Renato Lisboa

Corneal Hysteresis as a Risk Factor for Glaucoma Progression: A Prospective Longitudinal Study

PURPOSE To evaluate the role of corneal hysteresis (CH) as a risk factor for the rate of visual field progression in a cohort of patients with glaucoma followed prospectively over time. DESIGN Prospective observational cohort study. PARTICIPANTS The study group included 114 eyes of 68 patients with glaucoma followed for an average of 4.0 ± 1.1 years. Visual fields were obtained with standard automated perimetry. Included eyes had a median number of 7 (range, 5-12) tests during follow-up. METHODS The CH measurements were acquired at baseline using the Ocular Response Analyzer (Reichert Instruments, Depew, NY). Evaluation of rates of visual field change during follow-up was performed using the visual field index (VFI). Linear mixed models were used to investigate the relationship between rates of visual field loss and baseline CH, baseline intraocular pressure (IOP), and central corneal thickness (CCT), while adjusting for potentially confounding factors. An interaction term between IOP and CH was included in the model to investigate whether the effect of IOP on rates of progression depended on the level of CH. MAIN OUTCOME MEASURES Effects of CH, IOP, and CCT on rates of VFI loss over time. RESULTS The CH had a significant effect on rates of visual field progression over time. In the univariable model including only CH as a predictive factor along with time and their interaction, each 1 mmHg lower CH was associated with a 0.25%/year faster rate of VFI decline over time (P<0.001). The multivariable model showed that the effect of IOP on rates of progression depended on CH. Eyes with high IOP and low CH were at increased risk for having fast rates of disease progression. The CH explained a larger proportion of the variation in slopes of VFI change than CCT (17.4% vs. 5.2%, respectively). CONCLUSIONS The CH measurements were significantly associated with risk of glaucoma progression. Eyes with lower CH had faster rates of visual field loss than those with higher CH. The prospective longitudinal design of this study supports the role of CH as an important factor to be considered in the assessment of the risk of progression in patients with glaucoma. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Diagnosing Preperimetric Glaucoma with Spectral Domain Optical Coherence Tomography

PURPOSE To evaluate the diagnostic accuracy of spectral domain optical coherence tomography (SD-OCT) for detection of preperimetric glaucoma and compare it with the performance of confocal scanning laser ophthalmoscopy (CSLO). DESIGN Cohort study. PARTICIPANTS A cohort of 134 eyes of 88 glaucoma suspects based on the appearance of the optic disc. METHODS Patients were recruited from the Diagnostic Innovations in Glaucoma Study (DIGS). All eyes underwent retinal nerve fiber layer (RNFL) imaging with Spectralis SD-OCT (Heidelberg Engineering, Carlsbad, CA) and topographic imaging with Heidelberg Retinal Tomograph III (HRT-III) (Heidelberg Engineering) CSLO within 6 months of each other. All patients had normal visual fields at the time of imaging and were classified on the basis of history of documented stereophotographic evidence of progressive glaucomatous change in the appearance of the optic nerve occurring before the imaging sessions. MAIN OUTCOME MEASURES Areas under the receiver operating characteristic curves (AUCs) were calculated to summarize diagnostic accuracies of the SD-OCT and CSLO. Likelihood ratios (LRs) were reported using the diagnostic categorization provided by each instrument after comparison to its normative database. RESULTS Forty-eight eyes of 42 patients had evidence of progressive glaucomatous change and were included in the preperimetric glaucoma group. Eighty-six eyes of 46 patients without any evidence of progressive glaucomatous change followed untreated for an average of 14.0 ± 3.6 years were included in the control group. The parameter with the largest AUC obtained with the SD-OCT was the temporal superior RNFL thickness (0.88 ± 0.03), followed by global RNFL thickness (0.86 ± 0.03) and temporal inferior RNFL thickness (0.81 ± 0.04). The parameter with the largest AUC obtained with the CSLO was rim area (0.72 ± 0.05), followed by rim volume (0.71 ± 0.05) and linear cup-to-disk ratio (0.66 ± 0.05). Temporal superior RNFL average thickness measured by SD-OCT performed significantly better than rim area measurements from CSLO (0.88 vs. 0.72; P=0.008). Outside normal limits results for SD-OCT parameters were associated with strongly positive LRs. CONCLUSIONS The RNFL assessment with SD-OCT performed well in detecting preperimetric glaucomatous damage in a cohort of glaucoma suspects and had a better performance than CSLO.

Comparison of Different Spectral Domain OCT Scanning Protocols for Diagnosing Preperimetric Glaucoma

PURPOSE To compare the ability of spectral-domain optical coherence tomography (SDOCT) retinal nerve fiber layer (RNFL), optic nerve head (ONH), and macular measurements to detect preperimetric glaucomatous damage. METHODS The study included 142 eyes from 91 patients suspected of having the disease based on the appearance of the optic disc. All eyes had normal visual fields before the imaging session. Forty-eight eyes with progressive glaucomatous damage were included in the preperimetric glaucoma group. Ninety-four eyes without any evidence of progressive glaucomatous damage and followed untreated for 12.8 ± 3.6 years were used as controls. Areas under the receiver operating characteristic curves (AUC) were calculated to summarize diagnostic accuracies of the parameters. RESULTS The three RNFL parameters with the largest AUCs were average RNFL thickness (0.89 ± 0.03), inferior hemisphere average thickness (0.87 ± 0.03), and inferior quadrant average thickness (0.85 ± 0.03). The three ONH parameters with the largest AUCs were vertical cup-to-disc ratio (0.74 ± 0.04), rim area (0.72 ± 0.05), and rim volume (0.72 ± 0.05). The three macular parameters with the largest AUCs were GCC average thickness (0.79 ± 0.04), GCC inferior thickness (0.79 ± 0.05), and GCC superior thickness (0.76 ± 0.05). Average RNFL thickness performed better than vertical cup-to-disc ratio (0.89 vs. 0.74; P = 0.007) and GCC average thickness (0.89 vs. 0.79; P = 0.015). CONCLUSIONS SDOCT RNFL measurements performed better than ONH and macular measurements for detecting preperimetric glaucomatous damage in a cohort of glaucoma suspects. (ClinicalTrials.gov number, NCT00221897.).

Retinal Ganglion Cell Count Estimates Associated with Early Development of Visual Field Defects in Glaucoma

PURPOSE To estimate retinal ganglion cell (RGC) losses associated with the earliest development of visual field defects in glaucoma. DESIGN Observational cohort study. PARTICIPANTS The study group included 53 eyes of 53 patients with suspected glaucoma who were followed as part of the Diagnostic Innovations in Glaucoma (DIGS) study. These eyes had normal standard automated perimetry (SAP) visual fields at baseline and developed repeatable (3 consecutive) abnormal test results during a median follow-up of 6.7 years. An age-matched control group of 124 eyes of 124 healthy subjects recruited from the general population was included. METHODS Estimates of RGC counts were obtained using a previously published model that combines estimates of RGC numbers from SAP sensitivity thresholds and retinal nerve fiber layer (RNFL) thickness measurements with spectral domain optical coherence tomography (SD-OCT). For eyes converting to glaucoma, estimates of RGC counts were obtained at the time (within ± 3 months) of the first abnormal visual field, representing the time of earliest detection of visual field losses. MAIN OUTCOME MEASURES Estimates of RGC counts in eyes converting to glaucoma versus healthy eyes. RESULTS The average RGC count estimate in the eyes with early visual field defects was 652057 ± 115829 cells, which was significantly lower than the average of 910 584 ± 142 412 cells found in healthy eyes (P < 0.001). Compared with the average number of RGCs in the healthy group, glaucomatous eyes had an average RGC loss of 28.4%, ranging from 6% to 57%, at the time of the earliest visual field defect on SAP. Retinal ganglion cell counts performed significantly better than the SD-OCT average RNFL thickness parameter in discriminating glaucomatous from healthy eyes with receiver operating characteristic curve areas of 0.95 ± 0.02 versus 0.88 ± 0.03, respectively (P = 0.001). CONCLUSIONS Glaucomatous eyes with the earliest detectable visual field loss on automated perimetry may already show substantial loss of RGCs. Empirical estimates of RGC counts combining structural and functional tests agreed closely with previous histologic reports on the number of RGCs associated with early visual fields defects on SAP.

Association Between Rates of Binocular Visual Field Loss and Vision-Related Quality of Life in Patients With Glaucoma

IMPORTANCE It is reasonable to hypothesize that for 2 patients with similar degrees of integrated binocular visual field (BVF) loss, the patient with a history of faster disease progression will report worse vision-related quality of life (VRQOL) than the patient with slowly progressing damage. However, to our knowledge, this hypothesis has not been investigated in the literature. OBJECTIVE To evaluate the association between binocular rates of visual field change and VRQOL in patients with glaucoma. DESIGN Observational cohort study. SETTING Patients were recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. PARTICIPANTS The study included 796 eyes of 398 patients with diagnosed or suspected glaucoma followed up from October 1, 1998, until January 31, 2012, for a mean (SD) of 7.3 (2.0) years. MAIN OUTCOME MEASURES The VRQOL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) at the last follow-up visit. The NEI VFQ-25 was completed for all patients during the period extending from December 1, 2009, through January 31, 2012. Integrated BVFs were calculated from the monocular fields of each patient. Linear regression of mean deviation values was used to evaluate rates of BVF change during the follow-up period. Logistic regression models were used to investigate the association between abnormal VRQOL and rates of BVF change, while adjusting for potentially confounding socioeconomic and demographic variables. RESULTS Thirty-two patients (8.0%) had abnormal VRQOL as determined by the results of the NEI VFQ-25. Patients with abnormal VRQOL had significantly faster rates of BVF change than those with normal VRQOL (-0.18 vs -0.06 dB/y; P < .001). Rates of BVF change were significantly associated with abnormality in VRQOL (odds ratio = 1.31 per 0.1 dB/y faster; P = .04), after adjustment for confounding variables. CONCLUSIONS AND RELEVANCE Patients with faster rates of BVF change were at higher risk of reporting abnormal VRQOL. Assessment of rates of BVF change may provide useful information in determining risk of functional impairment in glaucoma.

Predicting progression in glaucoma suspects with longitudinal estimates of retinal ganglion cell counts.

PURPOSE We evaluated the ability of baseline and longitudinal estimates of retinal ganglion cell (RGC) counts in predicting progression in eyes suspected of having glaucoma. METHODS The study included 288 glaucoma suspect eyes of 288 patients followed for an average of 3.8 ± 1.0 years. Participants had normal standard automated perimetry (SAP) at baseline. Retinal nerve fiber layer thickness assessment was performed with optical coherence tomography (OCT). Progression was defined as development of repeatable abnormal SAP or glaucomatous progressive optic disc changes. Estimates of RGC counts were obtained by combining data from SAP and OCT according to a previously described method. Joint longitudinal survival models were used to evaluate the ability of baseline and rates of change in estimated RGC counts for predicting progression over time, adjusting for confounding variables. RESULTS A total of 48 eyes (17%) showed progression during follow-up. The mean rate of change in estimated RGC counts was -18,987 cells/y in progressors versus -8,808 cells/y for nonprogressors (P < 0.001). Baseline RGC counts and slopes of RGC loss were significantly predictive of progression, with HRs of 1.56 per 100,000 cells lower (95% confidence interval [CI], 1.18-2.08; P = 0.002) and 2.68 per 10,000 cells/y faster loss (95% CI, 1.22-5.90; P = 0.014), respectively. The longitudinal model including estimates of RGC counts performed significantly better than models including only structural or functional indexes separately. CONCLUSIONS Baseline and longitudinal estimates of RGC counts may be helpful in predicting progression and performed significantly better than conventional approaches for risk stratification of glaucoma suspects.

Incorporating Risk Factors to Improve the Assessment of Rates of Glaucomatous Progression

PURPOSE To present and evaluate a new method of integrating risk factors into the analysis of rates of visual field progression in glaucoma. METHODS The study included 352 eyes of 250 glaucoma patients followed up for an average of 8.1 ± 3.5 years. Slopes of change over time were evaluated by the mean deviation (MD) from standard automated perimetry. For each eye, the follow-up time was divided into two equal periods: the first half was used to obtain the slopes of change and the second period was used to test the predictions. Slopes of change were calculated with two methods: the conventional approach of ordinary least squares (OLS) linear regression and a Bayesian regression model incorporating information on risk factors and presence of progressive optic disc damage on stereophotographs. The mean square error (MSE) of the predictions was used to compare the predictive performance of the different methods. RESULTS Higher mean IOP, thinner central corneal thickness (CCT), and presence of progressive optic disc damage were associated with faster rates of MD change. Incorporation of risk factor information into the calculation of individual slopes of MD change with the Bayesian method resulted in better prediction of future MD values than with the OLS method (MSE: 4.31 vs. 8.03, respectively; P < 0.001). CONCLUSIONS A Bayesian regression model incorporating structural and risk factor information into the estimation of glaucomatous visual field progression resulted in more accurate and precise estimates of slopes of functional change than the conventional method of OLS regression. (ClinicalTrials.gov number, NCT00221897.).

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.

Use of Statistical Analyses in the Ophthalmic Literature

PURPOSE To identify the most commonly used statistical analyses in the ophthalmic literature and to determine the likely gain in comprehension of the literature that readers could expect if they were to add knowledge of more advanced techniques sequentially to their statistical repertoire. DESIGN Cross-sectional study. METHODS All articles published from January 2012 through December 2012 in Ophthalmology, the American Journal of Ophthalmology, and Archives of Ophthalmology were reviewed. A total of 780 peer-reviewed articles were included. Two reviewers examined each article and assigned categories to each one depending on the type of statistical analyses used. Discrepancies between reviewers were resolved by consensus. MAIN OUTCOME MEASURES Total number and percentage of articles containing each category of statistical analysis were obtained. Additionally, we estimated the accumulated number and percentage of articles that a reader would be expected to be able to interpret depending on their statistical repertoire. RESULTS Readers with little or no statistical knowledge would be expected to be able to interpret the statistical methods presented in only 20.8% of articles. To understand more than half (51.4%) of the articles published, readers would be expected to be familiar with at least 15 different statistical methods. Knowledge of 21 categories of statistical methods was necessary to comprehend 70.9% of articles, whereas knowledge of more than 29 categories was necessary to comprehend more than 90% of articles. Articles related to retina and glaucoma subspecialties showed a tendency for using more complex analysis when compared with articles from the cornea subspecialty. CONCLUSIONS Readers of clinical journals in ophthalmology need to have substantial knowledge of statistical methodology to understand the results of studies published in the literature. The frequency of the use of complex statistical analyses also indicates that those involved in the editorial peer-review process must have sound statistical knowledge to appraise critically the articles submitted for publication. The results of this study could provide guidance to direct the statistical learning of clinical ophthalmologists, researchers, and educators involved in the design of courses for residents and medical students.