Faculty Bibliography

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details.

PURPOSE/OBJECTIVE:We developed human cornea organoids (HCOs) from induced pluripotent stem cells (iPSCs) where single-cell RNA-sequence (scRNA-seq) analysis suggested similarity with developing rather than mature human corneas. We performed immunohistology to determine the presence of corneal glycosaminoglycans as an assessment of maturity. We undertook a detailed comparison of the HCO scRNA-seq data with a recent scRNA-seq study of human fetal corneas at different stages to gauge the HCO's maturity. METHODS:We generated HCOs from a second iPSC line, NCRM-1, to assess the reproducibility of HCO development. We stained sections from both HCO lines with Alcian blue and picrosirius red to determine deposition of sulfated glycosaminoglycans and fibrillar collagens. We immunolocalized glycosaminoglycan biosynthetic enzymes and proteoglycan core proteins. The scRNA-seq data from IMR90.4 HCOs were compared to that of fetal corneas using MetaNeighbor analysis to assess the similarity of HCOs to different stages of human corneal development. RESULTS:The MetaNeighbor analysis suggests closer alignment of the IMR90.4 HCOs with 17-18 post-conception week fetal human corneas. HCOs from both iPSC lines deposit sulfated glycosaminoglycans and fibrillar collagens. Immunohistology showed chondroitin/dermatan sulfate (CS/DS) and keratan sulfate in the presumptive stromal and some epithelial layers. The NCRM-1-derived HCOs show increased CS/DS staining compared to the IMR90.4 derived HCOs. CONCLUSIONS:Both HCO lines show similar developmental patterns and timeline. The NCRM-1 HCO line may have more glycosaminoglycan deposition. Overall, the glycosaminoglycan deposition pattern is consistent with an immature tissue. Optimizations based on our current findings may yield more mature stromal cells and cornea-typical proteoglycans.

We report the case of a 33-year-old woman with a history of hypothyroidism and ocular history of mild myopia who presented with a spontaneous filtering bleb. Extensive systemic rheumatologic evaluation was unrevealing. The bleb was observed for many months, until the patient's vision declined secondary to the development of hypotony maculopathy. The filtering bleb was closed using an allogenic scleral patch graft, resulting in normotensive intraocular pressure and improved best-corrected visual acuity. A unilateral, spontaneous filtering bleb is a rare occurrence and is typically associated with systemic or ocular conditions. Complications such as hypotony can lead to visual impairment, and intervention is required. Early diagnosis and repair with donor scleral patch graft can prevent complications and provide an excellent cosmetic outcome.

PURPOSE/UNASSIGNED:To determine the characteristics of normal tension glaucoma referrals at a tertiary care center and risk factors associated with unilateral versus bilateral disease. PATIENTS AND METHODS/UNASSIGNED:Medical records were reviewed of patients who were referred to a single glaucoma provider at a tertiary care center and were given a presumptive diagnosis of normal tension glaucoma (NTG) between the years 2018 and 2021. Data collected included demographics, medical and family history, ophthalmic history, ophthalmic examination findings, neuro-ophthalmology referrals, and magnetic resonance imaging (MRI) results. RESULTS/UNASSIGNED:A total of 98 patients were included in this study. The majority of patients (82%) had bilateral disease at initial presentation. Most patients (65%) had a history of systemic disease, including hypertension (32%), cardiovascular disease (19%), diabetes (12%), obstructive sleep apnea (10%), or orthostatic hypotension (4%). Conditions associated with vascular dysregulation were identified in 24% of patients. Sixty six percent of patients had a family history of glaucoma, while nearly half (49%) were myopic. Of patients with unilateral disease, 39% had workup or consideration of other neuro-ophthalmic diagnoses compared to 13% of patients with bilateral disease (P = 0.01). CONCLUSION/UNASSIGNED:Patients referred for NTG commonly present with disc changes in both eyes. Clinicians should assess for the presence of systemic diseases associated with vascular dysregulation, myopia, and a family history of glaucoma. Patients with unilateral disease consistent with NTG may benefit from additional workup including neuroimaging or a neuro-ophthalmic evaluation.

PURPOSE/UNASSIGNED:To investigate whether consensus can be reached on the acceptability of end-stage atrophy onset as a clinical end point in early intervention trials of age-related macular degeneration (AMD), and the criteria for defining such an end point. DESIGN/UNASSIGNED:A modified Delphi study. PARTICIPANTS/UNASSIGNED:International panel of experts in AMD, retinal imaging, and histopathology that are part of the Classification of Atrophy Meetings group. METHODS/UNASSIGNED:A modified Delphi study was undertaken to determine if there is consensus on the acceptability of the onset of end-stage atrophic AMD as a clinical end point to evaluate early interventions and the criteria for defining such an end point. Two initial rounds of online surveys were conducted. Aggregate results and anonymized comments were provided after each round, followed by a face-to-face meeting before a final survey round was completed. MAIN OUTCOME MEASURES/UNASSIGNED:Statements where consensus was reached, defined as ≥80% of responses within the 3-point bracket for agreement or disagreement based on a 9-point Likert rating scale, from a total of 33 statements included in the final round of the survey. RESULTS/UNASSIGNED:Consensus was reached for the statement that the onset of end-stage atrophic AMD was an appropriate clinical end point to evaluate early interventions (82% responses in agreement). Consensus was also reached for the statement that such an end point should be defined based on anatomical changes that have been previously shown in clinical studies to be associated with marked, but not necessarily complete, functional loss (95% responses in agreement). Consensus was nearly reached for the specific criterion that ≥90% of such atrophic AMD lesions should have ≥1 test location that was ≤10 decibels on 2 microperimetry tests (77% responses in agreement). CONCLUSIONS/UNASSIGNED:There was expert group consensus that the onset of end-stage atrophy is an appropriate clinical end point to evaluate early interventions in AMD, and that such an end point should show evidence of marked functional loss in prior clinical studies. We believe these findings will help to define incident clinical end points that are acceptable to regulatory authorities. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

INTRODUCTION/UNASSIGNED:A standardized multidisciplinary treatment protocol for NVG was developed in 2020 at the University of Chicago and has been termed Salvaging the Conventional Outflow Pathway in Neovascular Glaucoma (SCOPING). We describe 9 eyes with anterior segment neovascularization and at least partially open angles that underwent the SCOPING protocol to suppress the underlying neovascular drive, control intraocular pressure, and medically or surgically salvage the angle whenever possible. METHODS/UNASSIGNED:Nine eyes from 8 patients with first-time anterior segment neovascularization, at least partially open angles, and normal or elevated IOP were treated with 6 serial monthly intravitreal bevacizumab injections interspersed with pan-retinal photocoagulation. RESULTS/UNASSIGNED:Five eyes with completely open angles without any peripheral anterior synechiae and each achieved and/or maintained physiologic IOP without requiring surgery. The other 4 eyes presented with partially open angles. Three out of these 4 eyes required subsequent IOP-lowering surgery. None of the 9 eyes developed recurrence of anterior segment neovascularization during the treatment protocol. DISCUSSION/UNASSIGNED:This protocol may be utilized to salvage the conventional outflow pathway for patients with partially or completely open angles. The etiology and diagnosis of neovascular glaucoma have been established. Current treatment strategies include reduction of neovascular drive including panretinal photocoagulation, intravitreal injections, intraocular pressure lowering medications, and filtration surgery. However, a protocol has not been developed to treat neovascular glaucoma (NVG). Our SCOPING protocol may be helpful for glaucoma specialists in treating patients with neovascular glaucoma.

Currently there are no surgical solutions to restore vision in the irreversibly blind. Whole eye transplantation (WET), is an appealing surgical approach for restoration, replacement, and reconstruction of nonfunctioning eyes. Development of a reliable animal model to test the integrity and functionality of the transplanted eye is an essential step towards clinical whole eye transplantation. This study presents a feasible vascularized orthotopic eye transplantation preclinical rat model to study the structural and functional outcomes of whole eye transplantation. Syngeneic orthotopic transplants were performed in rats, involving anastomoses between carotid arteries, external jugular veins, and optic nerve coaptations of donors and recipients. The transplanted and recipient native eyes were assessed by ocular exam under anesthesia, optical coherence tomography (OCT), histology, magnetic resonance imaging and electroretinography. A 100% surgical survival rate of recipients with maintained long-term health demonstrated this to be a reliable and reproducible model. Assessment from clinical examination under anesthesia revealed that segments of native eyes appeared normal throughout the duration of the study, but transplanted eyes presented mild chemosis of the eye lids, mild ciliary flush of the conjunctiva, cornea neovascularization, mild engorgement of the vessels in the iris, and mild opacities in the lens in some animals. Most of these findings improved over time after transplantation. Doppler optical coherence tomography corroborated the presence of blood flow in transplanted retinas. There was no significant difference in measured IOP between native and transplanted eyes. Both histology and OCT scans demonstrated increased central corneal thickness and decreased total retinal thickness in transplanted eyes. Transplanted eyes exhibit minimal scotopic and photopic ERG responses. To date, no other vascularized orthotopic rodent WET transplantation models have been described in the literature. As functional visual return remains the ultimate goal, this model provides a foundation for future translational strategies and is ideal for testing immunomodulatory, neuroprotective, and neuroregenerative approaches either individually or in combination, as required for total human eye allotransplantation (THEA) to become a clinical reality.

Glaucoma patients often have higher injurious fall rates compared to healthy older adults. However, little is known about the underlying neural mechanisms. Recent evidence shows cerebral changes beyond the visual pathway of glaucoma patients, yet it remains unclear whether the cerebellum, which plays an important role in balance and motor control, is involved in glaucoma. In this study, we sought to investigate cerebellar functional connectivity changes in glaucoma by comparing 32 glaucoma subjects and 10 age-matched healthy control subjects who underwent resting-state functional magnetic resonance imaging at 3 Tesla with eyes closed. After conducting both regions-of-interest and seed-to-voxel analyses, we found that the functional connectivity within the cerebellum tended to be weakened in glaucoma patients compared to healthy controls, whereas the functional connectivity between some cerebral and cerebellar regions showed opposite changes in the same glaucoma subjects. Our findings underscore the potential role of cerebellar and cerebro-cerebellar dysfunction in postural and cognitive control in glaucoma patients. Taken together, these observations implicate the widespread brain changes in glaucoma beyond the cerebral regions into the cerebellum that may underlie the neural underpinnings of impaired balance control in this disease.

PURPOSE/UNASSIGNED:We evaluated the efficacy of varenicline solution nasal spray (VNS) in treating dry eye disease (DED) associated with moderate to severe Sjogren's disease and analyzed tear film cytokine levels of patients with DED and Sjogren's disease before and after VNS use. METHODS/UNASSIGNED:This was a pilot study involving a single-center, single-arm investigator-initiated trial. Patients with moderate to severe Sjogren's disease were given VNS 0.03 mg twice daily for 28 days. Patients were assessed on day 0 before VNS use, day 14 and day 28. Clinical exam findings, symptomatology as measured by the eye dryness score, and tear cytokines were assessed at baseline and day 28. RESULTS/UNASSIGNED:Thirty-nine subjects were included. Between day 0 and day 28, there was a statistically significant improvement in the eye dryness score (p = 0.01), corneal staining (p < 0.001), and conjunctival staining (p = 0.04). There was a statistically significant increase in tear secretion by unanesthetized Schirmer's in subjects with a baseline Schirmer's ≤5 mm (n = 35 eyes, p = 0.02) and a non-statistically significant increase in tear secretion in subjects with a baseline Schirmer's of 6-10 mm (n = 16 eyes, p = 0.79). There was a statistically significant decrease in tear film cytokine concentration of IFNγ (p = 0.0003), IL-12p70 (p < 0.0001), IL-17a (p = 0.004), IL-1β (p = 0.007), IL-2 (p < 0.0001), IL-4 (p = 0.01), and TNF-α (p = 0.02), and no significant change in IL-6 (p = 0.56) and IL-10 (p = 0.18). CONCLUSION/UNASSIGNED:Our findings add to existing evidence that VNS improves subjective dry eye symptoms, corneal and conjunctival staining, and tear secretion in a subset of tear-deficient patients, while providing new evidence that VNS reduces concentration of pro-inflammatory cytokines in the tear film. CLINICAL TRIAL REGISTRATION NUMBER/UNASSIGNED:NCT05700422.