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Glaucoma care has evolved dramatically over the past generation, with changes that have incorporated new technology and improved understanding of the disease process. A major need is to construct a useful definition of glaucomatous optic neuropathy that can be used to compare data across clinical research studies. The treatment of glaucoma should now be based on achievement of a goal target for intraocular pressure, unique to each patient. Adherence with eye drop treatment is far from ideal and can be improved using reminder systems. Sustained delivery of glaucoma medication is on the horizon. New surgical approaches to glaucoma are being actively studied but have not as yet found their place in its care, with rigorous testing against present treatments needed.

Purpose: To quantify peripapillary choroidal thickness (PCT) and the factors that influence it in healthy participants who represent the racial and ethnic composition of the U.S. population., Methods: A total of 362 healthy participants underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head with a 24 radial B-scan pattern aligned to the fovea to Bruch's membrane opening axis. Bruch's membrane, anterior scleral canal opening (ASCO), and the anterior scleral surface were manually segmented. PCT was measured at 100, 300, 500, 700, 900, and 1100 μm from the ASCO globally and within 12 clock-hour sectors. The effects of age, axial length, intraocular pressure, ethnicity, sex, sector, and ASCO area on PCT were assessed by ANOVA and univariable and multivariable regressions., Results: Globally, PCT was thicker further from the ASCO border and thinner with older age, longer axial length, larger ASCO area, European descent, and female sex. Among these effectors, age and axial length explained the greatest proportion of variance. The rate of age-related decline increased further from the ASCO border. Sectorally, the inferior-temporal sectors were thinnest (10.7%-20.0% thinner than the thickest sector) and demonstrated a higher rate of age-related loss (from 15.6% to 20.7% faster) at each ASCO distance., Conclusions: In healthy eyes, PCT was thinnest in the inferior temporal sectors and thinner PCT was associated with older age, European descent, longer axial length, larger ASCO area, and female sex. Among these associations, age had the strongest influence, and its effect was greatest within the inferior temporal sectors.

Purpose: The purpose of this study is to determine the sensitivity and specificity of detecting age-related macular degeneration (AMD) using portable optical coherence tomography (OCT) operated by nonexpert photographers on undilated patients., Methods: In this case-control study, 92 individuals were recruited from the glaucoma and retina clinics at the Wilmer Eye Institute (Johns Hopkins University, Baltimore, MD). Using the portable iVue (Optovue, Inc, Fremont, CA) spectral-domain OCT (SD-OCT), 2 nonexpert photographers acquired retina map scans on undilated eyes of all participants. In total, 33 AMD eyes and 105 control eyes were evaluated and graded by ophthalmologists masked to the diagnoses., Results: Detection of AMD on the portable OCT by ophthalmologists exhibited sensitivities of 0.91 and 0.94 and specificities of 0.88 and 0.89, for graders 1 and 2, respectively. A strong intergrader agreement was observed (κ = 0.87)., Conclusions: Nonexpert photographers can use a portable OCT on undilated eyes to acquire images for the detection of AMD. These findings present the potential utility of implementing a portable OCT in community screenings for earlier detection and treatment of disease., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To evaluate the diagnostic performance characteristics of the Van Herick assessment (VHA) for identifying angle closure compared to gold-standard gonioscopy, as conducted by trained observers of varying expertise., Design: Reliability analysis., Methods: Patients (n = 131) from a glaucoma referral clinic aged ≥50 years without prior ocular surgery or iridotomy underwent unilateral VHA by 1 of 11 trained ophthalmic technicians, followed by VHA and indirect gonioscopy by 1 of 15 ophthalmology residents and 1 of 4 glaucoma specialist attending physicians. Observers were masked to others' gradings. Cohen's kappa (κ) assessed test reproducibility. VHA sensitivity and specificity for identifying gonioscopic angle closure were calculated., Results: Mean patient age was 62.0 ± 8.7 years, 56% of patients were male, and 84% were African American. Angles were gonioscopically closed in 14.5% of eyes. Moderate agreement was observed comparing technician or resident VHA to attending VHA (κ = 0.48 and κ = 0.56, respectively). Resident and attending gonioscopy demonstrated excellent agreement (κ = 0.94). Sensitivities of technician, resident, and attending VHA for detecting angle closure were 57.9% (95% confidence interval: 34.0%-78.9%), 78.9% (53.9%-93.0%), and 68.4% (43.5%-86.4%), respectively. Specificities were 88.5% (80.3%-93.6%), 88.2% (80.3%-93.3%), and 87.5% (79.6%-92.8%), respectively., Conclusions: VHA, even when performed by experienced ophthalmologists, misses a substantial proportion of angle closure while incorrectly identifying roughly 1 in 8 open-angle eyes as closed. These results suggest that clinical assessment of anterior chamber angle configuration is best accomplished with gonioscopy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To compare the identification of optic nerve head (ONH) structures in optical coherence tomography images by observers and automated algorithms., Methods: ONH images in 24 radial scan sets by optical coherence tomography were obtained in 51 eyes of 29 glaucoma patients and suspects. Masked intraobserver and interobserver comparisons were made of marked endpoints of Bruch's membrane opening (BMO) and the anterior lamina cribrosa (LC). BMO and LC positional markings were compared between observer and automated algorithm. Repeated analysis on 20 eyes by the algorithm was compared. Regional ONH data were derived from the algorithms., Results: Intraobserver difference in BMO width was not significantly different from zero (P ≥ 0.32) and the difference in LC position was less than 1% different (P = 0.04). Interobserver were slightly larger than intraobserver differences, but interobserver BMO width difference was 0.36% (P = 0.63). Mean interobserver difference in LC position was 14.74 μm (P = 0.004), 3% of the typical anterior lamina depth (ALD). Between observer and algorithm, BMO width differed by 1.85% (P = 0.23) and mean LC position was not significantly different (3.77 μm, P = 0.77). Repeat algorithmic analysis had a mean difference in BMO area of 0.38% (P = 0.47) and mean ALD difference of 0.54 ± 0.72%. Regional ALD had greater variability in the horizontal ONH regions. Some individual outlier images were not validly marked by either observers or algorithm., Conclusions: Automated identification of ONH structures is comparable to observer markings for BMO and anterior LC position, making BMO a practical reference plane for algorithmic analysis.

Purpose: To compare outcomes of transscleral diode cyclophotocoagulation with the treatment parameters used., Patients and Methods: This was a retrospective chart review of a random, 50% sample of diode procedures using the G-probe over 10 years for uncontrolled glaucoma. The main outcome measure was intraocular pressure (IOP) reduction by 20% and final IOP≤21 mm Hg., Results: In 236 eyes (persons) treated by 5 glaucoma specialists, most eyes had severe glaucoma, with 75% having <20/200 acuity. Median follow-up was 2.7 years. In eyes receiving only 1 treatment, IOP success criterion was met in 72% (129/180). Success was significantly related to power per delivery and median total joules per treatment (successes=135 J, failures=98 J; P=0.0009), but not to number of deliveries, nor to extent of circumference treated. Greater success was associated with 3 or 4 second duration per delivery, power level based on audible cues, and firm pressure on the sclera. Using a standard 2000 mW, 2 seconds, 20 deliveries in each eye had the lowest success (49%). Of those with no preoperative pain, 40 persons (57%) had no postoperative pain, whereas 20 reported pain of 1-3/10 (29%). Phthisis occurred in 7 eyes (3%), 5 of which had severe secondary eye disease. Nine eyes had no light perception preoperatively, whereas 50 eyes were no light perception at last follow-up, many after additional surgeries for other conditions., Conclusions: Diode cyclophotocoagulation achieved reasonable IOP lowering, often without severe postoperative pain or complication. Greater success was achieved when audible effects were used to tailor the power settings to individual responses. Diode treatments with no intraoperative effect adjustment or using standardized protocols may not achieve optimal success.

The purpose of this study was to compare younger and older mice after chronic intraocular pressure (IOP) elevation lasting up to 4 days with respect to mitochondrial density, structure, and movement, as well as axonal integrity, in an ex vivo explant model. We studied 2 transgenic mouse strains, both on a C57BL/6J background, one expressing yellow fluorescent protein (YFP) in selected axons and one expressing cyan fluorescent protein (CFP) in all mitochondria. Mice of 4 months or 14 months of age were exposed to chronic IOP by anterior chamber microbead injection for 14 h, 1, 3, or 4 days. The optic nerve head of globe--optic nerve explants were examined by laser scanning microscopy. Mitochondrial density, structure, and movement were quantified in the CFP explants, and axonal integrity was quantified in YFP explants. In control mice, there was a trend towards decreased mitochondrial density (# per mm2) with age when comparing younger to older, control mice, but this was not significant (1947 ± 653 vs 1412 ± 356; p = 0.19). Mitochondrial density decreased after IOP elevation, significantly, by 31%, in younger mice (p = 0.04) but trending towards a decrease, by 22%, in older mice (p = 0.82) compared to age matched controls. Mitochondrial mean size was not altered after chronic IOP elevation for 14 h or more (p ≥ 0.16). When assessing mitochondrial movement, in younger mice, 5% were mobile at any given time; 4% in the anterograde direction and 1% retrograde. In younger untreated tissue, only 75% of explants had moving mitochondria (mean = 15.8 moving/explant), while after glaucoma induction only 24% of explants had moving mitochondria (mean = 4.2 moving/explant; difference from control, p = 0.03). The distance mitochondria traveled in younger mice was unchanged after glaucoma exposure, but in older glaucoma explants the distance traveled was less than half of older controls (p < 0.0003). In younger mice, mitochondrial speed increased after 14 h of elevated IOP (p = 0.006); however, in older glaucoma explants, movement was actually slower than controls (p = 0.02). In RGC-YFP explants, axonal integrity declined significantly after 4 days of IOP elevation to a similar degree in both younger and older mice. Older mice underwent greater loss of mitochondrial movement with chronic IOP elevation than younger mice, but suffered similar short-term axonal fragmentation in C57BL/6J mice. These transgenic strains, studied in explants, permit observations of alterations in intracellular structure and organelle activity in experimental glaucoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To determine the frequency with which retinal tissues other than the nerve fibre layer, hereafter referred to as protruded retinal layers (PRL), are a component of optical coherence tomography (OCT) neuroretinal rim measurements., Methods: Ninety healthy (30 White, Black and Japanese, respectively) subjects were included in the study. A radial scan pattern (24 B-scans centred on Bruch's membrane opening [BMO]) was used. For each of the 48 minimum rim width (MRW) measurement points, we determined whether PRL were present, absent or indeterminate. When present, the proportion of PRL within the MRW was quantified., Results: Protruded retinal layers were present in 503 (11.6%), absent in 3805 (88.1%) and indeterminate in 12 (0.3%) measurement points. Overall, 69 (76.6%) subjects had ≥1 points with PRL, with White subjects having the highest frequency and Japanese the lowest (29 [97%] and 18 [60%], respectively; p < 0.01). PRL were present in one-third of points in the temporal sector, but ≤5% in other sectors. When present, the median PRL thickness was 53.0 (interquartile range [IQR]: 33.0 to 78.5) μm, representing 20.6 (IQR: 13.0 to 28.5)% of MRW. Globally, the median PRL thickness comprised 1.3 (IQR: 0.2 to 3.5)% of the MRW; however, in the temporal sector, it exceeded 30% of MRW in some subjects., Conclusions: Protruded retinal layers are a component of MRW measurements in most normal subjects, occurring in almost 12% of all measurement points analysed. There were racial variations in the presence of PRL and a significantly higher frequency of PRL in the temporal sector., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: In this study, we measured the effect of the removal of sulfated glycosaminoglycans (sGAGs) on the pressure-induced strains of the human lamina cribrosa (LC)., Methods: We applied an ex vivo inflation method to measure the three-dimensional (3D) deformation response of six human LCs to pressure, before and after the degradation of chondroitin and dermatan sulfates. The experiment used a laser-scanning microscope (LSM) to acquire the second harmonic generation (SHG) signal of the collagen structure in the LC. Digital volume correlation (DVC) was used to calculate the deformation in the LC after a change in pressure from 5 to 45 mm Hg., Results: The average strains between 5 and 45 mm Hg in the LC decreased significantly after sGAG degradation (P ≤ 0.03), with the greatest change occurring in regions of previously high strain (P ≤ 0.003) and the peripheral regions of the LC (P ≤ 0.02). The stiffening effect was greater in the LC of middle-aged (42-49 years) donors compared with those of older (64-88 years) donors (P < 0.0001)., Conclusions: The LC experienced less strain at the same pressures after most sGAGs were removed. These results suggest that the natural decrease in sGAGs within the LC with age may contribute to the stiffer inflation response of older LC to IOP. Likewise, the increase in the amount of sGAGs observed in the LC of glaucomatous eyes, may contribute to a more compliant LC, which may affect the susceptibility and progression of axon damage.

Purpose: To quantify the influence of ocular and demographic factors on central laminar depth (LD) in healthy participants., Methods: A total of 362 normal subjects underwent optical coherence tomography (OCT) enhanced depth imaging of the optic nerve head (ONH) with a 24 radial B-scan pattern aligned to the fovea-to-Bruch's membrane opening (BMO) axis. BMO, anterior lamina, anterior scleral canal opening (ASCO), Bruch's membrane (BM), and the peripapillary scleral surface were manually segmented. The extent of laminar segmentation was quantified within 72 ASCO subsectors. Central LD was quantified relative to four reference planes: BMO, ASCO, BM, and scleral. The effects of age, sex, ethnicity, IOP, BMO area, ASCO area, and axial length on LD were assessed., Results: Laminar visibility was most consistent within the central ASCO (median 89%, range, 69%-95%). LDBMO and LDBM were significantly shallower in eyes with greater age, BMO area, and axial length and in females. LDASCO was shallower in eyes with greater ASCO area and axial length and in European and Hispanic descent compared to African descent eyes. LDSclera behaved similarly, but was not associated with axial length. BMO and ASCO area were not different between African descent and European descent eyes., Conclusions: Central LD was deeper in African descent eyes and influenced least by age, axial length, and sex, but more by ASCO area, when measured relative to the ASCO and sclera. However, the magnitude of these effects for all four reference planes was small, and their clinical importance in the detection of glaucoma and its progression remains to be determined.

Purpose: To determine if one injection of a sustained release formulation of dorzolamide in biodegradable microparticles (DPP) reduces retinal ganglion cell (RGC) loss in a rat model of glaucoma., Methods: We injected either DPP or control microparticles intravitreally in rats. Two days later, unilateral ocular hypertension was induced by translimbal, diode laser treatment by a surgeon masked to treatment group. IOP and clinical exams were performed until sacrifice 6 weeks after laser treatment. RGC loss was measured by masked observers in both optic nerve cross-sections and RGC layer counts from retinal whole mounts., Results: Cumulative IOP exposure was significantly reduced by DPP injection (49 ± 48 mm Hg × days in treated versus 227 ± 191 mm Hg × days in control microparticle eyes; P = 0.012, t -test). While control-injected eyes increased in axial length by 2.4 ± 1.7%, DPP eyes did not significantly enlarge (0.3 ± 2.2%, difference from control, P = 0.03, t -test). RGC loss was significantly less in DPP eyes compared with control microparticle injection alone (RGC axon count reduction: 21% vs. 52%; RGC body reduction: 25% vs. 50% [beta tubulin labeling]; P = 0.02, t -test)., Conclusions: A single injection of sustained release DPP protected against RGC loss and axial elongation in a rat model of IOP glaucoma., Translational Relevance: Sustained release IOP-lowering medications have the potential to stop glaucoma progression.

This chapter provides an overview over the use of animal models in glaucoma research from a historical perspective. Strengths and limitations of various models are considered, and the challenges of translating results in animal experiments to successful clinical trials in humans are discussed.

Purpose: This pilot study was conducted to assess optical coherence tomography (OCT) as a screening tool for glaucoma when used by nonexpert personnel., Methods: This prospective case-control study included 54 patients with open-angle glaucoma and 54 age-matched comparison individuals. Optovue iVue SD-OCT imaging was performed by nonprofessional photographers on undilated patients. The sensitivity, specificity, negative predictive value, and positive predictive value of iVue scan parameters for detecting open-angle glaucoma were evaluated., Results: The iVue cup to disc vertical ratio had a sensitivity of 0.96 [95% confidence interval (CI), 0.90-1.00] at 90% specificity and was strongly correlated with both the Cirrus HD-OCT cup to disc vertical ratio (Pearson coefficient=0.84) and the cup to disc ratio observed on dilated clinical examination by faculty ophthalmologists (Pearson coefficient=0.80). The retinal nerve fiber layer (RNFL) parameters performed robustly, but the ganglion cell complex parameters showed limited diagnostic value. The inferior quadrant thickness was among the best performing RNFL parameters, with a sensitivity of 0.87 (95% CI, 0.78-0.96) and a specificity of 0.88 (95% CI, 0.80-0.97) using the iVue normative database thresholds for abnormality., Conclusions: OCT imaging may be performed by nonprofessional photographers on undilated patients, and quantitative parameters derived from the resultant images, particularly the vertical cup to disc ratio and the RNFL inferior quadrant thickness, demonstrate sensitivities and specificities that may be adequately robust for glaucoma screening in the community setting.

Purpose: To determine the effect of wearing a protective eye shield (mask) on limbal strain magnitude and variability in glaucoma eyes when sleeping with 1 side of the face down (FD) against a pillow., Methods: A prospective, randomized, interventional trial was conducted at the Wilmer Eye Institute with 36 glaucoma patients. A contact lens sensor measured limbal strain (output in equivalent millivolts) during intervals of up to 60 minutes in lateral decubitus, FD, and supine positions. Eighteen subjects wore a mask during 1 of 2 FD intervals, with randomized assignment of the interval. Data from additional trials with no mask were included in some analyses. In addition, some facial-feature dimensions from 3D scanned images of 23 subjects were compared with limbal strain data., Results: Wearing a mask trends toward a reduced mean change in contact lens sensor output (limbal strain) on moving to a FD positions [+34.1 mVeq, P=0.01 reduced by -22.3 mVeq, P=0.09 (n=36)]. Mask wearing reduced variability in strain while FD [-22.8 mVeq, P=0.04 (n=18)]. In eyes with past progressive visual field loss, the effect of the mask reduced mean strain change when moving to FD [-44.8 mVeq, P=0.02 (n=31)]. Longer corneal apex to nose-tip and to temple lengths were associated with reduced variability while FD [P=0.02 and 0.04, respectively (n=23)]. Treating both lengths as confounding factors increased statistical significance, particularly for analysis of the no-mask change in strain data moving to and from the FD position [P=0.004 to 0.002 and P=0.03 to 0.01 (n=23)]., Conclusion and Relevance: Wearing a mask reduced limbal strain and variation in limbal strain during simulated FD sleep, particularly in eyes with past field worsening, as did some facial features.

We developed an explant model of the mouse eye and optic nerve that facilitates the study of retinal ganglion cell axons and mitochondria in the living optic nerve head (ONH) in an ex vivo environment. Two transgenic mouse strains were used, one expressing yellow fluorescent protein in selected axons and a second strain expressing cyan fluorescent protein in all mitochondria. We viewed an explanted mouse eye and optic nerve by laser scanning microscopy at and behind the ONH, the site of glaucoma injury. Explants from previously untreated mice were studied with the intraocular pressure (IOP) set artificially at normal or elevated levels for several hours. Explants were also studied from eyes that had undergone chronic IOP elevation from 14 h to 6 weeks prior to ex vivo study. Image analysis in static images and video of individual mitochondria or axonal structure determined effects of acute and chronic IOP elevation. At normal IOP, fluorescent axonal structure was stable for up to 3 h under ex vivo conditions. After chronic IOP elevation, axonal integrity index values indicated fragmentation of axon structure in the ONH. In mice with fluorescent mitochondria, the normal density decreased with distance behind the ONH by 45% (p = 0.002, t-test). Density increased with prior chronic IOP elevation to 21,300 ± 4176 mitochondria/mm 2 compared to control 16,110 ± 3159 mitochondria/mm 2 (p = 0.025, t-test), but did not increase significantly after 4 h, acute IOP elevation (1.5% decrease in density, p = 0.83, t-test). Mean normal mitochondrial length of 2.3 ± 1.4 μm became 13% smaller after 4 h of IOP elevation ex vivo compared to baseline (p = 0.015, t-test, N-10). Normal mitochondrial speed of movement was significantly slower in the anterograde direction (towards the brain) than retrograde, but there were more mitochondria in motion and traveling longer lengths in anterograde direction. The percent of mitochondria in motion decreased by >50% with acute IOP increase to 30 mm Hg after 60 min. A new ocular explant model implemented with eyes from transgenic mice with fluorescent cellular components provided real time measurement of the early events in experimental glaucoma and quantitative outcomes for neuroprotection therapy experiments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To determine if retinal ganglion cell (RGC) axon loss in experimental mouse glaucoma is uniform in the optic nerve., Methods: Experimental glaucoma was induced for 6 weeks with a microbead injection model in CD1 (n = 78) and C57BL/6 (B6, n = 68) mice. From epoxy-embedded sections of optic nerve 1 to 2 mm posterior to the globe, total nerve area and regional axon density (axons/1600 μm2) were measured in superior, inferior, nasal, and temporal zones., Results: Control eyes of CD1 mice have higher axon density and more total RGCs than control B6 mice eyes. There were no significant differences in control regional axon density in all mice or by strain (all P > 0.2, mixed model). Exposure to elevated IOP caused loss of RGC in both strains. In CD1 mice, axon density declined without significant loss of nerve area, while B6 mice had less density loss, but greater decrease in nerve area. Axon density loss in glaucoma eyes was not significantly greater in any region in either mouse strain (both P > 0.2, mixed model). In moderately damaged CD1 glaucoma eyes, and CD1 eyes with the greatest IOP elevation exposure, density loss differed by region (P = 0.05, P = 0.03, mixed model) with the greatest loss in the temporal and superior regions, while in severely injured B6 nerves superior loss was greater than inferior loss (P = 0.01, mixed model, Bonferroni corrected)., Conclusions: There was selectively greater loss of superior and temporal optic nerve axons of RGCs in mouse glaucoma at certain stages of damage. Differences in nerve area change suggest non-RGC responses differ between mouse strains.

The objective of this study was to measure the pressure-induced deformation response of the human lamina cribrosa (LC) and analyze for variations with age and anatomical region. The posterior scleral cup of 8 eyes from 6 human donors was mounted onto a custom inflation chamber. A laser-scanning microscope was used for second harmonic generation (SHG) imaging of the collagen structure in the posterior volume of the LC at pressures from 5mmHg to 45mmHg. The SHG volumes were analyzed by the Fast-Fourier Iterative Digital Volume Correlation (DVC) algorithm for the three dimensional (3D) displacement field. The components of the Green-Lagrange strain tensor and the in-plane principal and maximum shear strains were evaluated from the DVC displacement field for the central and peripheral regions of the LC and the nasal, temporal, inferior, and superior quadrants surrounding the central retinal artery and vein. Among the major findings were that older age was associated with lower strains, the maximum shear strain was larger in the peripheral than central region, and the maximum principal strain was lower in the nasal quadrant. The elliptical shape of the LC was also predictive of the biaxial strain ratio. Age-related and structure-related variations in the pressure-induced strains of the LC may contribute to the susceptibility and severity of optic nerve damage in glaucoma, and regional variations may explain the progression of axonal damage and tissue remodeling observed in the LC in glaucoma., Statement of Significance: Glaucoma causes vision loss through progressive damage of the retinal ganglion axons at the lamina cribrosa (LC), the connective tissue structure that supports the axons as they leave the eye. Mechanical characterization of the LC is challenging because of the complex 3D shape and inaccessibility of the tissue. We present a new method using digital volume correlation to map the 3D displacement and strain fields in the LC under inflation. We report for the first time significant regional variations in the strains that are consistent with the pattern of optic nerve damage in early glaucoma. Thus regional strain variations may be predictive of the progression of axonal damage in glaucoma., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular pressure. There is currently a great potential for research surrounding neuroprotection as it relates to glaucoma. Anatomical targets for neuroprotection should focus on upstream rather than downstream factors, and could include any part of the retinal ganglion cell, the glia, especially astrocytes or Muller cells, and vasculature. The great number of anatomical targets is exceeded only by the number of possible biochemical pathways and potential treatments. Successful treatment may be accomplished through the targeting of one or even a combination of multiple pathways. Once a treatment is shown effective in vitro, it should be evaluated in vivo with carefully chosen animal models and studied in sufficient numbers to detect statistically and clinically significant effects. Such a drug should have few systemic side effects and its delivery should be optimized so as to encourage compliance. There are still a multitude of possible screens available to test the efficacy of a neuroprotective drug and a single gold standard is ideal for the accurate assessment and comparison of new drugs. Future studies in neuroprotection should investigate the genetic component of the disease, novel pharmaceutical agents for new or known pathways, modulations of scleral biomechanics, and relation to research of other complex disorders of the central nervous system., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To develop an ex vivo explant system using multiphoton microscopy and digital volume correlation to measure the full-field deformation response to intraocular pressure (IOP) change in the peripapillary sclera (PPS) and in the optic nerve head (ONH) astrocytic structure., Methods: Green fluorescent protein (GFP)-glutamate transporter-GLT1 (GLT1/GFP) mouse eyes were explanted and imaged with a laser-scanning microscope under controlled inflation. Images were analyzed for regional strains and changes in astrocytic lamina and PPS shape. Astrocyte volume fraction in seven control GLT1/GFP mice was measured. The level of fluorescence of GFP fluorescent astrocytes was compared with glial fibrillary acidic protein (GFAP) labeled astrocytes using immunohistochemistry., Results: The ONH astrocytic structure remained stable during 3 hours in explants. Control strain-globally, in the central one-half or two-thirds of the astrocytic lamina-was significantly greater in the nasal-temporal direction than in the inferior-superior or anterior-posterior directions (each P≤ 0.03, mixed models). The PPS opening (perimeter) in normal eye explants also became wider nasal-temporally than superior-inferiorly during inflation from 10 to 30 mm Hg (P = 0.0005). After 1 to 3 days of chronic IOP elevation, PPS area was larger than in control eyes (P = 0.035), perimeter elongation was 37% less than controls, and global nasal-temporal strain was significantly less than controls (P = 0.007). Astrocyte orientation was altered by chronic IOP elevation, with processes redirected toward the longitudinal axis of the optic nerve., Conclusions: The explant inflation test measures the strain response of the mouse ONH to applied IOP. Initial studies indicate regional differences in response to both acute and chronic IOP elevation within the ONH region.

Purpose: To compare anterior segment optical coherence tomography (ASOCT) angle morphology before and after laser peripheral iridotomy (LPI) in a cohort of South Indian subjects with primary angle-closure suspect (PACS) or primary angle-closure/primary angle-closure glaucoma (PAC/PACG) and to examine baseline parameters associated with angle widening., Design: Prospective observational study., Participants: A total of 244 subjects aged ≥30 years with PACS or PAC/PACG in at least 1 eye., Methods: The ASOCT images and angle gonioscopic grades were analyzed for all subjects at baseline and 2 weeks after LPI. Multivariable linear and logistic regression models were used to determine predictors of angle widening (change in mean angle opening distance [AOD750]) and angle opening (all 4 quadrants with trabecular meshwork [TM] visible on gonioscopy after LPI)., Main Outcome Measures: Change in ASOCT parameters with LPI and baseline predictors of angle widening., Results: Laser peripheral iridotomy resulted in angle widening on ASOCT with significant increases in AOD750, angle recess area, and trabecular iris surface area (P < 0.05 for all). Gonioscopically, 44.7% of all subjects had open angles in all 4 quadrants after LPI, with a greater percentage of angles open in the PACS group compared with the PAC/PACG group (52.4% vs. 36.4%; P = 0.01). In multivariable regression analyses, greater postoperative angle widening as defined by change in AOD750 was associated with shorter baseline AOD750 and axial length, and greater baseline anterior chamber depth, iris curvature, and lens vault (P ≤ 0.002 for all). Gonioscopic angle opening after LPI was more common with wider baseline angle width (modified Shaffer grade) and lower cup-to-disc ratio (P < 0.001 for both)., Conclusions: In a South Indian population with PACS or PAC/PACG, LPI results in significant anterior chamber angle widening seen on both ASOCT and gonioscopy, although some degree of persistent iridotrabecular contact was present in approximately half of PACS eyes and approximately two thirds of PAC/PACG eyes on gonioscopy. The greatest widening by ASOCT was observed in eyes with features most consistent with greater baseline pupillary block., (Copyright © 2016 American Academy of Ophthalmology. All rights reserved.)

Glaucoma is a complex disorder of aging defined by the death of retinal ganglion cells and remodeling of connective tissues at the optic nerve head. Intraocular pressure-induced axonal injury at the optic nerve head leads to apoptosis. Loss of retinal ganglion cells follows a slowly progressive sequence. Clinical features of the disease have suggested and corroborated pathological events. The death of retinal ganglion cells causes secondary loss of neurons in the brain, but only as a by-product of injury to the retinal ganglion cells. Although therapy to lower intraocular pressure is moderately effective, new treatments are being developed to alter the remodeling of ocular connective tissue, to interrupt the injury signal from axon to soma, and to upregulate a variety of survival mechanisms.

Topical medications that inhibit the enzyme carbonic anhydrase (CAI) are widely used to lower intraocular pressure in glaucoma; however, their clinical efficacy is limited by the requirement for multiple-daily dosing, as well as side effects such as blurred vision and discomfort on drop instillation. We developed a biodegradable polymer microparticle formulation of the CAI dorzolamide that produces sustained lowering of intraocular pressure after subconjunctival injection. Dorzolamide was ion paired with sodium dodecyl sulfate (SDS) and sodium oleate (SO) with 0.8% and 1.5% drug loading in poly(lactic-co-glycolic acid) (PLGA), respectively. Encapsulating dorzolamide into poly(ethylene glycol)-co-poly(sebacic acid) (PEG3-PSA) microparticles in the presence of triethylamine (TEA) resulted in 14.9% drug loading and drug release that occurred over 12 days in vitro. Subconjunctival injection of dorzolamide-PEG3-PSA microparticles (DPP) in Dutch belted rabbits reduced IOP as much as 4.0 ± 1.5 mmHg compared to untreated fellow eyes for 35 days. IOP reduction after injection of DPP microparticles was significant when compared to baseline untreated IOPs (P < 0.001); however, injection of blank microparticles (PEG3-PSA) did not affect IOP (P = 0.9). Microparticle injection was associated with transient clinical vascularity and inflammatory cell infiltration in conjunctiva on histological examination. Fluorescently labeled PEG3-PSA microparticles were detected for at least 42 days after injection, indicating that in vivo particle degradation is several-fold longer than in vitro degradation. Subconjunctival DPP microparticle delivery is a promising new platform for sustained intraocular pressure lowering in glaucoma., Competing Interests: Notes The authors declare no competing financial interest.

We report a case of a suspected Sturge-Weber syndrome variant diagnosed at the age of 58 with the help of enhanced depth imaging spectral-domain ocular coherence tomography (EDI-SDOCT). A 58-year-old female with unilateral glaucoma was suspected to have choroidal vascular lesion, conjunctival angioma, and no facial port-wine stain who presented to the clinic with bleb dysesthesia many years after trabeculectomy. EDI-SDOCT was performed and revealed markedly increased choroidal thickness in the affected eye. EDI-SDOCT may be helpful in diagnosing Sturge-Weber variants without facial involvement and may aid in the investigation of the pathogenesis of this disease.

We characterized the structural and mechanical changes after experimental digestion of sulfated glycosaminoglycans (s-GAGs) in the human posterior sclera, using ultrasound thickness measurements and an inflation test with three-dimensional digital image correlation (3D-DIC). Each scleral specimen was first incubated in a buffer solution to return to full hydration, inflation tested, treated in a buffer solution with chondroitinase ABC (ChABC), then inflation tested again. After each test series, the thickness of eight locations was measured. After enzymatic treatment, the average scleral thickness decreased by 13.3% (p < 0.001) and there was a stiffer overall stress-strain response (p < 0.05). The stress-strain response showed a statistically significant increase in the low-pressure stiffness, high-pressure stiffness and hysteresis. Thus, s-GAGs play a measurable role in the mechanical behaviour of the posterior human sclera., (© 2016 The Author(s).)

Importance: Eyes of patients with glaucoma may be damaged during sleep., Objective: To measure strains in glaucoma eyes and control eyes produced by mechanical force or deformation of the eye from contact when one side of the face rests against a pillow., Design, Setting, and Participants: This study took place in a clinic-based setting among 22 patients with glaucoma and 11 age-matched controls. The research was conducted at Wilmer Eye Institute between February 4, 2014, and December 2, 2014. Data analysis was done from June 3, 2014, to June 30, 2015., Main Outcomes and Measures: We used a contact lens sensor (CLS) to measure change in limbal strain associated with placing one side of the face down (FD) on a pillow in simulated sleep. Baseline intraocular pressure (IOP) was measured with a tonometer. The CLS data were collected every 5 minutes during intervals of up to 60 minutes in various positions, including sitting, lateral decubitus, FD (with the CLS-instrumented eye toward the pillow), and supine. Measured changes in limbal strain were related to estimated changes in IOP and to modeled strain produced by changes in IOP., Results: Among 22 patients with glaucoma and 11 controls, 17 were female. The mean age for the glaucoma group was 62.6 years, while the mean age for the control group was 61.4 years (P = .68). Baseline IOP was also similar for the 2 groups. The mean IOP sitting at the start was 13.7 mm Hg for the glaucoma group and 13.8 mm Hg for the control group (P = .73), and the mean IOP lying at the start was 17.5 mm Hg for the glaucoma group and 16.0 mm Hg for the control group (P = .88). By multivariable linear regression, FD position was associated with an increase in limbal strain in glaucoma eyes (mean [SE], 44.1 [20.4] mV Eq; P = .03) but not in control eyes (mean [SE], 13.6 [13.9] mV Eq, P = .33). While FD, the increased CLS values in patients with glaucoma did not decrease over time (slope, 0.275 mV Eq/min; P = .53 by univariable linear regression). Magnitudes of measured changes in limbal strain were greater in glaucoma eyes with past visual field worsening (P = .006 by multivariable linear modeling). The mean limbal strain increase among patients with glaucoma in FD position was equivalent to strain expected for a mean (SE) IOP increase of 2.5 (1.1) mm Hg from a baseline IOP of 14.2 mm Hg., Conclusions and Relevance: Contact with a pillow in FD position during simulated sleep produced a sustained strain increase in glaucoma eyes, particularly those eyes with past progressive visual field loss. The mean FD change in glaucoma eyes was equivalent to strain increase associated with a mean (SE) sustained IOP elevation of 2.5 (1.1) mm Hg. Further experiments are planned to determine if facial features or a protective eye shield prevents sleep position-induced limbal strains during a mean 8-hour sleep period.

Purpose: To determine how often glaucoma specialists set a target intraocular pressure (IOP) and how they respond when the target is not achieved., Methods: We reviewed 250 randomly selected charts of glaucoma patients seen by 5 glaucoma specialists to identify whether a target IOP was specifically set and to detail the plan of action when the target was exceeded., Results: A target IOP was present for at least 1 eye in 66% of patients (165/250). Among the patients of 5 physicians, the percentage with a target IOP for both eyes ranged from 90% to 34%. Half of eyes with no target had an explaining feature, whereas the other half did not. The study visit IOP exceeded the target in at least 1 eye in 29% (50/173) of patients. When the target was not met, 66% (33/50) had a notation of action taken, with no significant difference among physicians in whether any action was taken (P=0.64). The significant differences among the 5 physicians in the use of target IOP were potentially associated with patient demographic and clinical features, such as age, race, treatment intensity, and visual field damage, which differed among the 5 practices (all P<0.05)., Conclusions: Target IOP was recorded in the large majority of patient charts, but its use varied by physician and patient characteristics. On nearly one third of visits, IOP exceeded the target, indicating the need for active decision-making and management changes.

Purpose: To study the detailed cellular and molecular changes in the mouse sclera subjected to experimental glaucoma., Methods: Three strains of mice underwent experimental bead-injection glaucoma and were euthanized at 3 days and 1, 3, and 6 weeks. Scleral protein expression was analyzed with liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) using (16)O/(18)O labeling for quantification in 1- and 6-week tissues. Sclera protein samples were also analyzed with immunoblotting with specific antibodies to selected proteins. The proportion of proliferating scleral fibroblasts was quantified with Ki67 and 4',6-diamidino-2-phenylindole (DAPI) labeling, and selected proteins were studied with immunohistochemistry., Results: Proteomic analysis showed increases in molecules involved in integrin-linked kinase signaling and actin cytoskeleton signaling pathways at 1 and 6 weeks after experimental glaucoma. The peripapillary scleral region had more fibroblasts than equatorial sclera (p=0.001, n=217, multivariable regression models). There was a sixfold increase in proliferating fibroblasts in the experimental glaucoma sclera at 1 week and a threefold rise at 3 and 6 weeks (p=0.0005, univariate regression). Immunoblots confirmed increases for myosin, spectrin, and actinin at 1 week after glaucoma. Thrombospondin-1 (TSP-1), HINT1, vimentin, actinin, and α-smooth muscle actin were increased according to immunohistochemistry., Conclusions: Scleral fibroblasts in experimental mouse glaucoma show increases in actin cytoskeleton and integrin-related signaling, increases in cell division, and features compatible with myofibroblast transition.

Purpose: To develop an ex vivo organotypic retinal explant culture system suitable for multiple time-point imaging of retinal ganglion cell (RGC) dendritic arbors over a period of 1 week, and capable of detecting dendrite neuroprotection conferred by experimental treatments., Methods: Thy1-YFP mouse retinas were explanted and maintained in organotypic culture. Retinal ganglion cell dendritic arbors were imaged repeatedly using confocal laser scanning microscopy. Maximal projection z-stacks were traced by two masked investigators and dendritic fields were analyzed for characteristics including branch number, size, and complexity. One group of explants was treated with brain derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) added to the culture media. Changes in individual dendritic fields over time were detected using pair-wise comparison testing., Results: Retinal ganglion cells in mouse retinal explant culture began to degenerate after 3 days with 52.4% surviving at 7 days. Dendritic field parameters showed minimal change over 8 hours in culture. Intra- and interobserver measurements of dendrite characteristics were strongly correlated (Spearman rank correlations consistently > 0.80). Statistically significant (P < 0.001) dendritic tree degeneration was detected following 7 days in culture including: 40% to 50% decreases in number of branch segments, number of junctions, number of terminal branches, and total branch length. Scholl analyses similarly demonstrated a significant decrease in dendritic field complexity. Treatment of explants with BDNF+CNTF significantly attenuated dendritic field degeneration., Conclusions: Retinal explant culture of Thy1-YFP tissue provides a useful model for time-lapse imaging of RGC dendritic field degeneration over a course of several days, and is capable of detecting neuroprotective amelioration of dendritic pruning within individual RGCs.

Purpose: To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice., Methods: We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry., Results: Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP., Conclusions: The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.

Objective: The biomechanical behavior of the sclera determines the level of mechanical insult from intraocular pressure to the axons and tissues of the optic nerve head, as is of interest in glaucoma. In this study, we measure the collagen fiber structure and the strain response, and estimate the material properties of glaucomatous and normal human donor scleras., Methods: Twenty-two posterior scleras from normal and diagnosed glaucoma donors were obtained from an eyebank. Optic nerve cross-sections were graded to determine the presence of axon loss. The specimens were subjected to pressure-controlled inflation testing. Full-field displacement maps were measured by digital image correlation (DIC) and spatially differentiated to compute surface strains. Maps of the collagen fiber structure across the posterior sclera of each inflated specimen were obtained using synchrotron wide-angle X-ray scattering (WAXS). Finite element (FE) models of the posterior scleras, incorporating a specimen-specific representation of the collagen structure, were constructed from the DIC-measured geometry. An inverse finite element analysis was developed to estimate the stiffness of the collagen fiber and inter-fiber matrix., Results: The differences between glaucoma and non-glaucoma eyes were small in magnitude. Sectorial variations of degree of fiber alignment and peripapillary scleral strain significantly differed between normal and diagnosed glaucoma specimens. Meridional strains were on average larger in diagnosed glaucoma eyes compared with normal specimens. Non-glaucoma specimens had on average the lowest matrix and fiber stiffness, followed by undamaged glaucoma eyes, and damaged glaucoma eyes but the differences in stiffness were not significant., Conclusion: The observed biomechanical and microstructural changes could be the result of tissue remodeling occuring in glaucoma and are likely to alter the mechanical environment of the optic nerve head and contribute to axonal damage.

The effects of diabetes on the collagen structure and material properties of the sclera are unknown but may be important to elucidate whether diabetes is a risk factor for major ocular diseases such as glaucoma. This study provides a quantitative assessment of the changes in scleral stiffness and collagen fiber alignment associated with diabetes. Posterior scleral shells from five diabetic donors and seven non-diabetic donors were pressurized to 30 mm Hg. Three-dimensional surface displacements were calculated during inflation testing using digital image correlation (DIC). After testing, each specimen was subjected to wide-angle X-ray scattering (WAXS) measurements of its collagen organization. Specimen-specific finite element models of the posterior scleras were generated from the experimentally measured geometry. An inverse finite element analysis was developed to determine the material properties of the specimens, i.e., matrix and fiber stiffness, by matching DIC-measured and finite element predicted displacement fields. Effects of age and diabetes on the degree of fiber alignment, matrix and collagen fiber stiffness, and mechanical anisotropy were estimated using mixed effects models accounting for spatial autocorrelation. Older age was associated with a lower degree of fiber alignment and larger matrix stiffness for both diabetic and non-diabetic scleras. However, the age-related increase in matrix stiffness was 87% larger in diabetic specimens compared to non-diabetic controls and diabetic scleras had a significantly larger matrix stiffness (p = 0.01). Older age was associated with a nearly significant increase in collagen fiber stiffness for diabetic specimens only (p = 0.06), as well as a decrease in mechanical anisotropy for non-diabetic scleras only (p = 0.04). The interaction between age and diabetes was not significant for all outcomes. This study suggests that the age-related increase in scleral stiffness is accelerated in eyes with diabetes, which may have important implications in glaucoma.

Background: Previous studies suggest there are large variations in adherence of ophthalmologists with the American Academy of Ophthalmology's Preferred Practice Patterns (PPPs). The purpose of this study was to compare rates of compliance with glaucoma care guidelines between resident and glaucoma faculty physicians at a single institution., Methods: Charts of resident continuity clinic or glaucoma faculty patients with primary open angle glaucoma (POAG), ocular hypertension (OHTN), or suspicion of glaucoma were reviewed during the 2005-6 academic year. Performance within care measures specified by the 2005 PPP guidelines was compared between resident and faculty physicians using univariate and multivariable logistic regression models., Results: 112 resident and 100 faculty charts were reviewed. The mean compliance rate for all 7 care measures for resident physicians was significantly lower than that of faculty physicians (78% vs. 96%, p < 0.001). As compared to glaucoma faculty, resident physicians were less likely to have documented 6 of the 7 individual care measures (p ≤ 0.001 for all); the exception was optic nerve (ON) description. In multivariable analyses, resident patients were more likely to have at least one undocumented care measure than faculty patients (OR = 10.1, 95% CI = 5.1 to 20.0, p < 0.001). Among resident patients, undocumented care measures were more common among patients with poorer visual acuity (VA) in the better eye., Conclusions: Though unmeasured differences in clinic structure and patient characteristics may have partially contributed to poorer resident performance, residents were more likely than faculty to omit PPP care measures and significantly underperformed faculty in global assessment of glaucoma care. Resident education should focus on integration of PPPs into residency training and monitoring of resident compliance with evidence-based guidelines.

The objective of this study was to measure the collagen fiber structure and estimate the material properties of 7 human donor scleras, from age 53 to 91. The specimens were subjected to inflation testing, and the full-field displacement maps were measured by digital image correlation. After testing, the collagen fiber structure was mapped using wide-angle X-ray scattering. A specimen-specific inverse finite element method was applied to calculate the material properties of the collagen fibers and interfiber matrix by minimizing the difference between the experimental displacements and model predictions. Age effects on the fiber structure and material properties were estimated using multivariate models accounting for spatial autocorrelation. Older age was associated with a larger matrix stiffness (p = 0.001), a lower degree of fiber alignment in the peripapillary sclera (p = 0.01), and a lower mechanical anisotropy in the peripapillary sclera (p = 0.03).

Purpose: The collagen structure of the human peripapillary sclera plays a significant role in determining optic nerve head (ONH) biomechanics, and is therefore of interest in the study of glaucoma. The aim of the current work was to map the anisotropic collagen structure of the normal human peripapillary sclera as a function of tissue depth., Methods: Wide-angle x-ray scattering was used to quantify collagen fibril orientation at 0.5 mm intervals across six 150 μm-thick serial sections through the peripapillary sclera of eight normal European-derived human eyes. Two structural parameters were measured: 1) the relative number of fibrils preferentially aligned at a given angle within the tissue plane, 2) the degree of collagen alignment (anisotropy)., Results: The inner-most one-third of the peripapillary scleral stroma (nearest to the choroid) was characterised by collagen fibrils either randomly arranged or preferentially aligned radially with respect to the ONH. In contrast, the outer two-thirds of the tissue was dominated by a circumferential arrangement of collagen encircling the ONH. In all tissue regions the degree of collagen anisotropy peaked in the mid-stroma and progressively decreased towards the tissue surfaces, with the largest depth variations occurring in the inferior-nasal quadrant, and the smallest occurring in the superior-nasal quadrant., Conclusions: Significant, region-specific variations in collagen structure are present in the human peripapillary sclera as a function of depth. In normal eyes, the circumferential collagen fibril architecture is most prominent in the outer two-thirds of the stroma, possibly as a mechanical adaption to more effectively support the lamina cribrosa at the level of its insertion into the scleral canal wall.

Glaucoma, the second most common cause of world blindness, results from loss of retinal ganglion cells (RGC). RGC die as a consequence of injury to their axons, as they pass through the transition between the environment within the eye and that of the retrobulbar optic nerve, as they course to central visual centers. At the optic nerve head (ONH), axonal transport becomes abnormal, at least in part due to the effect of strain induced by intraocular pressure (IOP) on the sclera and ONH. Animal glaucoma models provide the ability to study how alterations in ocular connective tissues affect this pathological process. New therapeutic interventions are being investigated to mitigate glaucoma blindness by modifying the remodeling of ocular tissues in glaucoma. Some genetically altered mice are resistant to glaucoma damage, while treatment of the sclera with cross-linking agents makes experimental mouse glaucoma damage worse. Inhibition of transforming growth factor β activity is strikingly protective. Treatments that alter the response of ocular connective tissues to IOP may be effective in protecting those with glaucoma from vision loss., (© 2015 Elsevier B.V. All rights reserved.)

Biomechanics is the study of the relationship between forces and function in living organisms and is thought to play a critical role in a significant number of ophthalmic disorders. This is not surprising, as the eye is a pressure vessel that requires a delicate balance of forces to maintain its homeostasis. Over the past few decades, basic science research in ophthalmology mostly confirmed that ocular biomechanics could explain in part the mechanisms involved in almost all major ophthalmic disorders such as optic nerve head neuropathies, angle closure, ametropia, presbyopia, cataract, corneal pathologies, retinal detachment and macular degeneration. Translational biomechanics in ophthalmology, however, is still in its infancy. It is believed that its use could make significant advances in diagnosis and treatment. Several translational biomechanics strategies are already emerging, such as corneal stiffening for the treatment of keratoconus, and more are likely to follow. This review aims to cultivate the idea that biomechanics plays a major role in ophthalmology and that the clinical translation, lead by collaborative teams of clinicians and biomedical engineers, will benefit our patients. Specifically, recent advances and future prospects in corneal, iris, trabecular meshwork, crystalline lens, scleral and lamina cribrosa biomechanics are discussed.

Pathological changes in scleral glycosaminoglycan (GAG) content and in scleral mechanical properties have been observed in eyes with glaucoma and myopia. The purpose of this study is to investigate the effect of GAG removal on the scleral mechanical properties to better understand the impact of GAG content variations in the pathophysiology of glaucoma and myopia. We measured how the removal of sulphated GAG (s-GAG) affected the hydration, thickness and mechanical properties of the posterior sclera in enucleated eyes of 6-9 month-old pigs. Measurements were made in 4 regions centered on the optic nerve head (ONH) and evaluated under 3 conditions: no treatment (control), after treatment in buffer solution alone, and after treatment in buffer containing chondroitinase ABC (ChABC) to remove s-GAGs. The specimens were mechanically tested by pressure-controlled inflation with full-field deformation mapping using digital image correlation (DIC). The mechanical outcomes described the tissue tensile and viscoelastic behavior. Treatment with buffer alone increased the hydration of the posterior sclera compared to controls, while s-GAG removal caused a further increase in hydration compared to buffer-treated scleras. Buffer-treatment significantly changed the scleral mechanical behavior compared to the control condition, in a manner consistent with an increase in hydration. Specifically, buffer-treatment led to an increase in low-pressure stiffness, hysteresis, and creep rate, and a decrease in high-pressure stiffness. ChABC-treatment on buffer-treated scleras had opposite mechanical effects than buffer-treatment on controls, leading to a decrease in low-pressure stiffness, hysteresis, and creep rate, and an increase in high-pressure stiffness and transition strain. Furthermore, s-GAG digestion dramatically reduced the differences in the mechanical behavior among the 4 quadrants surrounding the ONH as well as the differences between the circumferential and meridional responses compared to the buffer-treated condition. These findings demonstrate a significant effect of s-GAGs on both the stiffness and time-dependent behavior of the sclera. Alterations in s-GAG content may contribute to the altered creep and stiffness of the sclera of myopic and glaucoma eyes., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The purpose of this study was to assess the effect of a scleral cross-linking agent on susceptibility to glaucoma damage in a mouse model.CD1 mice underwent 3 subconjunctival injections of 0.5 M glyceraldehyde (GA) in 1 week, then had elevated intraocular pressure (IOP) induced by bead injection. Degree of cross-linking was measured by enzyme-linked immunosorbent assay (ELISA), scleral permeability was measured by fluorescence recovery after photobleaching (FRAP), and the mechanical effects of GA exposure were measured by inflation testing. Control mice had buffer injection or no injection in 2 separate glaucoma experiments. IOP was monitored by Tonolab and retinal ganglion cell (RGC) loss was measured by histological axon counting. To rule out undesirable effects of GA, we performed electroretinography and detailed histology of the retina. GA exposure had no detectable effects on RGC number, retinal structure or function either histologically or electrophysiologically. GA increased cross-linking of sclera by 37% in an ELISA assay, decreased scleral permeability (FRAP, p = 0.001), and produced a steeper pressure-strain behavior by in vitro inflation testing. In two experimental glaucoma experiments, GA-treated eyes had greater RGC axon loss from elevated IOP than either buffer-injected or control eyes, controlling for level of IOP exposure over time (p = 0.01, and 0.049, multivariable regression analyses). This is the first report that experimental alteration of the sclera, by cross-linking, increases susceptibility to RGC damage in mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Glaucoma is the leading cause of global irreversible blindness. Present estimates of global glaucoma prevalence are not up-to-date and focused mainly on European ancestry populations. We systematically examined the global prevalence of primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG), and projected the number of affected people in 2020 and 2040., Design: Systematic review and meta-analysis., Participants: Data from 50 population-based studies (3770 POAG cases among 140,496 examined individuals and 786 PACG cases among 112 398 examined individuals)., Methods: We searched PubMed, Medline, and Web of Science for population-based studies of glaucoma prevalence published up to March 25, 2013. Hierarchical Bayesian approach was used to estimate the pooled glaucoma prevalence of the population aged 40-80 years along with 95% credible intervals (CrIs). Projections of glaucoma were estimated based on the United Nations World Population Prospects. Bayesian meta-regression models were performed to assess the association between the prevalence of POAG and the relevant factors., Main Outcome Measures: Prevalence and projection numbers of glaucoma cases., Results: The global prevalence of glaucoma for population aged 40-80 years is 3.54% (95% CrI, 2.09-5.82). The prevalence of POAG is highest in Africa (4.20%; 95% CrI, 2.08-7.35), and the prevalence of PACG is highest in Asia (1.09%; 95% CrI, 0.43-2.32). In 2013, the number of people (aged 40-80 years) with glaucoma worldwide was estimated to be 64.3 million, increasing to 76.0 million in 2020 and 111.8 million in 2040. In the Bayesian meta-regression model, men were more likely to have POAG than women (odds ratio [OR], 1.36; 95% CrI, 1.23-1.52), and after adjusting for age, gender, habitation type, response rate, and year of study, people of African ancestry were more likely to have POAG than people of European ancestry (OR, 2.80; 95% CrI, 1.83-4.06), and people living in urban areas were more likely to have POAG than those in rural areas (OR, 1.58; 95% CrI, 1.19-2.04)., Conclusions: The number of people with glaucoma worldwide will increase to 111.8 million in 2040, disproportionally affecting people residing in Asia and Africa. These estimates are important in guiding the designs of glaucoma screening, treatment, and related public health strategies., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: The organization of scleral collagen helps to determine the eye's biomechanical response to intraocular pressure (IOP), and may therefore be important in glaucoma. This study provides a quantitative assessment of changes in scleral collagen fibril organization in bead-induced murine experimental glaucoma., Methods: Wide-angle X-ray scattering was used to study the effect of bead-induced glaucoma on posterior scleral collagen organization in one eye of 12 CD1 mice, with untreated fellow eyes serving as controls. Three collagen parameters were measured: the local preferred fibril directions, the degree of collagen anisotropy, and the total fibrillar collagen content., Results: The mouse sclera featured a largely circumferential orientation of fibrillar collagen with respect to the optic nerve head canal. Localized alteration to fibril orientations was evident in the inferior peripapillary sclera of bead-treated eyes. Collagen anisotropy was significantly (P<0.05) reduced in bead-treated eyes in the superior peripapillary (Treated: 43±8%;, Control: 49±6%) and midposterior (Treated: 39±4%;, Control: 43±4%) sclera, and in the peripapillary region overall (Treated: 43±6%;, Control: 47±3%). No significant differences in total collagen content were found between groups., Conclusions: Spatial changes in collagen fibril anisotropy occur in the posterior sclera of mice with bead-induced chronic IOP elevation and axonal damage. These results support the idea that dynamic changes in scleral form and structure play a role in the development of experimental glaucoma in mice, and potentially in human glaucoma., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Importance: Laser trabeculoplasty (LTP) is routinely used to treat open-angle glaucoma; hence, understanding variations in its use over time and region is important., Objective: To determine trends over time and the regional variation in the performance of LTP., Design, Setting, and Participants: Database analysis of a 5% random sample of all Medicare beneficiaries 65 years or older with continuous Part B (medical insurance) coverage and no enrollment in a health maintenance organization for each year from 2002 through 2009., Interventions: We counted unique claims with a Current Procedural Terminology code of 65855 (LTP) submitted by ophthalmologists, optometrists, ambulatory surgery centers, or outpatient hospitals by region for each year. We examined trends over time and regional variation in LTP rates in 9 large geographic regions., Main Outcomes and Measures: Rate of LTP per 10,000 Medicare beneficiary person-years and per 10,000 diagnosed open-angle glaucoma (OAG) person-years., Results: The LTP rates per 10,000 Medicare beneficiary person-years were 36.3, 60.1, and 53.5 for 2002, 2006, and 2009, respectively. The 65.6% increase between 2002 and 2006 and the 11.0% decrease between 2006 and 2009 were statistically significant (tests for linear trend, P = .009 and P < .001, respectively). Similarly, the LTP rate among Medicare beneficiaries with OAG increased from 507.9 per 10,000 person-years in 2002 to 824.3 per 10,000 person-years in 2006 (62.3% increase; P = .009) and then decreased to 741 per 10,000 person-years by 2009 (10.1% decrease; P = .004). The rates per 10,000 OAG person-years differed significantly by region, ranging from 314 in the East South-Central region to 607 in the East North-Central region in 2002 (93.2% higher; P < .001). A similar range of variation was observed in subsequent years., Conclusions and Relevance: The rate of LTP for Medicare patients with OAG peaked in 2006 and then decreased through 2009. Nearly twice as many LTP procedures per Medicare beneficiary were performed in some regions compared with others throughout the period.

Purpose: To determine differences in scleral permeability, as measured by diffusion of macromolecules, by using fluorescence recovery after photobleaching (FRAP), with reference to differences by mouse strain, scleral region, and the effect of experimental glaucoma., Methods: In three mouse strains (B6, CD1, and B6 mice with mutation in collagen 8α2 [Aca23]), we used FRAP to measure the diffusion of fluorescein isothiocyanate-dextran, molecular weight 40 kDa, into a photobleached zone of sclera. Scleral regions near the optic nerve head (peripapillary) and two successively more anterior regions were compared. Sclera from mouse eyes subjected to chronically elevated intraocular pressure after bead injection into the anterior chamber were compared to fellow eye controls. FRAP data were compared against estimated retinal ganglion cell axon loss in glaucomatous eyes., Results: Diffusion rates of dextran molecules in the sclera were significantly greater in Aca23 and B6 mice than in CD1 mice in a multivariate model adjusted for region and axial length (P < 0.0001). Dextran diffusion significantly decreased in glaucomatous eyes, and the decline increased with greater axon loss (P = 0.0003, multivariable model). Peripapillary scleral permeability was higher in CD1 than B6 and Aca23 mice (P < 0.05, multivariable model, adjusted by Bonferroni)., Conclusions: Measurement of the diffusion rates of dextran molecules in the sclera showed that glaucoma leads to decreased scleral permeability in all three mouse strains tested. Among mouse strains tested, those that were more susceptible to glaucomatous loss of retinal ganglion cells had a lower scleral permeability at baseline.

Purpose: To identify risk factors associated with primary angle closure (AC) using anterior segment optical coherence tomography (ASOCT) measurements of the iris and to determine if these risk factors differ according to geographic origin., Methods: Anterior segment OCT images were collected on 267 persons (eyes) whose family origin was determined by a standardized method. In the 257 eyes with pupil diameter increase in the dark of 0.5 mm or more, findings were compared between bright light conditions and those in a dark room. In 130 eyes, comparison was made after pharmacological pupil dilation. After marking the position of the scleral spur, an automated program quantified many angle and iris parameters, with use of a manual method for a minority that the software could not analyze., Results: Iris area in bright light was larger with increasing age (univariate regression, P = 0.0005), largest in European and African-derived, and smallest in Korean and Chinese eyes (multivariable regression, P = 0.0001), and was significantly larger in AC groups compared with normal and open angle glaucoma groups (univariate regression, P < 0.0001). The absolute iris area loss per mm pupil dilation was significantly less in Chinese persons than African-derived persons (multivariable regression, P < 0.05 adjusted Tukey). Furthermore, in persons with past acute AC attack, the baseline iris area was not different from others, but their iris area lost per millimeter dilation was significantly less than in persons without past acute AC attack (multivariable regression, P = 0.04). The odds of AC disease significantly increased in eyes with smaller percent iris area lost and percent iris area lost per millimeter pupil increase, but when adjusted for geographic origin, this was significant only in persons of Chinese origin (interaction regression model). Apparent gain of iris volume on pupil dilation, due to an artifact in calculation from iris area loss, may indicate a detrimental shift in iris tissue toward the angle., Conclusions: Chinese persons in this cohort had relatively low baseline iris area, but less loss of iris area on pupil dilation than other groups, a feature also associated with greater prevalence of past acute AC attack. Disproportionate peripheral redistribution of iris area on dilation may contribute to AC.

Purpose: To improve the neurological hemifield test (NHT) using visual field data from both eyes to detect and classify visual field loss caused by chiasmal or postchiasmal lesions., Methods: Visual field and clinical data for 633 patients were divided into a training set (474 cases) and a validation set (159 cases). Each set had equal numbers of neurological, glaucoma, or glaucoma suspect cases, matched for age and for mean deviation between neurological and glaucoma cases. NHT scores as previously described and a new NHT laterality score were calculated. The ability of these scores to distinguish neurological from other fields was assessed with receiver operating characteristic (ROC) analysis. Three machine classifier algorithms were also evaluated: decision tree, random forest, and least absolute shrinkage and selection operator (LASSO). We also evaluated the ability of NHT to identify the type of neurological field defect (homonymous or bitemporal)., Results: The area under the ROC curve (AUC) for the maximum NHT score was 0.92 (confidence interval [CI]: 0.87, 0.97). Using NHT laterality scores from each eye combined with the sum of NHT scores, the AUC improved to 0.93 (CI: 0.88, 0.98). The largest AUC for machine learning algorithms was for the LASSO method (0.96, CI: 0.92, 0.99). The NHT scores identified the type of neurological defect in 96% (158/164) of patients., Conclusions: The new NHT distinguished neurological field defects from those of glaucoma and glaucoma suspects, providing accurate categorization of defect type. Its implementation may identify unsuspected neurological disease in clinical visual field testing.

The purpose of this research was to study the effects of age and genetic alterations in key connective tissue proteins on susceptibility to experimental glaucoma in mice. We used mice haploinsufficient in the elastin gene (EH) and mice without both alleles of the fibromodulin gene (FM KO) and their wild type (WT) littermates of B6 and CD1 strains, respectively. FM KO mice were tested at two ages: 2 months and 12 months. Intraocular pressure (IOP) was measured by Tonolab tonometer, axial lengths and widths measured by digital caliper post-enucleation, and chronic glaucoma damage was measured using a bead injection model and optic nerve axon counts. IOP in EH mice was not significantly different from WT, but FM KO were slightly lower than their controls (p = 0.04). Loss of retinal ganglion cell (RGC) axons was somewhat, but not significantly greater in young EH and younger or older FM KO strains than in age-matched controls (p = 0.48, 0.34, 0.20, respectively, multivariable regression adjusting for IOP exposure). Older CD1 mice lost significantly more RGC axons than younger CD1 (p = 0.01, multivariable regression). The CD1 mouse strain showed age-dependence of experimental glaucoma damage to RGC in the opposite, and more expected, direction than in B6 mice in which older mice are more resistant to damage. Genetic alteration in two genes that are constituents of sclera, fibromodulin and elastin do not significantly affect RGC loss., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To assess methods for and variations in identifying the scleral spur (SS) position in anterior segment optical coherence tomography., Methods: In images of 51 eyes (patients) with open and closed anterior chamber angles, we compared the success rate and the variability of 3 approaches for identifying the SS: the ciliary muscle (CM), bump, and Schwalbe line (SL) methods using mixed effects regression models. The effect of incremental variation in SS position on anterior chamber parameters using the Anterior Segment Analysis Program (ASAP) was analyzed in 8 images. Automated ASAP measurements were compared with manual ImageJ measurements in 46 images., Results: The SS could be identified in 98% of images by each observer using the 3 methods in combination. The SL and CM approaches more successfully identified the SS (82% and 81% success, respectively) than the bump method (59%, P<0.001). The intraobserver, interobserver, and intermethod variabilities of the CM and bump methods were superior to those of the SL method. The SS was more likely to be identified in open angle than angle closure eyes (OR=2.26, P=0.03) and brown eyes were less likely than blue eyes (OR=0.36, P=0.04). Movement of SS position resulted in substantial differences in the angle parameters and iris concavity ratio, whereas iris area and volume were less affected., Conclusions: The CM method was the most successful and least variable method of SS marking, which was more difficult in narrow angle and brown eyes. Variability of SS placement had a large effect on angle parameters and iris concavity ratio.