To compare spectral-domain optical coherence tomography (SDOCT) measured circumpapillary retinal nerve fiber layer (cpRNFL) among 4 glaucomatous optic disc phenotypes in early glaucoma.
Clinical cohort study
In this study, 218 early glaucoma eyes that had at least 3 years of follow-up and a minimum of 4 SDOCT scans were recruited. The optic discs were classified into 4 types based on appearance: 76 generalized cup enlargement (GE), 53 focal ischemic (FI), 22 myopic glaucomatous (MY), and 67 senile sclerotic (SS). A linear mixed effects model was used to compare the rates of global and regional cpRNFL thinning among optic disc phenotypes.
After adjusting for confounders, the SS group (mean [95% CI]: –1.01 [–1.30, –0.73] µm/y) had the fastest mean rate of global cpRNFL thinning followed by FI (–0.77 [–0.97, –0.57] µm/y), MY (0.59 [–0.81, –0.36] µm/y), and GE (–0.58 [–0.75, –0.40] µm/y) at P < .001. The inferior temporal sector had the fastest rate of cpRNFL thinning among the regional measurements except for the MY group (–0.68 [–1.10, –0.26] µm/y, P = .002). In the multivariable analysis, GE ( P = .002) and MY ( P = .010) phenotypes were associated with significantly slower global rates of cpRNFL thinning compared with the SS phenotype.
Rates of cpRNFL thinning were different among the 4 glaucomatous optic disc phenotypes. Those patients with early glaucoma with SS phenotype have the fastest cpRNFL thinning. These patients may benefit from more frequent monitoring and the need to advance therapy if cpRNFL thinning is detected.
G laucoma is an optic neuropathy characterized by progressive structural changes, loss of retinal ganglion cells and their axons, and damage to the visual field (VF). , The chronic and progressive nature of glaucoma requires timely detection of the disease through analysis of structural and functional changes. Optical coherence tomography (OCT) quantifies structural parameters of the optic disc and circumpapillary retinal nerve fiber layer (cpRNFL) with good precision and reproducibility. In early glaucoma, cpRNFL thinning can occur without VF changes and can be detected using OCT. Moreover, a faster rate of global cpRNFL loss has been implicated with a higher risk of developing VF defect in glaucoma suspects.
Glaucomatous damage to the optic disc can manifest with different morphologic patterns. It has been proposed that certain patterns of optic disc damage are secondary to specific pathophysiological mechanisms, and patients can be categorized into 4 clinical subtypes based on the appearance of the optic nerve. , Morphologic subtypes of glaucomatous optic disc damage may therefore help to differentiate the wide clinical spectrum of open-angle glaucoma.
This study determined patterns of cpRNFL thinning in the 4 glaucomatous optic disc phenotypes of patients with early glaucoma followed prospectively for several years.
This was an observational cohort study in participants from a prospective longitudinal study designed to evaluate optic nerve structure and visual function in glaucoma (Diagnostic Innovations Glaucoma Study [DIGS] and African Descent and Glaucoma Evaluation Study [ADAGES]). Participants in these cohorts were longitudinally evaluated according to a pre-established protocol that included regular follow-up visits in which patients underwent a clinical examination, imaging, and functional tests. All participants from the DIGS and ADAGES study who met the inclusion criteria described below were enrolled in the current study. Informed consent was obtained from all participants. The University of California, San Diego, Human Subject Committee approved all protocols, and the methods described adhered to tenets of the Declaration of Helsinki.
All patients underwent an annual comprehensive ophthalmologic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, dilated fundus examination, stereoscopic optic disc photography, ultrasonographic pachymetry, and standard automated perimetry (SAP) in both eyes. Semiannual examinations included intraocular pressure (IOP) measurement, spectral-domain optical coherence tomography (SDOCT) imaging, and SAP testing.
Glaucoma was defined as the presence of glaucomatous optic nerve damage (ie, the presence of focal thinning, notching, or localized or diffuse atrophy of the RNFL) with reliable (fixation losses <33%, false negatives <33%, and false positives <33%) and repeatable abnormal SAP tests using the 24-2 Swedish Interactive Threshold Algorithm with either a Pattern Standard Deviation outside the 95% normal limits or a Glaucoma Hemifield Test result outside the 99% normal limits. Patients with baseline 24-2 mean deviation (MD) >−6.0 dB were included in this study.
Inclusion criteria included (1) age ≥18 years, (2) open angles on gonioscopy, (3) best-corrected visual acuity of 20/40 or better, and (4) ≥3 years of follow-up with a minimum of 4 SDOCT scanning sessions.
Exclusion criteria included (1) history of trauma or intraocular surgery (except for uncomplicated cataract surgery or glaucoma surgery), (2) coexisting retinal disease, (3) uveitis, or (4) nonglaucomatous optic neuropathy. Participants with a diagnosis of Parkinson disease, Alzheimer disease, dementia, or a history of stroke were also excluded. Those with unreliable VFs or poor-quality SDOCT scans were also excluded from this report.
Optic Disc Classification
All color simultaneous stereophotographs were taken using a Nidek Stereo Camera Model 3-DX (Nidek Inc, Palo Alto, California, USA) after maximal pupil dilation. All photograph evaluations were performed using a simultaneous stereoscopic viewer (Asahi Pentax Stereo Viewer II; Pentax, Tokyo, Japan) with a standard fluorescent light bulb. As described by Nicolela and Drance and then in our previous study, the optic discs were classified into 4 types based on appearance: generalized cup enlargement (GE), focal ischemic (FI), myopic glaucomatous (MY), and senile sclerotic (SS). For optic discs with GE, the cup is concentrically enlarged and there are no localized areas of neuroretinal rim loss or pallor. For focal optic disc damage, the neuroretinal rim has a localized notch inferiorly or superiorly, while the remaining tissue is relatively well preserved. For optic discs classified as the high myopia phenotype, there is a tilted appearance, shallow cupping, and a myopic crescent of peripapillary atrophy. Optic discs with sclerotic damage have shallow cupping with marked areas of peripapillary atrophy. The classification of optic disc phenotype was evaluated by 2 experienced graders (E.E. and S.M.) using a stereoscopic viewer. Each grader was masked to the subject’s identity and the other test results. All included photographs were judged to be of adequate quality or better. Discrepancies between the 2 graders were resolved by consensus or adjudication by a third experienced grader. Inability to reach a consensus led to exclusion of the case.
The Spectralis SDOCT (software version 22.214.171.124; Heidelberg Engineering, Inc, Heidelberg, Germany) was used to obtain cpRNFL measurements. Details of its operation have been discussed elsewhere. The high-resolution protocol was used, obtaining 1536 A-scans from a 3.45-mm circle centered at the optic disc, providing an axial resolution of 3.9 µm and a lateral resolution of 6 µm. The Spectralis SDOCT included an automatic real time function that gathers multiple frames (B-scans) to increase image quality. The images were then averaged for noise reduction. The quality score ranges from 0 dB (poor) to 40 dB (excellent). To be included, all images were reviewed by experienced graders of the Imaging Data Evaluation and Assessment (IDEA) Center for noncentered scans, accurate segmentation, and a signal strength >15 dB. The cpRNFL measurements evaluated in this study included the mean global index, temporal quadrant (316-45 degrees), superior temporal sector (46-90 degrees), superior nasal sector (91-135 degrees), nasal quadrant (136-225 degrees), inferior nasal sector (226-270 degrees), and inferior temporal sector (271-315 degrees).
Descriptive statistics were calculated as the mean and 95% confidence interval (95% CI). Categorical variables were compared using the χ 2 test. The kappa value was used to estimate the extent of agreement between the 2 observers. Mixed effects modeling was used to compare ocular parameters among groups. Models were fitted with ocular measurements as response variable and classification groups as fixed effects. Measurements of bilateral eyes were nested within subject to account for the fact that eyes from the same individual were more likely to have similar measurements. Contributory factors affecting cpRNFL thinning were examined using a univariable and multivariable linear mixed model. Multivariable models were constructed including the following potential confounding factors: age, gender, baseline 24-2 mean deviation (MD), and any other ocular parameters in which the P value was <0.1 in univariable analysis.
The evaluation of the effect of optic disc phenotype parameters on mean rates of change in cpRNFL in each group were performed using a linear mixed model with random intercepts and random slopes. In this model, the average evolution of the outcome variable (cpRNFL measurements) was explored using a linear function of time, and random intercepts and random slopes were introduced with patient- and eye-specific deviations from this average evolution. The model can account for the fact that different eyes can have different rates of cpRNFL thinning over time, while accommodating correlations between both eyes of the same individual. , Because cpRNFL decline may depend on disease severity, an unstructured covariance between random effects was assumed, allowing for correlation between intercepts and slopes of change. In addition to putative predictors to examine the effect of variables on the baseline cpRNFL, interaction terms between time and predictors were included in the model to explore whether there is a significant effect of the predictor on changes of the outcome variable over time. Age, race, baseline 24-2 MD, and mean IOP during follow-up were used as predictors in this investigation. In the evaluation of progressors, individual slopes in each phenotype were classified into groups according to a pre-established range for mean rates of global cpRNFL thinning: slow, if change was greater than –1.0 µm/y; moderate, if between –1.0 and –2.0 µm/y; and fast, if change was less than –2.0 µm/y.
All statistical analyses were performed with commercially available software (Stata version 14; StataCorp, College Station, Texas, USA). Statistical significance for tests was set at P ≤.05.
Overall, 218 eyes from 173 glaucoma subjects met our inclusion criteria and were enrolled in this longitudinal study. Of these eyes, the optic disc appearance of 76 eyes were classified as GE, 53 eyes as FI, 22 eyes as MY, and 67 eyes as SS. The kappa value for interobserver agreement in classification into the 4 types of glaucomatous optic disc phenotypes was good at 0.833 (95% CI: 0.807, 0.840).
The baseline demographics of the subjects with GE, FI, MY, and SS groups, are summarized in Table 1 . The mean baseline age of the SS group (74.3 years) was the highest compared with the other 3 groups ( P = .001). The GE group was predominantly of African American descent (54.1%, P = .001). The incidence of self-reported diabetes mellitus was higher in the GE (29.5%), especially when compared with the FI and MY groups ( P = .004). The MY group had a longer mean axial length (AL) among the groups and was statistically significant compared with the GE and FI groups ( P = .051). Baseline 24-2 MD was higher in the GE and MY groups than in the SS and FI groups ( P < .001). Similarly, the GE and MY groups had significantly thicker baseline global cpRNFLs compared with the FI and SS groups ( P < .001). The SS group had higher central corneal thickness measurements among phenotypes and was statistically significant compared with the GE group ( P = .160). Other variables including baseline IOP, mean IOP during follow-up, follow-up time, and number of OCT follow-up scans were comparable among phenotype groups.
|By subject (no.)||61||46||18||48|
|Age, y||66.8 |
§ ¶ #
|Race: Non-African American / African American||28/33||30/16||13/5||36/12||.001 |
† ‡ §
|Self-reported HTN, n (%)||41 (67.2%)||24 (52.2%)||13 (72.2%)||33 (68.8%)||.235|
|Self-reported DM, n (%)||18 (29.5%)||4 (8.7%)||7 (38.9%)||9 (18.8%)||.004 |
|By eye, n||76||53||22||67|
|Axial length, mm||23.8 |
|CCT, µm||530.0 |
|531.9 (519.3, 544.5)||545.5 (522.4, 568.5)||550.0 |
|Baseline IOP, mm Hg||14.6 |
|Mean IOP, mm Hg||14.4 |
|Baseline 24-2 MD, dB||–1.4 |
† § ‖ #
|Baseline global cpRNFL, µm||83.7 |
† § ‖ #
|Follow-up, y||5.9 |
|Number of SDOCT follow-up scans||10.5 |