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1.  Retinal Ganglion Cell Layer Thickness and Local Visual Field Sensitivity in Glaucoma 
Archives of ophthalmology  2011;129(12):1529-1536.
Objective
To compare loss in sensitivity measured using standard automated perimetry (SAP) with local retinal ganglion cell layer (RGC) thickness measured using frequency-domain optical coherence tomography in the macula of patients with glaucoma.
Methods
To compare corresponding locations of RGC thickness with total deviation (TD) of 10-2 SAP for 14 patients with glaucoma and 19 controls, an experienced operator hand-corrected automatic segmentation of the combined RGC and inner plexiform layer (RGC + IPL) of 128 horizontal B-scans. To account for displacement of the RGC bodies around the fovea, the location of the SAP test points was adjusted to correspond to the location of the RGC bodies rather than to the photoreceptors, based on published histological findings. For analysis, RGC + IPL thickness vs SAP (TD) data were grouped into 5 eccentricities, from 3.4° to 9.7° radius on the retina with respect to the fovea.
Results
The RGC + IPL thickness correlated well with SAP loss within approximately 7.2° of the fovea (Spearman ρ = 0.71–0.74). Agreement was worse (0.53–0.65) beyond 7.2°, where the normal RGC layer is relatively thin. A linear model relating RGC + IPL thickness to linear SAP loss provided a reasonable fit for eccentricities within 7.2°.
Conclusion
In the central 7.2°, local RGC + IPL thickness correlated well with local sensitivity loss in glaucoma when the data were adjusted for RGC displacement.
doi:10.1001/archophthalmol.2011.352
PMCID: PMC4331118  PMID: 22159673
2.  Modifying the Conventional Visual Field Test Pattern to Improve the Detection of Early Glaucomatous Defects in the Central 10° 
Purpose
To simulate modified versions of the 24-2 (6° grid) visual field (VF) test pattern by adding points from the 10-2 (2° grid) test pattern, and to assess their ability to detect early glaucomatous defects in the central 10°.
Methods
One hundred forty-four eyes of 144 glaucoma patients and suspects with 24-2 mean deviations better than −6 dB were tested with 10-2 and 24-2 VFs. Based upon both 10-2 VF and optical coherence tomography probability plots, 63 hemifields were defined as abnormal, while 121 hemifields were defined as normal. Three modified 24-2 VF test patterns, called 24-2 +4, 24-2 +16 (Even), and 24-2 +16 (Empirical), were simulated by adding 4 or 16 test points from the 10-2 VF.
Results
Based upon the number of abnormal points (P ≤ 5%), the area under the ROC curves (AROC scores) of the three modified 24-2 VFs were significantly greater than that of the 24-2 VF for both the upper and lower VF. For a specificity of 85%, the number of true positives was 25 (24-2), 30 (24-2 +4), 31 (24-2 +16, even), and 32 (24-2 +16, empirical) of 34 total true positives for the upper VF and 23, 26, 27, and 28 of 29 for the lower VF.
Conclusions
Adding points from the 10-2 test pattern to the 24-2 test pattern significantly improved its ability to detect macular defects without employing more test points than a single 10-2 test.
Translational Relevance
Additional central points should be added to the 24-2 pattern to improve the detection of macular damage.
doi:10.1167/tvst.3.6.6
PMCID: PMC4315509  PMID: 25653884
glaucoma; macula; visual fields; perimetry
3.  Evaluation of a One-Page Report to Aid in Detecting Glaucomatous Damage 
Purpose
We assessed the use of a customized, one-page structure + function report for aiding in detection of glaucomatous damage.
Methods
Two individuals (report specialists), experienced in analyzing optical coherent tomography (OCT) and visual field (VF) results, examined a customized one-page report for 50 eyes from 50 patients who either had glaucoma or were glaucoma suspects. The report contained key features of OCT scans with VF information. All patients had 24-2 VFs with a mean deviation (MD) better than −6 dB. The report specialists classified each hemifield and eye as either glaucomatous or nonglaucomatous based upon only the customized report, either without (phase 1) or with (phase 2) 24-2 VF information included on the report. Their results were compared to the classifications made by 3 ophthalmologists (glaucoma specialists) based upon traditional measures, namely stereo photographs, 24-2 VFs, and a commercially available, OCT disc scan report.
Results
The two report specialists agreed on all but one eye and four hemifields in phase 1, and on all eyes and all but one hemifield in phase 2. In phase 2, they judged 31 eyes abnormal. Of these 31 eyes, 30 were judged abnormal by all three glaucoma specialists and the 31st by two of the three. Without the VF information (phase 1), one report specialist classified 1, and the other 2, of these 31 “abnormal” eyes as normal.
Conclusions
When using the one-page report, the experienced readers showed excellent inter-rater repeatability and diagnostic ability relative to glaucoma specialists.
Translational Relevance
This condensed report may help the clinician assess glaucomatous damage.
doi:10.1167/tvst.3.6.8
PMCID: PMC4319536
glaucoma; optical coherence tomography; visual fields; optic disc; retinal ganglion cell
4.  Clusterin and Complement Activation in Exfoliation Glaucoma 
Purpose.
The study was done to better understand the biological significance of clusterin co-localization with the exfoliation deposits (XF deposits), and provide insight into a pathogenic mechanism involving activation of the complement system and its pro-inflammatory consequences in patients with exfoliation glaucoma.
Methods.
Exfoliation lens deposits were analyzed by high resolution atomic force microscopy imaging and confocal immunofluorescence. Levels of clusterin and vitronectin, as well as of the complement activation products C3a and soluble C5b-9, were assessed via ELISA.
Results.
Atomic-force microscopy examination of lenses with exfoliation syndrome (XFS) revealed a dense fibrillar network on the anterior, aqueous-bathed surface of the lens, while the epithelial side displayed no discernible structural features at the same resolution. Clusterin colocalized with XF deposits, demonstrating integral association with the fibrils. Levels of activation-derived complement components C3a and soluble C5b-9, as well as the complement inhibitors clusterin and vitronectin, were found significantly elevated (1.7-fold, P < 0.05; 4.1-fold, P < 0.05; 1.8-fold, P < 0.01; and 3.0-fold, P < 0.01, respectively) in aqueous humor from glaucoma patients with XFS compared to non-XFS glaucoma controls.
Conclusions.
The data provide compelling evidence for the activation of the complement system in XFS, highlighting the generation of subproducts with potent proinflammatory activity, which are capable of triggering and chronically maintaining levels of subclinical inflammation, suggesting novel targets for therapeutic intervention. The colocalization of clusterin in exfoliation fibrils suggests a failed attempt to prevent tissue accumulation of protein aggregates, as seen in other protein folding disorders, likely due to the abnormal high levels of misfolded proteins overwhelming its chaperone capacity.
This study provides experimental evidence for the involvement of the multifunctional extracellular chaperone clusterin and the generation of proinflammatory complement activation subproducts in exfoliation glaucoma.
doi:10.1167/iovs.13-12941
PMCID: PMC3993868  PMID: 24550356
exfoliation syndrome; complement system; extracellular chaperones; protein misfolding disorders
5.  Latrunculin B Reduces Intraocular Pressure in Human Ocular Hypertension and Primary Open-Angle Glaucoma 
Purpose
To evaluate the safety, tolerability, and intraocular pressure (IOP)-lowering effect of Latrunculin-B (Lat-B), a marine macrolide that disrupts the actin cytoskeleton, in patients with ocular hypertension (OHT) or early primary open-angle glaucoma (POAG).
Methods
In this Phase I, multicenter, double-masked, randomized, placebo-controlled, ascending-dose study, subjects with bilateral OHT or early POAG (>22 mm Hg) received one of four concentrations of INS115644 (Lat-B ophthalmic solutions, 0.005%, 0.01%, 0.02%, or 0.05%) in one eye over 3 days (5 single-dose instillations, separated by 12 hours). One eye was randomly assigned to active drug, the other to placebo. IOP was measured prior to treatment initiation (day 0) and on days 1 and 3.
Results
Baseline IOPs were 22.9 ± 2.4 mm Hg and 23.5 + 3.1 mm Hg in the 0.02% and 0.05% dose groups, respectively. At 4 hours post instillation of the first dose, 0.02% INS115644 reduced IOP from baseline (mean ± SE) by 3.8 ± 0.7 mm Hg (P = 0.002) and 0.05% by 3.9 ± 1.0 mm Hg (P = 0.004). A maximum IOP decrease of 24% was noted at 4 hours after the fifth instillation of 0.02%. Adjusting for diurnal baseline and IOP in the contralateral, placebo-treated eye, the maximal 12-hour hypotensive effect was 4.0 ± 0.5 mm Hg (adjusted mean ± SE), a 17% decrease, following the fifth instillation of 0.02% (day 3). Adverse events were few and consisted mainly of mild redness, irritation, and a transient, clinically insignificant increase (≤2.5%) in central corneal thickness.
Conclusions
In OHT or POAG patients, twice daily Lat-B significantly lowered IOP compared with contralateral, placebo-treated eyes, with few and mild ocular adverse events.
Translational Relevance
Lat-B may be a potential therapeutic agent for glaucoma.
doi:10.1167/tvst.3.5.1
PMCID: PMC4164113  PMID: 25237590
intraocular pressure; trabecular meshwork; cytoskeleton
6.  High-Resolution Ocuar Imaging: Combining Advanced Optics and Microtechnology 
Recent developments in imaging technologies offer great potential for the assessment of retinal ganglion cell disorders, with particular relevance to glaucoma. In particular, advances in this field have allowed unprecedented in vivo access to the retinal layers, using many different properties of light to differentiate cellular structures. This article is a summary of currently available and investigational advanced, high-resolution imaging technologies and their potential applications to glaucoma. It represents the topics of discussion at the annual Optic Nerve Rescue and Restoration Think Tank, sponsored by The Glaucoma Foundation, entitled “High Resolution Imaging of the Eye: Advanced Optics, Microtechnology and Nanotechnology” and held in New York, New York, September 28-29, 2007.
doi:10.3928/15428877-20090901-07
PMCID: PMC4145242  PMID: 19772272
7.  Early Glaucoma Involves Both Deep Local, and Shallow Widespread, Retinal Nerve Fiber Damage of the Macular Region 
Purpose.
To better understand the nature of early glaucomatous damage of the macula by comparing the results from 10-2 visual fields, optical coherence tomography (OCT) macular cube scans, and OCT circumpapillary circle scans.
Methods.
One eye of each of 66 glaucoma patients or suspects, with a mean deviation (MD) on the 24-2 visual field (VF) test of better than −6 decibels (dB), was prospectively tested with 10-2 VFs and OCT macular cube and circumpapillary circle scans. Thickness and probability maps of the retinal ganglion cell plus inner plexiform (RGC+) layers were generated. A hemifield was considered abnormal if both the macular RGC+ and the 10-2 probability plots were abnormal (cluster criteria). The thickness plots of the circumpapillary retinal nerve fiber layer (RNFL) were analyzed in the context of a model that predicted the region of the disc associated with macular damage.
Results.
Twenty-seven hemifields (20 eyes) had abnormal 10-2 and RGC+ probability plots: 7 in upper VF/inferior retina, 6 in lower VF/superior retina, and 7 in both hemifields. Both shallow widespread and deep local thinning of the circumpapillary RNFL were observed. The local defects were more common and closer to fixation in the upper VF/inferior retina as predicted.
Conclusions.
A model of glaucomatous damage of the macula predicted the location of both the widespread and local defects in the temporal and inferior disc quadrants. Optical coherence tomography scans of the circumpapillary RNFL and the macular RGC+ layer can aid in the identification of these defects and help in the interpretation of 24-2 and 10-2 VF tests.
Early glaucomatous damage to the macula is due to widespread and/or local circumpapillary RNFL defects. A model of glaucomatous damage of the macula predicts the location of both these widespread and local defects.
doi:10.1167/iovs.13-13130
PMCID: PMC3912939  PMID: 24370831
glaucoma; optical coherence tomography; visual fields; optic disc; retinal nerve fiber layer
8.  Flammer syndrome 
The EPMA Journal  2014;5(1):11.
The new term Flammer syndrome describes a phenotype characterized by the presence of primary vascular dysregulation together with a cluster of symptoms and signs that may occur in healthy people as well as people with disease. Typically, the blood vessels of the subjects with Flammer syndrome react differently to a number of stimuli, such as cold and physical or emotional stress. Nearly all organs, particularly the eye, can be involved. Although the syndrome has some advantages, such as protection against the development of atherosclerosis, Flammer syndrome also contributes to certain diseases, such as normal tension glaucoma. The syndrome occurs more often in women than in men, in slender people than in obese subjects, in people with indoor rather than outdoor jobs, and in academics than in blue collar workers. Affected subjects tend to have cold extremities, low blood pressure, prolonged sleep onset time, shifted circadian rhythm, reduced feeling of thirst, altered drug sensitivity, and increased general sensitivity, including pain sensitivity. The plasma level of endothelin-1 is slightly increased, and the gene expression in lymphocytes is changed. In the eye, the retinal vessels are stiffer and their spatial variability larger; the autoregulation of ocular blood flow is decreased. Glaucoma patients with Flammer syndrome have an increased frequency of the following: optic disc hemorrhages, activated retinal astrocytes, elevated retinal venous pressure, optic nerve compartmentalization, fluctuating diffuse visual field defects, and elevated oxidative stress. Further research should lead to a more concise definition, a precise diagnosis, and tools for recognizing people at risk. This may ultimately lead to more efficient and more personalized treatment.
doi:10.1186/1878-5085-5-11
PMCID: PMC4113774  PMID: 25075228
Flammer syndrome; Primary vascular dysregulation; Vasospasm; Cold extremities; Systemic hypotension; Normal tension glaucoma; Tinnitus; Optic disc hemorrhages; Retinal vein occlusion; Predictive preventive personalized medicine
9.  Improving Glaucoma Detection Using Spatially Correspondent Clusters of Damage and by Combining Standard Automated Perimetry and Optical Coherence Tomography 
Purpose.
To improve the detection of glaucoma, techniques for assessing local patterns of damage and for combining structure and function were developed.
Methods.
Standard automated perimetry (SAP) and frequency-domain optical coherence tomography (fdOCT) data, consisting of macular retinal ganglion cell plus inner plexiform layer (mRGCPL) as well as macular and optic disc retinal nerve fiber layer (mRNFL and dRNFL) thicknesses, were collected from 52 eyes of 52 healthy controls and 156 eyes of 96 glaucoma suspects and patients. In addition to generating simple global metrics, SAP and fdOCT data were searched for contiguous clusters of abnormal points and converted to a continuous metric (pcc). The pcc metric, along with simpler methods, was used to combine the information from the SAP and fdOCT. The performance of different methods was assessed using the area under receiver operator characteristic curves (AROC scores).
Results.
The pcc metric performed better than simple global measures for both the fdOCT and SAP. The best combined structure-function metric (mRGCPL&SAP pcc, AROC = 0.868 ± 0.032) was better (statistically significant) than the best metrics for independent measures of structure and function. When SAP was used as part of the inclusion and exclusion criteria, AROC scores increased for all metrics, including the best combined structure-function metric (AROC = 0.975 ± 0.014).
Conclusions.
A combined structure-function metric improved the detection of glaucomatous eyes. Overall, the primary sources of value-added for glaucoma detection stem from the continuous cluster search (the pcc), the mRGCPL data, and the combination of structure and function.
SAP and fdOCT data were searched for contiguous clusters of abnormal points, converted to a continuous metric. This combined structure-function metric improved the detection of glaucomatous eyes.
doi:10.1167/iovs.13-12351
PMCID: PMC3908820  PMID: 24408977
glaucoma; glaucomatous; detection; diagnosis; sensitivity; specificity; visual fields; standard automated perimetry; optical coherence tomography; retinal nerve fiber layer; retinal ganglion cells; macula
10.  A Test of a Model of Glaucomatous Damage of the Macula With High-Density Perimetry: Implications for the Locations of Visual Field Test Points 
Purpose
To use high-density perimetry to test a model of local glaucomatous damage to the macula (central visual field [VF]) and to assess the optimal placement of stimuli used to detect this damage.
Methods
Thirty-one eyes of 31 patients showing glaucomatous arcuate damage within the upper hemifield of the central 10° were tested with a customized VF with double the density of the 10-2 (2° grid) test. Individual plots of total deviation (TD) values were generated. A model, which predicts a “vulnerable macular region” (VMR) and a “less vulnerable macular region” (LVMR), was compared with the TD values without (standard model) and with (aligned model) scaling and rotating to align it with the patient's fovea-to-disc axis. Computer simulations assessed alternative VF locations for adding two points to the 6° grid pattern (e.g., 24-2 VF) typically used in the clinic.
Results
There were significantly more abnormal points in the VMR than in the LVMR. However, the aligned model did no better than the standard model in describing the data. The optimal locations for adding two points to the 24-2 (6° grid) test were (−1°, 5°) and (1°, 5°), both within the VMR.
Conclusions
The model describes the region of the superior VF vulnerable to arcuate damage.
Translational Relevance
The model can be used to determine the optimal locations for adding test points to the commonly used VF test pattern (24-2). It does not seem necessary to adjust the location of VF test points based upon interindividual differences in the fovea-to-disc axis.
doi:10.1167/tvst.3.3.5
PMCID: PMC4064621  PMID: 24959387
glaucoma; macula; visual fields; perimetry; test point location
11.  Alzheimer’s Disease and Glaucoma: Mechanistic Similarities and Differences 
Journal of glaucoma  2013;22(0 5):S36-S38.
Alzheimer’s disease (AD) is the most common form of dementia. Intraneuronal neurofibrillary tangles, extracellular Aβ amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy, and synaptic and neuronal loss co-exist in the brain parenchyma, with the limbic areas being the most severely affected. The classic clinical findings are personality changes, progressive cognitive dysfunction, and loss of ability to perform activities of daily living. Visual impairment is common and appears related to disease severity, suggesting that visual testing may provide a method of screening and tracking AD changes. Although still not fully understood, research and clinical findings point to a possible common causal relationship between AD and glaucoma. These two chronic neurodegenerative disorders share biological and mechanistic features, among them (1) a strong age-related incidence, (2) retinal ganglion cell degeneration, and (3) extracellular fibrillar deposits in exfoliation syndrome, the most common recognizable cause of glaucoma, suggesting that both diseases may originate from similar misfolding mechanisms. A presentation of common pathogenetic pathways associated with these disorders, including cell death mechanisms, reactive oxygen species (ROS) production, mitochondrial dysfunction and vascular abnormalities, will serve as an initiation point for further exploration.
doi:10.1097/IJG.0b013e3182934af6
PMCID: PMC3955061  PMID: 23733125
12.  The Locations of Circumpapillary Glaucomatous Defects Seen on Frequency-Domain OCT Scans 
Purpose.
To examine the locations of local glaucomatous damage around the optic disc as seen in the circumpapillary retinal nerve fiber layer (RNFL) on frequency domain optical coherence tomography (fdOCT).
Methods.
Optic disc fdOCT volume scans from 54 healthy control eyes and 114 patient eyes, classified as suspected or mild glaucoma, were analyzed. All patient eyes had 24-2 visual fields (VFs) with mean deviations better than −5.5 dB. By hand-correcting automated segmentation, the RNFL thickness profile was obtained for a circumpapillary circle. RNFL defects were defined as regions where the patient's RNFL thickness fell below the 99% confidence limit of control values. The location of a defect was defined as the point of greatest difference between the patient's thickness and the 99% limit. The locations of major blood vessels (BVs) were marked, and separated into superior-nasal (SN), superior-temporal (ST), inferior-temporal (IT), and inferior-nasal (IN) groups.
Results.
Of the 114 patient eyes, 45 exhibited a total of 75 RNFL defects. The locations of these defects clustered around the ST, SN, and IT, but not the IN BVs.
Conclusions.
The absence of defects in the IN region indicates that the locations of local defects are not simply related to either BV location or RNFL thickness. The local defects in the ST and IT regions can be related to arcuate defects seen on 24-2 and 10-2 VFs. However, the defects in the SN region suggest the presence of VF defects that may be overlooked because they fall largely outside the 24-2 test grid.
The peripapillary locations of local glaucomatous defects are not simply related to either BV location or control values of RNFL thickness. The presence of defects in the SN region of the disc suggests there are visual field defects that fall outside the 24-2 test commonly used in the clinic.
doi:10.1167/iovs.13-12680
PMCID: PMC3823545  PMID: 24135758
glaucoma; optical coherence tomography; visual fields; optic disc; retinal nerve fiber layer
13.  Investigation of Known Genetic Risk Factors for Primary Open Angle Glaucoma in Two Populations of African Ancestry 
Purpose.
Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG.
Methods.
We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤21 mm Hg) and high pressure glaucoma (HPG, IOP >21 mm Hg).
Results.
In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples.
Conclusions.
POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population.
We examined the association of 57 SNPs in five genomic loci in African American individuals and those from Ghana, West Africa, with POAG overall as well as high- and normal-pressure POAG. We confirmed the association with variants in the CDKN2B-AS1 and SIX6/SIX1 regions in the African Americans.
doi:10.1167/iovs.13-12779
PMCID: PMC3776712  PMID: 23963167
association; genetics; POAG; African; African American
14.  Congenital cataracts: de novo gene conversion event in CRYBB2 
Molecular Vision  2014;20:1579-1593.
Purpose
To identify the cause of congenital cataracts in a consanguineous family of Ashkenazi Jewish ancestry.
Methods
We performed genome-wide linkage analysis and whole-exome sequencing for the initial discovery of variants, and we confirmed the variants using gene-specific primers and Sanger sequencing.
Results
We found significant evidence of linkage to chromosome 22, under an autosomal dominant inheritance model, with a maximum logarithm of the odds (LOD) score of 3.91 (16.918 to 25.641 Mb). Exome sequencing identified three nonsynonymous changes in the CRYBB2 exon 5 coding sequence that are consistent with the sequence of the corresponding region of the pseudogene CRYBB2P1. The identification of these changes was complicated by possible mismapping of some mutated CRYBB2 sequences to CRYBB2P1. Sequencing with gene-specific primers confirmed that the changes—rs2330991, c.433 C>T (p.R145W); rs2330992, c.440A>G (p.Q147R); and rs4049504, c.449C>T (p.T150M)—present in all ten affected family members are located in CRYBB2 and are not artifacts of cross-reaction with CRYBB2P1. We did not find these changes in six unaffected family members, including the unaffected grandfather who contributed the affected haplotype, nor did we find them in the 100 Ashkenazi Jewish controls.
Conclusions
Our data are consistent with a de novo gene conversion event, transferring 270 base pairs at most from CRYBB2P1 to exon 5 of CRYBB2. This study highlights how linkage mapping can be complicated by de novo mutation events, as well as how sequence-analysis pipeline mapping of short reads from next-generation sequencing can be complicated by the existence of pseudogenes or other highly homologous sequences.
PMCID: PMC4225141  PMID: 25489230
15.  Evaluation of community eye outreach programs for early glaucoma detection in Nigeria 
Purpose
To evaluate the relevance of community eye outreach programs in the early detection of glaucoma patients in southwest Nigeria.
Methods
This was a retrospective, cross-sectional study that was conducted among glaucoma patients referred to the eye clinic of the University College Hospital (UCH), Ibadan, Nigeria, between January 2009 and December 2010 from different sources, including community eye outreach programs. The source of referral, stage of glaucoma, and visual field were recorded.
Results
Six hundred and fifty-three patients were studied during this period. The mean age was 56.3 years ± 16.6 years, with a median age of 60 years. Patients referred from eye outreach programs were more likely to have mild to moderate disease than patients referred from other sources, who were more likely to have severe disease according to both the optic nerve head assessment (P < 0.01, Pearson’s Chi-square = 10.67, odds ratio = 1.7 [confidence interval = 1.23–2.31]) and visual field assessment (24–2) (P < 0.01, Pearson’s Chi-square = 6.07, odds ratio = 1.5 [confidence interval = 1.08–2.03]).
Conclusion
Community eye outreach programs appear highly useful in the earlier detection of glaucoma in sub-Saharan Africa.
doi:10.2147/OPTH.S46823
PMCID: PMC3772764  PMID: 24043924
community eye outreach; early glaucoma detection; Nigeria glaucoma detection; glaucoma awareness; sub-Saharan Africa
16.  Series Length Used during Trend Analysis Affects Sensitivity to Changes in Progression Rate in the Ocular Hypertension Treatment Study 
Purpose.
Trend analysis techniques to detect glaucomatous progression typically assume a constant rate of change. This study uses data from the Ocular Hypertension Treatment Study to assess whether this assumption decreases sensitivity to changes in progression rate, by including earlier periods of stability.
Methods.
Series of visual fields (mean 24 per eye) completed at 6-month intervals from participants randomized initially to observation were split into subseries before and after the initiation of treatment (the “split-point”). The mean deviation rate of change (MDR) was derived using these entire subseries, and using only the window length (W) tests nearest the split-point, for different window lengths of W tests. A generalized estimating equation model was used to detect changes in MDR occurring at the split-point.
Results.
Using shortened subseries with W = 7 tests, the MDR slowed by 0.142 dB/y upon initiation of treatment (P < 0.001), and the proportion of eyes showing “rapid deterioration” (MDR <–0.5 dB/y with P < 5%) decreased from 11.8% to 6.5% (P < 0.001). Using the entire sequence, no significant change in MDR was detected (P = 0.796), and there was no change in the proportion of eyes progressing (P = 0.084). Window lengths 6 ≤ W ≤ 9 produced similar benefits.
Conclusions.
Event analysis revealed a beneficial treatment effect in this dataset. This effect was not detected by linear trend analysis applied to entire series, but was detected when using shorter subseries of length between six and nine fields. Using linear trend analysis on the entire field sequence may not be optimal for detecting and monitoring progression. Nonlinear analyses may be needed for long series of fields. (ClinicalTrials.gov number, NCT00000125.)
Linear trend analysis was applied to sequences of visual fields from the OHTS. Using shortened series of length between 6 and 9 fields before and after treatment initiation, the rate of change significantly slowed. However, when using the entire sequence, no significant difference was observed.
doi:10.1167/iovs.12-10218
PMCID: PMC3597197  PMID: 23349433
17.  Noninvasive intracranial pressure estimation by orbital subarachnoid space measurement: the Beijing Intracranial and Intraocular Pressure (iCOP) study 
Critical Care  2013;17(4):R162.
Introduction
The orbital subarachnoid space surrounding the optic nerve is continuous with the circulation system for cerebrospinal fluid (CSF) and can be visualized by using magnetic resonance imaging (MRI). We hypothesized that the orbital subarachnoid space width (OSASW) is correlated with and can serve as a surrogate for intracranial pressure (ICP). Our aim was to develop a method for a noninvasive measurement of the intracranial CSF-pressure (CSF-P) based on MRI-assisted OSASW.
Methods
The prospective observational comparative study included neurology patients who underwent lumbar CSF-P measurement and 3.0-Tesla orbital magnetic resonance imaging (MRI) for other clinical reasons. The width of the orbital subarachnoid space (OSASW) around the optic nerve was measured with MRI at 3, 9, and 15 mm behind the globe. The study population was randomly divided into a training group and a test group. After adjusting for body mass index (BMI) and mean arterial blood pressure (MABP), algorithms for the associations between CSF-P and OSASW were calculated in the training group. The algorithms were subsequently verified in the test group. Main outcome measures were the width of the orbital subarachnoid space (OSASW) and the lumbar cerebrospinal fluid pressure (CSF-P).
Results
Seventy-two patients were included in the study. In the training group, the algorithms for the associations between CSF-P and OSASW were as follows: (a) CSF-P = 9.31 × OSASW (at 3 mm) + 0.48 × BMI + 0.14 × MABP-19.94; (b) CSF-P = 16.95 × OSASW (at 9 mm) + 0.39 × BMI + 0.14 × MABP-20.90; and (c) CSF-P = 17.54 × OSASW (at 15 mm) + 0.47 × BMI + 0.13 × MABP-21.52. Applying these algorithms in the independent test group, the measured lumbar CSF-P (13.6 ± 5.1 mm Hg) did not differ significantly from the calculated MRI-derived CSF-P (OSASW at 3 mm: 12.7 ± 4.2 mm Hg (P = 0.07); at 9 mm: 13.4 ± 5.1 mm Hg (P = 0.35); and at 15 mm: 14.0 ± 4.9 mm Hg (P = 0.87)). Intraclass correlation coefficients (ICCs) were higher for the CSF-P assessment based on OSASW at 9 mm and at 15 mm behind the globe (all ICCs, 0.87) than for OSASW measurements at 3 mm (ICC, 0.80).
Conclusions
In patients with normal, moderately decreased or elevated ICP, MRI-assisted measurement of the OSASW appears to be useful for the noninvasive quantitative estimation of ICP, if BMI and MABP as contributing parameters are taken into account.
Trial registration
Clinical trial registered with the Chinese Clinical Trial Registry: ChiCTR-OCC-11001271
doi:10.1186/cc12841
PMCID: PMC4056099  PMID: 23883736
18.  Immunoproteomic Analysis of Potential Serum Biomarker Candidates in Human Glaucoma 
Purpose.
Evidence supporting the immune system involvement in glaucoma includes increased titers of serum antibodies to retina and optic nerve proteins, although their pathogenic importance remains unclear. This study using an antibody-based proteomics approach aimed to identify disease-related antigens as candidate biomarkers of glaucoma.
Methods.
Serum samples were collected from 111 patients with primary open-angle glaucoma and an age-matched control group of 49 healthy subjects without glaucoma. For high-throughput characterization of antigens, serum IgG was eluted from five randomly selected glaucomatous samples and analyzed by linear ion trap mass spectrometry (LC-MS/MS). Serum titers of selected biomarker candidates were then measured by specific ELISAs in the whole sample pool (including an additional control group of diabetic retinopathy).
Results.
LC-MS/MS analysis of IgG elutes revealed a complex panel of proteins, including those detectable only in glaucomatous samples. Interestingly, many of these antigens corresponded to upregulated retinal proteins previously identified in glaucomatous donors (or that exhibited increased methionine oxidation). Moreover, additional analysis detected a greater immunoreactivity of the patient sera to glaucomatous retinal proteins (or to oxidatively stressed cell culture proteins), thereby suggesting the importance of disease-related protein modifications in autoantibody production/reactivity. As a narrowing-down strategy for selection of initial biomarker candidates, we determined the serum proteins overlapping with the retinal proteins known to be up-regulated in glaucoma. Four of the selected 10 candidates (AIF, cyclic AMP-responsive element binding protein, ephrin type-A receptor, and huntingtin) exhibited higher ELISA titers in the glaucomatous sera.
Conclusions.
A number of serum proteins identified by this immunoproteomic study of human glaucoma may represent diseased tissue-related antigens and serve as candidate biomarkers of glaucoma.
This immunoproteomic study identified antigenic targets of serum antibodies in glaucoma and initiated validation studies to assess their value as disease biomarkers. A number of serum proteins presented may represent diseased tissue-specific antigens and serve as candidate biomarkers of glaucoma.
doi:10.1167/iovs.12-10076
PMCID: PMC3522442  PMID: 23150628
19.  The Nature of Macular Damage in Glaucoma as Revealed by Averaging Optical Coherence Tomography Data 
Purpose
To better understand the nature of glaucomatous damage, especially to the macula, the inner retinal thickness maps obtained with frequency domain optical coherence tomography (fdOCT) were averaged.
Methods
Frequency domain optical coherence tomography macular and optic disc cube scans were obtained from 54 healthy eyes and 156 eyes with glaucomatous optic neuropathy. A manually corrected algorithm was used for layer segmentation. Patients’ eyes were grouped both by mean deviation (MD) and hemifield classification using standard categories and 24-2 (6° grid) visual fields (VFs). To obtain average difference maps, the thickness of retinal nerve fiber (RNF) and retinal ganglion cell plus inner plexiform (RGC+) layers were averaged and subtracted from the average control values.
Results
On the average difference maps, RGC+ and RNF layer thinning was seen in the patient groups with VFs classified as normal. The pattern of the thinning was the same, but the degree of thinning increased with decreased MD and with classification category (from normal to arcuate). This RGC+ thinning was largely within the central four points of the 24-2 (6° grid) field, after correcting for RGC displacement.
Conclusion
1. VF categories represent different degrees of the same pattern of RGC+ and RNFL layer thinning. 2. RGC+ damage occurs in the central macula even in patients with VFs classified as normal. 3. The 6° grid (24-2) pattern is not optimally designed to detect macular damage. 4. A schematic model of RGC projections is proposed to explain the pattern of macular loss, including the greater vulnerability of the inferior retinal region.
Translational relevance
The 24-2 is not an optimal test pattern for detecting or following glaucomatous damage. Further, we suggest clinical fdOCT reports include RGC+ and RNFL probability plots combined with VF information.
doi:10.1167/tvst.1.1.3
PMCID: PMC3634586  PMID: 23626924
glaucoma; optical coherence tomography; perimetry; visual fields; macula
20.  Effect of Treatment on the Rate of Visual Field Change in the Ocular Hypertension Treatment Study Observation Group 
Purpose.
The goal in this study was to compare rates of visual field (VF) change before and after the initiation of treatment in participants originally randomized to the observation arm of the Ocular Hypertension Treatment Study (OHTS).
Methods.
We included OHTS participants originally randomized to observation and excluded those who reached non-POAG endpoints. VF progression was determined using trend analysis. Global and localized rates of VF change were calculated based on linear regression over time of mean deviation (MD) and threshold sensitivity values for each test location. MD rates (MDR) and pointwise linear regression (PLR) analysis were also assessed using six VF tests before and after the initiation of treatment. A PLR endpoint was defined as a VF test location progressing faster than −0.5 dB/year at P < 0.01.
Results.
We included 780 eyes from 432 OHTS participants. Following the initiation of treatment, the mean MDR decreased from −0.23 ± 0.6 to −0.06 ± 0.5 dB/year (P < 0.01) and the number of VF locations reaching a PLR endpoint decreased from 2.13 ± 6.0 to 1.00 ± 4.0 (P < 0.01). The benefit of treatment was significant both among participants who did not convert (−0.17 ± 0.6 vs. −0.01 ± 0.5 dB/year, P < 0.01) and among those who converted to glaucoma (−0.51 ± 0.8 vs. −0.27 ± 0.7 dB/year, P < 0.01) based on the OHTS event-based endpoint.
Conclusions.
The initiation of ocular hypotensive medication among OHTS participants originally randomized to observation significantly reduced the velocity of VF progression. (ClinicalTrials.gov number, NCT00000125.)
The initiation of ocular hypotensive medication among the Ocular Hypertension Treatment Study participants originally randomized to the observation arm significantly reduced the velocity of visual field progression as measured using trend analysis.
doi:10.1167/iovs.11-8186
PMCID: PMC3342789  PMID: 22395889
21.  Glaucomatous damage of the macula 
There is a growing body of evidence that early glaucomatous damage involves the macula. The anatomical basis of this damage can be studied using frequency domain optical coherence tomography (fdOCT), by which the local thickness of the retinal nerve fiber layer (RNFL) and local retinal ganglion cell plus inner plexiform (RGC+) layer can be measured. Based upon averaged fdOCT results from healthy controls and patients, we show that: 1. For healthy controls, the average RGC+ layer thickness closely matches human histological data; 2. For glaucoma patients and suspects, the average RGC+ layer shows greater glaucomatous thinning in the inferior retina (superior visual field (VF)); and 3. The central test points of the 6° VF grid (24-2 test pattern) miss the region of greatest RGC+ thinning. Based upon fdOCT results from individual patients, we have learned that: 1. Local RGC+ loss is associated with local VF sensitivity loss as long as the displacement of RGCs from the foveal center is taken into consideration; and 2. Macular damage is typically arcuate in nature and often associated with local RNFL thinning in a narrow region of the disc, which we call the macular vulnerability zone (MVZ). According to our schematic model of macular damage, most of the inferior region of the macula projects to the MVZ, which is located largely in the inferior quadrant of the disc, a region that is particularly susceptible to glaucomatous damage. A small (cecocentral) region of the inferior macula, and all of the superior macula (inferior VF), project to the temporal quadrant, a region that is less susceptible to damage. The overall message is clear; clinicians need to be aware that glaucomatous damage to the macula is common, can occur early in the disease, and can be missed and/or underestimated with standard VF tests that use a 6° grid, such as the 24-2 VF test.
doi:10.1016/j.preteyeres.2012.08.003
PMCID: PMC3529818  PMID: 22995953
Glaucoma; OCT; Macula; Retinal ganglion cell; Visual field
22.  Outcomes of Trabeculectomy with 5-Fluorouracil at a Nigerian Tertiary Hospital 
Purpose
To report the outcomes of trabeculectomy with adjunctive 5-Fluorouracil (5- FU) at a Nigerian tertiary hospital.
Methods
In this prospective study, all patients with glaucoma undergoing trabeculectomy with 5-FU at the University College Hospital, Ibadan, Nigeria, from June 2009 to May2010 were enrolled. Each patient had a complete ophthalmic evaluation. Intraocular pressure (IOP), visual acuity (VA) and complications post-trabeculectomy were assessed at one year. Success of the procedure was defined as complete when no additional medications were required to achieve an IOP of ≤18mmHg, or qualified when additional medications were required to achieve the same goal.
Results
A total of 47 eyes of 31 patients with mean age of 48.9±19.6 (range 14-77; median 52) years including 21 (67.7%) male subjects underwent trabeculectomy with 5-FU. Mean presenting IOP was 31.8±12.2 mmHg. Mean deviation (MD) on Humphrey visual fields was -15.9±9.7dB with the majority of the patients (18 subjects 58.1%) presenting with advanced glaucoma based on MD worse than -12dB and severe glaucomatous optic neuropathy (cup to disc ratio of 0.9-1.0). At 1 year postoperatively, 95.1% achieved qualified success while 83% had complete success.
Conclusion
This prospective study adds to the existing knowledge that trabeculectomy with 5-FU is effective at controlling IOP in Nigerian patients.
PMCID: PMC3740464  PMID: 23943687
Trabeculectomy; 5-fluorouracil; Nigeria
24.  Understanding Disparities Among Diagnostic Technologies in Glaucoma 
Archives of ophthalmology  2012;130(7):833-840.
Objective
To investigate causes of disagreement among 3 glaucoma diagnostic techniques: standard automated achromatic perimetry (SAP), the multifocal visual evoked potential technique (mfVEP), and optical coherence tomography (OCT).
Methods
In a prospective cross-sectional study, 138 eyes of 69 patients with glaucomatous optic neuropathy were tested using SAP, the mfVEP, and OCT. Eyes with the worse and better mean deviations (MDs) were analyzed separately. If the results of 2 tests were consistent for the presence of an abnormality in the same topographic site, that abnormality was considered a true glaucoma defect. If a third test missed that abnormality (false-negative result), the reasons for disparity were investigated.
Results
Eyes with worse MD (mean [SD], −6.8 [8.0] dB) had better agreements among tests than did eyes with better MD (−2.5 [3.5] dB, P<.01). For the 94 of 138 hemi-fields with abnormalities of the more advanced eyes, the 3 tests were consistent in showing the same hemifield abnormality in 50 hemifields (53%), and at least 2 tests were abnormal in 65 of the 94 hemifields (69%). The potential explanations for the false-negative results fell into 2 general categories: inherent limitations of each technique to detect distinct features of glaucoma and individual variability and the distribution of normative values used to define statistically significant abnormalities.
Conclusions
All the cases of disparity could be explained by known limitations of each technique and inter-individual variability, suggesting that the agreement among diagnostic tests may be better than summary statistics suggest and that disagreements between tests do not indicate discordance in the structure-function relationship.
doi:10.1001/archophthalmol.2012.786
PMCID: PMC3498487  PMID: 22776920
25.  Clinical use of multifocal visual-evoked potentials in a glaucoma practice: a prospective study 
Purpose
To test a framework that describes how the multifocal visual-evoked potential (mfVEP) technique is used in a particular glaucoma practice.
Methods
In this prospective, descriptive study, glaucoma suspects, ocular hypertensives and glaucoma patients were referred for mfVEP testing by a single glaucoma specialist over a 2-year period. All patients underwent standard automated perimetry (SAP) and mfVEP testing within 3 months. Two hundred and ten patients (420 eyes) were referred for mfVEP testing for the following reasons: (1) normal SAP tests suspected of early functional loss (ocular hypertensives, n = 43; and glaucoma suspects on the basis of suspicious optic disks, n = 52); (2) normal-tension glaucoma patients with suspected central SAP defects (n = 33); and (3) SAP abnormalities needing confirmation (n = 82).
Results
All the glaucoma suspects with normal SAP and mfVEP results remained untreated. Of those with abnormal mfVEP results, 68 % (15/22) were treated because the abnormal regions on the mfVEP were consistent with the abnormal regions seen during clinical examination of the optic disk. The mfVEP was abnormal in 86 % (69/80) of eyes with glaucomatous optic neuropathy and SAP damage, even though it did not result in an altered treatment regimen. In NTG patients, the mfVEP showed central defects in 44 % (12 of 27) of the eyes with apparently normal central fields and confirmed central scotomata in 92 % (36 of 39), leading to more rigorous surveillance of these patients.
Conclusions
In a clinical practice, the mfVEP was used when clinical examination and subjective visual fields provided insufficient or conflicting information. This information influenced clinical management.
doi:10.1007/s10633-012-9324-3
PMCID: PMC3498911  PMID: 22476612
mfVEP; Glaucoma; Perimetry; Electrophysiology

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