire ocular surface, including corneal and conjunctival epithelial stem cells. In patients with severe OSDs, the long-term prognosis for limbal transplantation is poor, and the related corneal opacity and cicatrization lead to devastating visual impairment. To date, there is no standardized treatment to improve vision in cases with severe OSD. Investigating novel treatment methods for severe OSDs, our group began cultivated oral mucosal epithelial transplantation in 2002 and developed a limbal-supported rigid-type contact lens that can be applied as a nonsurgical treatment. When used in combination, these treatment methods make it possible to successfully restore vision in cases with severe OSDs.