Association between Intraocular Pressure and Rates of Retinal Nerve Fiber Layer Loss Measured by Optical Coherence Tomography.

PURPOSE: To evaluate the relationship between intraocular pressure (IOP) and rates of retinal nerve fiber layer (RNFL) thickness change over time measured by spectral-domain (SD) optical coherence tomography (OCT). DESIGN: Observational cohort study. PARTICIPANTS: The study involved 547 eyes of 339 patients followed up for an average of 3.9±0.9 years. Three hundred eight (56.3%) had a diagnosis of glaucoma and 239 (43.7%) were considered glaucoma suspects. METHODS: All eyes underwent imaging using the Spectralis SD OCT (Heidelberg Engineering GmbH, Heidelberg, Germany), along with IOP measurements and standard automated perimetry (SAP). Glaucoma progression was defined as a result of "Likely Progression" from the Guided Progression Analysis software for SAP. Linear mixed models were used to investigate the relationship between average IOP during follow-up and rates of RNFL thickness change, while taking into account potential confounding factors such as age, race, corneal thickness, and baseline disease severity. MAIN OUTCOME MEASURES: The association between IOP and rates of global and sectorial RNFL thickness loss measured by SD OCT. RESULTS: Forty-six eyes (8.4%) showed progression on SAP during follow-up. Rates of global RNFL thickness change in eyes that progressed by SAP were faster than in those that did not progress (-1.02 vs. -0.61 µm/year, respectively; P = 0.002). For progressing eyes, each 1-mmHg higher average in IOP during follow-up was associated with an additional average loss of 0.20 µm/year (95% confidence interval [CI]: 0.08 to 0.31 µm/year; P < 0.001) of global RNFL thickness versus only 0.04 µm/year (95% CI: 0.01 to 0.07 µm/year; P = 0.015) for nonprogressing eyes. The largest associations between IOP and rates of RNFL change were seen for measurements from the temporal superior and temporal inferior sectors, whereas the smallest association was seen for measurements from the nasal sector. CONCLUSIONS: Higher levels of IOP during follow-up were associated with faster rates of RNFL loss over time measured by SD OCT. These findings support the use of SD OCT RNFL thickness measurements as biomarkers for the evaluation of the efficacy of IOP-lowering therapies to slow down the rate of disease progression.

Asymmetric Macular Structural Damage Is Associated With Relative Afferent Pupillary Defects in Patients With Glaucoma.

PURPOSE: We examined the relationship between relative afferent pupillary defects (RAPDs) and macular structural damage measured by macular thickness and macular ganglion cell-inner plexiform layer (mGCIPL) thickness in patients with glaucoma. METHODS: A cross-sectional study was done of 106 glaucoma patients and 85 healthy individuals from the Diagnostic Innovations in Glaucoma Study. All subjects underwent standard automated perimetry (SAP) and optic nerve and macular imaging using Cirrus Spectral Domain Optical Coherence Tomography (SDOCT). Glaucoma was defined as repeatable abnormal SAP or progressive glaucomatous changes on stereo photographs. Pupil responses were assessed using an automated pupillometer, which records the magnitude of RAPD (RAPD score), with additional RAPD scores recorded for each of a series of colored stimuli (blue, red, green, and yellow). The relationship between RAPD score and intereye differences (right minus left eye) in circumpapillary retinal nerve fiber layer (cpRNFL) thickness, mGCIPL, macular thickness, and SAP mean deviation (MD), was examined using linear regression. RESULTS: There was fair correlation between RAPD score and asymmetric macular structural damage measured by intereye difference in mGCIPL thickness (R(2) = 0.285, P < 0.001). The relationship between RAPD score and intereye difference in macular thickness was weaker (R(2) = 0.167, P < 0.001). Intereye difference in cpRNFL thickness (R(2) = 0.350, P < 0.001) and SAP MD (R(2) = 0.594, P < 0.001) had stronger association with RAPD scores compared to intereye difference in mGCIPL and macular thickness. CONCLUSIONS: Objective assessment of pupillary responses using a pupillometer was associated with asymmetric macular structural damage in patients with glaucoma.

Association between progressive retinal nerve fiber layer loss and longitudinal change in quality of life in glaucoma.

IMPORTANCE: Evaluation of structural optic nerve damage is a fundamental part of diagnosis and management of glaucoma. However, the relationship between structural measurements and disability associated with the disease is not well characterized. Quantification of this relationship may help validate structural measurements as markers directly relevant to quality of life. OBJECTIVE: To evaluate the relationship between rates of retinal nerve fiber layer (RNFL) loss and longitudinal changes in quality of life in glaucoma. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study including 260 eyes of 130 patients with glaucoma followed up for a mean (SD) of 3.5 (0.7) years. All patients had repeatable visual field defects on standard automated perimetry (SAP) at baseline. The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was performed annually, and spectral-domain optical coherence tomography and SAP were performed at 6-month intervals. A joint model was used to investigate the association between change in NEI VFQ-25 Rasch-calibrated scores and change in RNFL thickness, adjusting for confounding socioeconomic and clinical variables. MAIN OUTCOMES AND MEASURES: Association between change in binocular RNFL thickness (RNFL thickness in the better eye at each point) and change in NEI VFQ-25 scores. RESULTS: Progressive binocular RNFL thickness loss was associated with worsening of NEI VFQ-25 scores over time. In a multivariable model adjusting for baseline disease severity and the rate of change in binocular SAP sensitivity, each 1-µm-per-year loss of RNFL thickness was associated with a decrease of 1.3 units (95% CI, 1.02-1.56) per year in NEI VFQ-25 scores (P < .001). After adjusting for the contribution from SAP, 26% (95% CI, 12%-39%) of the variability of change in NEI VFQ-25 scores was associated uniquely with change in binocular RNFL thickness. The P value remained less than .001 after adjusting for potential confounding factors. CONCLUSIONS AND RELEVANCE: Progressive binocular RNFL thickness loss was associated with longitudinal loss in quality of life, even after adjustment for progressive visual field loss. These findings suggest that rates of binocular RNFL change are valid markers for the degree of neural loss in glaucoma with significant relationship to glaucoma-associated disability.

Predicting progression of glaucoma from rates of frequency doubling technology perimetry change.

PURPOSE: To evaluate the ability of longitudinal frequency doubling technology (FDT) to predict the development of glaucomatous visual field loss on standard automated perimetry (SAP) in glaucoma suspects. DESIGN: Prospective, observational cohort study. PARTICIPANTS: The study included 587 eyes of 367 patients with suspected glaucoma at baseline selected from the Diagnostic Innovations in Glaucoma Study (DIGS) and the African Descent and Glaucoma Evaluation Study (ADAGES). These eyes had an average of 6.7 ± 1.9 FDT tests during a mean follow-up time of 73.1 ± 28.0 months. METHODS: Glaucoma suspects had intraocular pressure (IOP) >21 mmHg or an optic disc appearance suspicious of glaucoma. All patients had normal or nonrepeatable abnormal SAP at baseline. Humphrey Matrix FDT (Carl Zeiss Meditec, Inc, Dublin, CA) testing was performed within 6 months of SAP testing. The study end point was the development of 3 consecutive abnormal SAP test results. Joint longitudinal survival models were used to evaluate the ability of rates of FDT pattern standard deviation (PSD) change to predict the development of visual field loss on SAP, adjusting for confounding variables (baseline age, mean IOP, corneal thickness, and follow-up measurements of SAP PSD). MAIN OUTCOME MEASURES: The R(2) index was used to evaluate and compare the predictive abilities of the model containing longitudinal FDT PSD data with the model containing only baseline data. RESULTS: Sixty-three of 587 eyes (11%) developed SAP visual field loss during follow-up. The mean rate of FDT PSD change in eyes that developed SAP visual field loss was 0.07 dB/year versus 0.02 dB/year in those that did not (P < 0.001). Baseline FDT PSD and slopes of FDT PSD change were significantly predictive of progression, with hazard ratios of 1.11 per 0.1 dB higher (95% confidence interval [CI], 1.04-1.18; P = 0.002) and 4.40 per 0.1 dB/year faster (95% CI, 1.08-17.96; P = 0.04), respectively. The longitudinal model performed significantly better than the baseline model with an R(2) of 82% (95% CI, 74-89) versus 11% (95% CI, 2-24), respectively. CONCLUSIONS: Rates of FDT PSD change were highly predictive of the development of SAP visual field loss in glaucoma suspects. This finding suggests that longitudinal FDT evaluation may be useful for risk stratification of patients with suspected glaucoma.

Combining structure and function to evaluate glaucomatous progression: implications for the design of clinical trials.

The selection of a suitable method for assessment of glaucomatous progression and estimation of rates of change is an essential component of the design of clinical trials investigating neuroprotective therapies for the disease. Due to the limitations of currently available tests, approaches combining structural and functional tests are essential in order to provide reliable detection of endpoints. This could also potentially enable shorter clinical trials with relatively smaller sample size requirements. A recent approach for estimating rates of retinal ganglion cell loss using a combination of structural and functional tests has been shown to perform better than isolated parameters from conventional tests for diagnosing, staging and detecting glaucoma progression and may prove useful as an outcome measure in clinical trials of the disease.

Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados.

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score = 6.64 at = 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E-09 and P < 1.21E-12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an Afro-Caribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG.