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Objectives: Hospital care accounts for up to one-third of the cost of inflammatory bowel disease (IBD) management. A select group of patients with IBD is responsible for a large proportion of this utilization, demonstrating the burden of frequent hospitalizations. We aim to better understand the burden of 30-day readmissions among patients with IBD using a national hospital database., Study Design: Retrospective cohort study of state-specific inpatient databases., Methods: The State Inpatient Databases for New York and Florida were used to identify patients with IBD hospitalized between 2009 and 2013. The prevalence of 30-day IBD-specific readmission was determined. The association between 30-day readmission and visit outcomes, specifically length of stay and a composite of comorbid conditions (venous thromboembolism, pneumonia, sepsis, Clostridium difficile infection, enteral and parenteral nutrition, and blood transfusion), was analyzed using multivariable logistic regression., Results: Patients with IBD accounted for 35,514 and 39,506 inpatient stays in New York and Florida, respectively. Of these stays, 13.7% to 16.2% resulted in a 30-day readmission. On multivariable analysis, 30-day readmissions were associated with a longer length of stay than index hospitalizations by 1.00 day (adjusted regression coefficient, 1.00; 95% CI, 0.73-1.26) and a higher likelihood of having a comorbid condition (adjusted odds ratio, 1.83; 95% CI, 1.68-1.99) in New York. Similar associations were confirmed in Florida., Conclusions: Nearly 1 in 7 hospitalizations of patients with IBD lead to a 30-day readmission. These IBD-specific readmissions are associated with increased utilization and comorbidity. Patients at risk for readmission need to be targeted to improve outcomes and IBD care quality.

Introduction: Although the Hospital Readmissions Reduction Program (HRRP) has decreased readmissions in targeted conditions, outcomes in high-risk subgroups are unknown. This study analyzed the impact of cirrhosis as a comorbidity on readmissions in conditions subjected to the HRRP., Methods: Using a longitudinal analysis of the New York, Florida, and Washington State inpatient databases from 2009 to 2013, adult Medicare beneficiaries with a diagnosis-related group of targeted conditions by the HRRP-pneumonia, congestive heart failure (CHF), and myocardial infarction (MI)-were included. Exclusion criteria included inability to assess for readmission, previous liver transplant, or having a readmission not subject to penalty under the HRRP. A sensitivity analysis used the International Classification of Diseases, 9th Revision, Clinical Modification codes to identify pneumonia, CHF, and MI hospitalizations. The primary outcome was 30-day readmission, with secondary outcomes including 90-day readmission, trends, and cirrhosis-specific risk factors for readmission., Results: Of the 797,432 patients included, 8,964 (1.1%) had cirrhosis. Patients with cirrhosis had significantly higher 30-day readmissions overall (29.3% vs 23.8%, P < 0.001) and specifically for pneumonia and CHF, but not for MI. Thirty-day readmission rates significantly decreased in patients without cirrhosis (annual percent change -1.8%, P < 0.001), but not in patients with cirrhosis (P = 0.39). Similar findings were present for 90-day readmissions. A sensitivity analysis confirmed these findings. On multivariable analysis, cirrhosis was associated with significantly higher 30-day readmissions (odds ratio 1.13, P < 0.001)., Discussion: When cirrhosis is comorbid in patients with conditions subjected to the HRRP, readmissions are higher and have not improved. Focused efforts are needed to improve outcomes in cirrhosis and other high-risk comorbidities within the HRRP cohort.

Background & Aims: Cirrhotics are at increased risk of Clostridioides difficile infection (CDI) and its associated high morbidity and mortality. However, the impact of CDI in cirrhotics over time remains unclear. This study analyses prevalence and mortality in CDI in hospitalized patients with advanced cirrhosis over 15 years and identifies trends., Methods: Using the Nationwide Inpatient Sample (NIS) from 1998 to 2014, 3 049 696 weighted patients with advanced cirrhosis (defined as evidence of decompensation or oesophageal varices) were identified using a validated algorithm of ICD-9-CM codes and included in the study. Trends were analysed using Cochran Armitage test and joinpoint regression and compared to the general population. Multivariable logistic regression was performed controlling for risk factors that affect mortality in cirrhotics., Results: CDI prevalence in advanced cirrhotics increased from 0.8% to 2.6%, annual percent change (APC) 8.8% (compared to 7.6% for the general population), while CDI-related mortality decreased from 20.7% to 11.3%, APC -3.4% (compared to -2.0% for the general population), from 1998 to 2014. CDI independently increased mortality in advanced cirrhotics (OR 1.47, P < 0.001) and was associated with acute kidney injury (AKI) (OR 2.09, P < 0.001), which itself significantly increased mortality (OR 4.54, P < 0.001). Hepatic encephalopathy and Hispanic ethnicity were interestingly associated with a lower prevalence of CDI., Conclusions: CDI is increasingly common in advanced cirrhotics, but on the contrary, its associated mortality is decreasing. Despite improvements in outcomes in patients with advanced cirrhosis, CDI is associated with an increased mortality, driven by AKI, and therefore, requires aggressive identification and therapy., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Blood flow in the optic nerve head (ONH) is known to be reduced in eyes with advanced glaucoma. However, experimental results from non-human primates suggest an initial increase in ONH blood flow at the earliest stages of damage. This study assesses flow and pulsatile hemodynamics across a range of severities to test the hypothesis that this also occurs in human glaucoma., Methods: Laser speckle flowgraphy was used to measure average mean blur rate (MBRave) within ONH tissue (a correlate of capillary blood flow) and the pulsatile waveform in 93 eyes with functional loss and 74 glaucoma suspect/fellow eyes without functional loss. These were compared against results from 92 healthy control eyes. Parameters produced by the instrument's software were age-corrected, then compared between groups using generalized estimating equation models., Results: The mean MBRave in the control eyes was 12.5 units. In glaucoma suspect/fellow eyes, the mean was 16.4 units, higher with P < 0.0001. In eyes with functional loss, the mean was 13.8 units, lower than eyes without functional loss with P < 0.0001, although still higher than control eyes with P = 0.0096. Analysis of the pulsatile waveform suggested that the deceleration in flow as it approaches its maximum across the cardiac cycle was delayed in glaucoma., Conclusions: Blood flow within ONH capillaries was higher in glaucoma suspect eyes than in healthy controls. It was less elevated in eyes that had developed functional loss. The mechanisms causing these changes and their relation to concurrent changes in pulsatile hemodynamics remain under investigation.

Background and Aim: Portal vein thrombosis (PVT) is increasingly common in cirrhotics, but its impact on mortality and outcomes is unclear. Studies evaluating PVT have been limited by small sample size. This study analyzes the trend of the prevalence of PVT and its associated mortality in hospitalized decompensated cirrhotics., Methods: The Nationwide Inpatient Sample, the largest nationally representative database of hospital discharges, was queried from 1998 to 2014. Inpatients older than 18 years with decompensated cirrhosis were included, while those who received liver transplantation or had hepatocellular carcinoma were excluded. The primary outcomes were the trend in prevalence and associated mortality with PVT. Secondary outcomes included identifying risk factors of PVT and the effect of PVT on complications of portal hypertension. Multivariable logistic regression evaluated the outcomes., Results: A total of 3 045 098 discharges were included, of which 1.5% had PVT. PVT prevalence increased from 0.7% to 2.4%, annual percent change of 9%. Mortality associated with PVT declined from 11.9% to 9.1%, annual percent change of -3.0%. In multivariable analysis controlling for factors associated with mortality in cirrhotics, PVT was associated with an increased risk of mortality (OR 1.12, P < 0.001). Multivariable logistic regression also demonstrated that PVT significantly increased the risk of acute kidney injury (OR 1.75, P < 0.001) and hepatorenal syndrome (OR 1.62, P < 0.001)., Conclusions: The prevalence of PVT is increasing while its associated mortality is decreasing. However, PVT still is associated with risk of mortality and kidney injury, implying a significant impact on cirrhotic outcomes., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Clinical examination of the optic disc is a fundamental component of any ophthalmic evaluation, but it is especially important for diagnosis and management of glaucoma. The purpose of this article is to: (1) review the limitations inherent to clinical examination; (2) outline the rationale for adopting into clinical practice quantitative measures of the optic nerve head neuro-retinal rim tissue integrity derived from current optical coherence tomography imaging approaches; (3) describe recent developments in this area; and (4) highlight a few avenues of active research that hold promise for future translation to clinical practice., (© 2018 Optometry Australia.)

PRéCIS:: There are errors in automated segmentation of the retinal nerve fiber layer (RNFL) in glaucoma suspects or patients with mild glaucoma that appear to persist over time; however, automated segmentation has greater repeatability than manual segmentation., Purpose: To identify whether optical coherence tomography (OCT) segmentation errors in RNFL thickness measurements persist longitudinally., Methods: This was a cohort study. We used spectral domain OCT (Spectralis) to measure RNFL thickness in a 6-degree peripapillary circle, and exported the native "automated segmentation only" results. In addition, we exported RNFL thickness results after "manual refinement" to correct errors in the automated segmentation, and used the differences in these measurements as "error" in segmentation. We used Bland-Altman plots and linear regression to determine the magnitude, location, and repeatability of RNFL thickness error in all twelve 30-degree sectors and compared the error at baseline to follow-up time points at 6 months, 2 years, 3 years, and 4 years., Results: We included 406 eyes from 213 participants. The 95% confidence interval for errors at baseline was -6.5 to +13.2 μm. The correlation between the baseline error and the errors in the follow-up time periods were high (r>0.5, P<0.001 for all). Automated segmentation had a smaller SD of residuals from the longitudinal trend line when compared to manual refinement (1.56 vs. 1.80 μm, P<0.001), and a higher ability (P=0.009) to monitor progression using an analysis of a longitudinal signal-to-noise ratio., Conclusions: Errors in automated segmentation remain relatively stable, and baseline error is highly likely to persist in the same direction and magnitude in subsequent time periods. However, automated segmentation (without manual refinement) is more repeatable and may be more sensitive to glaucomatous progression. Future segmentation algorithms could exploit these findings to improve automated segmentation in the future.

Background: The importance of the accessory enzymes such as α-L-arabinofuranosidases (AFases) in synergistic interactions within cellulolytic mixtures has introduced a paradigm shift in the search for hydrolytic enzymes. The aim of this study was to characterize novel AFase genes encoding enzymes with differing temperature optima and thermostabilities for use in hydrolytic cocktails., Results: Three fosmids, pFos-H4, E3 and D3 were selected from the cloned metagenome of high temperature compost, expressed in Escherichia coli and subsequently purified to homogeneity from cell lysate. All the AFases were clustered within the GH51 AFase family and shared a homo-hexameric structure. Both AFase-E3 and H4 showed optimal activity at 60 °C while AFase-D3 had unique properties as it showed optimal activity at 25 °C as well as the ability to maintain substantial activity at temperatures as high as 90 °C. However, AFase-E3 was the most thermostable amongst the three AFases showing full activity even at 70 °C. The maximum activity was observed at a pH profile between pH 4.0-6.0 for all three AFases with optimal activity for AFase H4, D3 and E3 at pH 5.0, 4.5 and 4.0, respectively. All the AFases showed K M range between 0.31 mM and 0.43 mM, K cat range between 131 s - 1 and 219 s - 1 and the specific activity for AFase-H4, AFases-E3 and was 143, 228 and 175 U/mg, respectively. AFases-E3 and D3 displayed activities against pNP-β-L-arabinopyranoside and pNP-β-L-mannopyranoside respectively, and both hydrolysed pNP-β-D-glucopyranoside., Conclusion: All three AFases displayed different biochemical characteristics despite all showing conserved overall structural similarity with typical domains of AFases belonging to GH51 family. The hydrolysis of cellobiose by a GH51 family AFase is demonstrated for the first time in this study.

Purpose: To examine the frequency of paravascular defects (PDs) and macular epiretinal membranes (ERMs) in eyes categorized as having mild glaucoma or glaucoma suspect using en-face slab analysis of optical coherence tomography (OCT) scans., Materials and Methods: Fifty-seven glaucomatous eyes, 44 low-risk suspect eyes, and 101 healthy control eyes were included in the study. The 101 glaucomatous and suspect eyes had a mean deviation better than -6 dB on the 24-2 visual field, and a spherical refractive error between±6 D or axial length <26.5 mm. Two OCT-graders masked to eye classification identified ERMs and PDs on en-face slab images of the macula and peripapillary retina using horizontal B-scans and derived vertical B-scans., Results: Glaucomatous eyes had a significantly higher number of PDs and ERMs than healthy controls (PD, P<0.001; ERM, P=0.046) and low-risk glaucoma suspects (PD, P=0.004; ERM, P=0.043). PDs and/or ERMs were present in 16 of 57 (28.1%) glaucomatous eyes, 2 of 44 (4.5%) suspect eyes, and 3 of 101 (3.0%) control eyes. Further, PDs were present in 11 of the 57 (19.3%) glaucomatous eyes, 1 of the 44 (2.3%) suspect eyes and 0 of the 101 (0%) control eyes, ERMs were seen in 7 of the 57 (12.3%) glaucomatous eyes, 1 of the 44 (2.3%) suspects, and 3 of the 101 (3.0%) control eyes., Conclusions: Eyes with early glaucoma have a higher frequency of PDs and ERMs than suspects or controls and exhibit PDs even in the absence of ERMs or high myopia.

Purpose: To assess glaucoma specialists' detection of optic nerve head (ONH) rim tissue that is thin by optical coherence tomography (OCT) criteria., Design: Reliability analysis., Methods: Five clinicians marked the disc margin (DM) and rim margin (RM) on stereophotographs of 151 glaucoma or glaucoma suspect eyes obtained within 3 months of OCT imaging. The photo and OCT infrared image for each eye were co-localized and regionalized into 12 sectors relative to the axis between the Bruch membrane opening (BMO) centroid and the fovea. For each clinician, the distance from BMO centroid to their DM (DM radius) and RM (RM radius) was used to generate sectoral rim width (RW) (DM radius-RM radius) and cup-to-disc ratio (CDR) (RM radius/DM radius) estimates. OCT minimum rim width (MRW) was determined by sector. Among all eyes, for each OCT MRW suspicious sector (<5% of OCT normative database), we determined each clinician's detection (clinician CDR ≥ 0.7)., Results: Clinicians most commonly failed to detect OCT suspicious rim tissue in the nasal sectors. Among 502 sectors with suspicious OCT MRW, all 5 clinicians rated CDR ≥ 0.7 in only 29.5% and all 5 clinicians rated CDR < 0.7 in 21%. OCT suspicious rim thickness was most common (32% of eyes) in the nasal and inferior sectors. MRW vs clinician RW discordance was greatest nasally, while BMO vs clinician DM discordance was greatest temporally., Conclusions: Clinicians most commonly failed to detect OCT suspicious rim thickness nasally where suspicious rim tissues were also most common., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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.

Objectives: Inflammatory bowel disease (IBD) is a complex chronic disease that often requires a multispeciality approach; thus, IBD patients are prone to care fragmentation. We aim to determine the prevalence of fragmentation among hospitalized IBD patients and identify associated predictors and visit-level outcomes., Methods: The State Inpatient Databases for New York and Florida were used to identify 90-day readmissions among IBD inpatients from 2009 to 2013. The prevalence of fragmentation, defined as a readmission to a non-index hospital, was reported. Characteristics associated with fragmented care were identified using multivariable logistic regression. Multivariable models were utilized to determine the association between fragmentation and outcomes (in-hospital mortality, readmission length of stay, and inpatient colonoscopy)., Results: Among IBD inpatients, 25,241 and 29,033 90-day readmission visits were identified, in New York and Florida, respectively. The prevalence of fragmentation was 26.4% in New York and 32.5% in Florida. Younger age, a non-emergent admission type, public payer or uninsured status, mood disorder, and substance abuse were associated with fragmented care, while female gender and a primary diagnosis of an IBD-related complication had an inverse association. Fragmented inpatient care is associated with a higher likelihood of in-hospital death, higher rates of inpatient colonoscopy, and a longer readmission length of stay., Conclusions: Over one in four IBD inpatient readmissions are fragmented. Disparities and differences in fragmentation exist and contribute to poor patient outcomes. Additional efforts targeting fragmentation should be made to better coordinate IBD management, reduce healthcare gaps, and promote high-value care.

Several retinal conditions have been recently revealed by optical coherence tomography (OCT) to occur more frequently in glaucoma than in healthy eyes: paravascular defects, peripapillary retinoschisis, and pseudo-cysts of the inner nuclear layer (INL). Here the clinical OCT findings described in these reports are reviewed and a framework that could explain why they are related and occur more frequently in glaucoma is proposed. Evidence suggests that these conditions all share in common a strong tendency to develop in association with severe and/or rapidly progressing disease and a likelihood of involving biomechanical forces and differential tissue deformation. Müller glia are mechanosensitive and known to react to shear and axial strain, and to participate in homeostasis of water and ion flux through the retina, and to provide spring-like capability to buffer of mechanical forces. Thus, Müller cell integrity is also likely to be involved in the development and/or response to such events. OCT has also revealed that Müller cell optical properties (scatter and attenuation) appear to be altered in at least two of these retinal conditions: peripapillary retinoschisis and pseudo-cysts of the INL. Future studies applying 3D strain mapping techniques might reveal structural changes over time (either acute or longer-term deformations) that predict the onset and location of these retinal defects and their relationship to progressive optic nerve head deformation, retinal nerve fiber layer, and retinal ganglion cell loss in glaucoma.

Purpose: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population., Methods: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length, and intraocular pressure. We further repeated analyses stratified into age tertiles., Results: In total, 5433 participants with HRT data and 3699 participants with GDxVCC data were included. Each "C" allele of rs33912345 was associated with a smaller rim area (-0.030 mm [95% CI -0.040, -0.020]; P=5.4×10), a larger VCDR (0.025 [95% CI 0.017, 0.033]; P=3.3×10) and a thinner RNFL (-0.39 μm [95% CI -0.62, -0.15]; P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles., Conclusions: The protein-coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.

Purpose: To quantify the variability of 5 glaucoma specialists' optic disc margin (DM), rim margin (RM), and rim width (RW) estimates., Design: Inter-observer reliability analysis., Methods: Clinicians viewed stereo-photographs from 214 subjects with glaucoma or ocular hypertension and digitally marked the DM and RM. For each photograph, the centroid of each clinician's DM was calculated, and an averaged DM centroid was determined. The axis between the DM centroid and the fovea was used to establish 12 30-degree sectors. Measurements from the DM centroid to each clinician's DM (DM radius ) and RM (RM radius ) were used to generate a RW (DM radius -RM radius ) and cup-to-disc ratio (CDR) (RM radius /DM radius ) by sector. Parameter means, standard deviations, and coefficient of variations (COVs) were calculated across all clinicians for each eye. Parameter means for each clinician, and intraclass correlation coefficients (ICC), were calculated across all eyes by sector., Results: Among all eyes, the median COV by sector ranged from 3% to 5% for DM radius , 20% to 25% for RM radius , and 26% to 30% for RW. Sectoral ICCs for CDR ranged from 0.566 to 0.668. Sectors suspicious for rim thinning by 1 clinician were frequently overlooked by others. Among 1724 sectors in which at least 1 clinician was suspicious for rim thinning (CDR ≥ 0.7), all 5 clinicians' CDRs were ≥ 0.7 in only 499 (29%), and 2 of the 5 clinicians failed to detect rim thinning (CDR < 0.7) in 442 (26%)., Conclusion: In this study, glaucoma specialist RM, DM, and RW discordance was frequent and substantial, even in sectors that were suspicious for rim thinning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To examine demographic and clinical factors associated with glaucomatous peripapillary retinoschisis (PPRS) and assess its association with glaucoma progression., Methods: Using a case control study design and longitudinal data from a cohort of 166 subjects with a diagnosis of glaucoma or glaucoma suspect, we compared functional, structural, clinical, and demographic characteristics between PPRS cases and controls., Results: The frequency of PPRS was 6.0% (12 eyes from 10/166 subjects) with two eyes having PPRS in different sectors for a total of 15 retinoschisis events. There were no significant differences (P > 0.05) in age, sex, visual acuity, central corneal thickness, intraocular pressure, or presence of vitreous adhesion between PPRS and controls. However, eyes with PPRS tended to have a higher cup-to-disc ratio (P = 0.06), thinner RNFL (P = 0.02), and worse visual field mean deviation (MD, P = 0.06) than controls. The rate of RNFL thinning was faster in PPRS (average: -2.8%/year; range: -7.4% to 0.0%/year) than controls (-1.3%/year; range: -4.4% to 0.6%/year; P = 0.021). The rate of visual field MD change was faster in PPRS (-0.49 dB/year; range: -2.0 to 0.9 dB/year) than controls (-0.06 dB/year; range: -0.8 to 0.3 dB/year; P = 0.030). OCT scans showed hyperreflective structures spanning the PPRS whose morphology and spacing (50 ± 7 μm) are consistent with Müller glia, causing signal attenuation casting "shadows" onto distal retina., Conclusions: This is the first report showing that glaucomatous PPRS is associated with a faster overall rate of RNFL thinning and visual field deterioration and to specifically identify OCT signs of Müller cell involvement.

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 compare morphologic changes on en face images derived from wide-field swept-source optical coherence tomography (ssOCT) to hypo- and hyperautofluorescent (hypoAF, hyperAF) areas on short-wavelength autofluorescence (SW-AF), and near-infrared (NIR)-AF in recessive Stargardt disease (STGD1)., Methods: Wide-field ssOCT cube scans were obtained from 16 patients (16 eyes). Averaged B-scans and SW-AF images were obtained using Spectralis HRA+OCT. NIR-AF images were obtained from 6 eyes. The inner/outer segment (IS/OS), OS/RPE, and RPE/Bruch's membrane boundaries were segmented, and en face slab images generated. A subRPE slab image was used to measure the abnormal RPE area, and an IS/OS slab image, the IS/OS junction loss area. These were compared to hypo- and abnormal SW-AF areas, and hypoNIR-AF areas. A preRPE(OS) slab image was used to evaluate the spatial and intraretinal locations of flecks., Results: For all eyes, RPE atrophy was visualized as a central hyperreflective area on the subRPE slab, and IS/OS junction loss as an abnormal reflective area on the IS/OS slab; the latter was significantly larger (P = 0.04). There was good agreement between the hyperreflective area on the subRPE slab image and hypoSW-AF area, and between the abnormal reflective area on the IS/OS slab and hypo-hyperSW-AF area; the hypoNIR-AF area indicated that the hyperreflective area on the subRPE slab underestimated RPE atrophy. The spatial locations of hyperreflective flecks on the en face preRPE(OS) slab image corresponded to those on the SW-AF images., Conclusions: Wide-field en face OCT imaging has the potential to be a clinically useful tool for the management of STGD1.

Ascites is the most common complication related to cirrhosis and is associated with increased morbidity and mortality. Ascites is a consequence of the loss of compensatory mechanisms to maintain the overall effective arterial blood volume due to worsening splanchnic arterial vasodilation as a result of clinically significant portal hypertension. In order to maintain effective arterial blood volume, vasoconstrictor and antinatriuretic pathways are activated, which increase overall sodium and fluid retention. As a result of progressive splanchnic arterial vasodilation, intestinal capillary pressure increases and results in the formation of protein-poor fluid within the abdominal cavity due to increased capillary permeability from the hepatic sinusoidal hypertension. In some patients, the fluid can translocate across diaphragmatic fenestrations into the pleural space, leading to hepatic hydrothorax. In addition, infectious complications such as spontaneous bacterial peritonitis can occur. Eventually, as the liver disease progresses related to higher portal pressures, loss of a compensatory cardiac output and further splanchnic vasodilation, kidney function becomes compromised from worsening renal vasoconstriction as well as the development of impaired solute-free water excretion and severe sodium retention. These mechanisms then translate into significant clinical complications, such as refractory ascites, hepatorenal syndrome and hyponatremia, and all are linked to increased short-term mortality. Currently, liver transplantation is the only curative option for this spectrum of clinical manifestations but ongoing research has led to further insight on alternative approaches. This review will further explore the current understanding on the pathophysiology and management of ascites as well as expand on two advanced clinical consequences of advanced liver disease, refractory ascites and hyponatremia.

Purpose: To compare diagnostic performance and structure-function correlations of multifocal electroretinogram (mfERG), full-field flash ERG (ff-ERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG)., Methods: At baseline and after induction of chronic unilateral IOP elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ff-ERG (red 0.42 log cd-s/m 2 flashes on blue 30 scotopic cd/m 2 background, LKC UTAS-E3000), and PERG (0.8° checks, 99% contrast, 100 cd/m 2 mean, 5 reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, >75 Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ff-ERG parameters included A-wave (at 10 ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger's test., Results: Study duration was 15 ± 8 months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9% above baseline (BL) to 58% below BL; 29/43 EG eyes (67%) and 0/43 of the fellow control eyes exhibited significant (>7%) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ff-ERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95% specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R = 0.65) than for PhNR (R = 0.59) or PERG N95 (R = 0.36), (p = 0.20, p = 0.0006, respectively). The PhNR flagged a few EG eyes at the final time point that had not been flagged by mfERG HFC or PERG., Conclusions: Diagnostic performance and structure-function correlation were strongest for mfERG HFC as compared with ff-ERG PhNR or PERG in NHP EG.

Purpose: We determine if several hours of controlled elevation of IOP (CEI) will produce the optic nerve head (ONH) gene expression changes and optic nerve (ON) damage pattern associated with early experimental glaucoma in rats., Methods: The anterior chambers of anesthetized rats were cannulated and connected to a reservoir to elevate IOP. Physiologic parameters were monitored. Following CEI at various recovery times, ON cross-sections were graded for axonal injury. Anterior ONHs were collected at 0 hours to 10 days following CEI and RNA extracted for quantitative PCR measurement of selected messages. The functional impact of CEI was assessed by electroretinography (ERG)., Results: During CEI, mean arterial pressure (99 ± 6 mm Hg) and other physiologic parameters remained stable. An 8-hour CEI at 60 mm Hg produced significant focal axonal degeneration 10 days after exposure, with superior lesions in 83% of ON. Message analysis in CEI ONH demonstrated expression responses previously identified in minimally injured ONH following chronic IOP elevation, as well as their sequential patterns. Anesthesia with cannulation at 20 mm Hg did not alter these message levels. Electroretinographic A- and B-waves, following a significant reduction at 2 days after CEI, were fully recovered at 2 weeks, while peak scotopic threshold response (pSTR) remained mildly but significantly depressed., Conclusions: A single CEI reproduces ONH message changes and patterns of ON injury previously observed with chronic IOP elevation. Controlled elevation of IOP can allow detailed determination of ONH cellular and functional responses to an injurious IOP insult and provide a platform for developing future therapeutic interventions.

Purpose: To determine how well rates of localized retinal nerve fiber layer thickness (RNFLT) change correlate with rates of sensitivity change at corresponding locations in the visual field in glaucoma., Design: Retrospective cohort study., Methods: Three hundred and sixty-four eyes of 191 participants with suspected or confirmed glaucoma, as judged by experienced clinicians, were tested every 6 months with perimetry and optical coherence tomography (OCT). For each 24-2 visual field location, the corresponding sectoral peripapillary RNFLT was defined using a 30-degree sector, centered on the angle of nerve fiber entry into the optic nerve head. Rates of change of pointwise sensitivity and sectoral RNFLT were calculated over the last 8 visits at which reliable data were obtained. Passing-Bablok regression was used to predict the rate of pointwise sensitivity change from the rate of sectoral RNFLT change, for each location., Results: Rates of sectoral RNFLT change were significantly predictive of rates of pointwise sensitivity change at all locations in the field. Correlations were modest, averaging 0.15, ranging from 0.03 to 0.25 depending on the location. A 1 μm/y more rapid thinning in corresponding sectors was associated with 0.3 dB/y more rapid loss in the superior visual field but less than 0.1 dB/y more rapid loss at many locations in the inferior visual field., Conclusions: Localized RNFL thinning is associated with sensitivity loss at corresponding locations in the visual field, and their rates of change are significantly correlated. Peripapillary RNFLT may be used to monitor localized changes caused by glaucoma that have measurable consequences for a patient's vision., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: We tested the hypothesis that experimental glaucoma (EG) results in greater thinning of the optic nerve head (ONH) neural rim tissue than the peripapillary retinal nerve fiber layer (RNFL) tissue., Methods: Longitudinal spectral-domain optical coherence tomography (SDOCT) imaging of the ONH and peripapillary RNFL was performed every other week under manometric IOP control (10 mm Hg) in 51 nonhuman primates (NHP) during baseline and after induction of unilateral EG. The ONH parameter minimum rim area (MRA) was derived from 80 radial B-scans centered on the ONH; RNFL cross-sectional area (RNFLA) from a peripapillary circular B-scan with 12° diameter., Results: In control eyes, MRA was 1.00 ± 0.19 mm2 at baseline and 1.00 ± 0.19 mm2 at the final session (P = 0.77), while RNFLA was 0.95 ± 0.09 and 0.95 ± 0.10 mm2, respectively (P = 0.96). In EG eyes, MRA decreased from 1.00 ± 0.19 mm2 at baseline to 0.63 ± 0.21 mm2 at the final session (P < 0.0001), while RNFLA decreased from 0.95 ± 0.09 to 0.74 ± 0.19 mm2, respectively (P < 0.0001). Thus, MRA decreased by 36.4 ± 20.6% in EG eyes, significantly more than the decrease in RNFLA (21.7 ± 19.4%, P < 0.0001). Other significant changes in EG eyes included increased Bruch's membrane opening (BMO) nonplanarity (P < 0.05), decreased BMO aspect ratio (P < 0.0001), and decreased MRA angle (P < 0.001). Bruch's membrane opening area did not change from baseline in either control or EG eyes (P = 0.27, P = 0.15, respectively)., Conclusions: Optic nerve head neural rim tissue thinning exceeded peripapillary RNFL thinning in NHP EG. These results support the hypothesis that axon bundles are compressed transversely within the ONH rim along with glaucomatous deformation of connective tissues.

Purpose: To compare optical coherence tomography (OCT) detected, optic nerve head (ONH) compliance within control and experimental glaucoma (EG) eyes of 15 monkeys at EG onset., Methods: Intraocular pressure (IOP) was chronically elevated in one eye of each animal using a laser. Experimental glaucoma onset was identified using confocal scanning laser tomography (CSLT). Optical coherence tomography ONH imaging (40 radial B-scans) was performed at 10 mm Hg before and after laser. At EG onset, OCT scans were obtained at IOP 10 and 30 mm Hg. Optical coherence tomography landmarks within the IOP 10/30 images were delineated to quantify IOP 10/30 differences (compliance) for anterior lamina cribrosa surface depth (ALCSD) relative to Bruch's membrane opening (BMO) (ALCSD-BMO), ALCSD relative to peripheral BM (ALCSD-BM), and BMO depth relative to peripheral BM (BMOD-BM). A linear mixed effects model assessed for acute IOP elevation effects, control versus EG eye effects, and their interaction., Results: Effects of IOP elevation were greater in EG versus control eyes for ALCSD-BMO (-46 ± 45 vs. -8 ± 13 μm, P = 0.0042) and ALCSD-BM (-92 ± 64 vs. -42 ± 22 μm, P = 0.0075). Experimental glaucoma eye-specific ALCSD-BMO and ALCSD-BM compliance exceeded the range of control eye compliance in 9 and 8 of the 15 EG eyes, respectively. Post-laser peak IOP (R2 = 0.798, P < 0.0001) and post-laser mean IOP (R2 = 0.634, P < 0.0004) most strongly correlated to EG versus control eye differences in ALCSD-BMO compliance., Conclusions: Laminar (ALCSD-BMO) and peripapillary scleral (ALCSD-BM) hypercompliance are present in most monkey eyes at the onset of EG.

Purpose: We compare spectral-domain optical coherence tomography (SDOCT) measurements of minimum rim width (MRW), minimum rim area (MRA), and peripapillary retinal nerve fiber layer thickness (RNFLT) to complete orbital optic nerve axon counts in nonhuman primates (NHP) with unilateral experimental glaucoma (EG)., Methods: Biweekly SDOCT measurements of MRW, MRA, and RNFLT were acquired under manometric IOP control (10 mm Hg) in 51 NHP during baseline (mean ± SD, 5.0 ± 1.6 sessions) and after laser photocoagulation was applied to the trabecular meshwork of one eye to induce chronic IOP elevation. At the study endpoint (predefined for each NHP), 100% axon counts were obtained from each optic nerve., Results: For SDOCT parameters at baseline, the correlation between the two eyes of each animal was strongest for RNFLT (R = 0.97) and MRW (R = 0.97), but lower for MRA (R = 0.85). At the final time point, average values in EG eyes relative to control eyes were: -22% for RNFLT, -38% for MRW, -36% for MRA, and -36% for optic nerve axons. The correlation with axon counts was strongest for RNFLT (R = 0.81), compared to MRW (R = 0.72, P = 0.001) or MRA (R = 0.70, P = 0.001). Diagnostic sensitivity was 75% for RNFLT, 90% for MRW, and 88% for MRA; all had 100% specificity., Conclusions: Peripapillary RNFLT was correlated more closely with total orbital optic nerve axon count than were the ONH parameters MRW or MRA. This is likely because glaucomatous deformation (beyond axon loss alone) has a greater influence on the ONH parameters MRW and MRA than on RNFLT.

Purpose: To examine the relationship between small hypodense regions ("holes") in the retinal nerve fiber layer (RNFL) seen on circumpapillary optical coherence tomography (OCT) images of glaucoma patients and suspects and the paravascular inner retinal defects (PIRDs) seen with OCT line scans near blood vessels in individuals without optic nerve disease but with high myopia and/or epiretinal membranes (ERMs)., Methods: Based upon the availability of wide-field, swept-source OCT scans, 19 eyes from 15 glaucoma patients or suspects were selected from a larger group of eyes with holes on circumpapillary frequency-domain OCT scans. Paravascular defects (PDs) were identified using en face slab images generated (ATL 3D-Suite) from 52-μm slabs just below the vitreal border of the inner limiting membrane by averaging reflective intensity. Paravascular defects were confirmed with B-scans from these images., Results: For 13 of the 19 eyes, the appearance of the PDs fit the previously described PIRDs and extended well beyond the circumpapillary region. In the other 6 eyes, the PDs were restricted to a small region and did not fit the previously described appearance of PIRDs. In these eyes, the holes were associated with an arcuate defect of the RNFL. Of the 13 with PIRDs, 9 had ERMs and/or high myopia previously associated with PIRDs in otherwise healthy eyes., Conclusions: Holes seen on circumpapillary OCT scans of glaucoma patients and suspects are associated with local glaucomatous damage, as well as with PIRDs associated with high myopia and ERMs.

Purpose: To evaluate structure and function of macular retinal layers in nonhuman primate (NHP) experimental glaucoma (EG)., Methods: Twenty-one NHP had longitudinal imaging of macular structure by SDOCT, 16 also had recordings of function by multifocal ERG. The average thickness over 15° was derived for seven individual SDOCT layers: macular nerve fiber layer (m-NFL), retinal ganglion cell layer (RGCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer+inner segments combined (ONL+IS), and outer segments (OS). Peripapillary RNFL thickness (ppRNFLT) was measured from a single circular B-scan with 12° diameter. Responses to a slow-sequence multifocal ERG (mfERG) stimulus (7F) were filtered (at 75 Hz) into low- and high-frequency components (LFC, HFC)., Results: At final follow-up, significant structural loss occurred only in EG eyes and only for ppRNFLT (-29 ± 23%), m-NFL (-17 ± 16%), RGCL (-22 ± 15%), and IPL (-19 ± 14%); though there was also a small increase in OPL (+6 ± 7%) and ONL+IS (4 ± 4%) and a similar tendency for INL. Macular structural loss was correlated with ppRNFLT only for the NFL, RGCL and IPL (R = 0.95, 0.93 and 0.95, respectively, P < 0.0001). Significant functional loss occurred only for HFC and N2 in EG eyes. Significant longitudinal structure-function correlations (P < 0.01) were observed only in EG eyes and only for mfERG HFC and N2: HFC was correlated with ppRNFLT (R = 0.69), macular NFL (R = 0.67), RGCL (R = 0.74), and IPL (R = 0.72); N2 was correlated with RGCL (R = 0.54) and IPL (R = 0.48). High-frequency components amplitude change was inversely correlated with outer retinal thickness change (= -0.66)., Conclusions: Macular structural and functional losses are correlated and specific to ganglion cells over a wide range of EG severity. Outer retinal changes are likely due to inner retinal loss.

Purpose: We determined whether longitudinal changes in retinal nerve fiber layer (RNFL) reflectance provide useful prognostic information about longitudinal changes in function in glaucoma., Methods: The reflectance intensity of each pixel within spectral-domain optical coherence tomography (SD-OCT) circle scans was extracted by custom software. A repeatability cohort comprising 53 eyes of 27 participants (average visual field mean deviation [MD] -1.65 dB) was tested five times within a few weeks. To minimize test-retest variability in their data, a reflectance intensity ratio was defined as the mean reflectance intensity of pixels within the RNFL divided by the mean between the RNFL and RPE. This was measured in a separate longitudinal cohort comprising 310 eyes of 205 participants tested eight times at 6-month intervals (average MD, -0.99 dB; median rate of change, -0.09 dB/y). The rate of change of this ratio, together with the rate of RNFL thinning, and their interaction, were used to predict the rate of change of MD., Results: In univariate analyses, the rate of RNFL thinning was predictive of the rate of MD change (P < 0.0001), but the rate of change of reflectance intensity ratio was not (P = 0.116). However, in a multivariable model, the interaction between these two rates significantly improved upon predictions of the rate of functional change made using RNFL thickness alone (P = 0.038)., Conclusions: For a given rate of RNFL thinning, a reduction in the RNFL reflectance intensity ratio is associated with more rapid functional deterioration. Incorporating SD-OCT reflectance information may improve the structure-function relation in glaucoma.

Purpose of Review: Electrophysiological measures of vision function have for decades generated interest among glaucoma researchers and clinicians alike because of their potential to help elucidate pathophysiological processes and sequence of glaucomatous damage, as well as to offer a potential complementary metric of function that might be more sensitive than standard automated perimetry. The purpose of this article is to review the recent literature to provide an update on the role of the electroretinogram (ERG) in glaucoma diagnosis., Recent Findings: The pattern reversal ERG (PERG) and the photopic negative response (PhNR) of the cone-driven full-field, focal or multifocal ERG provide objective measures of retinal ganglion cell function and are all sensitive to glaucomatous damage. Recent studies demonstrate that a reduced PERG amplitude is predictive of subsequent visual field conversion (from normal to glaucomatous) and an increased rate of progressive retinal nerve fiber layer thinning in suspect eyes, indicating a potential role for PERG in risk stratification. Converging evidence indicates that some portion of PERG and PhNR abnormality represents a reversible aspect of dysfunction in glaucoma., Summary: PERG and PhNR responses obtained from the central macula are capable of detecting early-stage, reversible glaucomatous dysfunction.

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

Purpose: To test the hypothesis that optic nerve head (ONH) blood flow (BF) and autoregulation compromise are consequences of optic nerve degeneration induced by surgical optic nerve transection (ONT)., Methods: In both eyes of five nonhuman primates, peripapillary retinal nerve fiber layer thickness (RNFLT) was measured by spectral-domain optical coherence tomography. Optic nerve head BF and dynamic autoregulation responses to a rapid manometric IOP increase (from 10-40 mm Hg) were measured by Laser Speckle Flowgraphy. The measurements were conducted every 10 to 15 days before and after unilateral ONT. Post-ONT measurements were repeated until RNFLT in the ONT eye was reduced by more than 40% of baseline value., Results: After ONT, RNFLT, and ONH BF progressively declined over time (P < 0.0001 and P = 0.02, respectively). Longitudinal changes between the two were highly correlated (P < 0.0001). When data was grouped by test session, the first significant decreases for RNFLT and BF were found 13 ± 0.8 and 24 ± 3.2 days post ONT, respectively (P < 0.05, both). At the final time point (55 ± 0.5 days post ONT), RNFLT, and BF were reduced by 44% ± 2.0% and 38 ± 5.0% from baseline, respectively. Dynamic autoregulation analysis showed marginal increased response time in post-ONT eyes (P = 0.05). Control eyes showed no longitudinal changes for any parameter., Conclusions: The close association between RNFLT loss and ONH BF decrease following optic nerve degeneration demonstrated a clear cause and effect relationship. Increased BF response time appears to be a sign of dynamic autoregulation dysfunction in this ONT model.

Purpose: Minimum rim width (MRW) and area (MRA) have been introduced as anatomically defensible measures of neuroretinal rim tissue observable using spectral-domain optical coherence tomography (SDOCT). They have been reported to change earlier than retinal nerve fiber layer thickness (RNFLT) in glaucoma. This study sought to determine which is better to distinguish subsequent change from variability, using the previously described longitudinal signal-to-noise ratio (LSNR)., Methods: Data from 157 eyes of 157 participants with high-risk ocular hypertension or non-end-stage glaucoma (mean deviation [MD] from -22 to +3 dB) were used. Participants were tested approximately every 6 months for at least six visits. For each eye, MRW, MRA, and RNFLT were regressed linearly against time. Longitudinal signal-to-noise ratio for each eye was defined as the rate of change over time (signal) divided by the standard deviation of residuals from this trend (noise). These were compared between parameters using a Wilcoxon signed rank test., Results: The median LSNRs were -0.58y⁻¹ for RNFLT (bootstrapped 95% confidence interval -0.69 to -0.48y⁻¹); -0.44y⁻¹ (-0.59 to -0.32y⁻¹) for MRW; and -0.23y⁻¹ (-0.32 to -0.08y⁻¹) for MRA. Longitudinal signal-to-noise ratios were significantly more negative for RNFLT than for MRW (P = 0.025) or for MRA (P < 0.001)., Conclusions: Retinal nerve fiber layer thickness measured by SDOCT had a better LSNR than MRW or MRA. Although MRW and MRA may be more sensitive for early detection of glaucomatous damage, these data suggest that RNFLT may be preferable for monitoring change.

Purpose: High-resolution images of glaucomatous damage to the retinal nerve fiber layer (RNFL) were obtained with an adaptive optics-scanning light ophthalmoscope (AO-SLO) and used as a basis for comparisons between en face slab images and thickness maps derived from optical coherence tomography (OCT) scans., Methods: Wide-field (9 × 12 mm) cube scans were obtained with swept-source OCT (DRI-OCT) from six eyes of six patients. All eyes had a deep defect near fixation as seen on a 10-2 visual field test. Optical coherence tomography en face images, based on the average reflectance intensity, were generated (ATL 3D-Suite) from 52-μm slabs just below the vitreal border of the inner limiting membrane. The RNFL thickness maps were generated from the same OCT data. Both were compared with the AO-SLO peripapillary images that were previously obtained., Results: On AO-SLO images, three eyes showed small regions of preserved and/or missing RNFL bundles within the affected region. Details in these regions were seen on the OCT en face images but not on the RNFL thickness maps. In addition, in the healthier hemi-retinas of two eyes, there were darker, arcuate-shaped regions on en face images that corresponded to abnormalities seen on AO-SLO. These were not seen on RNFL thickness maps., Conclusions: Details of local glaucomatous damage, missing or easily overlooked on traditional OCT RNFL thickness analysis used in clinical OCT reports, were seen on OCT en face images based on the average reflectance intensity. While more work is needed, it is likely that en face slab imaging has a role in the clinical management of glaucoma.

Purpose: To relate changes in retinal function and retinal nerve fiber layer (RNFL) retardance to loss of RNFL thickness and optic nerve axon counts in a nonhuman primate (NHP) model of experimental glaucoma (EG)., Methods: Bilateral longitudinal measurements of peripapillary RNFL thickness (spectral-domain optical coherence tomography, SDOCT; Spectralis), retardance (GDxVCC), and multifocal electroretinography (mfERG; VERIS) were performed in 39 NHP at baseline (BL; median, 5 recordings; range, 3-10) and weekly after induction of unilateral EG by laser photocoagulation of the trabecular meshwork. Multifocal ERG responses were high-pass filtered (>75 Hz) to measure high- and low-frequency component (HFC and LFC) amplitudes, including LFC features N1, P1, and N2. High-frequency component amplitudes are known to specifically reflect retinal ganglion cell (RGC) function. Complete (100%) axon counts of orbital optic nerves were obtained in 31/39 NHP., Results: Postlaser follow-up was 10.4 ± 7.9 months; mean and peak IOP were 18 ± 5 and 41 ± 11 mm Hg in EG eyes, 11 ± 2 and 18 ± 6 mm Hg in control (CTL) eyes. At the final available time point, RNFL thickness had decreased from BL by 14 ± 14%, retardance by 20 ± 11%, and the mfERG HFC by 30 ± 17% (P < 0.0001 each). Longitudinal changes in retardance and HFC were linearly related to RNFL thickness change (R2 = 0.51, P < 0.0001 and R2 = 0.22, P = 0.002, respectively); LFC N2 was weakly related but N1 or P2 (N1: R2 = 0.07, P = 0.11; P1: R2 = 0.04, P = 0.24; N2: R2 = 0.13, P = 0.02). At zero change from BL for RNFL thickness (Y-intercept), retardance was reduced by 11% (95% confidence interval [CI]: -15.3% to -6.8%) and HFC by 21.5% (95% CI: -28.7% to -14.3%). Relative loss of RNFL thickness, retardance, and HFC (EG:CTL) were each related to axon loss (R2 = 0.66, P < 0.0001; R2 = 0.42, P < 0.0001; R2 = 0.42, P < 0.0001, respectively), but only retardance and HFC were significantly reduced at zero relative axon loss (Y-intercept; retardance: -9.4%, 95% CI: -15.5% to -3.4%; HFC: -10.9%, 95% CI: -18.6% to -3.2%; RNFL thickness: +1.8%, 95% CI: -4.9% to +5.4%)., Conclusions: Retinal nerve fiber layer retardance and RGC function exhibit progressive loss from baseline before any loss of RNFL thickness or orbital optic nerve axons occurs in NHP EG. These in vivo measures might serve as potential biomarkers of early-stage glaucomatous damage preceding axon loss and RGC death.

Purpose: To test the hypothesis that blood flow autoregulation in the optic nerve head has less reserve to maintain normal blood flow in the face of blood pressure-induced ocular perfusion pressure decrease than a similar magnitude intraocular pressure-induced ocular perfusion pressure decrease., Materials and Methods: Twelve normal non-human primates were anesthetized by continuous intravenous infusion of pentobarbital. Optic nerve blood flow was monitored by laser speckle flowgraphy. In the first group of animals (n = 6), the experimental eye intraocular pressure was maintained at 10 mmHg using a saline reservoir connected to the anterior chamber. The blood pressure was gradually reduced by a slow injection of pentobarbital. In the second group (n = 6), the intraocular pressure was slowly increased from 10 mmHg to 50 mmHg by raising the reservoir. In both experimental groups, optic nerve head blood flow was measured continuously. The blood pressure and intraocular pressure were simultaneously recorded in all experiments., Results: The optic nerve head blood flow showed significant difference between the two groups (p = 0.021, repeat measures analysis of variance). It declined significantly more in the blood pressure group compared to the intraocular pressure group when the ocular perfusion pressure was reduced to 35 mmHg (p < 0.045) and below. There was also a significant interaction between blood flow changes and the ocular perfusion pressure treatment (p = 0.004, adjusted Greenhouse & Geisser univariate test), indicating the gradually enlarged blood flow difference between the two groups was due to the ocular perfusion pressure decrease., Conclusions: The results show that optic nerve head blood flow is more susceptible to an ocular perfusion pressure decrease induced by lowering the blood pressure compared with that induced by increasing the intraocular pressure. This blood flow autoregulation capacity vulnerability to low blood pressure may provide experimental evidence related to the hemodynamic pathophysiology in glaucoma.

Purpose: To compare in young and old rats longitudinal measurements of retinal nerve fiber layer thickness (RNFLT) and axonal transport 3-weeks after chronic IOP elevation., Method: IOP was elevated unilaterally in 2- and 9.5-month-old Brown-Norway rats by intracameral injections of magnetic microbeads. RNFLT was measured by spectral domain optical coherence tomography. Anterograde axonal transport was assessed from confocal scanning laser ophthalmolscopy of superior colliculi (SC) after bilateral intravitreal injections of cholera toxin-B-488. Optic nerve sections were graded for damage., Results: Mean IOP was elevated in both groups (young 37, old 38 mmHg, p = 0.95). RNFL in young rats exhibited 10% thickening at 1-week (50.9±8.1 µm, p<0.05) vs. baseline (46.4±2.4 µm), then 7% thinning at 2-weeks (43.0±7.2 µm, p>0.05) and 3-weeks (43.5±4.4 µm, p>0.05), representing 20% loss of dynamic range. RNFLT in old rats showed no significant change at 1-week (44.9±4.1 µm) vs. baseline (49.2±5.3 µm), but progression to 22% thinning at 2-weeks (38.0±3.7 µm, p<0.01) and 3-weeks (40.0±6.6 µm, p<0.05), representing 59% loss of dynamic range. Relative SC fluorescence intensity was reduced in both groups (p<0.001), representing 77-80% loss of dynamic range and a severe transport deficit. Optic nerves showed 75-95% damage (p<0.001). There was greater RNFL thinning in old rats (p<0.05), despite equivalent IOP insult, transport deficit and nerve damage between age groups (all p>0.05)., Conclusion: Chronic IOP elevation resulted in severely disrupted axonal transport and optic nerve axon damage in all rats, associated with mild RNFL loss in young rats but a moderate RNFL loss in old rats despite the similar IOP insult. Hence, the glaucomatous injury response within the RNFL depends on age.

Purpose: To determine the relationship between longitudinal in vivo measurements of retinal nerve fiber layer thickness (RNFLT) and retinal ganglion cell (RGC) density after unilateral optic nerve transection (ONT)., Methods: Nineteen adult Brown-Norway rats were studied; N = 10 ONT plus RGC label, N = 3 ONT plus vehicle only (sans label), N = 6 sham ONT plus RGC label. RNFLT was measured by spectral domain optical coherence tomography (SD-OCT) at baseline then weekly for 1 month. RGCs were labeled by retrograde transport of fluorescently conjugated cholera toxin B (CTB) from the superior colliculus 48 hours prior to ONT or sham surgery. RGC density measurements were obtained by confocal scanning laser ophthalmoscopy (CSLO) at baseline and weekly for 1 month. RGC density and reactivity of microglia (anti-Iba1) and astrocytes (anti-GFAP) were determined from post mortem fluorescence microscopy of whole-mount retinae., Results: RNFLT decreased after ONT by 17% (p<0.05), 30% (p<0.0001) and 36% (p<0.0001) at weeks 2, 3 and 4. RGC density decreased after ONT by 18%, 69%, 85% and 92% at weeks 1, 2, 3 and 4 (p<0.0001 each). RGC density measured in vivo at week 4 and post mortem by microscopy were strongly correlated (R = 0.91, p<0.0001). In vivo measures of RNFLT and RGC density were strongly correlated (R = 0.81, p<0.0001). In ONT-CTB labeled fellow eyes, RNFLT increased by 18%, 52% and 36% at weeks 2, 3 and 4 (p<0.0001), but did not change in fellow ONT-eyes sans CTB. Microgliosis was evident in the RNFL of the ONT-CTB fellow eyes, exceeding that observed in other fellow eyes., Conclusions: In vivo measurements of RNFLT and RGC density are strongly correlated and can be used to monitor longitudinal changes after optic nerve injury. The strong fellow eye effect observed in eyes contralateral to ONT, only in the presence of CTB label, consisted of a dramatic increase in RNFLT associated with retinal microgliosis.

Purpose: To characterize age-related differences in the magnitude of spectral-domain optical coherence tomography (SD-OCT) structural change in early experimental glaucoma (EG)., Methods: Both eyes from four young (1.4-2.6 years) and four old (18.6-21.9 years) rhesus monkeys were imaged at least three times at baseline, and then every 2 weeks after laser-induced, chronic, unilateral IOP elevation until the onset of EG (confocal scanning laser tomographic surface change confirmed twice). Two to 20 weeks after EG onset, animals were euthanized and optic nerve axon counts for all eyes were performed. Masked operators delineated retinal and ONH landmarks in 40 radial B-scans from each eye and imaging session to quantify change from baseline in five SD-OCT neural and connective tissue parameters. The effects of EG, age, and EG × age interactions on the magnitude, rate (magnitude per postlaser time), and IOP responsiveness (magnitude per cumulative IOP insult) of postlaser parameter change were individually assessed using general estimating equation models., Results: Presac SD-OCT RNFLT and minimum rim width change and postmortem axon loss was not significantly different in old compared with young EG eyes. The rate of change and IOP responsiveness of the parameters anterior lamina cribrosa surface depth relative to Bruch's membrane opening (BMO) and BMO depth relative to peripheral Bruch's membrane were significantly lower (P < 0.05) in the old compared with the young EG eyes., Conclusions: At similar postlaser times, levels of cumulative IOP insult and axonal damage, SD-OCT-detected ONH connective tissue structural change is greater in young compared with old monkey EG eyes., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To evaluate the effect of age on optic nerve axon counts, spectral-domain optical coherence tomography (SDOCT) scan quality, and peripapillary retinal nerve fiber layer thickness (RNFLT) measurements in healthy monkey eyes., Methods: In total, 83 healthy rhesus monkeys were included in this study (age range: 1.2-26.7 years). Peripapillary RNFLT was measured by SDOCT. An automated algorithm was used to count 100% of the axons and measure their cross-sectional area in postmortem optic nerve tissue samples ( N = 46). Simulation experiments were done to determine the effects of optical changes on measurements of RNFLT. An objective, fully-automated method was used to measure the diameter of the major blood vessel profiles within each SDOCT B-scan., Results: Peripapillary RNFLT was negatively correlated with age in cross-sectional analysis ( P < 0.01). The best-fitting linear model was RNFLT (μm) = -0.40 × age (years) + 104.5 μm ( R 2 = 0.1, P < 0.01). Age had very little influence on optic nerve axon count; the result of the best-fit linear model was axon count = -1364 × Age (years) + 1,210,284 ( R 2 < 0.01, P = 0.74). Older eyes lost the smallest diameter axons and/or axons had an increased diameter in the optic nerve of older animals. There was an inverse correlation between age and SDOCT scan quality ( R = -0.65, P < 0.0001). Simulation experiments revealed that approximately 17% of the apparent cross-sectional rate of RNFLT loss is due to reduced scan quality associated with optical changes of the aging eye. Another 12% was due to thinning of the major blood vessels., Conclusions: RNFLT declines by 4 μm per decade in healthy rhesus monkey eyes. This rate is approximately three times faster than loss of optic nerve axons. Approximately one-half of this difference is explained by optical degradation of the aging eye reducing SDOCT scan quality and thinning of the major blood vessels., Translational Relevance: Current models used to predict retinal ganglion cell losses should be reconsidered.

Purpose: To use a novel dynamic autoregulation analysis (dAR) to test the hypothesis that the optic nerve head (ONH) blood flow (BF) autoregulation is disrupted during early stages of experimental glaucoma (EG) in nonhuman primates., Methods: Retinal nerve fiber layer thickness (RNFLT, assessed by optical coherence tomography) and ONH BF (assessed by laser speckle imaging technique) were measured biweekly before and after unilateral laser treatment to the trabecular meshwork. Each nonhuman primate was followed until reaching either an early stage of damage (RNFLT loss < 20%, n = 6) or moderate to advanced stages of damage (RNFLT loss > 20%, n = 9). At each test, dAR was assessed by characterizing ONH BF changes during the first minute of rapid manometrical intraocular pressure (IOP) elevation from 10 to 40 mm Hg. The dAR analysis extracted the following parameters: baseline BF, average BF 10 seconds before IOP elevation; BFΔmax, maximum BF change from baseline BF; Tr, time from baseline BF to the BFΔmax; Kr, average descending BF rate., Results: Mean postlaser IOP was 20.2 ± 5.9 and 12.3 ± 2.6 mm Hg in EG and control eyes, respectively (P < 0.0001). Compared with prelaser values, baseline BF was higher in early EG, but lower in moderate to advanced EG (P = 0.01). Tr was increased and Kr was reduced in both stages (P < 0.01). BFΔmax was smaller in the early EG (P = 0.05) and remained low in the moderate to advanced EG (P = 0.15). No changes in the parameters were observed in control eyes., Conclusions: Chronic IOP elevation causes ONH autoregulation dysfunction in the early stage of EG, characterized by a disrupted BF response and delayed Tr, revealed by dAR analysis., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To quantify the effects of using the fovea to Bruch's membrane opening (FoBMO) axis as the nasal-temporal midline for 30° sectoral (clock-hour) spectral domain optical coherence tomography (SDOCT) optic nerve head (ONH) minimum rim width (MRW) and area (MRA) calculations., Methods: The internal limiting membrane and BMO were delineated within 24 radial ONH B-scans in 222 eyes of 222 participants with ocular hypertension and glaucoma. For each eye the fovea was marked within the infrared reflectance image, the FoBMO angle (θ) relative to the acquired image frame (AIF) horizontal was calculated, the ONH was divided into 30° sectors using a FoBMO or AIF nasal/temporal axis, and SDOCT MRW and MRA were quantified within each FoBMO vs. AIF sector. For each sector, focal rim loss was calculated as the MRW and MRA gradients (i.e. the difference between the value for that sector and the one clockwise to it divided by 30°). Sectoral FoBMO vs. AIF discordance was calculated as the difference between the FoBMO and AIF values for each sector. Generalized estimating equations were used to predict the eyes and sectors of maximum FoBMO vs. AIF discordance., Results: The mean FoBMO angle was -6.6±4.2° (range: -17° to +7°). FoBMO vs. AIF discordance in sectoral mean MRW and MRA was significant for 7 of 12 and 6 of 12 sectors, respectively (p<0.05, Wilcoxon test, Bonferroni correction). Eye-specific, FoBMO vs. AIF sectoral discordance was predicted by sectoral rim gradient (p<0.001) and FoBMO angle (p<0.001) and achieved maximum values of 83% for MRW and 101% for MRA., Conclusions: Using the FoBMO axis as the nasal-temporal axis to regionalize the ONH rather than a line parallel to the AIF horizontal axis significantly influences clock-hour SDOCT rim values. This effect is greatest in eyes with large FoBMO angles and sectors with focal rim loss.

Purpose: To assess the effect of age on spectral-domain optical coherence tomography (SDOCT)-detected lamina cribrosa depth while controlling for visual field (VF) status and retinal nerve fiber layer thickness (RNFLT) in 221 high-risk ocular hypertension and glaucoma patients enrolled in the Portland Progression Project., Methods: In this cross-sectional study, each participant underwent 870-nm SDOCT to obtain high-resolution radial B-scans centered on the optic nerve head (ONH) and a standardized ophthalmologic examination, including automated perimetry, on the same day. For each ONH, an anterior lamina cribrosa surface depth (ALCSD) parameter was generated as the average perpendicular distance from each anterior lamina cribrosa surface point relative to Bruch's membrane opening (BMO) reference plane within all 24 delineated B-scans. The relative effects of age, age-corrected VF status (mean deviation [MD]), and RNFLT on ALCSD were analyzed., Results: The mean age ± SD of participants was 64 ± 11 years (range, 33-90 years). The relationship between ALCSD and MD was age-dependent. ALCSD = 407.68 - 67.13 × MD - 0.08 × Age + 0.89 × MD × Age (MD, P = 0.001; MD × Age, P = 0.004). The relationship between ALCSD and RNFLT may also be age-dependent but did not achieve significance (interaction term, P = 0.067). ALCSD increased with worse VF status in younger eyes but not in older eyes. In older eyes, the anterior lamina was shallower than in younger eyes for the same VF status and RNFLT., Conclusions: These data are consistent with the concept that structure/structure and structure/function relationships change with age.

Acute esophageal variceal hemorrhage is one of the clinical events that define decompensated cirrhosis and is associated with high rates of morbidity and mortality. Although recent treatment strategies have led to improved outcomes, variceal hemorrhage still carries a 6-week mortality rate of 15-20%. Current standards in its treatment include antibiotic prophylaxis, infusion of a vasoactive drug and endoscopic variceal ligation. The placement of a transjugular intrahepatic portosystemic shunt (TIPS) is considered for patients that have treatment failure or recurrent bleeding. Recurrent hemorrhage is prevented with the combination of a non-selective beta-blocker and endoscopic variceal ligation. These recommendations however assume that all patients with cirrhosis are equal. Based on a review of recent evidence, a strategy in which patients are stratified by Child class, the main predictor of outcomes, is proposed.

Purpose: To test whether the minimum rim area assessed by spectral domain optical coherence tomography (SD-OCT), based on the shortest distance from the Bruch membrane opening (BMO) to the inner limiting membrane, corresponds more closely to retinal nerve fiber layer (RNFL) thickness and visual field mean deviation (MD) than current rim measures in early glaucoma., Design: Prospective cross-sectional study., Methods: We studied 221 participants with non-endstage glaucoma or high-risk ocular hypertension and performed standard automated perimetry. We received SD-OCT and confocal scanning laser ophthalmoscopy (CSLO) scans on the same day. Rim area measured by CSLO was compared with 3 SD-OCT rim measures from radial B-scans: horizontal rim area between BMO and inner limiting membrane within the BMO plane; mean minimum rim width (BMO-MRW); and minimum rim area (BMO-MRA) optimized within sectors and then summed. Correlations between these measures and either MD from perimetry or RNFL thickness from SD-OCT were compared using the Steiger test., Results: RNFL thickness was better correlated with BMO-MRA (r = 0.676) or BMO-MRW (r = 0.680) than with either CSLO rim area (r = 0.330, P < 0.001) or horizontal rim area (r = 0.482, P < 0.001). MD was better correlated with BMO-MRA (r = 0.534) or BMO-MRW (r = 0.546) than with either CSLO rim area (r = 0.321, P < 0.001) or horizontal rim area (0.403, P < 0.001). The correlation between MD and RNFL thickness was r = 0.646., Conclusions: Minimum rim measurements from SD-OCT are significantly better correlated to both RNFL thickness and MD than rim measurements within the BMO plane or based on the clinical disc margin. They provide new structural parameters for both diagnostic and research purposes in glaucoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To characterize the static blood flow autoregulation in the optic nerve head (ONH), and to investigate its role in hemodynamic changes in experimental glaucoma (EG)., Methods: Unilateral elevation of intraocular pressure (IOP) was induced in 15 adult rhesus macaques by laser treatment to the trabecular meshwork. Prior to and after laser treatment, retinal nerve fiber layer thickness (RNFLT) was assessed, biweekly, by spectral-domain optical coherence tomography. Optic nerve head static autoregulation was assessed by determining the percentage blood flow (BF) change after the IOP was acutely increased from 10 to 30, 40, or 50 mm Hg manometrically, utilizing a laser speckle flowgraphy device., Results: Postlaser IOP (measured during average 7.7 ± 2.6 months) was 20.2 ± 5.9 mm Hg in EG eyes and 12.3 ± 2.6 mm Hg in control eyes (P < 0.0001). Retinal nerve fiber layer thickness was reduced by 33 ± 22% of the baseline values (P < 0.001) on average in EG eyes and by 0.4 ± 2.3% in control eyes (P > 0.05). The ONH BF remained at a constant level within a range of ocular perfusion pressure (OPP), 41 mm Hg and above. The autoregulation curves, created by all 723 tests in control and 352 tests in EG, were not significantly different (P = 0.71)., Conclusions: Optic nerve head BF in normal nonhuman primate (NHP) eyes is effectively regulated within a range of OPP approximately 41 mm Hg and above. Chronic IOP elevation causes no remarkable change to the static autoregulation within the ONH of EG eyes.

Purpose: To compare in vivo retinal nerve fiber layer thickness (RNFLT) and axonal transport at 1 and 2 weeks after an 8-hour acute IOP elevation in rats., Methods: Forty-seven adult male Brown Norway rats were used. Procedures were performed under anesthesia. The IOP was manometrically elevated to 50 mm Hg or held at 15 mm Hg (sham) for 8 hours unilaterally. The RNFLT was measured by spectral-domain optical coherence tomography. Anterograde and retrograde axonal transport was assessed from confocal scanning laser ophthalmoscopy imaging 24 hours after bilateral injections of 2 μL 1% cholera toxin B-subunit conjugated to AlexaFluor 488 into the vitreous or superior colliculi, respectively. Retinal ganglion cell (RGC) and microglial densities were determined using antibodies against Brn3a and Iba-1., Results: The RNFLT in experimental eyes increased from baseline by 11% at 1 day (P < 0.001), peaked at 19% at 1 week (P < 0.0001), remained 11% thicker at 2 weeks (P < 0.001), recovered at 3 weeks (P > 0.05), and showed no sign of thinning at 6 weeks (P > 0.05). There was no disruption of anterograde transport at 1 week (superior colliculi fluorescence intensity, 75.3 ± 7.9 arbitrary units [AU] for the experimental eyes and 77.1 ± 6.7 AU for the control eyes) (P = 0.438) or 2 weeks (P = 0.188). There was no obstruction of retrograde transport at 1 week (RCG density, 1651 ± 153 per mm(2) for the experimental eyes and 1615 ± 135 per mm(2) for the control eyes) (P = 0.63) or 2 weeks (P = 0.25). There was no loss of Brn3a-positive RGC density at 6 weeks (P = 0.74) and no increase in microglial density (P = 0.92)., Conclusions: Acute IOP elevation to 50 mm Hg for 8 hours does not cause a persisting axonal transport deficit at 1 or 2 weeks or a detectable RNFLT or RGC loss by 6 weeks but does lead to transient RNFL thickening that resolves by 3 weeks.

Purpose: We determined if the detection of spectral-domain optical coherence tomography (SDOCT) optic nerve head (ONH) change precedes the detection of confocal scanning laser tomography (CSLT) ONH surface, SDOCT retinal nerve fiber layer (RNFL), scanning laser perimetry (SLP), and multifocal electroretinography (mfERG) change in eight experimental glaucoma (EG) eyes., Methods: Both eyes from eight monkeys were tested at least three times at baseline, and then every 2 weeks following laser-induced chronic unilateral IOP elevation. Event and trend-based definitions of onset in the control and EG eyes for 11 SDOCT neural and connective tissue, CSLT surface, SDOCT RNFL, SLP, and mfERG parameters were explored. The frequency and timing of onset for each parameter were compared using a logrank test., Results: Maximum post-laser IOP was 18 to 42 mm Hg in the EG eyes and 12 to 20 mm Hg in the control eyes. For event- and trend-based analyses, onsets were achieved earliest and most frequently within the ONH neural and connective tissues using SDOCT, and at the ONH surface using CSLT. SDOCT ONH neural and connective tissue parameter change preceded or coincided with CSLT ONH surface change in most EG eyes. The SDOCT and SLP measures of RNFL thickness, and mfERG measures of visual function demonstrated similar onset rates, but occurred later than SDOCT ONH and CSLT surface change, and in fewer eyes., Conclusions: SDOCT ONH change detection commonly precedes or coincides with CSLT ONH surface change detection, and consistently precedes RNFLT, SLP, and mfERG change detection in monkey experimental glaucoma.

Purpose: To determine which of three estimates of retinal nerve fiber layer thickness (RNFLT) correlate best with visual field sensitivity measured using standard automated perimetry (SAP)., Methods: Data were collected from 400 eyes of 209 participants enrolled in the Portland Progression Project. These individuals ranged from high-risk suspects to having non-end-stage glaucoma. In each eye, three measures of average RNFLT (spectral domain optical coherence tomography [SDOCT], scanning laser polarimetry [SLP], confocal scanning laser tomography [CSLT]) and SAP (Humphrey HFAII) were performed on the same day. Mean deviation (MD), mean sensitivity (MS), and pattern standard deviation (PSD) were linearized using the equations MD(Lin) = 10(MD*0.1), MS(Lin) = 10(MS*0.1), and PSD(Lin) = 10(PSD*-0.1). Correlations between each of the estimates of RNFLT and each of the functional metrics were calculated (nine total). Pearson correlations and generalized estimating equations (GEE) were used to calculate the strength and significance of the correlations., Results: Linearized MS had the strongest correlation with SDOCT (r = 0.57), intermediate with SLP (r = 0.40), and weakest with CSLT (r = 0.13). When multiple RNFLT measures were included in a GEE model to predict MS(Lin), SDOCT was consistently predictive (p < 0.001) whereas CSLT was never predictive in these multivariate models. Similar findings were observed for MD(Lin) and PSD(Lin)., Conclusions: Average RNFLT estimated from SDOCT predicts SAP status significantly better than average RNFLT estimated from SLP or CSLT.

Purpose: To test the hypothesis that optic nerve head (ONH) deformation manifesting as changes in its mean surface height precedes thinning of the peripapillary retinal nerve fiber layer (RNFL) in experimental glaucoma (EG)., Methods: 68 rhesus macaque monkeys each had three or more baseline imaging sessions under manometric intraocular pressure (IOP) control to obtain average RNFL thickness (RNFLT) and the ONH surface topography parameter mean position of the disc (MPD). Laser photocoagulation was then applied to the trabecular meshwork of one eye to induce chronic, mild-to-moderate IOP elevation and bi-weekly imaging continued. Event analysis was applied to determine for each parameter when an 'endpoint' occurred (signficant change from baseline) for eight different endpoint criteria. Specificity was assessed in the group of 68 fellow control eyes. Classical signal detection theory and survival analysis were used to compare MPD with RNFLT., Results: Regardless of the endpoint criterion, endpoints were always more frequent for MPD than for RNFLT. The discriminability index (d') was 2.7 ± 0.2 for MPD and 1.9 ± 0.2 for RNFLT (p<0.0001). Endpoints were reached by MPD an average of 1-2 months earlier than by RNFLT (p<0.01). At the onset of the first specific, detectable MPD change in EG eyes, there was still no significant change in RNFLT on average (p=0.29) and only 25% of individual eyes exhibited signficant reduction. In contrast, at onset of signficant RNFLT change, MPD had already changed an average of 101 µm from baseline (p<0.0001) and 71% of the individual eyes had exhibited significant change. The magnitude of MPD change was more than could be explained on the basis of axon loss alone., Conclusions: This study demonstrates that the average surface height of the ONH changes prior to any detectable loss of average peripapillary RNFL thickness in non-human primate eyes with experimental glaucoma.