Faculty Bibliography

Purpose:To characterize the visual pathway integrity of five glaucoma animal models using diffusion tensor imaging (DTI). Methods:Two experimentally induced and three genetically determined models of glaucoma were evaluated. For inducible models, chronic IOP elevation was achieved via intracameral injection of microbeads or laser photocoagulation of the trabecular meshwork in adult rodent eyes. For genetic models, the DBA/2J mouse model of pigmentary glaucoma, the LTBP2 mutant feline model of congenital glaucoma, and the transgenic TBK1 mouse model of normotensive glaucoma were compared with their respective genetically matched healthy controls. DTI parameters, including fractional anisotropy, axial diffusivity, and radial diffusivity, were evaluated along the optic nerve and optic tract. Results:Significantly elevated IOP relative to controls was observed in each animal model except for the transgenic TBK1 mice. Significantly lower fractional anisotropy and higher radial diffusivity were observed along the visual pathways of the microbead- and laser-induced rodent models, the DBA/2J mice, and the LTBP2-mutant cats compared with their respective healthy controls. The DBA/2J mice also exhibited lower axial diffusivity, which was not observed in the other models examined. No apparent DTI change was observed in the transgenic TBK1 mice compared with controls. Conclusions:Chronic IOP elevation was accompanied by decreased fractional anisotropy and increased radial diffusivity along the optic nerve or optic tract, suggestive of disrupted microstructural integrity in both inducible and genetic glaucoma animal models. The effects on axial diffusivity differed between models, indicating that this DTI metric may represent different aspects of pathological changes over time and with severity.

OBJECTIVE:To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS:To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts, and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS:One hundred sixteen authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point-checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans; we suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS:The modified Delphi method resulted in an expert-led guideline (evidence class III, GRADE criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, fundoscopic imaging, post-acquisition data selection, post-acquisition analysis, nomenclature and abbreviations, and statistical approach. It will still be essential to update these recommendations to new research and practices regularly.

Purpose : Intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, yet glaucoma can continue to progress despite controlled IOP. Thus, development of glaucoma neurotherapeutics remains an unmet need. Scutellarin is a flavonoid that exhibits a number of neuroprotective effects on the brain and the eye. Here, we investigated the neurobehavioral effects of oral scutellarin treatment in a novel experimental model of chronic glaucoma. Methods : Ten adult C57BL/6J mice (Group 1) were unilaterally injected with an optically clear hydrogel into the anterior chamber to obstruct aqueous outflow and induce chronic IOP elevation. Eight other mice (Group 2) received a unilateral intracameral injection of phosphate-buffered saline only. Another eight mice (Group 3) with hydrogel-induced unilateral chronic IOP elevation also received daily oral gavage of 300 mg/kg scutellarin from 1 week before to 2 weeks after hydrogel injection. Tonometry, optical coherence tomography, and optokinetic visuobehavioral testing were performed longitudinally to monitor the IOP, total retinal thickness, visual acuity, and contrast threshold of bilateral eyes in all three groups. Results : Intracameral hydrogel injection resulted in unilateral chronic IOP elevation with no significant IOP difference between scutellarin treatment and untreated groups (Figure site uses cookies. By continuing to use our website, you are agreeing to 1). With scutellarin treatment, the hydrogel-injected eyes showed less retinal thinning and reduced visual behavioral deficits when compared to the untreated, hydrogel-injected eyes (Figure 2). No significant difference in retinal thickness or optokinetic measures was found in the non-injected eyes over time or between all groups. Conclusions : Oral scutellarin treatment appeared to preserve retinal structure and visual function in experimental glaucoma induced by chronic IOP elevation. Scutellarin may be a possible candidate as a novel neurotherapeutic agent for glaucoma treatment

Purpose : To investigate the least variable sampling location for OCT retinal nerve fiber layer (RNFL) thickness measurements on rhesus macaque monkeys, for determining the preferred sampling location. Methods : In vivo three-dimensional spectral-domain OCT scans (Leica, Chicago, IL) were obtained as raster scan data (400x400x1024) in a 5x5x1.6 mm region (human equivalent, not the actual size in the monkey eye) centered on the optic nerve head (ONH) of 33 healthy adult rhesus macaques (19 males, 14 females; ages 3.0-10.7 years). The ONH scans of 48 eyes were analyzed using OCT segmentation software of our own design to calculate point-by-point RNFL thickness measurements. Mean RNFL thickness was computed on consecutive concentric circles within the scan window, centered on the geometric ONH center and starting at the optic disc margin (between 64-119 circles). The least variable RNFL measurement area was identified in the vicinity of the RNFL peak within the 2 mum deviation. Results : The least variable RNFL was observed in between 98.88+/-11.82 and 114.4+/-11.32 pixels from the ONH center with the peak RNFL at 106.42+/-11.55 pixels (Figure 1). Note that the number of available eyes in each sampling location varied as detailed in Figure 2. For comparison, the radius of the OCT scan circle conventionally used in humans is 1.7 mm, or 136 pixels, from the center of the ONH. Conclusions : In order to obtain less variable circumpapillary RNFL thickness measurements on rhesus macaque monkey eyes, it is recommended to use a sampling circle with a radius of approximately 106 pixels from the ONH center, which is smaller than the human equivalent

Purpose : Compare the speed of glaucoma progression as measured by global visual field (VF) and optical coherence tomography (OCT) metrics. Methods : Glaucoma suspect, pre-perimetric glaucoma (PPG) and perimetric glaucoma (PG) participants of Advanced Imaging for Glaucoma study, who had at least 7 visits with visual field (VF) and OCT ONH scan, were analyzed. Severity was staged by the modified Hodapp-Parrish-Anderson Criteria. Eyes with significant cataract progression were excluded. Spectral-domain OCT (RTVue, Optovue) and VF testing were performed every 6 months. The nerve fiber layer (NFL) thickness was measured from ONH scan. The NFL mean deviation (MD) were VF-equivalent dB-scale quantities based on sectorwise nonlinear regression of NFL thickness with VF deviation using cross-sectional data over a wide range of glaucoma severity. Linear regression was used to estimate the glaucoma progression speed. Results : Seventy-five glaucoma suspect eyes (VF MD-0.1+/-1.2dB), 160 PPG eyes (0.2+/-1.3 dB), 77 early PG eyes (-0.9+/-1.6dB) and 20 moderate+severe PG (-10.8+/-3.2dB) eyes were analyzed. The follow-up duration was 54 months +/- 8 months (mean +/- SD). For both VF MD and NFL MD, the speed of progression increased monotonically with glaucoma severity (Table 1). For overall NFL thickness, the progression speed was greatest in the PPG and early PG stages, but slowed down at the moderate+severe stages. The ratios of progression speed for NFL thickness relative to VF were significantly different between stages (p<0.006, one-way ANOVA). The ratios of progression speed for NFL MD relative to VF MD was generally slower (0.58-0.72), but not significantly different across disease stages (p=0.08). The progression speed of both NFL-MD and VF-MD were associated with baseline parameters (faster progression in eyes with more severe disease at baseline), while progression speed of NFL thickness was not (Table 2). Conclusions : Compared to VF MD, NFL thickness tends to overestimate the progression speed in the early stages of glaucoma and underestimate it in the later stages. Clinicians should be aware of the discrepancy in the apparent speed of disease progression as measured by structural and functional metrics, which strongly depend on the stage of disease severity. Converting the NFL thickness profile to NFL MD may provide a progression metric more consistent with VF MD over a wider range of glaucoma severity

Purpose : Dampened cerebrovascular reactivity (CVR) impairs blood delivery to brain regions. Multiple studies have suggested a role of the basal forebrain (BF) in glaucoma (PMID: 31242454; ARVO 2020: 4336). However, CVR changes in BF with glaucoma severity have yet to be explored. Recently, relative CVR (rCVR) mapping was introduced using resting-state functional MRI (rsfMRI) without gas challenges. Here, we investigate rCVR changes in the visual cortex and basal forebrain with glaucoma severity. Methods : Normal (n=22), early-stage (n=18), and advanced-stage (n=19) glaucoma patients underwent anatomical MRI and rsfMRI. The optic nerve and optic chiasm volumes were measured using ImageJ. rCVR maps and regional rCVR values were generated and extracted with MriCloud online tool. Age, optical coherence tomography measurements, and Humphrey visual field perimetry were obtained from clinical records. Results are presented as mean+/-SEM. One-way ANOVA followed by post-hoc Bonferroni's multiple comparisons test, and trend analysis were applied. Results : Demographics, clinical ophthalmic assessments, and volumetric MRI assessments illustrated the characteristics of the anterior visual pathways in the normal control, earlystage glaucoma and advance-stage glaucoma groups (Fig. 1). The averaged rCVR map from normal controls is consistent with previous studies (PMID: 27888058, 32278094) (Fig. 2). Advanced-stage glaucoma patients [1.03+/-0.03 relative unit (r.u.); p<0.05] have significantly lower rCVR in the visual cortex compared to normal controls (1.20+/-0.06 r.u.; early-stage: 1.09+/-0.05 r.u.), and exhibit a decreasing trend in more severe disease. These corroborate with a previous Doppler ultrasound study (PMID: 23816432). Interestingly, rCVR in BF has an increasing trend with severity. No significant rCVR change was observed in the somatosensory cortex. Conclusions : Visual cortical rCVR decreases with glaucoma severity, while rCVR in the basal forebrain increases with severity. Our results verify visual cortical CVR reduction in glaucoma patients and further solidify that the basal forebrain plays a role in glaucoma

Purpose : Alterations in retinal oxygen metabolism are implicated in blindness causing diseases, such as diabetic retinopathy and glaucoma. Therefore, a non-invasive clinical tool to assess oxygen saturation (sO2) in retinal vessels is desirable. Recent development of visible-light optical coherence tomography (vis-OCT) enabled non-invasive sO measurements in retinal blood vessels at micrometer-scale resolution by threedimensional (3D) spectroscopic analysis. Nevertheless, such measurements are susceptible to spectral contaminants from the complex retina anatomy and vis-OCT signal detection and processing, decreasing measurement reliability. To overcome limitations posed by spectral contaminants, we developed adaptive-spectroscopic OCT (AS-OCT), a processing technique that enables non-invasive, 3D, environment-independent sO measurements in the human retina. Methods : We used vis-OCT to image the retinas of 18 healthy volunteers. Light exposure in the eye was < 250 muW and imaging acquisition time was 5 sec. We used adaptive spectroscopic OCT (AS-OCT) to identify and remove contaminants from retinal tissues, chromatic aberrations, and spectrally-dependent roll-off. Then, we automatically selected the optimal depths in the vessel for sO measurement. Finally, we measured the attenuation spectrum in the blood vessel and used a least-squares regression fit with known spectra to determine the sO value. Results : We measured sO in 125 unique retinal vessels near the optic disc (vessel diameters ranging from 37 mum to 176 mum). Major arteries had sO2= 97.9 +/-2.9 % (mean +/-standard deviation) (n = 36), small arteries (diameter < 100 had sO2= 93.2 +/-5.0 % (n = 36), and veins had sO2= 58.5 +/-4.3 % (n = 53). Repeated measurement standard deviations were 2.21% and 2.32% for all arteries and veins, respectively. Fig. 1 shows an oximetry map of the optic disc in the retina of a healthy 23 year-old volunteer. Conclusions : AS-OCT enables environment-independent retinal oximetry in the clinical setting. Repeatability in arteries and veins < 2.5 % indicates robust measurements that are promising for clinical use

PURPOSE/OBJECTIVE:To describe the efficacy and safety of open versus closed conjunctival implantation of the XEN45 Gel Stent (Allergan Inc). DESIGN/METHODS:Retrospective, multicenter study. PARTICIPANTS/METHODS:A total of 137 patients with glaucoma who underwent XEN45 implantation via open or closed conjunctival methods. The XEN45 was implanted as a stand-alone procedure or at the time of cataract surgery by 5 surgeons. METHODS:Patient demographics, diagnoses, preoperative and postoperative clinical data, outcome measures including intraocular pressure (IOP), use of glaucoma medications, visual acuity, and complications were collected. Statistical analyses were performed with P < 0.05 as significant. MAIN OUTCOME MEASURES/METHODS:Failure was defined as less than 20% reduction of IOP from medicated baseline or IOP >21 mmHg at 2 consecutive visits at postoperative month 1 and beyond, the need for subsequent operative intervention or additional glaucoma surgery, or a catastrophic event such as loss of light perception. Eyes that had not failed by these criteria and were not on glaucoma medications were considered complete successes. Eyes that had not failed but required glaucoma medications were defined as qualified successes. RESULTS:Complete success was achieved in 31% and 56% of the closed and open groups, respectively (P = 0.01). Qualified success was achieved in 53% and 71% of the closed and open groups, respectively (P = 0.06). At postoperative month 12, the open conjunctiva group was using fewer glaucoma medications than the closed group (0.9 vs. 1.8, respectively; P = 0.02). At postoperative month 12, the open group had a significantly greater percentage of IOP reduction compared with the closed group (43.1% vs. 24.8%, respectively; P = 0.02). Postoperative needling rates were higher in the closed group compared with the open group (36.1% vs. 11.8%, P = 0.001). CONCLUSIONS:Implantation of the XEN45 with opening of the conjunctiva is a safe and efficacious procedure to lower IOP with comparable success rate and lower needling rate compared with the closed conjunctiva technique. Prospective evaluation of the various methods for XEN45 implantation will allow for further comparison.

Purpose : Rhesus macaques are a common animal model in ophthalmology because of the high similarity of their eyes and visual pathway to human. The characterization of optic nerve head (ONH) and peripapillary region in monkeys reported so far mostly involved a manual process which is laborious and subjected to operator errors. It is also usually generated from a cohort of similar age group. In this cross-sectional observational study, we deploy automated and manual segmentations to evaluate the OCT retinal nerve fiber layer (RNFL) thickness, ONH and lamina cribrosa (LC) microstructure parameters in a cohort of free roaming macaques. Methods : In-vivo ONH spectral-domain OCT scans (Leica, Chicago, IL) were obtained by a single experienced operator after excluding eyes with any retinal pathologies. The margins of the optic disc were drawn manually and the resultant scans were analyzed using an automated segmentation software of our own design. The LC microstructure parameters were obtained through a previously described segmentation algorithm. The other parameters of ONH, namely the cup-to-disc (C/D) ratio and minimum rim width (MRW) were assessed manually. Wilcoxon rank sum test was used to test the association of LC parameters, C/D ratio and MRW with age, while the rest of the parameters were analyzed using mixed effects model accounting for age, sex and intra-subject correlation. Results : 29 eyes from 19 monkeys (11 females, 8 males) with age ranging from 4.2 to 23.8 years were analyzed. Males were overall bigger and significantly heavier than females in our cohort (Table 1). Superior RNFL was thicker in male and is the only RNFL parameter that was associated with age or sex in this healthy cohort. No significant association was detected for any of the ONH parameters with age or sex. LC was more visible and thicker in male with higher beam to pore ratio and connective tissue fraction than in female. Conclusions : The characterization of normal macaque eyes from a cohort of free roaming animals is useful as a standard reference to assess pathological changes in future experimental studies

Purpose : Current Optical Coherence Tomography (OCT) denoising techniques mainly focus on denoising 2-dimensional (2D) B-scans, especially for deep learning (DL) methods, which assume spatial integrity among neighboring samplings. However, OCT signal is essentially one dimensional (1D), and eye movements during scanning often violate the assumption. The purpose of this study was to see if 1D denoising is a feasible approach for clinical OCT imaging. Methods : 3D SD-OCT data within 6x6x2mm volumes centered on optic nerve head were obtained from 121 eyes (79 patients). Clean reference scans were constructed by registering and averaging 6 OCT scans obtained on the same day using ANTs software. As shown in Figure 1, we used a 5-layer U-shape net (UNet) for both 2D denoiser (Figure 1.(a)) and 1D denoiser (Figure1.(b)). In addition, both 2D and 1D approaches are combined by using the 2D denoised B-scan as a mask to selectively remove high signal peaks in the 1D denoised B-scan (Figure 1.(c)). Peak signal-to-noise ratio (PSNR) and contrast-to-noise ratio (CNR) were calculated to compare the performance. Results : Subjectively, the 2D denoiser generated smoother edges but tended to oversmooth textual information within the retinal layers, while the 1D denoiser preserved more textual information but caused more jittering at retinal edges due to the lack of structural information from neighboring A-scans. Quantitatively, the 1D denoiser showed similar PSNR to the 2D denoiser, while outperforming in CNR (PSNR: 31.20 (1D) V.S. 31.20 dB (2D), p=0.963; CNR: 4.23 (1D) V.S. 3.90 dB (2D), p<0.001, paired t-test, Table 1). The combined denoiser further improved CNR (4.39 (combined) V.S. 3.90 dB (2D), p<0.001). Combining 1D and 2D denoisers, the denoised B-scan showed more continuous edges compared to the 1D denoiser and did not lose the texture information compared to the 2D denoiser (Figure 2). Conclusions : Quantitatively, 1D denoiser performance is as good as 2D denoiser or even better. A combination of 1D and 2D approaches may provide well-balanced image enhancement in clinical applications