2022

BACKGROUND: Supranuclear vertical gaze palsies and slowed vertical saccades are characteristic clinic features of progressive supranuclear palsy (PSP). The "hummingbird sign," reflective of midbrain atrophy, is a classic radiographic sign of PSP. Correlation between eye movement abnormalities and radiographic findings in PSP has been reported previously. However, due to the use of clinical criteria not commonly employed in neuro-ophthalmic practice and neuroimaging techniques that are not widely available, it remains unclear whether correlation between midbrain structure and characteristic ocular-motor disturbances can be helpful to neuro-ophthalmologists seeking to adjudicate difficult or unusual diagnostic cases. METHODS: Patients with a diagnosis of probable PSP according to Movement Disorders Society criteria were studied retrospectively. A neuroradiologist calculated brainstem volumes in enrolled participants and normal controls. Spearman correlations were used to correlate the extent of eye movement limitation as assessed by 2 neuro-ophthalmologists with brainstem volumes. RESULTS: Fourteen participants with PSP and 15 healthy controls with similar age and gender distribution were enrolled and evaluated retrospectively. All 14 participants with PSP had undergone MRIs. Midbrain atrophy significantly correlated with the PSP rating scale (P < 0.001). PSP patients had significantly reduced volumes in the midbrain (P -0.0026), tegmentum (0.0001), tectum (0.0001), and medulla (P = 0.0024) compared with normal controls. Notes documenting quantified ocular motor function were available in 7 of 14 participants with PSP. Midbrain atrophy significantly correlated with in the extent of upward gaze limitation (P = 0.03). CONCLUSIONS: The severity of upward gaze limitation correlates with the severity of midbrain atrophy in patients with PSP. Recognition of this correlation may help to adjudicate diagnostic dilemmas and guide further evaluation.

The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.

BACKGROUND: Variants in RCBTB1 were recently described to cause a retinal dystrophy with only eight families described to date and a predominant phenotype of macular atrophy and peripheral reticular degeneration. Here, we further evaluate the genotypic and phenotypic characteristics of biallelic RCBTB1-associated retinal dystrophy in a North American clinic population. METHODS: A retrospective analysis of genetic and clinical features was performed in individuals with biallelic variants in RCBTB1. RESULTS: Three unrelated individuals of French-Canadian descent with rare biallelic RCBTB1 variants were identified. All individuals shared a novel p.(Ser342Leu) missense variant; one patient was homozygous whereas the other two each possessed a second unique novel variant p.(Gln120*) and p.(Pro224Leu). All three had macula-predominant disease with symptom onset in the fifth decade of life. CONCLUSION: This report adds to the genetic diversity of RCBTB1-associated disease. These cases confirm the later-onset, relative to many other retinal dystrophies, and macular focus of disease described in most cases to-date. They are thus a reminder of considering hereditary disease in the differential for later-onset macular atrophy.

PURPOSE: To review the published literature assessing the safety and effectiveness of laser refractive surgery to treat anisometropic amblyogenic refractive error in children aged ≤ 18 years. METHODS: A literature search of the PubMed database was conducted in October 2021 with no date limitations and restricted to publications in English. The search yielded 137 articles, 69 of which were reviewed in full text. Eleven articles met the criteria for inclusion and were assigned a level of evidence rating. RESULTS: The 11 included articles were all level III evidence and consisted of 1 case-control study and 10 case series. Six studies used laser-assisted in situ keratomileusis (LASIK), 1 used photorefractive keratectomy (PRK), 1 used refractive lenticule extraction/small incision lenticule extraction, and the rest used a combination of LASIK, PRK, laser epithelial keratomileusis (LASEK), or refractive lenticule extraction/small incision lenticule extraction. Five studies enrolled patients with anisometropic myopia, 2 studies enrolled patients with anisometropic hyperopia, and the remainder were mixed. Although all studies demonstrated an improvement in best-corrected visual acuity (BCVA), the magnitude of improvement varied widely. As study parameters varied, a successful outcome was defined as residual refractive error of 1 diopter (D) or less of the target refraction because this was the most commonly used metric. Successful outcomes ranged between 38% and 87%, with a mean follow-up ranging from 4 months to 7 years. Despite this wide range, all studies demonstrated an improvement in the magnitude of anisometropia. Regression in refractive error occurred more frequently and to a greater degree in myopic eyes and eyes with longer follow-up, and in younger patients. Although one study reported 2 free flaps, most studies reported no serious adverse events. The most common complications were corneal haze and striae. CONCLUSIONS: Findings from included studies suggest that laser refractive surgery may address amblyogenic refractive error in children and that it appears to decrease anisometropia. However, the evidence for improvement in amblyopia is unclear and long-term safety data are lacking. Long-term data and well-designed clinical studies that use newer refractive technologies in standardized patient populations would help address the role of refractive surgery in children and its potential impact on amblyopia.

The increasing morbidity and mortality of patients due to post-surgery complications of coronary artery bypass grafts (CABPG) are related to blood-material interactions. Thus, the characterization of the thrombogenicity of the biomaterial for cardiovascular devices is of particular interest. This research evaluated the anti-thrombogenic activity of polyurethanes-starch composites. We previously synthesized polyurethane matrices that were obtained from polycaprolactone diol (PCL), polyethylene glycol (PEG), pentaerythritol (PE), and isophorone diisocyanate (IPDI). In addition, potato starch (AL-N) and zwitterionic starch (AL-Z) were added as fillers. The anti-thrombogenic property was characterized by the clot formation time, platelet adhesion, protein absorption, TAT complex levels, and hemolysis. Additionally, we evaluated the cell viability of the endothelial and smooth muscle cells. Statically significant differences among the polyurethane matrices (P1, P2, and P3) were found for protein absorption and the blood clotting time without fillers. The polyurethanes composites with AL-Z presented an improvement in the anti-thrombogenic property. On the other hand, the composites with AL-Z reduced the viability of the endothelial cells and did not significantly affect the AoSCM (except for P1, which increased). These results classify these biomaterials as inert; therefore, they can be used for cardiovascular applications.

PURPOSE: To determine prevalence of probable polypoidal choroidal vasculopathy (PCV) among White patients with neovascular age-related macular degeneration (nAMD) using non-indocyanine green angiography (ICGA) criteria DESIGN: Multicenter, multinational, retrospective, cross-sectional study. METHODS: A total of 208 treatment-naive eyes from Hispanic and non-Hispanic White individuals diagnosed with nAMD were included. All underwent color fundus photography (CFP), optical coherence tomography (OCT), and fluorescein angiography (FFA). De-identified images of study eyes were sent to 2 groups of graders. Group 1 reviewed CFP, OCT, and FFA to confirm nAMD diagnosis. Group 2 reviewed CFP and OCT to determine highly suggestive features for PCV. Probable PCV diagnosis defined as the presence of ≥2 of 4 highly suggestive features for PCV: notched or fibrovascular pigment epithelial detachment (PED) on CFP, sharply-peaked PED, notched PED, and hyperreflective ring on OCT. RESULTS: Eleven eyes were excluded because of poor image quality (6) or non-nAMD diagnosis (5). Of 197 eligible eyes (197 patients), the mean age (SD) was 78.8 years (8.9), 44.2% were men, 26.4% were Hispanic, and 73.6% were non-Hispanic White individuals; 41.1%, 23.4%, 9.1%, and 2.5% had ≥1, ≥2, ≥3, and 4 highly suggestive features. Results showed that 23.4% (95% CI, 17.6%-29.9%) had probable PCV diagnosis. Predominantly occult CNV was more frequently found in probable PCV than nAMD subgroup (84.8% vs 64.9%, P = .01). Hispanic White individuals had a lower prevalence of probable PCV than non-Hispanic White individuals (9.6% vs 28.2%, P = .006) CONCLUSIONS: These findings suggest that probable PCV occurs between 17.6% and 29.9% in White individuals with nAMD, and more commonly in non-Hispanic than in Hispanic White individuals.

PRCIS: Glaucoma cascade screening in first-degree relatives (FDRs) of young Haitian glaucoma patients had high yield for diagnosing manifest and suspected glaucoma in 30.8% of those screened despite modest participation. PURPOSE: To evaluate the outcomes of glaucoma cascade screening in FDRs (parents, siblings, and offspring) of Haitian juvenile open-angle glaucoma (JOAG) patients. PATIENTS AND METHODS: Consecutive index patients (Haitians with JOAG) were identified, and the number/type of FDRs residing in South Florida were recorded. These FDRs were invited for free glaucoma screening, which included a comprehensive ophthalmic exam, gonioscopy, automated visual field testing and optical coherence tomographic analysis of the retinal nerve fiber layers. FDR characteristics and clinical findings from screening are reported. RESULTS: A total of 77 FDRs were invited, 26 (33.8%) agreed to undergo screening (18 females, 9 males), which revealed 2 (7.7%) with manifest glaucoma (mean age 77.5 y; one of whom was previously unaware of his glaucoma diagnosis), 6 (23.1%) with suspected glaucoma (mean age 29.8±18.3 y), and 18 (69.2%) without manifest or suspected glaucoma (mean age 37.2±21.8 y). Siblings of index patients were least likely to participate in cascade glaucoma screening when compared with index patients' parents or offspring. FDR eyes with manifest glaucoma had significantly worse best-corrected visual acuities, higher intraocular pressures, thinner central corneal thicknesses, and thinner circumferential papillary retinal nerve fiber layer thicknesses than those without glaucoma. CONCLUSION: Glaucoma cascade screening of Haitian JOAG patients' FDRs revealed that 30.8% had suspected or manifest glaucoma. Future efforts centered on provider-initiated recruitment and improving public glaucoma awareness and education may increase screening participation.

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the ophthalmic findings associated with peripapillary hyperreflective ovoid mass-like structures (PHOMS) in both adult and pediatric patients. RECENT FINDINGS: PHOMS have recently been identified in a number of different ophthalmic disease entities ranging from nonpathologic to pathologic, including but not limited to anatomic abnormalities (tilting in myopia), optic nerve head drusen, optic disc edema from inflammation (optic neuritis, white dot syndromes), vascular insults (ischemic optic neuropathy, retinal vascular occlusion), and papilledema. The mechanism underlying the formation of PHOMS has not been fully elucidated although it has been hypothesized that PHOMS occur secondary to axoplasmic stasis from crowding at the optic nerve head. SUMMARY: Although the clinical significance of the presence of PHOMS remains unclear, PHOMS are associated with several disease processes. Understanding the mechanism behind their formation and their impact on optic nerve head structure and visual function may be relevant in patients with optic nerve head pathology. The presence of PHOMS may also correlate with disease severity and duration. Future studies to evaluate whether the formation of PHOMS may be useful as an early indicator of disease or a prognostic tool are warranted.

AIMS: To identify single-nucleotide polymorphisms (SNPs) associated with central serous chorioretinopathy (CSCR) by a systematic review and meta-analysis, and to compare the association profiles between CSCR, neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We searched the EMBASE, PubMed and Web of Science for genetic studies of CSCR from the starting dates of the databases to 12 September 2020. We then performed meta-analyses on all SNPs reported by more than two studies and calculated the pooled OR and 95% CIs. We also conducted sensitivity analysis and adopted the funnel plot to assess potential publication bias. RESULTS: Totally 415 publications were reviewed, among them 10 were eligible for meta-analysis. We found 10 SNPs that have been reported at least twice. Meta-analysis and sensitivity analysis confirmed significant associations between CSCR and six SNPs in three genes, namely age-related maculopathy susceptibility 2 (ARMS2) (rs10490924, OR=1.37; p=0.00064), complement factor H (CFH) (rs800292, OR=1.44; p=7.80×10-5; rs1061170, OR=1.34; p=0.0028; rs1329428, OR=1.40; p=0.012; and rs2284664, OR=1.36; p=0.0089) and tumour necrosis factor receptor superfamily, member 10a (TNFRSF10A) (rs13278062, OR=1.34; p=1.44×10-15). Among them, only TNFRSF10A rs13278062 showed the same trend of effect on CSCR, nAMD and PCV, while the SNPs in ARMS2 and CFH showed opposite trends in the SNP associations. CONCLUSIONS: This study confirmed the associations of ARMS2, CFH and TNFRSF10A with CSCR, and revealed that ARMS2, CFH and TNFRSF10A may affect different phenotypic expressions of CSCR, nAMD and PCV.

This study aimed to develop a miltefosine-eluting contact lens (MLF-CL) device that would allow sustained and localized miltefosine release for the treatment of Acanthamoeba keratitis. MLF-CLs were produced in three different miltefosine doses by solvent-casting a thin miltefosine-polymer film around the periphery of a methafilcon hydrogel, which was then lathed into a contact lens. During seven days of in vitro testing, all three formulations demonstrated sustained release from the lens at theoretically therapeutic levels. Based on the physicochemical characterization of MLF-CLs, MLF-CL's physical properties are not significantly different from commercial contact lenses in terms of light transmittance, water content and wettability. MLF-CLs possessed a slight reduction in compression modulus that was attributed to the inclusion of polymer-drug films but still remain within the optimal range of soft contact lenses. In cytotoxicity studies, MLF-CL indicated up to 91% viability, which decreased proportionally as miltefosine loading increased. A three-day biocompatibility test on New Zealand White rabbits revealed no impact of MLF-CLs on the corneal tissue. The MLF-CLs provided sustained in vitro release of miltefosine for a week while maintaining comparable physical features to a commercial contact lens. MLF-CL has a promising potential to be used as a successful treatment method for Acanthamoeba keratitis.

Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we use a systems genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.

PURPOSE: To assess test-retest repeatability of the accommodative response (AR) in children with and without amblyopia and adults using the Grand Seiko autorefractor. DESIGN: Prospective reliability assessment. METHODS: Test-retest of accommodation was obtained while participants viewed 20/150 sized letters at 33 cm using the Grand Seiko autorefractor in children 5 to <11 years with amblyopia (n=24) and without amblyopia (n=36), and adults 18 to <35 years (n=34). Bland-Altman 95% limits of agreement (LOA) and intraclass correlation coefficients (ICCs) were used to assess repeatability and reliability. The AR between the fellow and amblyopic eyes of children with amblyopia and eye 1 and eye 2 of the visually normal participants was assessed using group comparisons. RESULTS: The 95% LOA of the AR was greatest in the amblyopic eyes (-1.25 diopters [D], 1.62 D) of children with amblyopia. The 95% LOA were similar between the fellow eyes (-0.88 D, 0.74 D) of children with amblyopia and both eyes of the children without amblyopia (eye 1: -0.68 D, 0.71 D; eye 2: -0.59 D, 0.70 D) and the adults (eye 1: 95% LOA = -0.49 D, 0.45 D; eye 2: LOA = -0.66 D, 0.67 D). ICCs revealed the Grand Seiko autorefractor as a reliable instrument for measuring AR. CONCLUSIONS: The Grand Seiko autorefractor was more repeatable and reliable when measuring the AR in children and adults without amblyopia than in the amblyopic eye in children with amblyopia. It is recommended that multiple measures of the AR be obtained in amblyopic eyes to improve the precision of measures.

PURPOSE: Many clinicians treat unilateral amblyopia with glasses alone and initiate patching when needed; others start glasses and patching simultaneously. In this study, we reviewed the outcomes of the two approaches at our institution. DESIGN: Retrospective nonrandomized clinical trial. METHODS: Setting: Institutional practice. PATIENT POPULATION: All patients diagnosed with amblyopia at Boston Children's Hospital between 2010 and 2014. INCLUSION CRITERIA: Unilateral amblyopia (visual acuity (VA) 20/40 to 20/200 with interocular difference ≥3 lines,) age 3 to 12 years, with a 6-month follow-up visit. EXCLUSION CRITERIA: Deprivation amblyopia, prior amblyopia treatment, treatment other than patching, surgery. Patients were categorized as "simultaneous treatment" (concurrent glasses and patching therapy at their first visit) or "sequential treatment" (glasses alone at first visit, followed by patching therapy at second visit.) Observation procedures: Patient demographics, VA, and stereopsis were compared. OUTCOME MEASURES: VA and stereopsis at the last visit on treatment. RESULTS: We identified 98 patients who met inclusion criteria: 36 received simultaneous treatment and 62 sequential treatment. Median amblyopic eye VA improved similarly between the simultaneous (∆0.40; interquartile range [IQR], 0.56-0.30 logMAR) and sequential (∆0.40; IQR, 0.52-0.27 logMAR) groups. Patients without stereopsis at first visit had better stereopsis outcomes with sequential treatment (5.12 [IQR, 4.00-7.51] log stereopsis) compared with simultaneous treatment (8.01 [IQR, 5.65-9.21]) log stereopsis, P = 0.046). CONCLUSIONS: VA improved approximately 4 lines regardless of treatment type. For children without stereopsis at first presentation, sequential patching yielded better stereopsis outcomes. These findings require further validation and highlight the importance of evaluating stereopsis in future studies.

A 13-year-old boy presented with 3 days of left-sided periorbital pain, swelling, mucoid discharge, and fever to 103°F, with onset 1 day after swimming in the ocean. Within 12 hours, he experienced rapid clinical deterioration with formation of a superomedial subperiosteal abscess and an epidural abscess with leptomeningitis despite treatment with broad-spectrum intravenous antibiotics. The patient underwent urgent left orbitotomy with abscess drainage and functional endoscopic sinus surgery. Intraoperative cultures grew Shewanella algae and Escherichia coli . The patient showed marked clinical improvement following surgical intervention and tailored antibiotic therapy. This is the first reported case of orbital abscess with acute bacterial rhinosinusitis due to infection with Shewanella algae .