Immediate and Delayed Effects of Punctal Plug Insertion on Tear Meniscus Height in Severe Aqueous-Deficient Dry Eye.

PURPOSE: The aim of this study was to assess the immediate and delayed effects of tear punctal occlusion with punctal plugs on tear meniscus height (TMH) in severe aqueous-deficient dry eye (ADDE) disease. METHODS: Consecutive patients with severe ADDE related to Sjögren syndrome or ocular graft-versus-host disease underwent inferior and superior occlusion with punctal plugs. TMH was measured using the LacryDiag ocular surface analyzer platform before, 10 minutes, and at least 1 month after punctal occlusion. The corneal fluorescein staining (CFS) score was graded with the Oxford scale (from 0 to 5). Ocular symptoms were graded with a visual analog scale (from 1 to 10). RESULTS: We included 24 eyes of 24 patients (mean age 61 ± 9 years; mean follow-up 7 ± 5 months). The mean TMH was 0.19 ± 0.06 mm at baseline and increased significantly to 0.41 ± 0.13 mm (P < 0.001) and 0.46 ± 0.17 mm (P < 0.001) at 10 minutes after punctal plug insertion and at the end of follow-up, respectively. The median CFS score decreased from 3 ± 1 before plug insertion to 1 ± 2 at the end of follow-up (P < 0.001). Many patients (67%; n = 16) reported subjective improvement of symptoms. TMH was negatively correlated with the CFS score and visual analog scale score assessing symptoms. CONCLUSIONS: Upper and lower punctal occlusion increased TMH in patients with severe ADDE as soon as 10 minutes after plug insertion. TMH remained stable over time, which led to the relief of symptoms and reduced corneal staining.

Double-Docking Technique for Femtosecond Laser-Assisted Deep Anterior Lamellar Keratoplasty: A Retrospective Consecutive Case Series Study of Advanced Keratoconus.

PURPOSE: The aim of this study was to report the clinical outcomes and prognosis of femtosecond laser (FSL)-assisted double-docking deep anterior lamellar keratoplasty (DD-DALK) for advanced keratoconus (AK). METHODS: Records of consecutive patients with keratoconus who underwent FSL-assisted DALK (DD-DALK) were reviewed. RESULTS: We analyzed 37 eyes from 37 patients who underwent DD-DALK. Sixty-eight percent of eyes had a successful big-bubble formation and 27% had a manual dissection to achieve the DALK deep dissection. Stromal scarring was associated with not achieving a big bubble. Intraoperative conversion to penetrating keratoplasty was conducted in 2 cases (5%). The best-corrected visual acuity improved from a median (± interquartile range) of 1.55 ±0.25 logMAR preoperatively to 0.2 ±0.2 logMAR ( P < 0.0001). The median postoperative spherical equivalent was -5.75 ±2.75 D with a median astigmatism of -3.5 ±1.3 D. BCVA, SE, and astigmatism were not statistically different between patients who underwent DD-DALK and patients who underwent manual DALK. Stromal scarring was associated with big-bubble (BB) formation failure ( P = 0.003). All patients with failed BB requiring manual dissection had anterior stromal scarring. CONCLUSIONS: DD-DALK is safe and reproducible. The success rate of BB formation is hampered by stromal scarring.

Severe Corneal Involvement Associated With Mpox Infection.

This article discusses 2 cases of severe corneal involvement during mpox.

Predictive factors of graft detachment and rebubbling after descemet membrane endothelial keratoplasty.

PURPOSE: To identify risk and predictive factors associated with the need of rebubbling in the eye of patients who underwent a descemet membrane endothelial keratoplasty (DMEK). METHODS: The records of patients who underwent DMEK were retrospectively analyzed. Data regarding comorbidities, intraoperative characteristics, and postoperative treatments or complications were collected. The central corneal thickness (CCT) was measured by optical coherence tomography before and the day after DMEK. Univariate and multivariate analyses were performed. RESULTS: Of the 333 DMEK, rebubbling was performed in 119 cases (36%). Preoperative subepithelial fibrosis and a history of penetrating keratoplasty (PK) were associated with significantly more graft detachment [OR of 3.55 (2.02-6.32; P < 0.001) and 5.89 (2.00-21.86; P = 0.003), respectively]. A decreased CCT the day after surgery reduced by 5.7-fold the risk of rebubbling (sensitivity/specificity of 0.42/0.93). Conversely, a 20% increase in the CCT the day after surgery increased by 4.5-fold the risk of rebubbling (sensitivity/specificity of 0.42/0.91). CONCLUSION: Variation of the CCT could be used as a predictive factor of rebubbling after DMEK. Patients with a 20% increase of CCT the day after surgery are at higher risk of graft detachment. Conversely, a reduced CCT the day after the surgery is associated with a reduced risk of rebubbling. Subepithelial fibrosis and history of PK were also identified as risk factors for rebubbling. Those predictive factors may help develop a customized approach for patients undergoing DMEK surgery.

Detecting Subclinical Corneal Edema Using Corneal Thickness Mapping in Patients Presenting Fuchs Endothelial Corneal Dystrophy.

PURPOSE: To determine whether local corneal thickness changes observed with optical coherence tomography (OCT) can detect subclinical corneal edema in Fuchs endothelial corneal dystrophy (FECD). SETTING: Retrospective cohort study. METHODS: A series of patients presenting FECD who underwent cataract surgery alone (45 eyes) or with concomitant Descemet membrane endothelial keratoplasty (triple procedure; 117 eyes). The study reviewed medical records, collected the preoperative corneal thickness map and calculated the differences and ratio of corneal thickness measured at 5, 7, and 9 mm from the central corneal thickness. Area under the receiver operating characteristic curves (AUCs) were calculated and thresholds were selected to obtain a specificity of 90%. RESULTS: The median difference between 5- and 2-mm corneal thickness in the supra-nasal quadrant (∆5-2mmSN) was 38 µm (interquartile range 34-46) in the cataract group and 17 µm (2-38) in the triple procedure group (P < .001). The corneal thickness ratios of supra-nasal 5- to 2-mm (R5/2mmSN) and 7- to 2-mm (R7/2mmSN) were 1.07 (1.06-1.08) and 1.15 (1.13-1.17)] in the cataract group and 1.03 (1.00-1.06) and 1.09 (1.06-1.14) in the triple procedure group (P < .001). The probability of corneal edema was increased 7-fold with ∆5-2mm SN < 27 µm (AUC = 0.76) and 9.4- and 7.4-fold with R5/2mmSN and R7/2mmSN < 1.045 (AUC = 0.77) and 1.118 (AUC = 0.76), respectively. CONCLUSIONS: Local changes in corneal thickness may be useful in detecting preclinical corneal edema, especially in patients with FECD undergoing cataract surgery.

Meganuclease targeting HSV-1 protects against herpetic keratitis: Application to corneal transplants.

Herpes simplex virus (HSV) infection is a leading cause of corneal blindness. However, keratoplasty is only rarely proposed due to the high frequency of graft failure and associated recurrences. Gene therapy of the corneal graft might provide sustained protection against HSV infection. To test that hypothesis, we designed a meganuclease specific to an HSV-1 DNA sequence coding for major capsid protein (UL19) and selected an adeno-associated virus type-2 as the vector. Meganuclease was transduced into corneas and its effect was challenged in vitro, ex vivo, and then in vivo in a rabbit HSV-1-infection model of stromal keratitis and endotheliitis. In vivo, meganuclease exposure resulted in fewer infected stromal and endothelial cells, and protected against corneal opacification and edema. Ex vivo, HSV-1 infection rates of meganuclease-treated human corneas were drastically reduced. Furthermore, genetically engineered corneas transplanted in vivo into rabbit eyes protected against HSV-1 infection. This genome-editing technology targeting HSV-1 opens new opportunities to manage severe post-herpetic corneal blindness by providing infected patients with genetically protected corneal transplants.

Clinical course and treatment of archipelago keratitis: a Herpesviridae keratitis subtype.

PURPOSE: Archipelago keratitis (ApK) is a subtype of Herpesviridae stromal keratitis that consists of subepithelial nummular inflammatory infiltrates arranged in a radial centripetal pattern. This rare and poorly described form is not often recognised early. We report the first large series of ApK, with an analysis of clinical settings at presentation, evolution of the disease with time and a description of factors associated with recurrence. METHODS: The clinical records of 82 patients (83 eyes) with a diagnosis of ApK between 2011 and 2021 in two centres were reviewed. RESULTS: The median age of the 82 patients at referral was 37±28 years. ApK was unilateral in all but one case. A total of 76% of patients had at least one second diagnostic criteria suggesting a herpetic aetiology. Overall, 44 (53%) eyes exhibited least one recurrence after a median of 12 months. Recurrence was frequently associated with neovascularisation (HR 2.1, 95% CI 1.1 to 3.9; p=0.02) and tapering corticosteroids (HR 3.5, 95% CI 1.8 to 7.1; p<0.01) or valaciclovir use (HR=2.3, 95% CI 1.2 to 4.6; p=0.01). Antiviral treatment was used in all patients, whereas local anti-inflammatory drugs such as corticosteroids and/or ciclosporin were used in 73 (88%) cases. CONCLUSION: ApK is a Herpesviridae stromal keratitis that is typically unilateral in presentation and features a high risk of recurrence. Combined treatment with antiviral and anti-inflammatory drugs are usually required over the long term. Topical ciclosporin can be useful as a corticosteroid-sparing treatment.

Alleviation of Endoplasmic Reticulum Stress Enhances Human Corneal Epithelial Cell Viability under Hyperosmotic Conditions.

Tear hyperosmolarity plays an essential role in the initiation and progression of dry-eye disease. Under a hyperosmotic environment, corneal epithelial cells experience perturbations in endoplasmic reticulum function that can lead to proinflammatory signaling and apoptosis. In this study, we investigated the effect of tauroursodeoxycholic acid (TUDCA), a chemical chaperone known to protect against endoplasmic reticulum stress, on corneal epithelial cells exposed to hyperosmotic conditions. We found that the expression of the genes involved in the activation of the unfolded protein response and the pro-apoptotic transcription factor DDIT3 were markedly upregulated in patients with Sjögren's dry-eye disease and in a human model of corneal epithelial differentiation following treatment with hyperosmotic saline. Experiments in vitro demonstrated that TUDCA prevented hyperosmotically induced cell death by reducing nuclear DNA fragmentation and caspase-3 activation. TUDCA supplementation also led to the transcriptional repression of CXCL8 and IL5, two inflammatory mediators associated with dry-eye pathogenesis. These studies highlight the role of hyperosmotic conditions in promoting endoplasmic reticulum stress in the cornea and identify TUDCA as a potential therapeutic agent for the treatment of dry-eye disease.

Glycogene Expression Profile of Human Limbal Epithelial Cells with Distinct Clonogenic Potential.

Glycans function as valuable markers of stem cells but also regulate the ability of these cells to self-renew and differentiate. Approximately 2% of the human genome encodes for proteins that are involved in the biosynthesis and recognition of glycans. In the present study, we evaluated the expression of a small subset of glycogenes in human limbal epithelial cells with distinct clonogenic potential. Individual clones were classified as abortive or clonogenic, based on the fraction of the terminal colonies produced; clones leading exclusively to terminal colonies were referred to as abortive while those with half or fewer terminal colonies were referred to as clonogenic. An analysis of glycogene expression in clonogenic cultures revealed a high content of transcripts regulating the galactose and mannose metabolic pathways. Abortive clones were characterized by increased levels of GCNT4 and FUCA2, genes that are responsible for the branching of mucin-type O-glycans and the hydrolysis of fucose residues on N-glycans, respectively. The expansion of primary cultures of human limbal epithelial cells for 10 days resulted in stratification and a concomitant increase in MUC16, GCNT4 and FUCA2 expression. These data indicate that the clonogenic potential of human limbal epithelial cells is associated with specific glycosylation pathways. Mucin-type O-glycan branching and increased fucose metabolism are linked to limbal epithelial cell differentiation.

Role of CD147 (EMMPRIN/Basigin) in Tissue Remodeling.

CD147, also known as extracellular matrix metalloproteinase inducer (EMMPRIN) or basigin, is expressed in a variety of cell types. It is involved in the regulation of extracellular matrix (ECM) remodeling during physiological and pathological processes including wound healing, inflammatory diseases, and cancer. CD147 is a diagnostic and therapeutic target in cancer and inflammatory diseases, either directly or indirectly, by targeting CD147 partners. It can trigger matrix metalloproteinase inductions involved in ECM degradation, cell adhesion, and cell-cell interactions. It can also induce myofibroblast differentiation associated with ECM deposition and contraction. The shift from fibrosis to lysis, and vice versa, is poorly understood and could involve CD147. This article provides an overview of the role of CD147 in the regulation of ECM remodeling processes and discusses the involvement of the microenvironment in the modulation of its downstream effects. Understanding CD147 regulation could help identify new therapeutic intervention. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

Neurotrophic keratitis: Frequency, etiologies, clinical management and outcomes.

PURPOSE: To determine neurotrophic keratitis (NK) frequency, etiologies and prognostic factors, and evaluate the outcome of its management. METHODS: In this retrospective epidemiologic study, we reviewed the electronic records of all patients consulting our tertiary referral eye hospital between November 2009 and October 2017. NK was defined as corneal hypoesthesia or anesthesia associated with epithelial irregularities. RESULTS: Among the 305,351 patients' files screened for eligibility, 335 (354 eyes) were included, yielding an NK frequency of 11/10,000 (0.11%). Their mean ± SD age was 63.1 ± 21.0 years. Eyes were equally divided among the Mackie classification 3 stages. The most frequent etiology was herpetic eye disease (114 eyes; 32.2%). A multifactorial cause was found for 121 (34.2%) eyes. Surgery required for 118 eyes (33.3%). Respective success rates for amniotic membrane transplantation (AMT) or matrix-regeneration of stages 2 and 3, and autologous serum of stage 1 were 57.2%, 63.6% and 21.7%, with mean healing times of 15.0, 16.3 and 85 days. The overall healing rate was 79.5%, with a mean of 44.8 days to healing. Advanced initial stage, diminished corrected-distance visual acuity (CDVA) and advanced age correlated with worse final CDVA. CONCLUSIONS: NK was more frequent than previously reported in the literature. Delayed diagnoses indicated we must increase ophthalmologists' awareness of this disease for patients with decreased corneal sensitivity and abnormal epithelium. To improve prognosis and final CDVA, NK-specific treatment should be initiated as soon as the diagnosis is suspected. Patient-centered combinations of different therapeutic components and close monitoring achieved promising results.

Therapeutic Challenges and Prognosis of Descemet's Membrane Endothelial Keratoplasty in Herpes Simplex Eye Disease.

PURPOSE: To describe the functional outcome, postoperative complications, and complication management of Descemet's membrane endothelial keratoplasty (DMEK) in corneal decompensation secondary to Herpes simplex eye disease (HED). METHODS: This retrospective interventional case series included 17 eyes that received DMEK for endothelial decompensation secondary to HED. Complete ophthalmological examination, including corrected-distance visual acuity (CDVA), anterior segment slit-lamp, and optical coherence tomography assessment, were performed preoperatively and postoperatively at regular follow-up intervals. Visual outcome and complication rates were compared with those of 72 consecutive eyes that received DMEK for Fuchs endothelial corneal dystrophy (FECD) and pseudophakic bullous keratopathy (PBK) during the same period. RESULTS: Mean follow-up time was 11.1 ± 5.9 months (range 6-27). CDVA improved from 1.16 ± 0.46 logMAR to 0.62 ± 0.44 logMAR (P = 0.001). Corneal pachymetry significantly decreased from 695 ± 53 µm at day 1 to 569 ± 88 µm at 2 months (P < 0.001). Postoperative complications occurred in 12 eyes, including primary graft failure (12%), endotheliitis (29%), corneal ulcers (35%), and cystoid macular edema (18%). Most complications occurred shortly after surgery, with a median delay of 2.5 months. In comparison, the complication rates for DMEK in FECD and PBK were significantly lower (no graft failure, P = 0.005; no endotheliitis, P < 0.001; no corneal ulcers, P < 0.001 and 3% cystoid macular edema, P = 0.046). CONCLUSIONS: DMEK surgery significantly improved CDVA in patients with endothelial decompensation due to HED. The rate of postoperative complications was higher than for FECD and PBK. Close follow-up is mandatory and the rate of postoperative inflammatory events suggests that patients should be kept on high doses of oral valacyclovir.

Artificial chamber and 3D printed iris: a new wet lab model for teaching Descemet's membrane endothelial keratoplasty.

PURPOSE: To describe a new wet lab model of Descemet membrane endothelial keratoplasty (DMEK) using human corneas mounted on an artificial anterior chamber with an artificial iris and to compare the performance time and scores between beginners and experienced anterior segment surgeons. METHODS: Corneas were mounted on an artificial chamber. To simulate an anterior chamber and to avoid loosing the graft into the tubing, a 3D printed iris was added. Each DMEK procedure required only one cornea for graft preparation, insertion, orientation, unfolding and centration. Ten human research corneas were used for training purposes. Intraoperative OCT was only used to validate the different steps of the procedure. Operators were divided into two groups, two beginners and three experienced DMEK surgeons. RESULTS: All DMEK procedures were successfully performed. Descemet's tears were frequent but harvesting was successful in all procedures. All combinations of graft unfolding techniques were possible. Experienced surgeons performed statistically better then beginners with faster harvesting (12.8 versus 28.2 min; p = 0.02) and insertion (13.5 versus 20.8 min; p = 0.05) times and better performance score (94 versus 52; p = 0.03). CONCLUSION: This DMEK wet lab model offers a close to reality, feasible, resource-sparing and valid teaching technique that permits to perform all DMEK surgical steps. It also offers the possibility of varying the surgical difficulty by changing the anterior chamber depth.

Double-Docking Technique for Femtosecond Laser-Assisted Deep Anterior Lamellar Keratoplasty.

PURPOSE: To describe a new and safe surgical technique of deep anterior lamellar keratoplasty (DALK) using the femtosecond laser (FSL) and intraoperative optical coherence tomography (iOCT) for surgical management of corneal thinning and/or opacities. The technique was coined the double-docking procedure for DALK (DD-DALK). METHODS: FSL-integrated iOCT was used for direct visualization and calibration to perform precise anterior lamellar and side cuts for the removal of the anterior stroma. Air was then injected in the residual posterior stroma to detach Descemet membrane [big-bubble (BB) formation]. Returning the residual posterior stroma into the docked position, a cylindrical vertical cut was made with the FSL to securely open the BB roof. Next, the stromal roof of the BB was removed with forceps leaving Descemet membrane intact, followed by a lamellar corneal graft. RESULTS: Anterior stroma resection, BB formation, and residual stromal resection were achieved in every case without perforation. The curved applanation surface helped to limit the formation of folds on the posterior stroma (ie, advanced thinning). CONCLUSIONS: DD-DALK is a reproducible and safe procedure for surgical management of corneal thinning and/or opacities. The precision of stromal cuts made by the FSL and iOCT guidance for air injection increases success in DD-DALK preparation.

TFOS DEWS II pathophysiology report.

The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjögren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

Management of severe and refractory Mooren's ulcers with rituximab.

PURPOSE: Management of severe and refractory Mooren's ulcers is challenging as it encompasses tectonic surgical treatment and aggressive immunosuppressive therapies. Efficacy of rituximab in the management of severe Mooren's ulcers has never been reported. METHODS: Five patients (six eyes) from the Cornea and External Disorders department at the Rothschild Ophthalmologic Foundation (Paris, France) were treated for severe Mooren's ulcer unresponsive to conventional treatments between 2008 and 2016. Conventional treatment included topical steroid and ciclosporin 2%, high doses of systemic corticosteroids and/or cyclophosphamide and conjunctival resection with amniotic membrane graft. These patients received two infusions of 1000 mg of rituximab at 2 weeks interval. Epithelial healing, inflammation, additional surgery, systemic corticosteroids and rituximab-related side effects were reported. RESULTS: The mean follow-up was 46.8 months. Following rituximab treatment, we observed a complete healing of Mooren's ulcer within 2 weeks in all patients. Peripheral lamellar keratoplasty was associated when peripheral corneal perforation occurred (5/6 affected corneas). Systemic corticosteroids had been discontinued in all patients. Two recurrences occurred 13 and 53 months after the first rituximab infusion and where successfully treated with a new infusion. No rituximab-related adverse events were reported. CONCLUSIONS: Rituximab was effective in the management of severe Mooren's ulcers and could be an alternative to cyclophosphamide. Additional studies should assess the role of this biotherapy in the management of immunological corneal ulcer.

Unusual Severe Interface Inflammation After Uneventful Small Incision Lenticule Extraction (SMILE).

PURPOSE: To describe a 40-year-old woman who complained of visual loss in her left eye 3 days after an uneventful bilateral myopic refractive surgery by small incision lenticule extraction (SMILE). METHODS: Case report. RESULTS: A 4 × 5 mm anterior central stromal infiltration was observed with moderate pain associated with decreased corneal sensitivity and neither discharge nor fluorescein staining. Bacterial and fungal smears and cultures from the SMILE interface were negative and local antibiotic ineffective. She was subsequently treated with peribulbar dexamethasone injections and oral valacyclovir. Corneal infiltration disappeared progressively, replaced by fibrotic stromal scarring. Optical coherence tomography displayed stromal hyperreflectivity mostly located above the lenticule cut with slight involvement of posterior stroma. In vivo confocal microscopy demonstrated activated keratocytes and highlighted the lack of subbasal corneal nerves in her left eye contrasting with her right eye. CONCLUSIONS: Stromal herpetic keratitis could be considered a potential differential diagnosis to this atypical lamellar keratitis after a SMILE procedure. [J Refract Surg. 2016;32(12):855-857.].

Sclerocorneal Intrastromal Lamellar Keratoplasty for Pellucid Marginal Degeneration.

PURPOSE: Surgical management of advanced pellucid marginal degeneration is challenging. To correct both corneal thinning and induced corneal astigmatism, we propose a modified intrastromal lamellar sclero-keratoplasty. METHODS: Corneal thinning was mapped using perioperative optical coherence tomography (OCT). Then through a scleral tunnel, an intrastromal pocket was created by stromal lamellar dissection under OCT guidance. A 300 µm-thick stromal lamellar graft was inserted in that pocket before closing the sclera to increase vertical median keratometry. RESULTS: Intrastromal lamellar sclero-keratoplasty enabled corneal thinning correction and increased corneal astigmatism correction (-11.6 diopters) without complications. CONCLUSIONS: Intrastromal lamellar keratoplasty with scleral tunnel is efficient in PMD. Corneal thinning is corrected with the intrastromal lamellar keratoplasty, and scleral tunnel closure allows increased corneal astigmatism correction. Perioperative OCT guidance allows better detection of the diseased cornea and is helpful for the lamellar dissection.