Faculty Bibliography

Background: Retinal imaging by optical coherence tomography (OCT) has gained increasing attention in multiple sclerosis and other neuroinflammatory and neurodegenerative disorders. Ambiguous and incomplete reporting of methodology and OCT-derived data have limited the ability to compare data and to apply and generalize findings in the past. To improve this situation, the Advised Protocol for Optical coherence tomography Study Terminology and Elements (APOSTEL) recommendations have been developed to outline core information to be provided when reporting quantitative OCT studies with help of a 9-point checklist (Cruz-Herranz and Balk et al., Neurology 2016). The APOSTEL recommendations currently have the evidence level of an expert opinion (Class IV). Objective: To advance the APOSTEL recommendations for OCT reporting in a formalized procedure towards evidence-based guidelines. Methods: Studies reporting quantitative OCT results published within the last 24 months have been identified by a Pubmed search. The corresponding authors of these 1472 articles will be contacted and asked to participate in an online survey to evaluate and give feedback on the initial APOSTEL recommendations. The feedback obtained will be anonymized and distributed to a panel of international experts for evaluation and revision of the recommendations. After the initial round the corresponding authors who gave feedback will be informed about the intermediate results and asked to participate in the survey for a second time. This procedure will be repeated if necessary following the consensus-building procedure of a DELPHI process. To this end, for each round the feedback obtained as well as any revisions made to the APOSTEL recommendations will be summarized and questionnaires will be used for evaluation in order to reach consensus and to develop evidencebased guidelines for prospective OCT studies. Results: The degree of consensus of the survey's participants will be reported for the initial and the revised versions of the recommendations as well as the revisions made to the initial version. Conclusion: Formal guidelines for the reporting of quantitative OCT studies will be presented as well as the process of how they were developed

Advances in imaging have made it increasingly common to study soft tissues without first embedding them in plastic or paraffin and without using labels or stains. The process, however, usually still involves fixation and cryosectioning, which could deform the tissues. Our goal was to quantify the morphological changes of ocular tissues caused by formalin fixation and cryosectioning. From each of 6 porcine eyes, 4 regions were obtained: cornea, equatorial and posterior sclera, and posterior pole containing the optic nerve head. Samples were imaged using visible light microscopy fresh, 1-minute and 24-hours post-fixation, and post-cryosectioning. Effects were assessed by 14 parameters representing sample size and shape. Overall, formalin fixation and sectioning caused only minimal changes to the ocular tissues, with average percentage parameter differences of 0.1%, 1%, and 1.2% between fresh and post-fixing by 1 minute, 24 hours, and post-cryosectioning, respectively. Parameter changes were not directional, and were only weakly dependent on the duration of fixation and the region of the eye. These results demonstrate that formalin fixation and cryosectioning are good choices for studying ocular tissue morphology and structure, as they do not cause the large tissue shrinkage or distortions typically associated with other, more complicated, techniques.

Glaucoma is a leading cause of blindness that leads to characteristic changes in the optic nerve head (ONH) region, such as nasalization of vessels. It is unknown whether the spatial location of this vessel shift inside the ONH occurs within the lamina cribrosa (LC) or the prelaminar tissue. The purpose of this study was to compare the location of the central retinal vessel trunk (CRVT) in the LC and prelaminar tissue in living healthy and glaucomatous eyes. We acquired 3-dimensional ONH scans from 119 eyes (40 healthy, 29 glaucoma suspect, and 50 glaucoma) using optical coherence tomography (OCT). The CRVT location was manually delineated in separate projection images of the LC and prelamina. We found that the CRVT in glaucoma suspect and glaucomatous eyes was located significantly more nasally compared to healthy eyes at the level of the prelamina. There was no detectable difference found in the location of the CRVT at the level of the LC between diagnostic groups. While the nasal location of the CRVT in the prelamina has been associated with glaucomatous axonal death, our results suggest that the CRVT in the LC is anchored in the tissue with minimal variation in glaucomatous eyes.

The purpose of this study was to characterize and determine the efficacy of a long-term, non-invasive gel/microsphere (GMS) eye drop for glaucoma. This novel drug delivery system is comprised of a thermoresponsive hydrogel carrier and drug-loaded polymer microspheres. In vitro release of brimonidine from the GMS drops and gel properties were quantified. A single brimonidine-loaded GMS drop was administered to 5 normotensive rabbits and intraocular pressure (IOP) was monitored for 28 days. Here we report that IOP reduction in rabbits receiving a single brimonidine GMS drop was comparable to that of rabbits receiving twice daily, standard brimonidine drops. GMS drops were retained in the inferior fornix in all animals for the length of the study. Our results suggest in vivo efficacy over 28 days from a single GMS drop and a potential decrease in systemic absorption, based on a lack of substantial IOP effects on the fellow untreated eye, compared to brimonidine twice-daily eye drops. To our knowledge, this represents the first long-term, drug-releasing depot that can be administered as a traditional eye drop.

Photoacoustic (PA) imaging detects acoustic signals generated by thermal expansion of a light-excited tissue or contrast agents. PA signal amplitude and image quality directly depend on the light fluence at the target depth. With conventional PA imaging systems, approximately 30% energy of incident light at the near-infrared region would be lost due to reflection on the skin surface. Such light loss directly leads to a reduction of PA signal and image quality. A new light delivery scheme that collects and redistributes reflected light energy was recently suggested, which is called the light catcher. In our previous study, proof of concept using a finite-element simulation model was shown and a laboratory-built prototype of the light catcher was applied on tissue-mimicking phantoms. In this paper, we present an elaborate prototype of a high-frequency PA probe with the light catcher fabricated using 3-D printing technology, which is conformal to a subcutaneous tumor in mice. The in vivo usefulness of the developed prototype was evaluated in a mouse tumor model. Equipped with the light catcher, PA signal amplitude from the clinical photosensitizer injected into the mouse tumor was enhanced by 33.7%, which is approximately equivalent to the percent light loss due to reflection on the skin.

Dry eye disease (DED) is a common ocular disorder affecting millions of individuals worldwide. The pathology of DED involves the infiltration of CD4⁺ lymphocytes, leading to tear film instability and destructive inflammation. In the healthy steady state, a population of immunosuppressive T-cells called regulatory T-cells (Treg) regulates proliferation of immune cells that would otherwise lead to a disruption of immunological homeostasis. For this reason, it has been suggested that Tregs could restore the immunological imbalance in DED. To this end, one possible approach would be to recruit the body's own, endogenous Tregs in order to enrich them at the site of inflammation and tissue destruction. Previously, we have demonstrated a reduction of inflammation and disease symptoms in models of periodontitis corresponding to recruitment of endogenous Tregs, which was accomplished by local placement of controlled release systems that sustain a gradient of the chemokine CCL22, referred to here as Treg-recruiting microspheres. Given that DED is characterized by a pro-inflammatory environment resulting in local tissue destruction, we hypothesized that the controlled release of CCL22 could also recruit Tregs to the ocular surface potentially mediating inflammation and symptoms of DED. Indeed, data suggest that Treg-recruiting microspheres are capable of overcoming the immunological imbalance of Tregs and CD4⁺ IFN-γ⁺ cells in the lacrimal gland. Administration of Treg-recruiting microspheres effectively mitigated the symptoms of DED as measured through a number of outcomes such as tear clearance, goblet cells density and corneal epithelial integrity, suggesting that recruitment of endogenous Treg can mitigate inflammation associated with DED.

Purpose: Although collagen microstructural crimp is a major determinant of ocular biomechanics, no direct measurements of optic nerve head (ONH) crimp have been reported. Our goal was to characterize the crimp period of the lamina cribrosa (LC) and peripapillary sclera (PPS) at low and normal IOPs. Methods: ONHs from 11 sheep eyes were fixed at 10-, 5-, or 0-mm Hg IOP and crimp periods measured manually from coronal cryosections imaged with polarized light microscopy (PLM). Using linear mixed-effect models, we characterized the LC and PPS periods, and how they varied with distance from the scleral canal edge. Results: A total of 17,374 manual collagen crimp period measurements were obtained with high repeatability (1.9 mum) and reproducibility (4.7 mum). The periods were smaller (P < 0.001) and less variable in the LC than in the PPS: average (SD) of 13.8 (3.1) mum in the LC, and 31.0 (10.4) mum in the PPS. LC crimp period did not vary with distance from the scleral canal wall (P > 0.1). PPS period increased with the square root of the distance to the canal (P < 0.0001). Conclusions: Small, uniform crimp periods within the sheep LC and immediately adjacent PPS may indicate that these tissues are setup to prevent large or heterogeneous deformations that insult the neural tissues within the canal. An increasing more variable period with distance from the canal provides a smooth transition of mechanical properties that minimizes stress and strain concentrations.

Purpose: To evaluate the ability of OCT optic nerve head (ONH) and macular parameters to detect disease progression in eyes with advanced glaucoma, including those reaching the practical minimal possible thickness measurements (floor effect). Methods: Subjects with advanced glaucoma with >= 4 visits, at least 5 months apart, with Swedish interactive thresholding algorithm 24-2 perimetry (SITA standard; Humphrey Field Analyzer; Zeiss) and spectral-domain OCT (Cirrus HD-OCT; Zeiss) were enrolled. Advanced glaucoma was defined as OCT average circumpapillary retinal nerve fiber layer (cRNFL) <=60um. The OCT measurements that were analyzed were average cRNFL, macular ganglion cell inner plexiform layer thickness (GCIPL), vertical C/D ratio and average C/D ratio, rim area and cup volume. The rate of change of each parameter was computed using a linear mixed effect model (LME) accounting for baseline age, gender and signal strength. Results: Forty-nine eyes (41 subjects) qualified for the study. The average age at baseline was 67 years (range 44-87) and the mean follow-up duration was 40.1 months. At baseline, subjects presented with visual field mean deviation (MD) of-11.38+/- 6.06dB and cRNFL of 55.20+/-3.60 mum. The rate of change for MD over the course of follow-up, while accounting for age at baseline and gender only, was statistically significant (-0.452 dB/yr (p=0.01)). In the same follow-up period, cRNFL rate of change was not significant (0.047 um/yr, p=0.743), while OCT parameters demonstrated a significant rate of change: GCIPL=-0.504 mum/yr (p<0.001); cup volume=0.006 mm³/yr (pO.001); rim area=-0.012 mm²/yr (p<0.001); vertical C/D ratio=0.006/yr (p<0.001); average C/D ratio=0.005/yr (p<0.001). Age, gender and signal strength were not significant in any of the models. Conclusions: Macula and ONH parameters might be useful in following subjects with advanced glaucoma reaching the floor effect of cRNFL measurements

Purpose: Task performance is affected by glaucomatous visual field loss. People often use a compensatory strategy singly or in combination to manage the effects of disease to perform daily life tasks. Yet, they may still have difficulty performing daily life tasks. This analysis of cross-sectional data explored the relationship between glaucoma severity and difficulty performing daily life tasks. Methods: We recruited community-dwelling adults aged 50 years and older with glaucoma, no other ocular comorbidities, who underwent full ophthalmic evaluation. We measured glaucoma severity (visual field mean deviation [MD]) and task difficulty (Assessment of Life Habits [LIFE-H]). LIFE-H assesses performance of daily life tasks, in particular task difficulty and use of compensatory strategy. Correlation analyses and logistic regression were conducted to evaluate the association between MD and task difficulty. Results: Subjects (n=87) on average were aged 60 years (range 50-89) and had early stage glaucoma (MD better-seeing eye [Median (Q1, Q3)],-2.45 dB [-4.28,-0.54]). Subjects reported difficulty performing daily life tasks even when they used a compensatory strategy: 48% reported difficulty when using an assistive device/adaptation, 89% reported difficulty when also receiving human assistance, 83% reported difficulty when using both an assistive device/adaptation and human assistance. MD had a negative relationship with task difficulty (Figure; Spearman rho=-0.37, p<0.01). For each 1 dB of worsening MD the odds of reporting difficulty performing daily life tasks increased 0.15 (OR=1.15, p<0.01; age-adjusted). Similar results were obtained with the worse-seeing eye. Conclusions: Our results indicate that task difficulty is related to glaucoma severity. As glaucoma progresses, clinicians need to be aware of its effect on performance of daily life tasks, suggesting consult with vision rehabilitation as disease deteriorates

Purpose: Glaucoma is the 2nd leading cause of irreversible blindness, and eye drop adherence rates are around 50%. Recent studies have shown that glaucoma patients have interest in using a free application to aid adherence. The purpose of this study is to investigate the demographics of patients interested in a behavioral economics based smartphone app developed by NYU Ophthalmology, Duke University, and Pattern Health, and measure their drop adherence, satisfaction and intraocular pressure during the study. Methods: After IRB-approved informed consent, patients with primary open angle glaucoma on at least two drops downloaded the app, and their glaucoma regimen was entered. Reminders were sent by push notifications and patients indicated adherence within the app. A virtual pet "Virgil the Turtle" was used to motivate adherence - the pet was happy with good adherence, but was despondent when users did not respond. Intraocular pressure was measured every 2-4 weeks. Post-study surveys are to be given at the study conclusion. Results: 5 of an expected 25 patients have entered the study. Mean age was 70.4 years (SD+13.2, range 57-85), 60% were Caucasian, and 3 were male. The most common reason for not enrolling was difficulty attending IOP checks. Of those refusing enrollment, average age was 70.9 (SD+13). 52% were male and 78% were Caucasian. In pre-study surveys, average expected experience using the app was 7.6 out of 10, SD +2.6 (range 4-10, 10 most positive). Average predicted drop adherence during the study was 9.2, SD +1.3, (range 7-10) vs pre-study, subjective adherence of 8, SD+ 1.6 (range 6-10). Patients rated their expected increase in compliance as a result of Virgil the turtle to be 5.6, SD +4.3 (range 1-10). The patient with the best adherence (100%), was noted to have the best IOP reduction, at 26%. The patient with the lowest adherence (39%) was noted to have the highest IOP increase, at 20%. Conclusions: Preliminary results suggest that a behavioral economics based smartphone app can enhance adherence, but Virgil the Turtle will play only a modest role. Comfort with the app was not dependent upon age. Better adherence as measured by the app was associated with improved IOP lowering. Future work aims to investigate alternate methods of motivation, and analyze long term adherence and IOP. Optimizing compliance can reduce costs and improve patient outcomes by avoiding expensive and invasive treatments