By Ji Liu, MD
RETINAL GANGLION CELL COUNT ESTIMATES ASSOCIATED WITH EARLY DEVELOPMENT OF VISUAL FIELD DEFECTS IN GLAUCOMA
Medeiros FA, Lisboa R, Weinreb RN, et al1
In this observational cohort study, Medeiros et al used an empirical formula2-4 that combines standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) measurements with spectral domain optical coherence tomography (SD-OCT) to estimate the retinal ganglion cell (RGC) numbers in glaucomatous eyes with earliest perimetric changes and compared the results to those in age-matched healthy eyes. The investigators analyzed 53 eyes with early glaucoma that were followed as a part of the Diagnostic Innovations in Glaucoma Study (DIGS) and 124 healthy eyes. All glaucomatous eyes had normal SAP visual fields at baseline and three consecutive abnormal test results during a median follow-up of 6.7 years. Estimates of RGC counts were obtained within 3 months of the first abnormal visual field, representing the earliest time at which visual field loss was detected in these eyes as they were becoming glaucomatous. According to the authors, the average estimated RGC count in eyes with early visual field defects was 652,057 ±115,829 cells. This was significantly lower than the average number of cells (910,584 ±142,412) found in healthy eyes (P < .001).
Compared with the age-matched healthy eyes, glaucomatous eyes had lost an average of 28.4% (6%-57%) of RGCs at the time of the earliest visual field defect on SAP. Further analysis found an excellent correlation of hemiretinal RGC estimates with corresponding superior or inferior hemifield defects. The investigators evaluated diagnostic accuracy using the receiver-operating characteristic curve and likelihood ratios (LRs). The estimated RGC counts performed significantly better in discriminating glaucomatous from healthy eyes than the average RNFL thickness parameter on SD-OCT, with the receiver-operating characteristic curve areas of 0.95 ±0.02 versus 0.88 ±0.03, respectively (P < .001). For 95% specificity, estimated RGC counts had a sensitivity of 68% for early glaucomatous damage detection with a positive LR of 13.6, whereas SD-OCT average RNFL thickness had a sensitivity of 53% with a positive LR of 10.6.
The glaucomatous eyes in this study were observed during the transitional period from normal to abnormal visual fields. The authors developed an empirical formula to estimate RGC numbers by combining structural (SD-OCT) and functional (Humphrey visual field; Carl Zeiss Meditec, Inc.) tests.3,4 The RGC estimates were found to be consistent with previous histologic reports on RGC numbers in healthy eyes and eyes associated with visual field defects on SAP.4,5 The result indicated that glaucomatous eyes may have already lost a substantial number of RGCs, even with the earliest development of visual field loss on automated perimetry. The authors found that, by adding the SAP data into this model, estimated RGC counts performed significantly better than SD-OCT RNFL average thickness alone in discriminating glaucomatous from healthy eyes and exhibited higher sensitivities at fixed specificities.
As suggested in many clinical studies, substantial RNFL loss can occur before visual field defects are detectable on SAP.5-10 The RGC estimate model in the study provided strong quantitative evidence that agreed with previous findings. This model may also carry significant implications for the diagnosis of glaucoma at its early stage by detecting and quantifying the loss of RGCs, even if it is not yet associated with detectable SAP losses.
THE RELATIONSHIP BETWEEN CUP-TO-DISC RATIO AND ESTIMATED NUMBER OF RETINAL GANGLION CELLS
Tatham AJ, Weinreb RN, Zangwill LM, et al11
Tatham et al investigated the relationship between cup-to-disc ratio (CDR) and estimated retinal ganglion cell (RGC) counts in this cross-sectional study. The data were collected from the African Descent and Glaucoma Evaluation Study (ADAGES)12 and the Diagnostic Innovations in Glaucoma Study (DIGS), both of which were designed to evaluate the structure of the optic nerve and visual function in glaucoma.11,12 A total of 156 healthy eyes, 53 eyes with suspected glaucoma, and 127 glaucomatous eyes from these two prospective longitudinal studies were included. The investigators estimated the number of RGCs using a model that combines RNFL measurements obtained with standard automated perimetry and spectral domain optical coherence tomography (SD-OCT).2-4 The mean estimated RGC count was 1,063,809 in healthy eyes; 828,522 in eyes with suspected glaucoma; and 774,200, 468,568, and 218,471 in eyes with early, moderate, and advanced glaucoma, respectively. Statistically significant differences in RGC estimates were found between all groups except for the eyes with suspected or early glaucoma.
The CDR was determined from stereoscopic photographs by at least two masked graders. A mean vertical CDR of 0.45 ±0.15 was found in healthy eyes versus 0.80 ±0.16 in glaucomatous eyes. Although the vertical CDRs were significantly larger in eyes with moderate and advanced glaucoma, no significant difference was found between the eyes of glaucoma suspects and eyes with early glaucoma. Vertical CDR determined by stereophotography showed excellent correlations with SD-OCT measurements (R2 = 0.825; P < .001). However, stereophotographic vertical CDR tended to be larger than SD-OCT measurements. A similarly strong correlation was also noted with average CDR between stereoscopic and SD-OCT assessments.
The study found that the stereophotographic vertical and average CDR increased with decreases in estimated RGC numbers, which represented a worsening severity of glaucoma. The relationship was best demonstrated by using a third-degree polynomial regression model. With the inclusion of age and optic disc area, this model accounted for 83.3% of the variation in estimated RGC numbers. By using this model, the authors estimated that a CDR change from 0.5 to 0.6 could occur with an approximate loss of 44,000 RGCs. In contrast, a change in CDR from 0.9 to 1.0 would be associated with a loss of nearly 300,000 RGCs.
CDRs are used extensively in clinical practice to document the status of the optic disc for the diagnosis and observation of glaucoma suspects and patients who have glaucoma.13 The progressive enlargement of the CDR in glaucomatous eyes represents continuous neuroretinal rim thinning due to RGC death. Clinicians’ ability to use CDRs to detect glaucoma and/or progressive structural changes is limited, however, due to the wide variability of CDRs in the normal population, the variability of the optic disc’s size, and relatively large intra- and interobserver variability.14-19 All of this makes it difficult for physicians to detect subtle CDR changes over time. Sometimes, at least 0.2 changes of CDR are needed for the progression to be detectable.16,19 Although such detectable changes are likely to correspond to the loss of large amounts of neural tissue, a quantitative study to evaluate the number of RGCs lost with the CDR changes was absent. This study was a pilot report that investigated the relationship of CDR changes with estimated RGC loss.
In addition to providing estimated RGC counts with different CDRs for patients of different ages, the study also found a nonlinear relationship between RGC estimates and CDRs. This indicated that eyes with a large CDR would have to lose large numbers of RGCs to exhibit a small increase in CDR. On the other hand, even relatively small changes in CDR in eyes with large CDRs may be associated with large losses of RGCs. For eyes with a small CDR, the loss of a relatively small number of RGCs could result in a large increase in CDR. The same decrease in RGCs in eyes with a large CDR would result in a relatively subtle and perhaps undetectable change in CDR.
The relationship between estimated RGC counts and CDR suggests that the assessment of change in CDR is a relatively insensitive method for evaluating progressive RGC losses in glaucoma, especially in eyes with moderate to large CDRs. In an eye with advanced glaucoma and a large CDR, it would therefore be difficult to detect further CDR changes unless the loss of neurons was substantial. These results are consistent with those of other studies and suggest optic disc evaluation by biomicroscopy or photographs may be relatively insensitive for the detection of glaucomatous progression in eyes with moderate to advanced disease.19-22
RETINAL NERVE FIBER LAYER ATROPHY IS ASSOCIATED WITH VISUAL FIELD LOSS OVER TIME IN GLAUCOMA SUSPECT AND GLAUCOMATOUS EYES
Sehi M, Zhang X, Greenfield DS, et al23
In a prospective, nonrandomized, longitudinal clinical trial, Sehi et al compared progressive retinal nerve fiber layer (RNFL) atrophy with visual field progression in glaucoma suspects and in patients with preperimetric or perimetric glaucoma. Participants were enrolled in the Advanced Imaging for Glaucoma (AIG) Study and were observed for at least 28 months. The study included 310 eyes with suspected or preperimetric glaucoma and 177 eyes with perimetric glaucoma. Visual field testing was performed on all eyes using standard automated perimetry and time domain optical coherence tomography every 6 months. Visual field progression was defined when a significant (P < .05) negative visual field index slope was first reached. RNFL progression or improvement was defined as a significantly negative or positive slope over time.
In the study, 89 eyes had visual field progression, and 101 eyes had RNFL progression. The average time to detect visual field progression was 35 ±13 months, and the average time to detect RNFL progression was 36 ±13 months. Seventy-five (15.4%) eyes with RNFL progression did not show visual field progression, and 63 (12.9%) eyes with visual field progression did not show RNFL progression. Only 26 eyes demonstrated progression using both methods (P = .35, McNemar test). The cumulative probability of visual field progression was significantly higher in eyes with overall RNFL progression than those without (Kaplan-Meier analysis; P < .014, log-rank test). The rate of visual field loss per year was significantly steeper for eyes with significant RNFL loss compared with those without RNFL loss in the perimetric glaucoma group. In multivariate Cox models, average and superior RNFL losses were associated with subsequent visual field index loss in the entire cohort (every 10-mm loss; hazard ratio, 1.38; P = .03; hazard ratio, 1.20; P = .01; respectively). Among the entire cohort of 487 eyes, 42 had significant visual field index improvement, and 55 had significant RNFL improvement (specificity, 91.4% and 88.7%, respectively; P = .80).
This prospective study was designed to explore whether RNFL loss was predictive of subsequent visual field loss. The investigators used trend-based analysis to compare RNFL progression with visual field progression. The authors found that average and superior RNFL were significant predictors of subsequent visual field loss in the entire cohort as time-dependent covariates. Multivariate Cox models suggested that every 10-mm decrease in average RNFL thickness was associated with a 38% higher chance of visual field progression, whereas every 10-mm decrease in superior RNFL thickness was associated with a 20% higher chance of visual field progression. Previous studies have similarly suggested that RNFL thinning may be a predictor of subsequent visual field loss.24,25
Of the 190 eyes with progressive disease detected by either RNFL or visual field loss, 70 eyes (37%) showed visual field progression without or before RNFL progression. This finding is consistent with some other reports that visual field loss can occur without or prior to detectable structural progression.26-29 The reason that functional progression may be found before structural changes are detected in some patients or vice versa is unclear. It may be because the tests clinicians normally use are still not sensitive enough. It is not uncommon for the structural and functional progression not to be detected simultaneously within a certain period, but with long-term follow-up, eventually, both structural and functional progression will correlate with and confirm each other. The current study suggests that both structure and function are useful for the detection of glaucomatous progression, given the discordance in the timing of detecting longitudinal changes in the optic nerve and visual field.23
Ji Liu, MD, is an assistant professor of ophthalmology and visual science in the Department of Ophthalmology & Visual Science at Yale School of Medicine in New Haven, Connecticut. He acknowledged no financial interest in the products or companies mentioned herein. Dr. Liu may be reached at email@example.com.
- Medeiros FA, Lisboa R, Weinreb RN, et al. Retinal ganglion cell count estimates associated with early development of visual field defects in glaucoma. Ophthalmology. 2013;120:736-744.
- Harwerth RS, Wheat JL, Fredette MJ, et al. Linking structure and function in glaucoma. Prog Retin Eye Res. 2010;29:249-271.
- Medeiros FA, Lisboa R, Weinreb RN, et al. A combined index of structure and function for staging glaucomatous damage. Arch Ophthalmol. 2012;130:1107-1116.
- Jonas JB, Schmidt AM, Muller-Bergh JA, et al. Human optic nerve fiber count and optic disc size. Invest Ophthalmol Vis Sci. 1992;33:2012-2018.
- Kerrigan-Baumrind LA, Quigley HA, Pease ME, et al. Number of ganglion cells in glaucoma eyes compared with threshold visual field tests in the same persons. Invest Ophthalmol Vis Sci. 2000;41:741-748.
- Quigley HA, Dunkelberger GR, Green WR. Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol. 1989;107:453-464.
- Medeiros FA, Alencar LM, Zangwill LM, et al. Prediction of functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol. 2009;127:1250-1256.
- Hood DC, Kardon RH. A framework for comparing structural and functional measures of glaucomatous damage. Prog Retin Eye Res. 2007;26:688-710.
- Wollstein G, Schuman JS, Price LL, et al. Optical coherence tomography longitudinal evaluation of retinal nerve fiber layer thickness in glaucoma. Arch Ophthalmol. 2005;123:464-470.
- Leung CK, Cheung CY, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a study on optical coherence tomography guided progression analysis. Invest Ophthalmol Vis Sci. 2010;51:217-222.
- Tatham AJ, Weinreb RN, Zangwill LM, et al. The relationship between cup-to-disc ratio and estimated number of retinal ganglion cells. Invest Ophthalmol Vis Sci. 2013;54:3205-3214.
- Sample PA, Girkin CA, Zangwill LM, et al. The African Descent and Glaucoma Evaluation Study (ADAGES): design and baseline data. Arch Ophthalmol. 2009;127:1136-1145.
- Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 2004;363:1711-1720.
- Lichter PR. Variability of expert observers in evaluating the optic disc. Trans Am Ophthalmol Soc. 1976;74:532-572.
- Tielsch JM, Katz J, Quigley HA, et al. Intraobserver and interobserver agreement in measurement of optic disc characteristics. Ophthalmology. 1988;95:350-356.
- Varma R, Steinmann WC, Scott IU. Expert agreement in evaluating the optic disc for glaucoma. Ophthalmology. 1992;99:215-221.
- Harper R, Reeves B, Smith G. Observer variability in optic disc assessment: implications for glaucoma shared care. Ophthalmic Physiol Opt. 2000;20:265-273.
- Sung VCT, Bhan A, Vernon SA. Agreement in assessing optic discs with a digital stereoscopic optic disc camera (Discam) and Heidelberg Retina Tomograph. Br J Ophthalmol. 2002;86:196-202.
- Jampel HD, Friedman D, Quigley H, et al. Agreement among glaucoma specialists in assessing progressive disc changes from photographs in open-angle glaucoma patients. Am J Ophthalmol. 2009;147:39-44.
- Read RM, Spaeth GL. The practical clinical appraisal of the optic disc in glaucoma: the natural history of cup progression and some specific disc-field correlations. Trans Am Acad Ophthalmol Otolaryngol. 1974;78:255-274.
- Coleman AL, Sommer A, Enger C, et al. Interobserver and intraobserver variability in the detection of glaucomatous progression of the optic disc. J Glaucoma. 1996;5:384-389.
- Spaeth GL, Lopes JF, Junk AK, et al. Systems for staging the amount of optic nerve damage in glaucoma: a critical review and new material. Surv Ophthalmol. 2006;51:293-315.
- Sehi M, Zhang X, Greenfield DS, et al. Retinal nerve fiber layer atrophy is associated with visual field loss over time in glaucoma suspect and glaucomatous eyes. Am J Ophthalmol. 2013;155(1):73-82.
- Leung CK, Liu S, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma a prospective analysis with neuroretinal rim and visual field progression.Ophthalmology. 2011;118(8):1551-1557.
- Leung CK, Chiu V, Weinreb RN, et al. Evaluation of retinal nerve fiber layer progression in glaucoma: a comparison between spectral-domain and time-domain optical coherence tomography. Ophthalmology. 2011;118:1558-1562.
- Medeiros FA, Alencar LM, Zangwill LM, et al. Prediction of functional loss in glaucoma from progressive optic disc damage. Arch Ophthalmol. 2009;127(10):1250-1256.
- Zhu H, Crabb DP, Fredette MJ, et al. Quantifying discordance between structure and function measurements in the clinical assessment of glaucoma. Arch Ophthalmol. 2011;129(9):1167-1174.
- Xin D, Greenstein VC, Ritch R, et al. A comparison of functional and structural measures for identifying progression of glaucoma. Invest Ophthalmol Vis Sci. 2011;52(1):519-526.
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713.