Publications by authors named "Sandra R Montezuma"

49 Publications

Impaired Mitochondrial Function in iPSC-Retinal Pigment Epithelium with the Complement Factor H Polymorphism for Age-Related Macular Degeneration.

Cells 2021 Apr 2;10(4). Epub 2021 Apr 2.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA.

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is characterized by loss of the retinal pigment epithelium (RPE). While the disease mechanism remains unclear, prior studies have linked AMD with RPE mitochondrial defects and genetic polymorphisms in the complement pathway. This study used RPE generated from induced pluripotent stem cells (iPSC-RPE), which were derived from human donors with or without AMD and genotyped for the complement factor H (CFH) AMD high-risk allele (rs1061170, Y402H) to investigate whether donor disease state or genotype had a detrimental effect on mitochondrial function and inflammation. Results show that cells derived from donors with AMD display decreased mitochondrial function under conditions of stress and elevated expression of inflammatory markers compared to iPSC-RPE from individuals without AMD. A more pronounced reduction in mitochondrial function and increased inflammatory markers was observed in CFH high-risk cells, irrespective of disease state. These results provide evidence for a previously unrecognized link between CFH and mitochondrial function that could contribute to RPE loss in AMD patients harboring the CFH high-risk genotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells10040789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066149PMC
April 2021

Cancer-Associated Retinopathy due to Clear Cell Renal Carcinoma.

Ocul Oncol Pathol 2021 Mar 18;7(1):31-35. Epub 2020 Dec 18.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.

An 84-year-old female presented with bilateral scotomas and progressive nyctalopia over 1 year. Best-corrected visual acuity was 20/50 in both eyes with reduced color vision. Goldmann visual field showed bilateral cecocentral scotomas and generalized constriction of the visual fields. This led to an electroretinogram showing an electronegative pattern consistent with autoimmune retinopathies. Infectious workup was negative. Anti-retinal antibodies were positive, leading to a presumed diagnosis of cancer-associated retinopathy (CAR). Imaging showed a previously unknown left renal lower pole mass, and she underwent a radical nephrectomy. Biopsy showed nuclear grade-3 clear cell renal carcinoma staged T1. The patient was treated with oral prednisone with no ocular improvement. We report on a rare case of clear cell renal carcinoma causing CAR. CAR is an important paraneoplastic syndrome to diagnose since the majority of ocular cases precede other manifestations of malignancy. Therefore, a timely diagnosis of CAR can be lifesaving or at least life-extending.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989776PMC
March 2021

Short term visual and structural outcomes of anti-vascular endothelial growth factor (anti-VEGF) treatment delay during the first COVID-19 wave: A pilot study.

PLoS One 2021 17;16(2):e0247161. Epub 2021 Feb 17.

Department of Ophthalmology and Visual Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States of America.

Regularly scheduled intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are essential to maintaining and/or improving many ocular conditions including: neovascular age-related macular degeneration (nAMD), diabetic retinopathy, and retinal vein occlusions with macular edema (RVO). This study aims to assess the effect of unintended delays in anti-VEGF treatment during the first wave of the COVID-19 pandemic. This retrospective case series identified patients receiving regularly scheduled anti-VEGF intravitreal injections based on current procedural terminology (CPT) code at two practices in Minnesota. Diagnoses were limited to nAMD, diabetic macular edema (DME), proliferative diabetic retinopathy, and RVO. Patients were divided into two groups based on whether they maintained or delayed their follow-up visit by more than two weeks beyond the recommended treatment interval during the COVID-19 lockdown. The 'COVID-19 lockdown' was defined as the period after March, 28th, 2020, when a lockdown was declared in Minnesota. We then compared the visual acuity and structural changes to the retina using ocular coherence tomography (OCT) to assess whether delayed treatment resulted in worse visual outcomes. A total of 167 eyes from 117 patients met criteria for inclusion in this study. In the delayed group, the average BCVA at the pre- and post-lockdown visits were 0.614 and 0.715 (logMAR) respectively (p = 0.007). Central subfield thickness (CST) increased from 341 to 447 in the DME delayed group (p = 0.03) while the CST increased from 301 to 314 (p = 0.4) in the nAMD delayed group. The results of this pilot study suggests that treatment delays may have a negative impact on the visual and anatomic outcomes of patients with nAMD and DME. Future studies with larger sample sizes are required for further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888661PMC
March 2021

Automating Human Induced Pluripotent Stem Cell Culture and Differentiation of iPSC-Derived Retinal Pigment Epithelium for Personalized Drug Testing.

SLAS Technol 2020 Dec 9:2472630320972110. Epub 2020 Dec 9.

Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.

Derivation and differentiation of human induced pluripotent stem cells (hiPSCs) provide the opportunity to generate medically important cell types from individual patients and patient populations for research and the development of potential cell therapies. This technology allows disease modeling and drug screening to be carried out using diverse population cohorts and with more relevant cell phenotypes than can be accommodated using traditional immortalized cell lines. However, technical complexities in the culture and differentiation of hiPSCs, including lack of scale and standardization and prolonged experimental timelines, limit the adoption of this technology for many large-scale studies, including personalized drug screening. The entry of reproducible end-to-end automated workflows for hiPSC culture and differentiation, demonstrated on commercially available platforms, provides enhanced accessibility of this technology for both research laboratories and commercial pharmaceutical testing. Here we have utilized TECAN Fluent automated cell culture workstations to perform hiPSC culture and differentiation in a reproducible and scalable process to generate patient-derived retinal pigment epithelial cells for downstream use, including drug testing. hiPSCs derived from multiple donors with age-related macular degeneration (AMD) were introduced into our automated workflow, and cell lines were cultured and differentiated into retinal pigment epithelium (RPE). Donor hiPSC-RPE lines were subsequently entered in an automated drug testing workflow to measure mitochondrial function after exposure to "mitoactive" compounds. This work demonstrates scalable, reproducible culture and differentiation of hiPSC lines from individuals on the TECAN Fluent platform and illustrates the potential for end-to-end automation of hiPSC-based personalized drug testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2472630320972110DOI Listing
December 2020

Improved mobility performance with an artificial vision therapy system using a thermal sensor.

J Neural Eng 2020 08 4;17(4):045011. Epub 2020 Aug 4.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States of America. Author to whom any correspondence should be addressed.

Objective: To evaluate the benefit of integrating thermal imaging into an artificial vision therapy system, the Argus II retinal prosthesis, in simplifying a complex scene and improving mobility performance in the presence of other persons.

Approach: Four Argus II retinal implant users were evaluated on two tasks: to locate and approach target persons in a booth, and to navigate a hallway while avoiding people. They completed the tasks using both the original Argus II system (the 'Argus II camera') and a thermal-integrated Argus II system (the 'thermal camera'). The safety and efficiency of their navigation were evaluated by their walking speed, navigation errors, and the number of collisions.

Main Results: Navigation performance was significantly superior when using the thermal camera compared to using the Argus II camera, including 75% smaller angle of deviation (p < 0.001), 48% smaller error of distance (p < 0.05), and 30% fewer collisions (p < 0.05). The thermal camera also brought the additional benefit of allowing the participants to perform the task in the dark as efficiently as in the light. More importantly, these benefits did not come at a cost of reduced walking speed.

Significance: Using the thermal camera in the Argus II system, compared to a visible-light camera, could improve the wearers' navigation performance by helping them better approach or avoid other persons. Adding the thermal camera to future artificial vision therapy systems may complement the visible-light camera and improve the users' mobility safety and efficiency, enhancing their quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1741-2552/aba4fbDOI Listing
August 2020

Improving retinal mitochondrial function as a treatment for age-related macular degeneration.

Redox Biol 2020 07 18;34:101552. Epub 2020 May 18.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address:

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Currently, there are no treatments for dry AMD, which is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors. Reports from human donors with AMD suggest that RPE mitochondrial defects are a key event in AMD pathology. Thus, the most effective strategy for treating dry AMD is to identify compounds that enhance mitochondrial function and subsequently, preserve the RPE. In this study, primary cultures of RPE from human donors with (n = 20) or without (n = 8) AMD were used to evaluate compounds that are designed to protect mitochondria from oxidative damage (N-acetyl-l-cysteine; NAC), remove damaged mitochondria (Rapamycin), increase mitochondrial biogenesis (Pyrroloquinoline quinone; PQQ), and improve oxidative phosphorylation (Nicotinamide mononucleotide, NMN). Mitochondrial function measured after drug treatments showed an AMD-dependent response; only RPE from donors with AMD showed improvements. All four drugs caused a significant increase in maximal respiration (p < 0.05) compared to untreated controls. Treatment with Rapamycin, PQQ, or NMN significantly increased ATP production (p < 0.05). Only Rapamycin increased basal respiration (p < 0.05). Notably, robust responses were observed in only about 50% of AMD donors, with attenuated responses observed in the remaining AMD donors. Further, within the responders, individual donors exhibited a distinct reaction to each drug. Our results suggest drugs targeting pathways involved in maintaining healthy mitochondria can improve mitochondrial function in a select population of RPE from AMD donors. The unique response of individual donors to specific drugs supports the need for personalized medicine when treating AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2020.101552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327959PMC
July 2020

Comparing fundus autofluorescence and infrared imaging findings of peripheral retinoschisis, schisis detachment, and retinal detachment.

Am J Ophthalmol Case Rep 2020 Jun 26;18:100666. Epub 2020 Mar 26.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.

Purpose: The primary goal of this study was to identify characteristic features of peripheral degenerative retinoschisis (RS), schisis detachment (SD) and retinal detachment (RD) on both fundus autofluorescence (FAF) and infrared (IR) imaging, using spectral domain optical coherence tomography (SD-OCT) imaging of the peripheral retina as the confirmatory imaging tool.

Methods: This is a descriptive case series study. A total of 27 eyes of 22 patients were included. Thirteen eyes of 10 patients diagnosed with RS, 4 eyes of 3 patients diagnosed with SD, and 10 eyes of 9 patients diagnosed with RD were included. Patients with images of poor quality were excluded. Heidelberg Spectralis HRA + OCT machine (Heidelberg Engineering, Heidelberg, Germany) were used to acquire the images.

Results: All conditions appeared as areas of hypo-AF on FAF and hypo-reflectance on IR imaging. Accentuated vasculature of the lesion was noted with IR imaging due to elevation of the RS and RD, which was less frequently observed with FAF. On FAF, a hyper-AF leading edge around the RS lesion indicated the presence of intraretinal or subretinal fluid and an extension of the RS. Retinal breaks/holes were best visualized with IR imaging. SD-OCT confirmed the diagnosis in all performed cases.

Conclusions: We were unable to differentiate between RS and RD based solely on findings from FAF and IR imaging. However, the combination of them with SD-OCT can assist in the diagnosis of RS from RD and in the evaluation of RS progression. OCT remains the main modality imaging to differentiate these conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajoc.2020.100666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125323PMC
June 2020

Improved localisation and discrimination of heat emitting household objects with the artificial vision therapy system by integration with thermal sensor.

Br J Ophthalmol 2020 12 9;104(12):1730-1734. Epub 2020 Mar 9.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.

Aim: To demonstrate the potential clinically meaningful benefits of a thermal camera integrated with the Argus II, an artificial vision therapy system, for assisting Argus II users in localising and discriminating heat-emitting objects.

Methods: Seven blind patients implanted with Argus II retinal prosthesis participated in the study. Two tasks were investigated: (1) localising up to three heat-emitting objects by indicating the location of the objects and (2) discriminating a specific heated object out of three presented on a table. Heat-emitting objects placed on a table included a toaster, a flat iron, an electric kettle, a heating pad and a mug of hot water. Subjects completed the two tasks using the unmodified Argus II system with a visible-light camera and the thermal camera-integrated Argus II.

Results: Subjects more accurately localised heated objects displayed on a table (p=0.011) and discriminated a specific type of object (p=0.005) presented with the thermal camera integrated with the Argus II versus the unmodified Argus II camera.

Conclusions: The thermal camera integrated with the artificial vision therapy system helps users to locate and differentiate heat-emitting objects more precisely than a visible light sensor. The integration of the thermal camera with the Argus II may have significant benefits in patients' daily life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjophthalmol-2019-315513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785158PMC
December 2020

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

Retina 2020 Feb;40(2):303-311

Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Purpose: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients.

Methods: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing.

Results: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years.

Conclusion: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IAE.0000000000002394DOI Listing
February 2020

N-Acetyl-L-cysteine Protects Human Retinal Pigment Epithelial Cells from Oxidative Damage: Implications for Age-Related Macular Degeneration.

Oxid Med Cell Longev 2019 14;2019:5174957. Epub 2019 Aug 14.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.

Age-related macular degeneration (AMD) involves the loss of retinal pigment epithelium (RPE) and photoreceptors and is one of the leading causes of blindness in the elderly. Oxidative damage to proteins, lipids, and DNA has been associated with RPE dysfunction and AMD. In this study, we evaluated oxidative stress in AMD and the efficacy of antioxidant, N-acetyl-L-cysteine (NAC), in protecting RPE from oxidative damage. To test this idea, primary cultures of RPE from human donors with AMD ( = 32) or without AMD (No AMD, = 21) were examined for expression of NADPH oxidase (NOX) genes, a source of reactive oxygen species (ROS). Additionally, the cells were pretreated with NAC for 2 hours and then treated with either hydrogen peroxide (HO) or -butyl hydroperoxide (-BHP) to induce cellular oxidation. Twenty-four hours after treatment, ROS production, cell survival, the content of glutathione (GSH) and adenosine triphosphate (ATP), and cellular bioenergetics were measured. We found increased expression of p22phox, a NOX regulator, in AMD cells compared to No AMD cells ( = 0.02). In both AMD and No AMD cells, NAC pretreatment reduced -BHP-induced ROS production and protected from HO-induced cell death and ATP depletion. In the absence of oxidation, NAC treatment improved mitochondrial function in both groups ( < 0.01). Conversely, the protective response exhibited by NAC was disease-dependent for some parameters. In the absence of oxidation, NAC significantly reduced ROS production ( < 0.001) and increased GSH content ( = 0.02) only in RPE from AMD donors. Additionally, NAC-mediated protection from HO-induced GSH depletion ( = 0.04) and mitochondrial dysfunction ( < 0.05) was more pronounced in AMD cells compared with No AMD cells. These results demonstrate the therapeutic benefit of NAC by mitigating oxidative damage in RPE. Additionally, the favorable outcomes observed for AMD RPE support NAC's relevance and the potential therapeutic value in treating AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/5174957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710748PMC
January 2020

Trade-Off Between Field-of-View and Resolution in the Thermal-Integrated Argus II System.

Transl Vis Sci Technol 2019 Jul 19;8(4):29. Epub 2019 Aug 19.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.

Purpose: To investigate the effect of a wider field-of-view (FOV) of a retinal prosthesis on the users' performance in locating objects.

Methods: One female and four male subjects who were blind due to end-stage retinitis pigmentosa and had been implanted with the Argus II retinal prosthesis participated (aged 63.4 ± 15.4). Thermal imaging was captured by an external sensor and converted to electrical stimulation to the retina. Subjects were asked to localize and to reach for heat-emitting objects using two different FOV mappings: a normal 1:1 mapping (no zoom) that provided 18° × 11° FOV and a 3:1 mapping (zoom out) that provided 49° × 35° FOV. Their accuracy and response time were recorded.

Results: Subjects were less accurate and took longer to complete the tasks with zoom out compared to no zoom. Localization accuracy decreased from 83% (95% confidence interval, 75%, 90%) with no zoom to 76% (67%, 83%) with zoom out ( = 0.07). Reaching accuracy differed between the two mappings only in one subject. Response time increased by 43% for the localization task (24%, 66%; < 0.001) and by 20% for the reaching task (0%, 45%; = 0.055).

Conclusions: Argus II wearers can efficiently find heat-emitting objects with the default 18° × 11° FOV of the current Argus II. For spatial localization, a higher spatial resolution may be preferred over a wider FOV.

Translational Relevance: Understanding the trade-off between FOV and spatial resolution in retinal prosthesis users can guide device optimization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1167/tvst.8.4.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701876PMC
July 2019

Increased serum proteins in non-exudative AMD retinas.

Exp Eye Res 2019 09 31;186:107686. Epub 2019 May 31.

F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 305 Stellar-Chance Laboratory, 422 Curie Blvd, Philadelphia, PA, 19104, USA. Electronic address:

The blood retinal barrier (BRB) closely regulates the retinal microenvironment. Its compromise leads to the accumulation of retinal fluid containing potentially harmful plasma components. While eyes with non-exudative age-related macular degeneration (AMD) were previously felt to have an intact BRB, we propose that the BRB in non-exudative AMD eyes may be subclinically compromised, allowing entry of retina-toxic plasma proteins. We test this hypothesis by measuring retinal levels of abundant plasma proteins that should not cross the intact BRB. Two cohorts of frozen, post mortem neurosensory retinas were studied by Western analysis. One cohort from Alabama had 4 normal controls and 4 eyes with various forms of AMD. Another cohort from Minnesota had 5 intermediate AMD eyes and 5 normals. Both cohorts were age/post mortem interval (PMI) matched. The non-exudative AMD retinas in the Alabama cohort had significantly higher levels of albumin and complement component 9 (C9) than normal controls. The positive control exudative AMD donor retina had higher levels of all but one serum protein. In both macular and peripheral neurosensory retina samples, intermediate AMD retinas in the Minnesota cohort had significantly higher levels of albumin, fibrinogen, IgG, and C9 than controls. Our results suggest that there may be moderate subclinical BRB leakage in non-exudative AMD. Potentially harmful plasma components including complement or iron could enter the neurosensory retina in AMD patients prior to advanced disease. Thus, therapies aiming to stabilize the BRB might have a role in the management of non-exudative AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2019.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703940PMC
September 2019

Author Correction: Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

Nat Genet 2019 Jun;51(6):1067

Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

In the version of this article initially published, in Supplementary Data 5, the logFC, FC, P value and adjusted P value for advanced AMD versus control (DE 4/1) without age correction did not correspond to the correct gene IDs. The errors have been corrected in the HTML version of the article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0430-yDOI Listing
June 2019

Quantitative fundus autofluorescence in smokers compared to non-smokers.

Exp Eye Res 2019 07 13;184:48-55. Epub 2019 Apr 13.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States. Electronic address:

Increased fundus autofluorescence is directly related to increased RPE lipofuscin deposition in the retina and has been observed in eyes with age-related macular degeneration (AMD). Smoking is the most significant modifiable risk factor for the development and progression of AMD, in which one of the main mechanisms is oxidative damage from smoking leading to RPE cell toxicity. The relationship between smoking and autofluorescence is not established and could provide insight into pathogenic mechanism of AMD. Therefore, our objective was to compare quantitative fundus autofluorescence (qAF) in the retinae of healthy non-smokers to smokers. We conducted a cross-sectional study at the 2016 Minnesota State Fair. Participants self-reported past medical and ocular history and underwent eye examination as well as qAF imaging with Spectralis confocal scanning laser ophthalmoscope (cSLO) equipped with an internal fluorescent reference. Two sets of images were obtained per eye. Stepwise multiple mixed effects regression model was used to examine the relationship between mean qAF values and smoking status. We enrolled 105 individuals (54 smokers, 61 females, mean age 41 years with range 18-78 years old). Fundus autofluorescence images were analyzable for 85 of 105 individuals contributing 161 eyes (80 right, 81 left). The repeatability coefficients between the first set and second set of images were ±21% of their mean qAF values. Older age and female gender were independently associated with higher qAF. Positive smoking history tended to result in higher qAF values after adjusting for age and gender but was not statistically significant (0.118, 95%CI -0.003, 0.240, P = 0.056). Among smokers, the number of pack-years smoked was not significantly associated with higher qAF. Our study's results are consistent with existing literature in which older age is predictive of intensified autofluorescence, while smoking history does not have as important of an impact on autofluorescence as hypothesized. Several large epidemiological studies have shown that smoking is significantly associated with AMD, and qAF is likely not the appropriate modality to clinically assess smoking's impact on retinae.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2019.04.004DOI Listing
July 2019

Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

Nat Genet 2019 04 11;51(4):606-610. Epub 2019 Feb 11.

Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD). We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0351-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441365PMC
April 2019

Retinal Anatomy and Electrode Array Position in Retinitis Pigmentosa Patients After Argus II Implantation: An International Study.

Am J Ophthalmol 2018 09 27;193:87-99. Epub 2018 Jun 27.

Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.

Purpose: To assess the retinal anatomy and array position in Argus II retinal prosthesis recipients.

Design: Prospective, noncomparative cohort study.

Methods: Setting: International multicenter study.

Patients: Argus II recipients enrolled in the Post-Market Surveillance Studies.

Procedures: Spectral-domain optical coherence tomography images collected for the Surveillance Studies (NCT01860092 and NCT01490827) were reviewed. Baseline and postoperative macular thickness, electrode-retina distance (gap), optic disc-array overlap, and preretinal membrane presence were recorded at 1, 3, 6, and 12 months.

Main Outcome Measures: Axial retinal thickness and axial gap along the array's long axis (a line between the tack and handle); maximal retinal thickness and maximal gap along a B-scan near the tack, midline, and handle.

Results: Thirty-three patients from 16 surgical sites in the United States and Germany were included. Mean axial retinal thickness increased from month 1 through month 12 at each location, but reached statistical significance only at the array midline (P = .007). The rate of maximal thickness increase was highest near the array midline (slope = 6.02, P = .004), compared to the tack (slope = 3.60, P < .001) or the handle (slope = 1.93, P = .368). The mean axial and maximal gaps decreased over the study period, and the mean maximal gap size decrease was significant at midline (P = .032). Optic disc-array overlap was seen in the minority of patients. Preretinal membranes were common before and after implantation.

Conclusions: Progressive macular thickening under the array was common and corresponded to decreased electrode-retina gap over time. By month 12, the array was completely apposed to the macula in approximately half of the eyes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajo.2018.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535141PMC
September 2018

Association of Optic Nerve Head Drusen with Best Vitelliform Macular Dystrophy: A Case Series.

Case Rep Ophthalmol 2018 Jan-Apr;9(1):76-86. Epub 2018 Jan 26.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.

Purpose: To report the association of optic nerve head (ONH) drusen with Best vitelliform macular dystrophy (BVMD).

Methods: Chart review.

Patients: Five patients from 3 families.

Results: Multimodal imaging and ophthalmic examination demonstrated findings consistent with ONH drusen, in association with BVMD, in 5 patients.

Conclusion: We report the association of BVMD with ONH drusen in 5 patients. This combination has previously been reported only once. We recommend that patients with a diagnosis of BVMD undergo autofluorescence and ultrasound imaging of the optic nerve to help facilitate this diagnosis, as some ONH drusen can be buried.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000485963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892333PMC
January 2018

Cataract, Vitritis, and Diffuse Hypofluorescent Retinal Dots on Fluorescein Angiography.

JAMA Ophthalmol 2018 05;136(5):581-582

University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2017.4426DOI Listing
May 2018

Knobloch syndrome associated with Polymicrogyria and early onset of retinal detachment: two case reports.

BMC Ophthalmol 2017 Nov 25;17(1):214. Epub 2017 Nov 25.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware St. SE, MMC 493, Minneapolis, MN, 55455-0501, USA.

Background: Knobloch Syndrome (KS) is a rare congenital syndrome characterized by occipital skull defects and vitreoretinal degeneration. Retinal detachment (RD) often occurs at the end of the first decade of life or later. Aside from occipital skull defects, central nervous system abnormalities are uncommon.

Case Presentations: We report on two siblings with KS. The first, a seven month old male, presented with nystagmus and was found to have a serous RD and a tessellated retinal appearance. His sister had a history of multiple visual abnormalities and had a similar retinal appearance although no signs of RD, but retina staphylomas. Genetic testing performed on both siblings showed a mutation in COL18A1, diagnostic of KS. MRI of both siblings demonstrated polymicrogyria but did not show occipital defects.

Conclusions: Although several families with KS have been described previously, our case is noteworthy for several reasons. The RD observed in our first patient occurred at an early age, and we find evidence of only one patient with KS who had an RD identified at an earlier age. The findings of polymicrogyria are not characteristic of KS, and we found only a few previous reports of this association. Additionally, we review potential treatment options for this condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12886-017-0615-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702215PMC
November 2017

A 61-year-old man with cystoid macular edema and chorioretinal folds after cataract surgery.

Digit J Ophthalmol 2017;23(3):81-84. Epub 2017 Aug 29.

Department of Ophthalmology and Visual Neuroscience, University of Minnesota.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5693/djo.03.2017.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683433PMC
June 2018

Ruptured Retinal Arterial Macroaneurysm Secondary to Toxoplasmic Kyrieleis Arteriolitis: A Case Report.

Case Rep Ophthalmol 2017 May-Aug;8(2):390-395. Epub 2017 Jul 24.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA.

Purpose: The aim of this report was to describe multimodal ocular imaging findings in a patient who presented with a ruptured retinal arterial macroaneurysm (RAM) associated with toxoplasmic Kyrieleis arteriolitis.

Methods: We report the case of a 64-year-old man with a history of systemic hypertension and dense amblyopia of the left eye who presented with decreased vision and new floaters in the left eye. Color fundus photography, spectral-domain optical coherence tomography, fluorescein angiography, and indocyanine green angiography were used as diagnostic imaging tools.

Results: No signs of hypertensive retinopathy were noted in the right eye. Multiple chorioretinal scars characteristic of previous toxoplasmosis were revealed in the left eye, with one covering most of the macula. Periarterial plaques or Kyrieleis arteriolitis were observed in retinal arteries surrounding the toxoplasmic retinal scars. Multiple RAMs were observed in these vessels, one of which was acutely ruptured. A perivenular plaque associated with a chronic branch retinal vein occlusion (BRVO) was noted along the same arcade at the arteriovenous crossing.

Conclusion: RAM formation and BRVO can present as possible long-term complications of toxoplasmic Kyrieleis arteriolitis. This is the first reported case demonstrating an association between toxoplasmic Kyrieleis arteriolitis and RAM formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000478720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597918PMC
July 2017

Altered bioenergetics and enhanced resistance to oxidative stress in human retinal pigment epithelial cells from donors with age-related macular degeneration.

Redox Biol 2017 10 1;13:255-265. Epub 2017 Jun 1.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address:

Age-related macular degeneration (AMD) is the leading cause of blindness among older adults. It has been suggested that mitochondrial defects in the retinal pigment epithelium (RPE) underlies AMD pathology. To test this idea, we developed primary cultures of RPE to ask whether RPE from donors with AMD differ in their metabolic profile compared with healthy age-matched donors. Analysis of gene expression, protein content, and RPE function showed that these cultured cells replicated many of the cardinal features of RPE in vivo. Using the Seahorse Extracellular Flux Analyzer to measure bioenergetics, we observed RPE from donors with AMD exhibited reduced mitochondrial and glycolytic function compared with healthy donors. RPE from AMD donors were also more resistant to oxidative inactivation of these two energy-producing pathways and were less susceptible to oxidation-induced cell death compared with cells from healthy donors. Investigation of the potential mechanism responsible for differences in bioenergetics and resistance to oxidative stress showed RPE from AMD donors had increased PGC1α protein as well as differential expression of multiple genes in response to an oxidative challenge. Based on our data, we propose that cultured RPE from donors phenotyped for the presence or absence of AMD provides an excellent model system for studying "AMD in a dish". Our results are consistent with the ideas that (i) a bioenergetics crisis in the RPE contributes to AMD pathology, and (ii) the diseased environment in vivo causes changes in the cellular profile that are retained in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.redox.2017.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466586PMC
October 2017

Generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age related macular degeneration.

PLoS One 2017 10;12(3):e0173575. Epub 2017 Mar 10.

Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, United States of America.

Fidelity in pluripotent stem cell differentiation protocols is necessary for the therapeutic and commercial use of cells derived from embryonic and induced pluripotent stem cells. Recent advances in stem cell technology, especially the widespread availability of a range of chemically defined media, substrates and differentiation components, now allow the design and implementation of fully defined derivation and differentiation protocols intended for replication across multiple research and manufacturing locations. In this report we present an application of these criteria to the generation of retinal pigmented epithelium from iPSCs derived from the conjunctiva of donors with and without age related macular degeneration. Primary conjunctival cells from human donors aged 70-85 years were reprogrammed to derive multiple iPSC lines that were differentiated into functional RPE using a rapid and defined differentiation protocol. The combination of defined iPSC derivation and culture with a defined RPE differentiation protocol, reproducibly generated functional RPE from each donor without requiring protocol adjustments for each individual. This successful validation of a standardized, iPSC derivation and RPE differentiation process demonstrates a practical approach for applications requiring the cost-effective generation of RPE from multiple individuals such as drug testing, population studies or for therapies requiring patient-specific RPE derivations. In addition, conjunctival cells are identified as a practical source of somatic cells for deriving iPSCs from elderly individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345835PMC
August 2017

Practice Patterns After Acute Embolic Retinal Artery Occlusion.

Asia Pac J Ophthalmol (Phila) 2017 Jan-Feb;6(1):37-39

Department of Ophthalmology, University of Minnesota.

Purpose: To compare stroke evaluations recommended by retina special-ists and neurologists for retinal artery occlusion (RAO).

Design: A cross-sectional survey.

Methods: An anonymous survey was emailed to members of the American Academy of Neurology Stroke Section listserv and vitreoretinal specialists registered with the American Academy of Ophthalmology. The survey was divided based on duration of symptoms before encounter: less than 12 hours, 24-48 hours, and more than 1 week. Institutional review board approval was obtained before data collection.

Results: Four hundred forty-eight surveys were completed (281 retinologists and 167 neurologists). Within 12 hours of RAO, most neurologists (75%) pursue a hospital-based evaluation, whereas the majority of retinologists (82%) pursue outpatient workup (P < 0.0001). Most neurologists (92%) and retinologists (98%) pursue outpatient stroke workup if symptoms have been present for more than 7 days.

Conclusions: Neurologists pursue higher acuity care after RAO, whereas most retinologists order outpatient evaluations. Retina specialists should consider urgent stroke evaluation to mitigate stroke risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.22608/APO.201690DOI Listing
March 2017

ENDOGENOUS NOCARDIA ENDOPHTHALMITIS PRESENTING AS A MASS LESION IN A PATIENT WITH METATSTATIC NONSMALL CELL CARCINOMA OF THE LUNG.

Retin Cases Brief Rep 2019 Spring;13(2):145-149

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota.

Purpose: To report a case of Nocardia cyriacigeorgica endophthalmitis.

Methods: Case report.

Results: A 71-year-old man on long-term steroid therapy for poor respiratory function from lung carcinoma and presumed recent liver metastases presented with a four week history of blurry vision in the left eye. Ophthalmic examination revealed a white elevated mass in the macula with hemorrhage, concerning for metastasis. The patient was treated for presumed ocular metastases but had poor response to radiotherapy and was diagnosed four weeks later with N. cyriacigeorgica by retinal biopsy. Despite intravitreal and systemic antibiotics, the patient had progression of disease and died of respiratory involvement.

Conclusion: Nocardia endogenous endophthalmitis can present as a mass retinal lesion in immunosuppressed patients with metastatic disease. Early vitreous and retinal biopsy may be required for definitive diagnosis and treatment. A pulmonary source of infection should be suspected and monitored closely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ICB.0000000000000545DOI Listing
May 2019

Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.

J Pathol 2017 04 20;241(5):583-588. Epub 2017 Feb 20.

Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357190PMC
April 2017

Chronic post-operative iris prosthesis endophthalmitis in a patient with traumatic aniridia: a case report.

BMC Ophthalmol 2016 Nov 9;16(1):197. Epub 2016 Nov 9.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware Street SE, MMC 493, Minneapolis, MN, 55455, USA.

Background: Post-operative endophthalmitis is a serious complication of intraocular surgery which may present acutely or chronically. Chronic post-operative endophthalmitis is characterized by decreased visual acuity, mild pain, and low-grade uveitis several weeks or months after intraocular surgery which may be responsive to corticosteroids, but recur upon tapering. Low virulence organisms such as Propionibacterium acnes are the most common culprit organisms, and treatment most often consists of both intravitreal antibiotic injections and surgery. Aniridia is a condition defined by total or partial loss of the iris and leads to decreased visual quality marked by glare and photophobia. Treatment of complex or severe cases of traumatic aniridia in which surgical repair is difficult may consist of implantation of iris prostheses, devices designed to reduce symptoms of aniridia. Though chronic, post-operative endophthalmitis has been associated with most intraocular surgeries including intraocular lens implantation after cataract removal, it has never been described in a patient with an iris prosthesis.

Case Presentation: In this case report, we describe the case of a 49 year old, male construction worker with traumatic aniridia who experienced chronic, recurrent low-grade intraocular inflammation and irritation for months after implantation of the Ophtec 311 prosthetic iris. Symptoms and signs of inflammation improved temporarily with sub-Tenon's capsule triamcinolone injections. Ultimately after more than 2 post-operative years, the iris prosthesis was explanted, and intravitreal cultures showed P. acnes growth after 5 days. Intravitreal antibiotics treated the infection successfully.

Conclusions: To our knowledge, this is the first reported case of chronic, post-operative endophthalmitis in a patient with an iris prosthesis. Chronic, post-operative endophthalmitis may be a difficult to identify in the context of traumatic aniridia and iris prosthesis implantation due to other potential etiologies of chronic intraocular inflammation such as implant-induced chafing. Clinicians should suspect chronic, post-operative endophthalmitis in any case of recurrent, low-grade intraocular inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12886-016-0383-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103383PMC
November 2016

The Effect of Scleral Buckling Surgery on Choroidal Thickness Measured by Enhanced Depth Optical Coherence Tomography: A Cross-Sectional Study.

Ophthalmol Ther 2016 Dec 6;5(2):215-222. Epub 2016 Sep 6.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.

Introduction: To assess the anatomical changes taking place in the choroid after a scleral buckle (SB) procedure for retinal detachment repair.

Methods: This cross-sectional study looked at 23 adults with a history of unilateral retinal detachment repaired with a SB or other encircling element. The subjects underwent bilateral Enhanced Depth Spectral Domain Optical Coherence Tomography to image the choroid. The choroidal thickness (CT) was measured, and the non-operative eye was used as an internal control.

Results: CT was measured to be 170.8 ± 60.9 µm (mean ± SD) in eyes with SBs compared to 175.1 ± 61.9 µm in non-operative eyes. There was no statistically significant difference between the two groups (mean 4.3 µm, 95% CI -8.7, 17.3, p value 0.4973, paired t test).

Conclusion: Placement of an SB as part of a surgery to repair retinal detachment did not significantly alter CT at the macula.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40123-016-0060-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125122PMC
December 2016

Success of patient training in improving proficiency of eyedrop administration among various ophthalmic patient populations.

Clin Ophthalmol 2016 10;10:1505-11. Epub 2016 Aug 10.

Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, USA.

Purpose: The purpose of this study is to evaluate the success and usefulness of patient education in eyedrop self-administration technique via an educational handout and a short instructional video.

Patients And Methods: We conducted a prospective study that included 34 patients who were self-administering ophthalmic drops. Of the total patients included, 12% had used drops for <12 months, and 88% had used drops for >12 months. Average age of patients in the study was 67 years, with an age range of 19-91 years. Of the total patients included, 82% had glaucoma, 6% had dry eyes, and 12% did not have a specific diagnosis. Subjects were video recorded and assessed by a trained observer on two occasions: at baseline and after they viewed a demonstrational video and handout. A maximum score of 15 points was awarded based on 15 criteria. A written self-assessment was administered at the end of each study.

Results: Pre- and post-teaching assessment scores improved significantly with education. Patients initially scored an average 2.53 points compared to a post-education score of 6.15 out of 15 points, demonstrating a 2.43 (P=0.008) factor of improvement. After education, 94% of patients versus 47% pre-teaching (P=0.0001) pulled down their lower eyelids. A total of 91% pre-teaching versus 59% post-teaching (P=0.0042) patients squeezed one drop into the lower fornix, 74% pre-teaching versus 26% post-teaching (P=0.0002) patients released the eyelid and closed the eye for 1 minute, and 56% pre-teaching versus 3% post-teaching (P=0.0001) patients applied nasal digital pressure on each eye. We found no significant difference in score changes between those who previously received education and those who had not (P=0.37). A total of 91% patients responded in a postassessment survey that they now feel more confident of their ability to self-administer eyedrops as their doctor prescribed and that the educational materials were responsible.

Conclusion: Participants demonstrated an immediate and statistically significant improvement in several areas of proper eyedrop self-administration after exposure to a demonstration video and instructional handout.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OPTH.S108979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986914PMC
August 2016