Double-Scroll Formation by Fluid Column Manipulation in Preloaded DMEK Grafts Prepared From Younger and Older Donor Tissue.

PURPOSE: The purpose of this study was to determine whether manipulation of preloaded single-scroll Descemet membrane endothelial keratoplasty (DMEK) grafts within the fluid column of an injector can safely and reliably result in formation of double-scroll DMEK grafts and whether there are differential effects on younger versus older donor tissue. METHODS: Pairs of DMEK grafts prepared from older (65-80 years) and younger (48-64 years) donors were preloaded into a Straiko modified Jones tube. One member of the pair was manipulated within the fluid column to form a double-scroll graft, and the other remained unmanipulated. Outcomes measured include success rate for double-scroll formation, endothelial cell loss (ECL), and relative scroll width. RESULTS: Older donor grafts formed double scrolls with a 100% success rate. ECL of older donor manipulated grafts was statistically higher than that of unmanipulated mate grafts (17.4% ± 3.5% vs. 13.0% ± 4.2%, P = 0.03), but was still within the acceptable range for transplant. Younger donor grafts were successfully manipulated into double scrolls with a 67% success rate, and there was no difference in the ECL of manipulated and unmanipulated grafts (15.5% ± 4.4% vs. 13.0% ± 4.5%, P = 0.24). For all grafts and conformations, there was a significant relationship between relative scroll width and ECL ( P < 0.01). CONCLUSIONS: Fluid column manipulation can be used reliably to form double-scroll DMEK grafts. For younger donor grafts, manipulation yields a double scroll without increasing ECL. For older donor grafts, manipulation results in a minimal, acceptable increase in ECL. Surgeons should weigh the advantage of an easily opened graft against the risk of increased ECL when considering this technique.

Retinoblastoma presenting as pseudohypopyon and preserved visual acuity.

PURPOSE: To describe a Case of retinoblastoma that presented subtly as a pseudohypopyon in a child with preserved visual acuity. OBSERVATIONS: A 3-year-old male was referred for concern of hypopyon in the left eye. Initial examination revealed 20/30 vision, a pseudohypopyon, and a large white mass on fundoscopy. Examination under anesthesia revealed extensive retinoblastoma with vitreous seeds and anterior chamber involvement. Enucleation was performed and histology demonstrated retinoblastoma with tumor cells found within the ciliary body, iris, iridocorneal angle, and Schlemm canal. Based on the high-risk histopathology findings, adjuvant chemotherapy was performed. CONCLUSIONS AND IMPORTANCE: Retinoblastoma is the most common primary intraocular malignancy in children. Though the classic presentation is leukocoria and/or strabismus, it can present in a variety of ways. Physicians should be aware that retinoblastoma, even severe forms, can present subtly with pseudohypopyon and preserved vision. Adjuvant chemotherapy for anterior segment involvement remains controversial.

Association of Metformin Use With Age-Related Macular Degeneration: A Case-Control Study.

Importance: Age-related macular degeneration (AMD), the leading cause of irreversible blindness in older adults, appears to have no effective preventive measures. The common antidiabetic drug metformin has been shown to have protective outcomes in multiple age-associated diseases and may have the potential to protect against the development of AMD. Objective: To determine whether metformin use is associated with reduced odds of developing AMD. Design, Setting, and Participants: This case-control study of patients from a nationwide health insurance claims database included a population-based sample of patients. Those aged 55 years and older with newly diagnosed AMD from January 2008 to December 2017 were defined as cases and matched with control participants. Data analyses were completed from June 2019 to February 2020. Exposures: Dosage of metformin and exposure to other prescribed medications, as identified from outpatient drug claims. Main Outcomes and Measures: Risk of developing AMD. Results: A total of 312 404 affected individuals were included (181 817 women [58.2%]). After matching, 312 376 control participants were included (172 459 women [55.2%]; age range, 55 to 107 years). The case group had a slightly higher percentage of participants with diabetes (81 262 participants [26.0%]) compared with the control group (79 497 participants [25.5%]). Metformin use was associated with reduced odds of developing AMD (odds ratio [OR], 0.94 [95% CI, 0.92-0.96]). This association was dose dependent, with low to moderate doses of metformin showing the greatest potential benefit (dosages over 2 years: 1-270 g, OR, 0.91 [95% CI, 0.88-0.94]; 271-600 g, OR, 0.90 [95% CI, 0.87-0.93]; 601-1080 g, OR, 0.95 [95% CI, 0.92-0.98]). Doses of more than 1080 g of metformin over 2 years did not have reduced odds of developing AMD. Both the reduction in odds ratio and the dose-dependent response were preserved in a cohort consisting only of patients with diabetes. Metformin use was associated with a decreased OR of AMD in patients with diabetes without coexisting diabetic retinopathy (OR, 0.93 [95% CI, 0.91-0.95]) but was a risk factor in patients with diabetic retinopathy (OR, 1.07 [95% CI, 1.01-1.15]). Conclusion and Relevance: In this study, metformin use was associated with reduced odds of developing AMD. This association was dose dependent, with the greatest benefit at low to moderate doses. When looking only at patients with diabetes, we saw a preservation of the dose-dependent decrease in the odds of patients developing AMD. Metformin does not appear to be protective in patients with diabetes and coexisting diabetic retinopathy. This study suggests that metformin may be useful as a preventive therapy for AMD and provides the basis for potential prospective clinical trials.

Severe Corneal Hydrops With Suspected Posterior Stromal Rupture Managed With Ultrathin Descemet-Stripping Automated Endothelial Keratoplasty.

PURPOSE: To describe severe acute corneal hydrops in a patient with previously undiagnosed keratoconus, in which anterior segment optical coherence tomography (AS-OCT) revealed a protruding ridge of tissue on either side of Descemet membrane (DM) break, treated successfully with ultrathin Descemet-stripping automated endothelial keratoplasty (UT-DSAEK). METHODS: A case report. RESULTS: A 32-year-old man presented with severe corneal hydrops in OS. He was treated conservatively with hypertonic saline. Serial AS-OCT revealed persistent edema and haze overlying a break in DM, with a ridge of protruding tissue on either side. Based on these findings, UT-DSAEK was performed. Intraoperatively, the ridge of tissue remained firmly adhered after DM removal and was felt to possibly represent posterior stroma. The patient's uncorrected visual acuity improved to 20/80. Literature review revealed 1 case with similar AS-OCT findings who underwent penetrating keratoplasty; histopathology was reported to show Descemet scrolls on either side of the break, but our analysis of this and other reports suggest that an additional layer of tissue is contained within the scroll along with DM. CONCLUSIONS: This case demonstrates severe corneal hydrops in the setting of keratoconus, in which AS-OCT revealed a ridge of protruding tissue on either side of a break in DM. UT-DSAEK led to resolution of corneal edema and improvement in stromal haze and visual acuity. Further research is required to determine the precise role of endothelial keratoplasty and potential role of posterior stromal rupture in some cases of acute corneal hydrops.

Update on the Surgical Management of Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the most common posterior corneal dystrophy and the leading indication for corneal transplantation in the United States. FECD is slowly progressive, and patients develop gradual corneal endothelial decompensation, eventually resulting in failure of the endothelium to maintain corneal deturgescence. Medical management consists of topical hyperosmotic agents to facilitate dehydration of the cornea, but surgical intervention is often required to regain corneal clarity. The surgical management of FECD has evolved over the past two decades as corneal transplantation techniques have allowed for more selective keratoplasty and replacement of only the diseased layers of the cornea. Prior surgical management consisted of penetrating keratoplasty (PK) that carried significant intraoperative risks associated with "open sky" as well as postoperative risks of graft rejection, wound dehiscence, postoperative astigmatism, and prolonged visual rehabilitation. In the past 15 years, endothelial keratoplasty (EK) has become the treatment of choice for endothelial disease, significantly reducing the risks associated with the surgical treatment of FECD. Here we discuss the current surgical management of FECD, including the introduction of Descemet stripping only (DSO), and highlight future investigative efforts.

Rho GTPase signaling promotes constitutive expression and release of TGF-ß2 by human trabecular meshwork cells.

Elevated intraocular pressure (IOP) is causally implicated in the pathophysiology of primary open-angle glaucoma (POAG). The molecular mechanisms responsible for elevated IOP remain elusive, but may involve aberrant expression and signaling of transforming growth factor (TGF)-ß2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-ß2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner. By comparison, perfusing segments with a TGFßRI/ALK-5 antagonist (SB-431542) unexpectedly elicited a significant and sustained increase in outflow facility, implicating a role for TM-localized constitutive expression and release of TGF-ß2. Consistent with this thesis, cultured primary or transformed (GTM3) quiescent human TM cells were found to constitutively express and secrete measurable amounts of biologically-active TGF-ß2. Disrupting monomeric GTPase post-translational prenylation and activation with lovastatin or GGTI-298 markedly reduced constitutive TGF-ß2 expression and release. Specifically, inhibiting the Rho subfamily of GTPases with C3 exoenzyme similarly reduced constitutive expression and secretion of TGF-ß2. These findings suggest that Rho GTPase signaling, in part, regulates constitutive expression and release of biologically-active TGF-ß2 from human TM cells. Localized constitutive expression and release of TGF-ß2 by TM cells may promote or exacerbate elevation of IOP in POAG.

Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium.

Primary cilia are required for several signaling pathways, but their function in cellular morphogenesis is poorly understood. Here we show that emergence of an hexagonal cellular pattern during development of the corneal endothelium (CE), a monolayer of neural crest-derived cells that maintains corneal transparency, depends on a precise temporal control of assembly of primary cilia that subsequently disassemble in adult corneal endothelial cells (CECs). However, cilia reassembly occurs rapidly in response to an in vivo mechanical injury and precedes basal body polarization and cellular elongation in mature CECs neighboring the wound. In contrast, CE from hypomorphic IFT88 mutants (Tg737(orpk)) or following in vivo lentiviral-mediated IFT88 knockdown display dysfunctional cilia and show disorganized patterning, mislocalization of junctional markers, and accumulation of cytoplasmic acetylated tubulin. Our results indicate an active role of cilia in orchestrating coordinated morphogenesis of CECs during development and repair and define the murine CE as a powerful in vivo system to study ciliary-based cellular dynamics.