Calcium-sensing receptor (CaSR) modulates ocular surface chloride transport and its inhibition promotes ocular surface hydration.

PURPOSE: Ocular surface hydration is critical for eye health and its impairment can lead to dry eye disease. Extracellular calcium-sensing receptor (CaSR) is regulator of ion transport in epithelial cells expressing cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel. CFTR is also a major ion channel in ocular surface epithelia, however the roles of CaSR in ocular surface are not well studied. This study aims to investigate expression and functional roles of CaSR in ocular surface. METHODS: CaSR immunostaining was performed in mouse and human cornea and conjunctiva. Ocular surface potential difference (OSPD) and tear fluid volume measurements were performed in mice with topically applied cinacalcet (CaSR activator) and NPS-2143 (CaSR inhibitor). RESULTS: CaSR is expressed in corneal and conjunctival epithelia of mice and humans. Topically administered CaSR activator cinacalcet inhibits cAMP agonist forskolin-induced Cl- secretion and CFTR activity up to 90 %. CaSR inhibitor NPS-2143 stimulates CFTR-mediated Cl- secretion in mouse ocular surface, after which cAMP agonist forskolin had minimal additional secretory effects. Single dose NPS-2143 treatment (as an eye drop) increases tear fluid volume in mice by ∼60 % compared to vehicle treatment. NPS-2143 effect on tear volume lasts at least 8 h after single dose. CONCLUSIONS: CaSR is a key regulator of ocular surface ion transport and CaSR inhibition promotes Cl- and tear secretion in the ocular surface. If they are found to be effective in in dry eye models, CaSR inhibitors (currently in clinical development) can potentially be repurposed as novel prosecretory treatments for dry eye disease.

Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs).

Purpose of Review: This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs). Recent Findings: ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity. Summary: Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

Keratoconus Diagnosis and Treatment: Recent Advances and Future Directions.

Keratoconus is a disorder characterized by progressive corneal thinning and steepening that may result in significant visual impairment secondary to high astigmatism, corneal scarring, or even corneal perforation. Early detection and screening of keratoconus are essential for effective management and treatment. Several screening methods, such as corneal topography and tomography, corneal biomechanics, and genetic testing, are being developed to detect keratoconus at an early stage. Once detected, prevention of progression is the mainstay of keratoconus management. Corneal collagen cross-linking is a minimally invasive treatment option that can slow or halt the progression of keratoconus. Additionally, recent studies have investigated the potential use of copper sulfate eye drops (IVMED-80) and extracellular vesicles to prevent the progression of keratoconus as non-invasive treatment options. For visual rehabilitation, currently available treatments include scleral lenses, intracorneal ring segments, corneal allogenic intrastromal ring segments, and deep anterior lamellar keratoplasty. The safety and efficacy of these emerging treatment options for keratoconus are currently being investigated.

Socioeconomic Correlates of Keratoconus Severity and Progression.

PURPOSE: The purpose of this study was to investigate the social determinants of health for keratoconus. METHODS: In this retrospective cohort study of patients with keratoconus, the electronic health record was reviewed for keratometry, treatments received, clinical comorbidities, and social characteristics. Outcomes included severe keratoconus at presentation (steep keratometry ≥52 diopters), disease progression (≥0.75 diopters increase from the first to the most recent clinical visit), and corneal transplantation. Logistic regression was used to evaluate factors associated with severity at presentation and corneal transplantation. Cox proportional hazards modeling was used to evaluate progression. RESULTS: A total of 1038 patients with keratoconus were identified, 725 (70%) of whom had baseline imaging. Compared with commercially insured patients, Medicaid recipients were more likely to have severe keratoconus, independent of social and clinical confounders [odds ratio (OR) 1.94, 95% confidence interval (CI), 1.12-3.35, P = 0.017]. Male sex was independently associated with progression (hazard ratio = 1.38, 95% CI, 1.03-1.84, P = 0.030). Medicare and Medicaid recipients were more likely to require transplantation compared with commercially insured patients (OR 2.71, 95% CI, 1.65-4.46, P < 0.001 and OR 1.74, 95% CI, 1.08-2.80, P = 0.022, respectively). Other social determinants of health, including non-White race/ethnicity, limited English proficiency, and unemployment, were associated with the outcomes only in univariate analysis. Obstructive sleep apnea, atopy, body mass index, and tobacco use were not associated with any outcome. CONCLUSIONS: Socioeconomic factors were more consistent predictors of keratoconus severity and corneal transplantation compared with clinical factors that have received relatively greater attention in the keratoconus literature.

Ocular Surface Ion Transport and Dry Eye Disease.

Purpose of Review: To review the role of ocular surface epithelial (corneal and conjunctival) ion transporters in the pathogenesis and treatment of dry eye disease (DED). Recent Findings: Currently, anti-inflammatory agents are the mainstay of DED treatment, though there are several agents in development that target ion transport proteins on the ocular surface, acting by pro-secretory or anti-absorptive mechanisms to increase the tear fluid Film volume. Activation or inhibition of selected ion transporters can alter tear fluid osmolality, driving water transport onto the ocular surface via osmosis. Several ion transporters have been proposed as potential therapeutic targets for DED, including the cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channels (CaCCs), and the epithelial sodium channel (ENaC). Summary: Ocular surface epithelial cell ion transporters are promising targets for pro-secretory and anti-absorptive therapies of DED.

Trends in Corneal Topography and Tomography Imaging for Keratoconus Management.

Purpose: To describe trends in the use of corneal topography and tomography for the management of keratoconus patients at a single academic institution and to identify how these trends may be associated with different procedural interventions. Patients and Methods: In this retrospective cohort study, keratoconus patients treated from 2012 to 2019 were identified. The electronic health record was reviewed for the presence of corneal topography or tomography imaging completed within seven days of the first visit and the highest level of intervention at the first and most recent visit. Patients were grouped as pediatric (<18 years) or adult (≥18 years). Chi-square tests and linear regressions were used to evaluate trends and to determine which factors were predictive for receiving corneal collagen cross-linking (CXL) versus other surgical interventions (intrastromal corneal ring segments, lamellar keratoplasty, or penetrating keratoplasty) by the most recent visit. Results: A total of 873 keratoconus patients met inclusion criteria. The use of corneal topography at the first visit remained relatively consistent from 2012 to 2019, while corneal tomography usage at the first visit increased from 3.9% in 2015, when corneal tomography was introduced, to 52.8% in 2019. Each year was associated with an 11.2% ± 1.9% increase in the use of corneal tomography at the first visit in pediatric patients and 6.7% ± 0.5% in adult patients. Use of corneal tomography at the first visit was a significant predictor for receiving CXL procedures (P < 0.001) and a negative predictor for requiring other surgical interventions (P = 0.032) when controlling for the year of the first visit. Conclusion: Obtaining corneal tomography at the first visit has become the standard of care in keratoconus, especially for pediatric patients. Moreover, the increase in corneal tomography imaging has coincided with an increase in CXL procedures and decrease in other surgical interventions.

Parental Keratoconus Literacy: A Socioeconomic Perspective.

Purpose: To assess the impact of parental socioeconomic status and keratoconus literacy on pediatric eye rubbing and keratoconus severity. Methods: In this mixed-methods study, pediatric keratoconus patients (age ≤ 18 years) were retrospectively identified. Sociodemographic and clinical characteristics were extracted from the electronic medical record (EMR). Telephone surveys were subsequently conducted to assess parental keratoconus literacy, receipt of counseling on keratoconus prevention, eye rubbing, and household socioeconomic factors not available in the EMR. Parents reporting poor keratoconus literacy were probed via semi-structured interview to explore barriers to their understanding. Results: Forty-eight patients met inclusion criteria, 22 (46%) of whom were reached by telephone. Most patients were insured by Medicaid (73%) and current eye rubbers (82%). Few parents reported good or excellent keratoconus literacy now (32%) or at the time of diagnosis (18%). Parents with a high-school education, limited English proficiency, lower income level, and Medicaid insurance tended to have lower keratoconus literacy, though this was not statistically significant. Parental keratoconus literacy was not correlated with disease severity. High-school education, limited English proficiency, lower income level, and Medicaid insurance were correlated with steeper keratometry readings, which was statistically significant for high-school education. In-depth interviews revealed parents felt unconfident with eye health in general and perceived a personal responsibility for learning more. Conclusion: This is the first study exploring keratoconus literacy from a socioeconomic perspective, demonstrating lower literacy among socioeconomically marginalized parents and a tendency toward more severe disease in their children.

Resident-performed immediate sequential bilateral cataract surgery during the COVID-19 pandemic.

Purpose: To assess visual outcomes and patient satisfaction for senior resident-performed immediate sequential bilateral cataract surgery (ISBCS) versus delayed sequential bilateral cataract surgery (DSBCS) during the COVID-19 pandemic, when minimizing healthcare-related exposures for patients and providers are paramount. Methods: This was a pilot retrospective cohort study of all ISBCS and DSBCS patients who underwent senior resident-performed cataract surgery from May to September 2020 at a single academic institution. Outcome measures were final corrected distance visual acuity (CDVA), final manifest refraction (MRx), intraoperative and postoperative complications rates, total number of visits, and patient satisfaction assessed postoperatively by telephone questionnaire. Results: Twenty-two eyes of 14 patients and 56 eyes of 28 patients underwent senior resident-performed ISBCS and DSBCS, respectively. Final CDVA was 20/25 or better in 21 (95%) ISBCS and 51 (91%) DSBCS eyes (P = 0.670). Deviation of final MRx from target refraction was within 0.50 D in 17 (77%) ISBCS and 47 (84%) DSBCS eyes (P = 0.522). There was no significant difference in intraoperative (P = 1.000) or postoperative (P = 1.000) complications. ISBCS patients averaged 3.5 fewer visits than DSBCS patients (5.9 vs 9.5, P < 0.001). All ISBCS and 20 DSBCS patients (87%) reported they were "very satisfied" or "satisfied" with their experience (P = 0.701). Five of six senior residents responded that they preferred performing ISBCS over DSBCS. Conclusion: This early experience suggests that senior resident-performed ISBCS is as safe and effective as DSBCS, with the added benefit of averaging fewer in-person visits. Residency programs should consider offering senior resident-performed ISBCS to select patients during the COVID-19 pandemic.

Ocular Surface Potential Difference Measured in Human Subjects to Study Ocular Surface Ion Transport.

Purpose: The epithelium lining the ocular surface, which includes corneal and conjunctival epithelia, expresses the prosecretory chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) and the proabsorptive epithelial sodium channel (ENaC). Here, methodology was established to measure the millivolt (mV) potential differences at the ocular surface, called ocular surface potential difference (OSPD), in human subjects produced by ion transport. Methods: OSPD was measured in human subjects in which a fluid-filled measuring electrode contacted a fluid pool created by eversion of the lateral lower eyelid, with a reference electrode placed subcutaneously in the forearm. Through the use of a high-impedance voltmeter, OSPD was measured continuously over 10 to 15 minutes in response to a series of perfusate fluid exchanges. Results: Baseline OSPD (± SEM) in six normal human subjects was -21.3 ± 3.6 mV. OSPD depolarized by 1.7 ± 0.6 mV following the addition of the ENaC inhibitor amiloride, hyperpolarized by 6.8 ± 1.5 mV with a zero chloride solution, and further hyperpolarized by 15.9 ± 1.6 mV following CFTR activation by isoproterenol. The isoproterenol-induced hyperpolarization was absent in two cystic fibrosis subjects lacking functional CFTR. OSPD measurement produced minimal epithelial injury. Conclusions: Our results establish the feasibility and safety of OSPD measurement in humans and demonstrate robust CFTR activity, albeit minimal ENaC activity, at the ocular surface. OSPD measurement may be broadly applicable to investigate fluid transport mechanisms and test drug candidates to treat ocular surface disorders. Translational Relevance: To the best of our knowledge, this is the first measurement of the electrical potential generated by the ocular surface epithelium in human subjects, offering a new approach to study ocular surface function and health.

Corneal Collagen Cross-Linking Under General Anesthesia for Pediatric Patients With Keratoconus and Developmental Delay.

PURPOSE: To report the clinical characteristics and outcomes of pediatric patients with keratoconus (KCN) who underwent corneal collagen cross-linking (CXL) under general anesthesia for developmental delay or inability to cooperate with topical anesthesia. METHODS: In this retrospective case series, we reviewed the medical charts of pediatric patients with KCN who had CXL under general anesthesia from January 2018 to April 2019. Baseline disease characteristics of patients with and without developmental delay were compared using the Pearson χ test and the t test. Main outcomes were anesthesia or surgical complications and postoperative best corrected visual acuity (BCVA), keratometry (K) values, and caregiver report of eye-rubbing behavior. RESULTS: Fourteen eyes of 9 patients were reviewed. All were habitual eye rubbers at baseline. Six (66.7%) were developmentally delayed. Compared with patients without developmental delay, developmentally delayed patients were diagnosed and treated at older ages (16.0 vs. 13.9 years), experienced longer delays from diagnosis to surgery (20.7 vs. 8.8 weeks), and had lower BCVA (20/70 vs. 20/40), higher steep K values (54.0 vs. 50.9), and a higher incidence of corneal scarring (75.0% vs. 33.3%) and monocular vision loss (50.0% vs. 0.0%) at baseline, although these differences were not statistically significant. No anesthesia or surgical complications occurred. BCVA and K values were stable at postoperative month 6, with no clinically or statistically significant change observed for either measure. Eight patients decreased or stopped eye rubbing. CONCLUSIONS: We demonstrate the efficacy and safety of CXL under general anesthesia in halting the progression of KCN for pediatric patients with developmental delay or an inability to cooperate with the procedure until topical anesthesia.

Remote corneal suturing wet lab: microsurgical education during the COVID-19 pandemic.

PURPOSE: To study the feasibility and efficacy of a new remote wet lab for microsurgical education using a corneal suturing task. SETTING: Department of Ophthalmology, University of California San Francisco, San Francisco, California, USA. DESIGN: Prospective randomized controlled study. METHODS: Ten ophthalmology residents were stratified by postgraduate year and randomized to perform a corneal suturing task consisting of placing the 4 cardinal sutures for a penetrating keratoplasty in porcine eyes with or without remote ophthalmology attending feedback. Subsequently, both groups repeated the same task without remote feedback to test whether initial remote feedback affected subsequent performance. Finally, the group without feedback was crossed over to repeat the same corneal suturing task with remote feedback. The effectiveness of the remote wet lab was assessed subjectively by survey and objectively by grading each suture pass. RESULTS: Resident-reported comfort with corneal suturing improved significantly after the remote wet lab for all residents. Residents and attendings rated the remote wet lab as equally or more effective compared with previous in-person wet labs and overall effective in corneal suturing. Attendings rated the remote wet lab as effective in multiple domains of microsurgical education using a modified microsurgical global rating scale. Objective corneal suturing performance was similar for both groups. CONCLUSIONS: The remote wet lab was feasible and effective for training ophthalmology residents in corneal suturing. This represents a new social distancing compliant platform for microsurgical education during the COVID-19 pandemic.

Nanomolar Potency Aminophenyltriazine CFTR Activator Reverses Corneal Epithelial Injury in a Mouse Model of Dry Eye.

Purpose: Dry eye disorders are a major health care burden. We previously reported the identification of N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine [cystic fibrosis transmembrane conductance regulator (CFTR)act-K267], which activated human wild-type CFTR chloride conductance with EC50 ∼ 30 nM. Here, we report in vivo evidence for CFTRact-K267 efficacy in an experimental mouse model of dry eye using a human compatible ophthalmic vehicle. Methods: CFTR activation in mice in vivo was demonstrated by ocular surface potential difference (OSPD) measurements. Ocular surface pharmacodynamics was measured in tear fluid samples obtained at different times after topical administration of CFTRact-K267. Dry eye was produced by lacrimal duct cautery (LDC) and corneal epithelial injury and was assessed by Lissamine green (LG) staining. Results: OSPD measurements demonstrated a hyperpolarization of -8.6 ± 3 mV (standard error of the mean, 5 mice) in response to CFTRact-K267 exposure in low chloride solution that was reversed by a CFTR inhibitor. Following single-dose topical administration of 2 nmol CFTRact-K267, tear fluid CFTRact-K267 concentration was >500 nM for more than 6 h. Following LDC, corneal surface epithelial injury, as assessed by LG staining, was substantially reversed in 10 of 12 eyes receiving 2 nmol CFTRact-K267 3 times daily starting on day 2, when marked epithelial injury had already occurred. Improvement was seen in 3 of 12 vehicle-treated eyes. Conclusion: These studies provide in vivo evidence in mice for the efficacy of a topical, human use compatible CFTRact-K267 formulation in stimulating chloride secretion and reversing corneal epithelial injury in dry eye.

Hyphema from Iris Melanocytoma.

Using multimodal imaging, we demonstrate a classic iris melanocytoma presenting with recurrent, spontaneous hyphema in a young female patient. The patient has been observed without tumor growth. Hyphema has not been previously reported to occur with iris melanocytoma.

Influence of corneal diameter on surgically induced astigmatism in small-incision cataract surgery.

OBJECTIVE: Clear corneal incisions (CCI) in cataract surgery create a variable amount of surgically induced astigmatism (SIA). As refractive outcomes become increasingly important, it is necessary to understand factors that impact SIA and refractive surprises. In this study, we evaluate the effect of horizontal corneal diameter (white-to-white, WTW) on SIA in 2.2 mm small-incision cataract surgery. DESIGN: Prospective study at an academic-university-based outpatient clinic (Duke Eye Center). PARTICIPANTS: We enrolled adults ≥18 years of age without prior corneal surgery or corneal pathology undergoing cataract surgery with a single surgeon (R.R.V.). METHODS: All surgeries were uncomplicated and performed through a manually constructed, limbal, temporal, or superotemporal 2.2 mm CCI. Enrolled participants received standard-of-care evaluations and postoperative management. SIA was calculated at the first postoperative month using the Jaffe and Clayman vector analysis equation. RESULTS: We enrolled 43 subjects (55 eyes) with a mean age of 71 years with WTW corneal diameter values ranging from 11.34 to 12.99 mm obtained from Lenstar® (Haag-Streit Group, Koeniz, Switzerland). Postoperative SIA ranged from 0.072 to 1.6 D (mean 0.47 D, standard deviation 0.33 D). SIA was plotted against WTW and best fit to a linear regression model with a slope of -0.056 and an R2 value of 0.006. CONCLUSIONS: In this prospective study, WTW diameter had minimal effects on the SIA in uncomplicated small-incisional cataract surgery through a 2.2 mm temporal or superotemporal CCI with a single surgeon. Our findings suggest that corneal diameter does not play a clinically significant role in this population undergoing small-incisional cataract surgery.

Intraocular Pressure and Big Bubble Diameter in Deep Anterior Lamellar Keratoplasty: An Ex-Vivo Microscope-Integrated OCT With Heads-Up Display Study.

PURPOSE: To investigate the relationship between intraocular pressure (IOP) and big bubble (BB) formation in a model of deep anterior lamellar keratoplasty (DALK). DESIGN: Ex-vivo. METHODS: Corneoscleral buttons from human donors were loaded onto an artificial anterior chamber connected to a column of balanced salt solution. A surgeon-in-training learned to perform DALK via the BB technique using swept-source microscope-integrated optical coherence tomography (SS-MIOCT) with heads-up display (HUD). DALK procedures were performed at 6 different IOPs (5, 10, 15, 20, 30, or 40 mm Hg; n = 6 per group) in a randomized fashion, with the surgeon-in-training masked to the pressure and guided by SS-MIOCT with HUD. For a subset of corneas within each pressure group, DALK was performed on matching donor tissue at a control IOP. BB diameter was recorded, and a diameter exceeding the trephine diameter was considered optimal. RESULTS: Wilcoxon rank sum test showed a difference in BB diameter among the different pressure groups (mean ± SD of 7.75 ± 1.60, 8.33 ± 1.99, 10.9 ± 0.92, 9.08 ± 1.07, 6.67 ± 3.33, and 3.42 ± 3.77 mm in the 5, 10, 15, 20, 30, and 40 mm Hg groups, respectively; P = 0.0014). Per Tukey test, this difference was attributable to comparisons between the 40 mm Hg group and the 5, 10, 15, or 20 mm Hg groups (P = 0.04, 0.02, 0.0001, 0.004, respectively). CONCLUSIONS: In this ex-vivo model of DALK, the BB technique guided by SS-MIOCT with HUD yielded bubbles of optimal diameters only at physiologic pressures (10‒20 mm Hg). Extremely high IOP (40 mm Hg) resulted in BBs of significantly smaller diameter than BBs obtained at physiologic and low (5 mm Hg) IOPs.

Four-dimensional Microscope-Integrated Optical Coherence Tomography to Visualize Suture Depth in Strabismus Surgery.

The authors report the use of swept-source microscope-integrated optical coherence tomography (SS-MIOCT), capable of live four-dimensional (three-dimensional across time) intraoperative imaging, to directly visualize suture depth during lateral rectus resection. Key surgical steps visualized in this report included needle depth during partial and full-thickness muscle passes along with scleral passes. [J Pediatr Ophthalmol Strabismus. 2017;54:e1-e5.].