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Mansberger S.L.,Devers Eye Institute
Journal of Glaucoma | Year: 2012

Introduction/Purpose: To determine the associations between medical, demographic, socioeconomic, and ocular factors and adherence to topical glaucoma ocular hypotensive therapy. Methods: One hundred sixteen patients with ocular hypertension or open-angle glaucoma from 2 tertiary glaucoma services participated in this prospective study. Adherence to ocular hypotensive therapy was measured using an electronic dose monitor (Travatan Dosing Aid, Alcon Laboratories Inc., Fort Worth, TX) and collected data at 3 months after enrollment. We used 3 different definitions of adherence: 1) Definition 1: the proportion of days taking the prescribed number of drops within 3 hours of the prescribed dosing time; 2) Definition 2: the proportion of days taking any drops within 3 hours of the prescribed dosing time; and 3) Definition 3: the proportion of days taking any drops within 6 hours of the prescribed dosing time. Univariate and multivariate models were used to determine the association between the 3 adherence definitions, medical, demographic, socioeconomic, and ocular factors at 3-month follow-up. The main outcome measures for this study were risk factors for poor objective medication adherence. Results: Adherence, using Definition 1, Definition 2, and Definition 3, was 64%, 75%, and 80%, respectively. Age, total number of other eye diseases, and race were significantly associated with full treatment adherence (Definition 1), with race alone significantly predicting 11% of full treatment adherence. For Definition 2, age, income, level of education, and total number of eye diseases were significantly associated with partial adherence (3 h), again race alone significantly predicted 15% of partial adherence (any drops within 3 h). For Definition 3, race, income, level of education, and total number of other eye diseases significantly predicted partial adherence (any drops within 6 h), both race and income predicted 19% of partial treatment adherence. Significant differences for adherence rates between patients of European descent and those of African descent were found for all 3 definitions with those who were less adherent more likely to be of African descent. Conclusions: Electronic dose monitors provide important information regarding adherence to topical ocular hypotensive medications in glaucoma patients. Electronic dose monitors show low adherence in a significant number of participants. Future studies are needed to determine the reasons for these differences in health behaviors related to glaucoma treatment, which should guide treatment of poor adherence with glaucoma therapy. © 2012 by Lippincott Williams & Wilkins.


Rosenbaum J.T.,University of Oregon | Rosenbaum J.T.,Devers Eye Institute
Clinical Rheumatology | Year: 2015

Uveitis is a common complication of spondyloarthritis. The “phenotype” of the uveitis characteristic of ankylosing spondylitis (sudden onset, anterior, unilateral, recurrent, more often male) may differ from the phenotype often seen with either psoriatic arthritis or inflammatory bowel disease (insidious onset, anterior and intermediate, bilateral, chronic, and/or more often female). The frequency of uveitis is also much greater in association with ankylosing spondylitis than with either inflammatory bowel disease or psoriasis. Uveitis may affect the choice of therapy and can rarely be a complication of therapy. Uveitis and arthritis also co-exist in several animal models. © 2015, International League of Associations for Rheumatology (ILAR).


Lin P.,Oregon Health And Science University | Suhler E.B.,Oregon Health And Science University | Rosenbaum J.T.,Oregon Health And Science University | Rosenbaum J.T.,Devers Eye Institute
Ophthalmology | Year: 2014

Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms. © 2014 by the American Academy of Ophthalmology.


Pasadhika S.,Southern Arizona Veterans Administration Health Care System | Rosenbaum J.T.,Devers Eye Institute
Biologics: Targets and Therapy | Year: 2014

Uveitis is one of the leading causes of blindness worldwide. Noninfectious uveitis may be associated with other systemic conditions, such as human leukocyte antigen B27-related spondyloarthropathies, inflammatory bowel disease, juvenile idiopathic arthritis, Behçet's disease, and sarcoidosis. Conventional therapy with corticosteroids and immunosuppressive agents (such as methotrexate, azathioprine, mycophenolate mofetil, and cyclosporine) may not be sufficient to control ocular inflammation or prevent non-ophthalmic complications in refractory patients. Off-label use of biologic response modifiers has been studied as primary and secondary therapeutic agents. They are very useful when conventional immunosuppressive therapy has failed or has been poorly tolerated, or to treat concomitant ophthalmic and systemic inflammation that might benefit from these medications. Biologic therapy, primarily infliximab, and adalimumab, have been shown to be rapidly effective for the treatment of various subtypes of refractory uveitis and retinal vasculitis, especially Behçet's disease-related eye conditions and the uveitis associated with juvenile idiopathic arthritis. Other agents such as golimumab, abatacept, canakinumab, gevokizumab, tocilizumab, and alemtuzumab may have great future promise for the treatment of uveitis. It has been shown that with proper monitoring, biologic therapy can significantly improve quality of life in patients with uveitis, particularly those with concurrent systemic symptoms. However, given high cost as well as the limited long-term safety data, we do not routinely recommend biologics as first-line therapy for noninfectious uveitis in most patients. These agents should be used with caution by experienced clinicians. The present work aims to provide a broad and updated review of the current and in-development systemic biologic agents for the treatment of noninfectious uveitis. © 2014 Pasadhika and Rosenbaum.


Chauhan B.C.,Dalhousie University | Burgoyne C.F.,Devers Eye Institute
American Journal of Ophthalmology | Year: 2013

Purpose: To review and interpret the anatomy of the optic nerve head (ONH) detected with spectral-domain optical coherence tomography (SD OCT) pertaining to the clinical examination of the optic disc and to propose that a paradigm change for clinical assessment of the ONH is necessary. Design: Perspective. Methods: Presently, the clinician evaluates neuroretinal rim health according to the appearance of the optic disc, the clinically visible surface of the ONH. Recent anatomic findings with SD OCT have challenged the basis and accuracy of current rim evaluation. We demonstrate why incorporation of SD OCT imaging of the ONH into the clinical examination of the disc is required. Results: Disc margin-based rim evaluation lacks a solid anatomic basis and results in variably inaccurate measurements for 2 reasons. First, the clinically visible disc margin is an unreliable outer border of rim tissue because of clinically and photographically invisible extensions of Bruch's membrane. Second, rim tissue orientation is not considered in width measurements. We propose alternative anatomically and geometrically accurate SD OCT-based approaches for rim assessment that have enhanced detection of glaucoma. We also argue for new data acquisition and analysis strategies with SD OCT that account for the large interindividual variability in the angle between the fovea and ONH. Conclusions: We propose a 4-point paradigm change for clinical assessment of the ONH that is anchored to the eye-specific anatomy and geometry of the ONH and fovea. Our approach is designed to enhance the accuracy and consistency of rim width, as well as of peripapillary and macular intraretinal thickness measurements. © 2013 Elsevier Inc. All rights reserved.


To describe an algorithm and software application (APP) for 100% optic nerve axon counting and to compare its performance with a semi-automated manual (SAM) method in optic nerve cross-section images (images) from normal and experimental glaucoma (EG) nonhuman primate (NHP) eyes. ON cross sections from eight EG eyes from eight NHPs, five EG and five normal eyes from five NHPs, and 12 normal eyes from 12 NHPs were imaged at 100×. Calibration (n = 500) and validation (n = 50) image sets ranging from normal to end-stage damage were assembled. Correlation between APP and SAM axon counts was assessed by Deming regression within the calibration set and a compensation formula was generated to account for the subtle, systematic differences. Then, compensated APP counts for each validation image were compared with the mean and 95% confidence interval of five SAM counts of the validation set performed by a single observer. Calibration set APP counts linearly correlated to SAM counts (APP = 10.77 + 1.03 [SAM]; R(2) = 0.94, P < 0.0001) in normal to end-stage damage images. In the validation set, compensated APP counts fell within the 95% confidence interval of the SAM counts in 42 of the 50 images and were within 12 axons of the confidence intervals in six of the eight remaining images. Uncompensated axon density maps for the normal and EG eyes of a representative NHP were generated. An APP for 100% ON axon counts has been calibrated and validated relative to SAM counts in normal and EG NHP eyes.


Burgoyne C.F.,Devers Eye Institute
Experimental Eye Research | Year: 2015

The purpose of this report is to summarize the current strengths and weaknesses of the non-human primate (NHP) experimental glaucoma (EG) model through sections devoted to its history, methods, important findings, alternative optic neuropathy models and future directions. NHP EG has become well established for studying human glaucoma in part because the NHP optic nerve head (ONH) shares a close anatomic association with the human ONH and because it provides the only means of systematically studying the very earliest visual system responses to chronic intraocular pressure (IOP) elevation, i.e. the conversion from ocular hypertension to glaucomatous damage. However, NHPs are impractical for studies that require large animal numbers, demonstrate spontaneous glaucoma only rarely, do not currently provide a model of the neuropathy at normal levels of IOP, and cannot easily be genetically manipulated, except through tissue-specific, viral vectors. The goal of this summary is to direct NHP EG and non-NHP EG investigators to the previous, current and future accomplishment of clinically relevant knowledge in this model. © 2015 Elsevier Ltd.


Fortune B.,Devers Eye Institute
Experimental Eye Research | Year: 2015

The goal of this review is to summarize the most common imaging methods currently applied for in vivo assessment of ocular structure in animal models of experimental glaucoma with an emphasis on translational relevance to clinical studies of the human disease. The most common techniques in current use include optical coherence tomography and scanning laser ophthalmoscopy. In reviewing the application of these and other imaging modalities to study glaucomatous optic neuropathy, this article is organized into three major sections: 1) imaging the optic nerve head, 2) imaging the retinal nerve fiber layer and 3) imaging retinal ganglion cell soma and dendrites. The article concludes with a brief section on possible future directions. © 2015 Elsevier Ltd.


Burgoyne C.F.,Devers Eye Institute
Experimental Eye Research | Year: 2011

This article is dedicated to Rosario Hernandez for her warm support of my own work and her genuine enthusiasm for the work of her colleagues throughout her career. I first met Rosario as a research fellow in Harry Quigley's laboratory between 1991 and 1993. Along with Harry, John Morrison, Elaine Johnson, Abe Clark, Colm O'Brien and many others, Rosario's work has provided lamina cribrosa astrocyte cellular mechanisms that are biomechanically plausible and in so doing provided credibility to early notions of the optic nerve head (ONH) as a biomechanical structure.We owe a large intellectual debt to Rosario for her dogged persistence in the characterization of the ONH astrocyte and lamina cribrosacyte in age and disease. Two questions run through her work and remain of central importance today. First, how do astrocytes respond to and alter the biomechanical environment of the ONH and the physiologic stresses created therein? Second, how do these physiologic demands on the astrocyte influence their ability to deliver the support to retinal ganglion cell axon transport and flow against the translaminar pressure gradient?The purpose of this article is to summarize what is known about the biomechanical determinants of retinal ganglion cell axon physiology within the ONH in the optic neuropathy of aging and Glaucoma. My goal is to provide a biomechanical framework for this discussion. This framework assumes that the ONH astrocytes and glia fundamentally support and influence both the lamina cribrosa extracellular matrix and retinal ganglion cell axon physiology. Rosario Hernandez was one of the first investigators to recognize the implications of this unique circumstance. Many of the ideas contained herein have been initially presented within or derived from her work (Hernandez, M.R., 2000. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 19, 297-321.; Hernandez, M.R., Pena, J.D., 1997. The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 115, 389-395.). © 2010 Elsevier Ltd.


Burgoyne C.,Devers Eye Institute
Journal of Neuro-Ophthalmology | Year: 2015

The clinical phenomenon of cupping has 2 principal pathophysiologic components in all optic neuropathies: prelaminar thinning and laminar deformation. We define prelaminar thinning to be the portion of cup enlargement that results from thinning of the prelaminar tissues due to physical compression and/or loss of retinal ganglion cell axons. We define laminar deformation or laminar cupping to be the portion of cup enlargement that results from permanent intraocular pressure (IOP)-induced deformation of the lamina cribrosa and peripapillary scleral connective tissues after damage and/or remodeling. We propose that the defining phenomenon of glaucomatous cupping is deformation and/or remodeling of the neural and connective tissues of the optic nerve head (ONH), which is governed by the distribution of IOP-related connective tissue stress and strain, regardless of the mechanism of insult or the level of IOP at which deformation and/or remodeling occurs. In other words, "glaucomatous cupping" is the term clinicians use to describe the clinical appearance and behavior the ONH assumes as its neural and connective tissues deform, remodel, or mechanically fail: 1) in a pattern and 2) by the several pathophysiologic processes governed by IOP-related connective tissue stress and strain. ONH biomechanics explains why a given ONH will demonstrate a certain form of "cupping" and at what level of IOP that might happen. Animal models are allowing us to tease apart the important components of cupping in IOP-related and non-IOP-related forms of optic neuropathy. A paradigm change in spectral domain optical coherence tomography ONH, retinal nerve fiber layer, and macular imaging should improve our ability to phenotype the ocular manifestations of many forms of damage to the visual system including glaucoma. © 2015 by North American Neuro-Ophthalmology Society.

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