Publications by authors named "K Thiran Jayasundera"

42 Publications

A Novel Think Tank Program to Promote Innovation and Strategic Planning in Ophthalmic Surgery.

Perioper Care Oper Room Manag 2021 Mar 10;22. Epub 2020 Nov 10.

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.

Background: Continuous quality improvement is a pillar of all surgical groups. Innovation is a critical aspect to continuously improve, but traditional staff retreats have several disadvantages which limit their utility in identifying needs and developing innovative solutions. To address these challenges, we designed the novel Think Tank Program to spur innovation and strategic planning for an academic ophthalmology department including the Kellogg Eye Center 6 operating rooms.

Methods: The Think Tank program is a structured seven-phase program for faculty in small teams to identify, innovate, and implement meaningful change. Participants brainstormed problems and possible solutions to those problems, formed teams, acquired data, and implemented meaningful change in clinical care, research, education, and administration.

Results: The program generated 19 novel proposals and significant faculty engagement and discussion in improving the department. A case example of improving the operating room (OR) utilization resulted in improved OR utilization from 63.8% to 74.6% over a 3 month period before and after implementation. It also resulted in a reduction of cancelled or rescheduled surgeries within 2 weeks or surgery from 29.8% to 15.2%. This resulted in an estimated positive financial margin of over $141,000 to the institution in addition to improvement in patient, surgeon, and staff satisfaction with the quality of care.

Conclusions: Engaged faculty, critical data analysis, and value proposition analysis with data-driven metrics and accountability can result in a significant increase in OR utilization and reduction in surgical cancellations. Think Tank serves as a model transformative program to assist practices and institutions to best fulfill their mission while actively engaging and retaining their members.
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http://dx.doi.org/10.1016/j.pcorm.2020.100147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993645PMC
March 2021

Calculation of test-retest variability in phase I/IIa clinical trials for Inherited Retinal Degenerations.

Ophthalmic Genet 2021 Mar 17:1-8. Epub 2021 Mar 17.

Department of Ophthalmology and Visual Sciences, Center for Eye Policy and Innovation, University of Michigan, Ann Arbor, Michigan, USA.

: Several novel treatments of inherited retinal degenerations have undergone phase I/IIa clinical trials with limited sample size, yet investigators must still determine if toxicity or an efficacy signal occurred or if the change was due to test-retest variability (TRV) of the measurement tool.: Synthetic datasets were used to compare three types of TRV estimators under different sample sizes, mean drift, skewness, and number of baseline measurements.: Mixed effects models underestimated the standard deviation of measurement error (SDEM); the unbiased change score estimator method (UBS) was more accurate. The fixed effect model had less bias and smaller standard deviation than UBS if >2 baseline measurements. The change score estimator had no bias; other estimators introduced bias for lower variability. With sample size <10, all estimators had high variance. With sample size ≥10, the differences between methods were often minimal. The pooled estimator model did not capture drift, whereas a fixed effect regression or mixed effects models accounted for drift while maintaining an accurate measure of variance. With small sample sizes, the bootstrap estimates of SDEM were severe underestimates, while the jackknife estimates were mildly low but much better. The jackknife was more accurate for the unbiased change score method than for the pooled estimator.: The ideal phase I/IIa study has ≥20 subjects and uses UBS or its fixed effect model generalization if >2 baseline measurements. With non-ideal study parameters, investigators should at least quantify the error estimate present in their data analysis.
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http://dx.doi.org/10.1080/13816810.2021.1897848DOI Listing
March 2021

Association of No-Cost Genetic Testing Program Implementation and Patient Characteristics With Access to Genetic Testing for Inherited Retinal Degenerations.

JAMA Ophthalmol 2021 Mar 4. Epub 2021 Mar 4.

W. K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.

Importance: The benefits of no-cost genetic testing initiatives have not been characterized. The no-cost My Retina Tracker Genetic Testing Study (MRT-GTS) research registry for inherited retinal degenerations (IRDs) was launched in 2017 in the US.

Objective: To investigate the associations of MRT-GTS implementation and patient characteristics with access to genetic testing for IRDs.

Design, Setting, And Participants: In a cross-sectional design, analysis of new patients evaluated 12 months before (July 1, 2016, to June 13, 2017) and 12 months after (June 14, 2017, to June 30, 2018) MRT-GTS implementation at a single academic referral eye center was conducted. Participants included 369 patients with IRD. Data analysis was conducted from February to June 2020.

Main Outcomes And Measures: Change in rates of successfully obtaining genetic testing, odds ratios (ORs) of association between patient characteristics and obtaining testing, and days elapsed from clinic visit to reporting of results.

Results: Among 369 patients (mean [SD] age, 39.5 [20.8] years; 193 [52.3%] women), 144 were evaluated in the pre-MRT-GTS period and 225 in the post-MRT-GTS period. The baseline rate of successfully obtaining testing was 51.4% (95% CI, 42.6%-60.2%). The initiation of MRT-GTS was associated with a 28.9-percentage point increase in testing rate (95% CI, 16.7%-41.1%; P < .001). Patient characteristics that increased the odds of obtaining testing were eligibility for MRT-GTS (OR, 14.15; 95% CI, 7.36-27.24; P < .001) and worse visual acuity (logMAR +1.0; Snellen equivalent decrease from 20/20 to 20/200) in the better-seeing eye (OR, 1.92; 95% CI, 1.27-2.91; P < .01). Patients had decreased odds when identifying as Black or African American (OR, 0.10; 95% CI, 0.04-0.24; P < .001) or other race (OR, 0.37; 95% CI, 0.15-0.91; P = .03) compared with White race, and when the primary language was not English (OR, 0.13; 95% CI, 0.03-0.55; P < .01). The proportion of test results reported within 90 days was 81.5% (95% CI, 74.8%-86.4%) when eligible for MRT-GTS compared with 48.1% (95% CI, 35.6%-58.1%) when not eligible (P < .001).

Conclusions And Relevance: In this study, the implementation of MRT-GTS was associated with an increase in the proportion of patients who successfully obtained testing, suggesting the potential clinical value of this approach. Patient-level demographic and clinical factors appear to be associated with decisions to pursue testing.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934082PMC
March 2021

Vision-related quality of life in adults with severe peripheral vision loss: a qualitative interview study.

J Patient Rep Outcomes 2021 Jan 13;5(1). Epub 2021 Jan 13.

Department of Ophthalmology and Visual Sciences, Center for Eye Policy and Innovation, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, USA.

Background: Existing patient-reported outcome (PRO) measures may not be relevant to the full range of functional and vision-related quality of life (VR-QOL) concerns of individuals with vision impairment due to severe peripheral field loss (PFL). Measurement of VR-QOL in severe PFL is important in order to determine the effectiveness of vision rehabilitation interventions for this population. The purpose of this study was to characterize the impact of severe PFL due to retinitis pigmentosa (RP) and glaucoma on VR-QOL as the initial phase in the development of a novel PRO measure.

Methods: Individuals with severe PFL due to RP or glaucoma were recruited from the Kellogg Eye Center and the Association for the Blind and Visually Impaired. Participants completed semi-structured qualitative interviews, the Impact of Vision Impairment (IVI) questionnaire and the RAND 36-Item Health Survey. Interviews were analyzed by two coders using thematic analysis. A matrix analysis was conducted to compare VR-QOL by cause of severe PFL. Sample size was determined by thematic saturation.

Results: The study included 37 participants (19 RP, 18 glaucoma). Median best-corrected visual acuity for those with RP and glaucoma was 20/40 and 20/27.5, while Pelli-Robson contrast sensitivity was 1.2 log contrast sensitivity (logCS) and 1.1 logCS, respectively. Median domain scores on the IVI (reading, mobility, well-being) ranged from a low of - 0.2 to a high of 0.7 logits in those with RP and from 0.5 to 1.2 logits in those with glaucoma. Qualitative interviews identified six VR-QOL themes relevant across participants with both RP and glaucoma, including activity limitations, driving, emotional well-being, reading, mobility, and social function. VR-QOL concerns were largely consistent among those with severe PFL due to RP and glaucoma. These overarching themes contained content relevant to specific challenges related to severe PFL.

Conclusions: There are commonly occurring VR-QOL concerns among individuals with severe PFL due to RP and glaucoma. The outlined themes will serve as the basis for development of the Low Vision Severely Constricted Peripheral Eyesight (LV-SCOPE) Questionnaire.
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http://dx.doi.org/10.1186/s41687-020-00281-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806695PMC
January 2021

Clinical trial design for neuroprotection in autosomal dominant retinitis pigmentosa; outcome measure considerations.

Ophthalmic Genet 2021 Apr 6;42(2):170-177. Epub 2021 Jan 6.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI, USA.

: To identify structural and functional outcome measures among patients with Rho-positive autosomal dominant Retinitis Pigmentosa (adRP) to aid neuroprotection trial design.: This was a retrospective cohort study of 52 patients with Rho-positive adRP. We measured Goldmann Visual Fields (GVF) constriction in four sectors (nasal, temporal, inferior, superior), and sectoral Ellipsoid Zone (EZ) width degeneration using Spectral Domain Optical Coherence Tomography (OCT) scans. Disease progression trajectories were projected using mixed effects modeling.: Superior GVF was most constricted at presentation and had the shallowest trajectory (less steep negative slope); Inferior GVF was less constricted (corrected < .001) and had a steeper negative slope (corrected = .019) than superior GVF. Temporal EZ was most stable on OCT with a relatively shallow negative trajectory (corrected = .011).: Patients' superior visual fields presented with more constriction and subsequently had a shallow negative slope suggesting the corresponding inferior retina may be "burned out" at presentation. Targeted therapies for adRP will likely show a greater efficacy signal if delivered to the superior and nasal retina, which may demonstrate more change on OCT and GVF over the course of a neuroprotection trial.: Mixed effects analysis of sectoral visual field constriction and EZ degeneration in Rho-positive adRP can prove useful in monitoring therapeutic efficacy and identifying targets for local therapies.
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http://dx.doi.org/10.1080/13816810.2020.1867752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987885PMC
April 2021

The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations.

Am J Ophthalmol 2020 Dec 9;225:137-146. Epub 2020 Dec 9.

Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address:

Objective: We sought to construct and validate a patient-reported outcome measure for screening and monitoring vision-related anxiety in patients with inherited retinal degenerations.

Design: Item-response theory and graded response modeling to quantitatively validate questionnaire items generated from qualitative interviews and patient feedback.

Methods: Patients at the Kellogg Eye Center (University of Michigan, Ann Arbor, Michigan, USA) with a clinical diagnosis of an inherited retinal degeneration (n = 128) participated in an interviewer-administered questionnaire. The questionnaire consisted of 166 items, 26 of which pertained to concepts of "worry" and "anxiety." The subset of vision-related anxiety questions was analyzed by a graded response model using the Cai Metropolis-Hastings Robbins-Monro algorithm in the R software mirt package. Item reduction was performed based on item fit, item information, and item discriminability. To assess test-retest variability, 25 participants completed the questionnaire a second time 4 to 16 days later.

Results: The final questionnaire consisted of 14 items divided into 2 unidimensional domains: rod function anxiety and cone function anxiety. The questionnaire exhibited convergent validity with the Patient Health Questionnaire for symptoms of depression and anxiety. This vision-related anxiety questionnaire has high marginal reliability (0.81 for rod-function anxiety, 0.83 for cone-function anxiety) and exhibits minimal test-retest variability (ρ = 0.81 [0.64-0.91] for rod-function anxiety and ρ = 0.83 [0.68-0.92] for cone-function anxiety).

Conclusions: The Michigan Vision-Related Anxiety Questionnaire is a psychometrically validated 14-item patient-reported outcome measure to be used as a psychosocial screening and monitoring tool for patients with inherited retinal degenerations. It can be used in therapeutic clinical trials for measuring the benefit of an investigational therapy on a patient's vision-related anxiety.
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http://dx.doi.org/10.1016/j.ajo.2020.12.001DOI Listing
December 2020

Modeling undergraduates' selection of course modality: A large sample, multi-discipline study.

Internet High Educ 2021 Jan 19;48:100776. Epub 2020 Oct 19.

Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 0A1, Canada.

Scholarly understanding is limited with regard to what influences students' choice to take a particular course fully online or in-person. We surveyed 650 undergraduates at a public Canadian university who were enrolled in courses that were offered in both modalities during the same semester, for roughly the same tuition cost. The courses spanned a wide range of disciplines, from archaeology to computing science. Twenty-five variables were gauged, covering areas including students' personal circumstances, their competence in the language of instruction, previous experience with online courses, grade expectations, and psychological variables including their regulation of their time and study environment, work avoidance and social goal orientation. Two logistic regression models (of modality of enrolment and modality of preference) both had good fit to the data, each correctly classifying roughly 75% of cases using different variables. Implications for instructional design and enrolment management are discussed.
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http://dx.doi.org/10.1016/j.iheduc.2020.100776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571457PMC
January 2021

Genetic testing for inherited retinal degenerations: Triumphs and tribulations.

Am J Med Genet C Semin Med Genet 2020 09 31;184(3):571-577. Epub 2020 Aug 31.

Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.

Inherited retinal degenerations (IRDs) are a genotypically and phenotypically diverse group of conditions. Great strides have been made toward identifying the genetic basis for these conditions over the last 30 years-more than 270 different genes involved in syndromic and nonsyndromic forms of retinal dystrophies have now been identified. The identification of these genes and the improvement of clinical laboratory techniques have led to the identification of the genetic basis of disease in 56-76% of patients with IRDs through next generation sequencing and copy number variant analysis. Genetic testing is an essential part of clinical care for patients affected with IRDs and is required to confirm the diagnosis, understand the inheritance of the condition, and determine eligibility for gene-specific treatments or clinical trials. Despite the success achieved in determining the genetic cause of these conditions, several challenges remain, which must be considered when providing genetic testing and genetic counseling to patients. For this reason, an integrated team of ophthalmic and genetic clinicians who are familiar with these challenges is necessary to provide optimal comprehensive care to these patients.
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http://dx.doi.org/10.1002/ajmg.c.31835DOI Listing
September 2020

The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome Instrument for Inherited Retinal Degenerations.

Am J Ophthalmol 2021 02 26;222:60-68. Epub 2020 Aug 26.

Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address:

Purpose: To create a psychometrically validated patient-reported outcome measure for inherited retinal degenerations.

Design: Qualitative and quantitative patient-reported outcome (PROs) questionnaire development using item response theory validation.

Methods: One hundred twenty-eight patients with a diagnosis of an inherited retinal degeneration at the Kellogg Eye Center (University of Michigan) were recruited and administered a 166-item questionnaire comprising 7 expert-defined domains. The questionnaire was re-administered 4-16 days later to a subset of 25 participants to assess test-retest variability. Graded response models were fit by Cai's Metropolis-Hastings Robbins-Monro algorithm using the R (version 3.6.3) package mirt. Model data were fit to assess questionnaire dimensionality, to estimate item information, and to score participants. Poorly functioning items were removed, and the model was refit to create the final questionnaire.

Results: The psychometrically validated PROs measure was reduced to a 59-item questionnaire measuring 7 unidimesnional domains: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. A total of 39 items were removed because of poor factor loading, low item information, poor person-ability differentiation, or high item-level interdependence. This novel questionnaire produces a reliable domain score for person ability that does not show significant test-retest variability across repeated administration.

Conclusions: The final PRO questionnaire, known as the Michigan Retinal Degeneration Questionnaire, is psychometrically validated and available for use in the evaluation of patients with inherited retinal degenerations.
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http://dx.doi.org/10.1016/j.ajo.2020.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907279PMC
February 2021

Correlation of Immunological Markers with Disease and Clinical Outcome Measures in Patients with Autoimmune Retinopathy.

Transl Vis Sci Technol 2020 06 16;9(7):15. Epub 2020 Jun 16.

Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Purpose: To determine if immunological markers (1) are significantly different between autoimmune retinopathy (AIR) patients and controls and (2) correlate with disease progression in AIR patients.

Methods: We enrolled patients with a possible AIR diagnosis, as well as control participants without eye disease, autoimmunity, or cancer. Immunological markers were tested in all participants. In addition, AIR patients had up to three blood draws for testing over their disease course. For AIR patients, clinical measures, including visual acuity (VA) and Goldmann visual field (GVF) area, were recorded at each draw. We used the Mann-Whitney test to compare the immunological markers between AIR patients and controls. We used multilevel mixed-effect regression to investigate the correlation between markers and clinical parameters over time in AIR patients.

Results: Seventeen patients with AIR and 14 controls were included. AIR patients had a higher percent of monocytes ( = 3.076, = 0.002). An increase in immunoglobulin G against recoverin was correlated with a VA decrease (β = 0.0044, < 0.0001). An increase in monocyte proportion was correlated with a decrease in GVF area (β = -7.27, = 0.0021). Several markers of B-cell depletion were correlated with GVF improvement.

Conclusions: Monocytes may play a role in AIR pathophysiology and be a disease activity marker. B-cell depletion markers correlated with clinical parameter improvement, particularly GVF.

Translational Relevance: This work elucidates immunologic markers that may improve the accuracy of diagnosis and treatment of AIR.
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http://dx.doi.org/10.1167/tvst.9.7.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414616PMC
June 2020

Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.
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http://dx.doi.org/10.1167/tvst.9.7.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414644PMC
June 2020

Content generation for patient-reported outcome measures for retinal degeneration therapeutic trials.

Ophthalmic Genet 2020 08 22;41(4):315-324. Epub 2020 Jun 22.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School , Ann Arbor, Michigan, USA.

Purpose: Generate content for a patient-reported outcome (PRO) measure for use in future clinical trials for inherited retinal degenerations.

Methods: Patients at the University of Michigan Kellogg Eye Center with a clinical diagnosis of inherited retinal degeneration with varying phenotypes were recruited for interviews. First, in-depth interviews were performed to solicit a wide range of patient experiences pertaining to visual function. Coders qualitatively analyzed the transcripts from these interviews using Atlas.ti software (Version 8.1.3 (522)) to draft questionnaire items. Next, the questionnaire was tested and refined based on participant feedback in cognitive interviews and administrator feedback in the pilot survey administration (pilot interviews).

Results: A total of 55 participants with a clinical diagnosis of inherited retinal degeneration were interviewed throughout the three study phases: in-depth interviews (n = 26), cognitive interviews (n = 16), and pilot interviews (n = 13). Coded items were analyzed for frequency of occurrence and related themes, then organized into common domains. Within each domain, PRO items were drafted to address the functional limitations or adaptations experienced by patients.

Conclusions: Items for a PRO measure have been drafted and evaluated for interpretability in the target inherited retinal degeneration patient population. Content validity for the items was established through a process of in-depth interviews, cognitive interviews, and pilot interviews.
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http://dx.doi.org/10.1080/13816810.2020.1776337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503769PMC
August 2020

Coats-like Exudative Vitreoretinopathy in Retinitis Pigmentosa: Ocular Manifestations and Treatment Outcomes.

Ophthalmol Retina 2021 Jan 9;5(1):86-96. Epub 2020 Apr 9.

W. K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: To provide a comprehensive review of the ocular manifestations, outcomes, and genetic findings in patients with Coats-like retinitis pigmentosa (RP).

Design: Multicenter, retrospective, nonconsecutive case series.

Participants: Patients with a diagnosis of RP demonstrating Coats-like exudative vitreoretinopathy between January 1, 2008, and October 1, 2019.

Methods: Evaluation of ocular findings at RP diagnosis and at time of presentation of Coats-like exudative vitreoretinopathy, pedigree analysis, genetic testing, retinal imaging, and anatomic outcomes after treatment.

Main Outcome Measures: Visual acuity, ophthalmoscopy results, OCT results, fluorescein angiography results, and identification of genetic mutations.

Results: Nine patients diagnosed with RP and demonstrating Coats-like exudative vitreoretinopathy were included. Median age at time of RP diagnosis was 8 years (range, 1-22 years), and median age at presentation of Coats-like exudative vitreoretinopathy was 18 years (range, 1-41 years). Seven patients were female, and 2 were male. The genetic cause of disease was identified in 6 patients. Three patients demonstrated Coats-like fundus findings at the time of RP diagnosis. Exudative retinal detachment (ERD) localized to the infratemporal periphery was present in all patients, with bilateral disease observed in 7 patients. In all treated patients, focal laser photocoagulation was used to treat leaking telangiectasias and to limit further ERD expansion. Cystoid macular edema refractory to carbonic anhydrase inhibitor therapy and ultimately amenable to treatment with intravitreal anti-vascular endothelial growth factor injection was observed in 4 patients.

Conclusions: Coats-like vitreoretinopathy is present in up to 5% of all RP patients. The term Coats-like RP is used colloquially to describe this disease state, which can present at the time of RP diagnosis or, more commonly, develops late during the clinical course of patients with longstanding RP. Coats-like RP is distinct from Coats disease in that exudative pathologic features occur exclusively in the setting of a coexisting RP diagnosis, is restricted to the infratemporal retina, can affect both eyes, and does not demonstrate a male gender bias. Given the risk of added vision loss posed by exudative vitreoretinopathy in patients with RP, a heightened awareness of this condition is critical in facilitating timely intervention.
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http://dx.doi.org/10.1016/j.oret.2020.03.026DOI Listing
January 2021

Patient-reported outcome measures in inherited retinal degeneration gene therapy trials.

Ophthalmic Genet 2020 02 26;41(1):1-6. Epub 2020 Feb 26.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Patient-reported outcome (PRO) measures have the potential to uniquely capture patient experience and serve as an outcome measure in inherited retinal degeneration (IRD) gene therapy trials. An IRD-specific patient-reported outcome measure may yield valuable information that has not been obtained from inherited retinal dystrophy gene therapy trials published to-date. Existing PRO measures have inherent limitations for use in IRD gene therapy trials. Developing an applicable patient-reported outcome measure for such trials needs to incorporate patient input from the target population, demonstrate sound psychometric properties, and be made in accordance with U.S. Food and Drug Administration (FDA) guidelines. This review will discuss the currently available PRO instruments, their limitations for IRD therapeutic trials, and suggestions for future PRO development in IRD populations. The PRO instruments highlighted were identified in PubMed search of English-language journals and previously published review articles.
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http://dx.doi.org/10.1080/13816810.2020.1731836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110960PMC
February 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

USC Institute for Biomedical Therapeutics, USC Roski Eye Institute, University of Southern California, Los Angeles, California; and.

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

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa.

Ophthalmol Retina 2020 05 18;4(5):510-520. Epub 2019 Nov 18.

Department of Genetics, University of Texas Health Science Center, Houston, Texas.

Purpose: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity.

Design: Cohort study.

Participants: Seventy-seven female carriers with RPGR mutations from 41 pedigrees.

Methods: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters.

Main Outcome Measures: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation.

Results: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002).

Conclusions: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.
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http://dx.doi.org/10.1016/j.oret.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211129PMC
May 2020

Comparison of Fundus-Guided Microperimetry and Multifocal Electroretinography for Evaluating Hydroxychloroquine Maculopathy.

Transl Vis Sci Technol 2019 Sep 27;8(5):19. Epub 2019 Sep 27.

Department of Ophthalmology and Visual Sciences, Medical School, University of Michigan, Ann Arbor, MI, USA.

Purpose: To compare retinal function by using fundus-guided microperimetry (MP) and multifocal electroretinography (mfERG) for detecting hydroxychloroquine (HCQ) maculopathy.

Methods: Forty-six eyes of 25 patients referred to our clinical practice for HCQ maculopathy assessment and 3 groups of normal control subjects were evaluated by mfERG and MP. Macular structure was assessed using spectral-domain optical coherence tomography (SD-OCT). Ring ratios from the three innermost mERG rings were compared with average sensitivity of each MP ring at approximately equivalent distances from the fovea. HCQ toxicity was defined as an mfERG ring ratio or mean MP ring sensitivity >2 standard deviations below the normal mean. The sensitivity and specificity of MP to detect HCQ toxicity relative to mfERG were evaluated.

Results: MP rings MR2 and MR3 were positively correlated with corresponding mfERG ring ratios (r = 0.52, = 0.002 and r = 0.56, < 0.001 respectively). Ring 2 and ring 3 measures of MP and mfERG were significantly worse in HCQ eyes than controls ( < 0.001). The sensitivity of MP to detect toxicity for MR1 through MR3 ranged from 33% to 88%, whereas specificity ranged from 72% to 85%. Through rings 1 to 3, the frequency of abnormal function ranged from 20% to 48% for MP, 11% to 35% for mfERG, and 41% to 45% for SD-OCT.

Conclusions: The frequency of detection of HCQ toxicity with MP was greater than with mfERG. MP showed an overall good sensitivity and moderate specificity in detecting HCQ-induced functional deficits.

Translational Relevance: Results from this study may allow clinicians to improve screening accuracy for HCQ toxicity by using the alternative modality of MP.
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http://dx.doi.org/10.1167/tvst.8.5.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779178PMC
September 2019

Phenotypic Spectrum of Pentosan Polysulfate Sodium-Associated Maculopathy: A Multicenter Study.

JAMA Ophthalmol 2019 Sep 5. Epub 2019 Sep 5.

Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia.

Importance: A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.

Objective: To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy.

Design, Setting, And Participants: In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019.

Main Outcomes And Measures: Drug exposure, visual acuity, and retinal imaging characteristics.

Results: Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (-0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes [53%]) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes [23%]; P < .001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities.

Conclusions And Relevance: These findings suggest that PPS-associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium-photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.
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http://dx.doi.org/10.1001/jamaophthalmol.2019.3392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735406PMC
September 2019

Prospective Evaluation of Patients With X-Linked Retinoschisis During 18 Months.

Invest Ophthalmol Vis Sci 2018 12;59(15):5941-5956

Applied Genetic Technologies Corporation, Alachua, Florida, United States.

Purpose: Prospective evaluation of patients with X-linked retinoschisis (XLRS).

Methods: Fifty-six males XLRS patients, age ≥7 years, had retinal structure and function tests performed every 6 months during an 18-month period.

Results: Best corrected visual acuity (BCVA) was abnormal (mean ± SD logMAR 0.57 ± 0.32 OD and 0.50 ± 0.27 OS), with weak correlation between visual acuity and age (R = -0.24, P = 0.0095). Mean cyst cavity volume (CCV) determined on optical coherence tomography showed weak correlation with age (R = -0.33, P = 0.0009) and no correlation with visual acuity. Subjects had modest reduction in mean kinetic and static perimetry results, reduced b-wave amplitude on electroretinography, abnormal reading speed results, and decreased visual function quality of life scores. Contrast sensitivity results were normal in 85 of 99 eyes tested. Most subjects had no meaningful change in BCVA during follow-up. Subjects who started carbonic anhydrase inhibitor (CAI) treatment at enrollment had improved BCVA (mean ± SD change 3.15 ± 7.8 ETDRS letters, with increase of ≥15 ETDRS letters at 8 of 110 visits [in 3 subjects]). There were no significant changes in other parameters tested.

Conclusions: Structural and functional results were stable during the 18-month follow-up period. Some patients starting CAI treatment at the baseline visit showed improvement in BCVA that was not correlated with changes in CCV. Natural history data such as these will be important for comparisons to the changes in measures of retinal structure and function following gene replacement therapy in patients with XLRS.
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http://dx.doi.org/10.1167/iovs.18-24565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295939PMC
December 2018

T Helper 1 Cellular Immunity Toward Recoverin Is Enhanced in Patients With Active Autoimmune Retinopathy.

Front Med (Lausanne) 2018 13;5:249. Epub 2018 Sep 13.

Department of Ophthalmology and Visual Sciences-Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, United States.

Autoimmune retinopathy (AIR) causes rapidly progressive vision loss that is treatable but often is confused with other forms of retinal degeneration including retinitis pigmentosa (RP). Measurement of anti-retinal antibodies (ARA) by Western blot is a commonly used laboratory assay that supports the diagnosis yet does not reflect current disease activity. To search for better diagnostic indicators, this study was designed to compare immune biomarkers and responses toward the retinal protein, recoverin, between newly diagnosed AIR patients, slow progressing RP patients and healthy controls. All individuals had measurable anti-recoverin IgG and IgM antibodies by ELISA regardless of disease status or Western blot results. Many AIR patients had elevated anti-recoverin IgG1 levels and a strong cellular response toward recoverin dominated by IFNγ. RP patients and controls responded to recoverin with a lower IFNγ response that was balanced by IL-10 production. Both AIR and RP patients displayed lower levels of total peripheral blood mononuclear cells that were due to reductions of CD4 T cells. A comparison of messenger RNA (mRNA) for immune-related genes in whole blood of AIR patients versus RP patients or controls indicated lower expression of ATG5 and PTPN22 and higher expression of several genes involved in T cell signaling/transcription and adhesion. These data indicate that an immune response toward recoverin is normal in humans, but that in AIR patients the balance shifts dramatically toward higher IFNγ production and cellular activation.
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http://dx.doi.org/10.3389/fmed.2018.00249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146138PMC
September 2018

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

Approach for a Clinically Useful Comprehensive Classification of Vascular and Neural Aspects of Diabetic Retinal Disease.

Invest Ophthalmol Vis Sci 2018 01;59(1):519-527

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States.

The Early Treatment Diabetic Retinopathy Study (ETDRS) and other standardized classification schemes have laid a foundation for tremendous advances in the understanding and management of diabetic retinopathy (DR). However, technological advances in optics and image analysis, especially optical coherence tomography (OCT), OCT angiography (OCTa), and ultra-widefield imaging, as well as new discoveries in diabetic retinal neuropathy (DRN), are exposing the limitations of ETDRS and other classification systems to completely characterize retinal changes in diabetes, which we term diabetic retinal disease (DRD). While it may be most straightforward to add axes to existing classification schemes, as diabetic macular edema (DME) was added as an axis to earlier DR classifications, doing so may make these classifications increasingly complicated and thus clinically intractable. Therefore, we propose future research efforts to develop a new, comprehensive, and clinically useful classification system that will identify multimodal biomarkers to reflect the complex pathophysiology of DRD and accelerate the development of therapies to prevent vision-threatening DRD.
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http://dx.doi.org/10.1167/iovs.17-21873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786342PMC
January 2018

The synthesis of planar chiral pseudo-gem aminophosphine pre-ligands based on [2.2]paracyclophane.

Org Biomol Chem 2017 Oct;15(42):8975-8984

Institute of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston North, New Zealand.

The synthesis of three planar chiral pseudo-gem disubstituted [2.2]paracyclophane-derived P,N-pre-ligands is reported along with preliminary results of their activity in the amination of aryl bromides and chlorides. The pseudo-gem aminophosphines were capable of mediating the coupling reaction at a loading of 1 mol%.
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http://dx.doi.org/10.1039/c7ob02393fDOI Listing
October 2017

Double hyperautofluorescent ring on fundus autofluorescence in ABCA4.

Ophthalmic Genet 2018 Jan-Feb;39(1):87-91. Epub 2017 Jul 20.

a Department of Ophthalmology and Visual Sciences , University of Michigan Medical School , Ann Arbor , Michigan , USA.

We report an unusual phenotype in a child with a clinical diagnosis of recessive Stargardt disease (STGD1) and two pathogenic variants in the ABCA4 gene. Typically, the diagnosis of early-onset STGD1 is challenging because children may present with a variety of fundus changes and a variable rate of progression. At the time of his initial visit, the 6-year-old boy presented with 20/200 OD (right eye) and 20/150 OS (left eye), symmetrical mild foveal atrophy without flecks on fundus exam, and foveal hypoautofluorescence surrounded by a homogeneous hyperautofluorescent background on wide-field fundus autofluorescence. Over 4 years of follow-up, the retinal atrophy continued to progress, resulting in two well-defined and concentric hyperautofluorescent rings: one ring located at the posterior pole and the other located around the peripapillary region. Visual acuity also deteriorated to counting fingers at 4ft OD and 20/500 OS. To the best of our knowledge, this phenotype has not been previously described with the ABCA4 gene.
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http://dx.doi.org/10.1080/13816810.2017.1335330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950710PMC
March 2018

Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials.

Ophthalmic Genet 2018 Jan-Feb;39(1):22-28. Epub 2017 Jul 13.

a Department of Ophthalmology and Visual Sciences , W. K. Kellogg Eye Center, University of Michigan Medical School , Ann Arbor , Michigan , USA.

Purpose: Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration.

Methods: Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed.

Results: Twenty-nine children (58 eyes), ages 5-16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mm (I4e, p = 0.012), 720 ± 155 mm (III4e, p < 0.001), and 759 ± 167 mm (IV4e, p < 0.001), with greater increases at earlier ages. Repeatability coefficients were 7381 mm (I4e), 9379 mm (III4e), and 10346 mm (IV4e), indicating a large variability. At 2.5 years after the baseline GVF the area increased ≥ 20%, the criterion for positive treatment outcome defined in recent published therapeutic trials, in 38% (I4e), 34% (III4e), and 33% (IV4e) of eyes.

Conclusion: In a substantial proportion of children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those < 12 years, despite progression or stability of disease. These findings suggest that change in GVF area in children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.
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http://dx.doi.org/10.1080/13816810.2017.1329447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938742PMC
March 2018

The synthesis of substituted amino[2.2]paracyclophanes.

Org Biomol Chem 2016 Nov;14(46):10848-10860

Institute of Fundamental Sciences, Massey University, Private Bag 11 222, Palmerston North, New Zealand.

Two methodologies for the formation of substituted amino[2.2]paracyclophane derivatives were developed. The first involves the direct amination of bromo[2.2]paracyclophanes with sodium azide. This permits the synthesis of simple mono- and disubstituted derivatives but fails to give sterically congested pseudo-gem derivatives. A 'one-pot' oxidation-Lossen rearrangement of [2.2]paracyclophane oximes provides access to a range of amino[2.2]paracyclophanes including the most efficient synthesis of the pseudo-gem planar chiral amino acid yet reported.
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http://dx.doi.org/10.1039/c6ob02150fDOI Listing
November 2016

Fungal Endophthalmitis Associated With DSAEK and Thermal Sclerostomy.

Ophthalmic Surg Lasers Imaging Retina 2016 07;47(7):691-3

An 85-year-old man with remote thermal sclerostomy and Descemet's stripping automated endothelial keratoplasty (DSAEK) in the right eye presented urgently for pain and blurred vision in that eye. Examination revealed bleb purulence and vitreous cellular aggregates concerning for endophthalmitis. Microscopy of a vitreous sample revealed yeast and pseudohyphae. He developed corneal infiltrates consistent with fungal infection. Therapy included topical, intravitreal, and systemic antifungals voriconazole and amphotericin. Fungal pathogens have very rarely been reported to cause bleb-associated endophthalmitis and should be considered in addition to bacterial pathogens. Vitreous aspiration should be performed in all cases of bleb-related endophthalmitis and include fungal studies. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:691-693.].
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http://dx.doi.org/10.3928/23258160-20160707-15DOI Listing
July 2016

Safety and Feasibility of Quantitative Multiplexed Cytokine Analysis From Office-Based Vitreous Aspiration.

Invest Ophthalmol Vis Sci 2016 06;57(7):3017-23

Penn State Hershey Eye Center, Hershey, Pennsylvania, United States.

Purpose: The goals of this study were to evaluate the safety of office-based vitreous sampling, and determine the utility of these samples with multiplex cytokine analysis.

Methods: Vitreous samples were collected from office-based needle aspiration and the rate of adverse events during follow-up was reviewed. The vitreous cytokine concentrations in a subset of patients with diabetic macular edema (DME) were analyzed using a 42 plex-cytokine bead array. These results were compared with vitreous cytokine concentrations in proliferative diabetic retinopathy (PDR) and controls (macular hole, epiretinal membrane, symptomatic vitreous floaters) from pars plana vitrectomy.

Results: An adequate volume of vitreous fluid (100-200 μL) was obtained in 52 (88%) of 59 office-based sampling attempts. The average length of follow-up was 300 days (range, 42-926 days). There were no complications, including cataract, retinal tear or detachment, and endophthalmitis. Two patients (3%) had posterior vitreous detachments within 3 months. Vitreous cytokine concentrations were measured in 44 patients: 14 controls, 13 with DME, and 17 with PDR. The concentration of ADAM11, CXCL-10, IL-8, and PDGF-A were higher in PDR compared with controls and DME. The concentration of IL-6 was higher in PDR compared with controls, but not compared with DME.

Conclusions: Office-based vitreous aspiration is safe and yields high-quality samples for multiplex vitreous cytokine analysis. Significant elevations of vitreous cytokines were found in PDR compared with DME and controls, including the novel finding of elevated ADAM11. As such, office-based aspiration is a safe and effective means to identify vitreous factors associated with vitreoretinal disease.
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http://dx.doi.org/10.1167/iovs.15-18721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904801PMC
June 2016