Purpose: To compare optic disc and neuroretinal rim area measurements from spectral-domain optical coherence tomography (SD-OCT) to those from confocal scanning laser ophthalmoscopy.Methods: Seventy-one eyes from 43 normal subjects or suspected/definite glaucoma patients were prospectively enrolled. All subjects had biometry with the IOLMaster and disc/retinal nerve fiber layer (RNFL) imaging with Cirrus SD-OCT (Optic Disc Cube 200x200) and Heidelberg Retina Tomograph (HRT). Keratometry-corrected (K-corrected) HRT measurements and uncorrected Cirrus disc and rim areas and disc measurements corrected for eye magnification with Bennett's formula (AL-corrected) along with 30-degree sectoral rim areas, vertical cup-to-disc ratio (VCDR), and cup volume were compared between the two devices. Results: The median (range) axial length (AL) was 24.2 mm (22.4-27.7 mm). Mean K-corrected HRT disc area measurements were larger than AL-corrected HRT and SD-OCT measurements (p<0.001 for both) and the difference was a function of K-readings. The AL-corrected HRT disc area and uncorrected/corrected Cirrus disc areas were not significantly different (p >0.481). HRT rim area was larger compared to Cirrus measurements (p<0.001) and the difference decreased with decreasing rim area. HRT VCDR and cup volume were significantly smaller than Cirrus measurements (p<0.001). The correlations for sectoral rim areas between the two devices were moderate at best (intraclass correlation coefficients=0.12-0.65).Conclusion: HRT overestimates optic disc area compared to SD-OCT. The difference in HRT and SD-OCT disc measurements is mainly due to HRT's magnification correction algorithm although variable definitions of the disc border are also contributory. Rim area measurements from HRT are larger than SD-OCT, likely a result of different definitions for the reference plane and differences in disc area measurements. Disc parameters from the two devices are not interchangeable.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10(-18)), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10(-11)). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10(-12)) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10(-10)). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Pediatric glaucoma surgery is challenging because of the differences in anatomy from the adult, differences in the behavior of the tissues of a child's glaucomatous eye, the variety in causes of the disease, and difficulties with postoperative management. Goniotomy and trabeculotomy are the preferred initial treatments for primary congenital glaucoma. Trabeculectomy with adjunctive mitomycin C is more likely to succeed in older, phakic patients, but carries the long-term risk of bleb-associated endophthalmitis. Glaucoma drainage devices may be preferred in younger children and in patients with aphakic glaucoma, but these devices can cause tube-related complications. Lastly, cyclodestructive procedures are reserved for patients in whom filtering surgery has failed, given its more unpredictable effects and serious complications.

Nell2 is a neuron-specific protein containing six epidermal growth factor-like domains. We have identified Nell2 as a retinal ganglion cell (RGC)-expressed gene by comparing mRNA profiles of control and RGC-deficient rat retinas. The aim of this study was to analyze Nell2 expression in wild-type and optic nerve axotomized retinas and evaluate its potential role in RGCs. Nell2-positive in situ and immunohistochemical signals were localized to irregularly shaped cells in the ganglion cell layer (GCL) and colocalized with retrogradely-labeled RGCs. No Nell2-positive cells were detected in 2 weeks optic nerve transected (ONT) retinas characterized with approximately 90% RGC loss. RT-PCR analysis showed a dramatic decrease in the Nell2 mRNA level after ONT compared to the controls. Immunoblot analysis of the Nell2 expression in the retina revealed the presence of two proteins with approximate MW of 140 and 90 kDa representing glycosylated and non-glycosylated Nell2, respectively. Both products were almost undetectable in retinal protein extracts two weeks after ONT. Proteome analysis of Nell2-interacting proteins carried out with MALDI-TOF MS (MS) identified microtubule-actin crosslinking factor 1 (Macf1), known to be critical in CNS development. Strong Macf1 expression was observed in the inner plexiform layer and GCL where it was colocalizied with Thy-1 staining. Since Nell2 has been reported to increase neuronal survival of the hippocampus and cerebral cortex, we evaluated the effect of Nell2 overexpression on RGC survival. RGCs in the nasal retina were consistently more efficiently transfected than in other areas (49% vs. 13%; n = 5, p<0.05). In non-transfected or pEGFP-transfected ONT retinas, the loss of RGCs was approximately 90% compared to the untreated control. In the nasal region, Nell2 transfection led to the preservation of approximately 58% more cells damaged by axotomy compared to non-transfected (n = 5, p<0.01) or pEGFP-transfected controls (n = 5, p<0.01).

Purpose: To explore structure-function relationships in early glaucoma with spectral-domain optical coherence tomography (SD-OCT) and standard achromatic perimetry.Methods: One hundred thirty-six eyes of 97 patients with suspected or early glaucoma were enrolled from the clinical database at UCLA's Glaucoma Division. All patients had good-quality peripapillary retinal nerve fiber layer (RNFL)/optic disc measurements (Optic Disc Cube 200x200, Cirrus HD-OCT) and a reliable 24-2 SITA-Standard Humphrey visual field (VF) within a 6-month period. Correlations of global and sectoral RNFL thickness and rim area (RA) measurements with corresponding global and regional VF sensitivities (both in logarithmic [dB] and 1/Lambert scales [1/L]) were investigated with components of variance model.Results: The average RNFL thickness, RA, and mean deviation (MD) were 85.6 ± 5.7 µ, 1.0 ± 0.3 mm2, and -1.3 ± 1.9 dB, respectively. Global RA demonstrated a stronger correlation with MD compared to average RNFL thickness (p=0.002). The highest correlations were observed between superonasal VF cluster (in dB scale) and inferotemporal RA (R2= 0.26, 95% CI: 0.15-0.40) or inferotemporal RNFL thickness (R2= 0.24, 95% CI: 0.13-0.37). In glaucoma suspects, the highest correlations were seen between superonasal VF cluster and inferotemporal RA (R2=0.16) in dB scale or RNFL thickness (R2=0.10) in 1/L scale. Correlations were slightly greater with dB scale than 1/L scale and tended to be linear with both scales.Conclusions: Structure-function relationships can be detected in early glaucoma with SD-OCT. Correlations of RA with VF thresholds tended to be higher compared to those of RNFL. Structure-function relationships were well described with a linear model.

Purpose: To explore whether pointwise rates of visual field progression group together in patterns consistent with retinal nerve fiber layer (RNFL) bundles.Methods: Three hundred eighty-nine eyes of 309 patients from the Advanced Glaucoma Intervention Study with ≥6 years of follow-up and ≥12 reliable visual field exams were selected. Linear and exponential regression models were used to estimate pointwise rates of change over time. Clustering of pointwise rates of progression was investigated with hierarchical cluster analysis using Pearson's correlation coefficients as distance measure and an average linkage scheme for building the hierarchy with cutoff value of r>0.7.Results: The average mean deviation (± SD) was -10.9 (± 5.4). The average (± SD) follow-up time and number of visual field exams were 8.1 (± 1.1) years and 15.7 (± 3.0), respectively. Pointwise rates of progression across the visual field grouped into clusters consistent with anatomic patterns of RNFL bundles with both linear (10 clusters) and exponential (6 clusters) regression models. One hundred forty-four (37%) eyes progressed according to the two-omitting pointwise linear regression.Conclusions: Pointwise rates of change in glaucoma patients cluster into regions consistent with RNFL bundle patterns. This finding validates the clinical significance of such pointwise rates. The correlations among pointwise rates of change can be used for spatial filtering purposes, facilitating detection or prediction of glaucoma progression.

Purpose:To investigate whether a recently described retinal ganglion cell (RGC) marker Rbpms (RNA binding protein with multiple splicing), could be used for RGC quantification in various models of RGC degeneration.Methods:Optic nerve crush, excitotoxicity and elevated intraocular pressure (IOP) rat models were used. Topographic analysis of Rbpms immunolabeling was performed on retinal wholemounts. Retrograde labeling with Fluorogold (FG) and III β-tubulin immunohistochemistry were compared.Results:In the optic nerve crush model, 37%, 87%, and 93% of Rbpms-positive cells were lost 1, 2, and 4 weeks, respectively. Significant loss of Rbpms-positive cells was noted 1 week after intravitreal injection of 12, 30 and 120 nmoles N-methyl-D-aspartate (NMDA) while co-injection of 120 nmoles of NMDA along with MK-801 increased the cell number from 10% to 59%. Over 95% of Rbpms-positive cells were FG- and III β-tubulin-positive after injury caused by optic nerve crush and NMDA injection. In rats with elevated IOP induced by trabecular laser photocoagulation, there was a significant loss of Rbpms-positive cells compared to contralateral controls (P=0.0004), and cumulative IOP elevation showed a strong linear relationship with the quantification of RGCs by Rbpms immunolabeling and retrograde labeling with FG. More than 99% of the remaining Rbpms-positive cells were double-labeled with FG.Conclusions:Rbpms can reliably be used as an RGC marker for quantitative evaluation in rat models of RGC degeneration, regardless of the nature and the location of the primary site of the injury and the extent of neurodegeneration.

Detection of visual field progression remains a challenging task despite the recent advances for better handling of longitudinal visual field data, some of which are incorporated in currently available perimeters. Standard achromatic perimetry remains the gold standard for detection of visual field progression. The authors present a practical and clinically relevant review of the main issues involved in detection of early glaucoma as well as detection of visual field progression in eyes with pre-existing glaucomatous damage. After discussing some basic concepts in perimetry, the authors present evidence-based recommendations for criteria to detect earliest evidence of glaucomatous damage with perimetry. The authors will review different event- and trend-based criteria and present data with regard to comparative performance of such criteria. Relevance of using absolute versus corrected threshold data with regard to different criteria is also addressed. At the end, the authors provide practical guidelines for detection of visual field progression in a clinical setting and review issues related to clinical trials.

PURPOSE To review the role of intervisit intraocular pressure (IOP) fluctuation as an independent risk factor for glaucoma. DESIGN Perspective after literature review. METHODS Analysis of pertinent publications in the peer-reviewed literature. RESULTS Disparate findings regarding the role of intervisit IOP variation have been published. IOP variation was a significant risk factor in the Advanced Glaucoma Intervention Study (AGIS), the Collaborative Initial Glaucoma Treatment Study, and other smaller studies. These studies have in common low IOPs (often after surgery) and moderately advanced disease. In the AGIS, when patients were stratified by mean IOP, only those patients with low IOPs showed the detrimental effects of IOP variation. IOP variation was not a significant risk factor in the Early Manifest Glaucoma Treatment Trial, and in 2 separate studies of ocular hypertensives. These studies have in common generally higher IOPs and an earlier stage of glaucoma (or no glaucoma at all). We believe these results are complementary rather than contradictory: existing data suggest that the effects of IOP variation depend on the characteristics of the patient, the baseline IOP, their stage of damage, the type of glaucoma, and other as-yet unknown factors. CONCLUSIONS Practitioners should consider whether patients who are progressing at low mean IOP may benefit from having IOP variation reduced. Single elevated measures of IOP may not be an anomaly or may not be related to compliance, but may identify patients who are at high risk for progressive glaucomatous damage, and thus should be monitored more carefully and potentially treated more aggressively.