Comparing the Rates of Retinal Nerve Fiber Layer and Ganglion Cell–Inner Plexiform Layer Loss in Healthy Eyes and in Glaucoma Eyes

Home , Inner plexiform layer

NAAMA HAMMEL, AKRAM BELGHITH, ROBERT N. WEINREB, FELIPE A. MEDEIROS, NADIA MENDOZA, AND LINDA M. ZANGWILL

PURPOSE: To compare the rates of circumpapillary severe glaucoma. (Am J Ophthalmol 2017;178: retinal nerve fiber layer (RNFL) and macular retinal gan- 38–50. Ó 2017 Elsevier Inc. All rights reserved.) glion cell–inner plexiform layer (GCIPL) change over time in healthy and glaucoma eyes. DESIGN: Cohort study. HE DIAGNOSIS OF GLAUCOMA IN CLINICAL PRAC- METHODS: The rates of circumpapillary RNFL and tice largely depends on identification of character- macular GCIPL loss in 28 healthy subjects and 97 T istic structural changes to the optic nerve head, glaucoma subjects from the Diagnostic Innovations in which are often accompanied by functional deficits on vi- 1,2 Glaucoma Study (DIGS) were compared using mixed- sual field testing. Advances in imaging technologies, effects models. especially the development of optical coherence RESULTS: The median follow-up time and number of tomography (OCT), provide a means for the objective visits were 1.7 years and 6 visits and 3.2 years and 7 visits evaluation of structural changes to the optic nerve head for healthy and glaucoma eyes, respectively. Significant and retina in glaucoma, and offer the potential for rates of loss of both global circumpapillary RNFL and improved detection of disease. It has been shown that average macular GCIPL thickness were detectable in circumpapillary retinal nerve fiber layer (RNFL) early and moderate glaucoma eyes; in severe glaucoma measurements from OCT have good ability to 3–5 eyes, rates of average macular GCIPL loss were signifi- differentiate glaucomatous and healthy eyes. cant, but rates of global circumpapillary RNFL loss Apoptosis of retinal ganglion cells (RGCs) and their were not. In glaucoma eyes, mean rates of global circum- axons, the hallmark of glaucoma, results not only in papillary RNFL thickness change (L0.98 mm/year [95% circumpapillary RNFL thinning but also in thinning of 6–10 confidence interval (CI), L1.20 to L0.76]) and normal- the retina in the macular region. As approximately ized global circumpapillary RNFL change (L1.7%/year 50% of RGCs are concentrated within 4.5 mm of the [95% CI, L2.1 to L1.3]) were significantly faster than fovea, comprising about 30%–35% of retinal thickness in average macular GCIPL change (L0.57 mm/year that area, changes in macular structure are likely to be a 6,11 [(95% CI, L0.73 to L0.41]) and normalized macular good indicator of glaucoma-related neural loss. Recent GCIPL change (L1.3%/year [95% CI, L1.7 studies have shown that OCT measurements of macular to L0.9]). The rates of global and inferior RNFL change structures such as macular ganglion cell complex (GCC) were weakly correlated with global and inferior macular may be useful for differentiating healthy and 12–16 GCIPL change (r ranges from 0.16 to 0.23, all P < .05). glaucomatous eyes. Macular GCC has been reported CONCLUSIONS: In this cohort, the rate of circumpapil- to have similar diagnostic performance to circumpapillary 13–16 lary RNFL thickness change was faster than macular RNFL ; however, some studies have suggested 17,18 GCIPL change for glaucoma eyes. Global circumpapillary measurement of circumpapillary RNFL to be better. RNFL thickness loss was detectable in early and moderate The macular GCC thickness measurement incorporates glaucoma, and average macular GCIPL thickness loss was several retinal layers, including ganglion cell layer, inner detectable in early, moderate, and severe glaucoma, plexiform layer, and overlying RNFL. Recent suggesting that structural changes can be detected in developments in spectral-domain OCT (SDOCT) provide the ability for segmentation of the ganglion cell containing macular ganglion cell–inner plexiform layer (GCIPL). The presence of age-related loss of RGCs and their axons has been demonstrated in human nonglaucomatous eyes by Accepted for publication Mar 6, 2017. 19–21 From the Hamilton Glaucoma Center, Department of Ophthalmology, both histologic and in vivo measurements using digital University of California, San Diego, La Jolla, California. technologies such as OCT and confocal scanning laser Inquiries to Linda M. Zangwill, Hamilton Glaucoma Center, Shiley Eye ophthalmoscopy (CSLO).22–26 The estimated rates of Institute and Department of Ophthalmology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0946; e-mail: lzangwill@ucsd. RGC loss in healthy eyes were remarkably similar when 27 edu examined histologically and when estimated combining

38 © 2017 ELSEVIER INC.ALL RIGHTS RESERVED. 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2017.03.008 structural and functional measurements,28 with an estimate (IOP) measurement using Goldmann applanation tonom- of about 7000 RGCs/year.27,28 There are a limited number etry, and dilated funduscopic examination. Stereoscopic of small longitudinal studies that have reported rates of age- optic disc photography (Kowa WX3D; Kowa Optimed, related and/or glaucomatous changes of macular and Inc, Torrance, California, USA or Nidek 3Dx; Nidek circumpapillary RNFL thickness measurements by Inc, Fremont, California, USA) and standard automated SDOCT, but none have directly compared the rate and perimetry with the 24-2 Swedish Interactive Threshold Al- pattern of circumpapillary RNFL and macular GCIPL loss gorithm (SAP-SITA, Humphrey Field Analyzer; Carl Zeiss in the same eyes.25,29 Understanding possible differences Meditec, Dublin, California, USA) were obtained. The in the rate and pattern of age-related circumpapillary quality of visual fields was reviewed by the Visual Field RNFL and macular GCIPL loss will improve our ability Assessment Center (VisFACT) staff according to a stan- to differentiate between age-related loss and glaucomatous dard protocol. Axial length was acquired with IOLMaster loss for clinical management decisions. (Carl Zeiss Meditec, Dublin, California, USA). The objective of this study was to compare the rates of Healthy eyes were defined as having a healthy appear- inner retinal layer thickness loss, specifically the macular ance on stereoscopic photographs, IOP of less than GCIPL, to circumpapillary RNFL thickness loss over 22 mm Hg, no history of elevated IOP, and at least 2 reli- time in healthy and glaucoma eyes. able normal visual fields, defined as a pattern standard deviation (PSD) within 95% confidence limits and a glaucoma hemifield test (GHT) result within normal limits. Glaucoma eyes were defined as eyes having METHODS glaucomatous-appearing optic discs (neuroretinal rim thinning, excavation, or circumpapillary RNFL defect) and/or PARTICIPANTS: Participants were enrolled in the longi- repeatable visual field damage (PSD outside 95% tudinal Diagnostic Innovations in Glaucoma Study confidence limits or GHT outside normal limits) at base- (DIGS) conducted at the Hamilton Glaucoma Center at line. The glaucoma eyes included eyes from early the University of California, San Diego (UCSD). DIGS (MD > 6 dB), moderate (12 dB < MD < 6 dB), is a prospective longitudinal study designed to evaluate op- and severe (MD < 12 dB) disease. tic nerve structure and visual function in glaucoma. Meth- odological details have been described previously.30,31 INSTRUMENTATION: Measurements of circumpapillary Enrollment of participants is based on the inclusion/ RNFL and macular GCIPL thicknesses were taken using exclusion criteria specified below. Informed consent was Cirrus HD-OCT (software v. 6.5; Carl Zeiss Meditec Inc, obtained from each participant and the institution’s Dublin, California, USA). The operation of this device Human Subjects Committee approved all methodology. has been described in detail previously.32 Cirrus HD- All methods adhered to the tenets of the Declaration of OCT uses a superluminescent diode scan with a center Helsinki for research involving human subjects and wavelength of 840 nm and an acquisition rate of 27 000 to the Health Insurance Portability and Accountability A-scans per second at an axial resolution of 5 mm. The pro- Act. DIGS was registered at http://cilincaltrials.gov tocol used for circumpapillary RNFL thickness measure- (NCT00221897) on September 14, 2005. ment was the optic disc cube 200 3 200 protocol with Eligible participants had best-corrected visual acuity of circumpapillary RNFL thickness measurements calculated 20/40 or better, spherical refraction within 65.0 diopter from a 3.46-mm-diameter circular scan (10 870 mmin (D), cylinder correction within 63.0 D, and open angles length) automatically placed around the optic disc. The on gonioscopy. All participants were older than 18 years. protocol used for macular GCIPL thickness measurement Participants were excluded if they had a history of intraoc- was the macular cube 200 3 200 protocol. This protocol ular surgery (except for uncomplicated cataract or glau- is based on a 3-dimensional scan centered on the macula coma surgery). Eyes with coexisting retinal disease, in which information from a 1024 (depth) 3 200 3 200- uveitis, or nonglaucomatous optic neuropathy were point parallelepiped is collected. The ganglion cell analysis excluded from the investigation. Diabetic participants algorithm automatically segmented the macular GCIPL with no evidence of retinal involvement were included. based on 3-dimensional data generated from the macular Self-reported information regarding systemic conditions, cube scan protocol. The algorithm identifies the outer medications, and risk factors associated with glaucoma boundary of RNFL and the outer boundary of inner plexi- was recorded. Each participant underwent a comprehen- form layer at the macular region; this segmented layer sive ophthalmologic examination including review of med- yielded macular GCIPL thickness. Image quality was eval- ical and family history, best-corrected visual acuity testing, uated by an experienced examiner from the UCSD Imaging central corneal thickness (CCT) measurement using an Data Evaluation and Assessment Reading Center. To be ultrasound pachymeter (Pachette GDH 500; DGH Tech- included in the analysis images were designated as good nology, Inc, Philadelphia, Pennsylvania, USA), slit-lamp quality, defined as focused images, signal strength greater biomicroscopy including gonioscopy, intraocular pressure than 6, and good centering on the optic disc or fovea for

VOL. 178 RATES OF CIRCUMPAPILLARY AND MACULAR LOSS IN GLAUCOMA EYES 39 the optic disc and macular cube protocols, respectively. glaucoma subjects). Demographic and baseline ocular Scans were also evaluated as to the adequacy of the characteristics are presented in Table 1. Glaucoma segmentation algorithm for detection of the circumpapil- subjects were older than healthy subjects (68 years lary RNFL and macular GCIPL. Only scans without overt [range, 32.3–89.6 years] and 47 years [range, 22.5–66.4 segmentation algorithm failure in detecting the retinal years], respectively, P < .001), had a smaller proportion borders were included in the study. Only eyes with both op- of women among the group (50% and 75%, respectively, tic nerve head and macular imaging on each visit were P ¼ .001), had thinner corneas (545 6 44 mm and 563 included in the analysis. 6 33 mm, respectively, P ¼ .005), had worse mean baseline SAP-SITA mean deviation (MD) (4.3 6 5.9 dB STATISTICAL ANALYSIS: Descriptive statistics were used and 0.1 6 1.8 dB, respectively, P < .001), had longer to compare demographic characteristics by group (healthy follow-up (median 3.2 years [interquartile range (IQR), and glaucoma subjects). x2 tests were used to compare 1.9–3.5 years] and 1.7 years [IQR, 1.4–2.0 years], respec- categorical variables and t tests were used to compare tively, P < .001), and had a slightly larger number of Cirrus continuous variables. visits (median 7 [IQR, 5–9] and 6 [IQR, 4–7], respectively, Mixed-effects models were used to calculate the rates of P ¼ .005). No statistically significant differences were change (slopes) for circumpapillary RNFL and macular found between healthy and glaucoma eyes with regard to GCIPL thickness loss from baseline. Models included race, mean IOP, or disc area. Early glaucoma eyes had mean IOP, group (healthy vs glaucoma and severity of higher mean IOP compared with moderate and severe glau- disease), time, and the interaction term group 3 time. coma eyes (15.2 6 2.9 mm Hg, 12 6 2.8 mm Hg, and 11.5 Comparisons between the rate of change in healthy and 6 4.0 mm Hg, respectively, P ¼ .01), thicker corneas glaucoma eyes also included age in the model to account (549 6 43 mm, 534 6 43 mm, and 531 6 47 mm, respec- for differences in age. Mixed-effects models with random tively, P ¼ .002), and a larger number of Cirrus visits intercepts and random slopes have been previously used (median 7 [IQR, 5–10], 6 [IQR, 4–11], and 5 [IQR, 4–7], in this setting to adjust for within-patient correlation in respectively, P ¼ .014). Follow-up time was longer in early measurements between eyes from the same participant and moderate glaucoma eyes compared with severe glau- and to account for the repeated measurements over coma eyes (median 3.2 [IQR, 2.2–3.6 years], 3.2 [IQR, time.33–36 1.4–3.4 years], and 1.8 [IQR, 1.4–2.6 years]). No statisti- Despite the fact that circumpapillary RNFL and macular cally significant differences were found between glaucoma GCIPL are both measured in micrometers, the measure- severity groups with regard to age or disc area. ments differ in magnitude and range. Therefore, in order Baseline global and sectoral circumpapillary RNFL and to compare circumpapillary RNFL and macular GCIPL macular GCIPL thickness measurements by group and dis- rates of change over time within each group we calculated ease severity are presented in Table 2. Healthy eyes had the rates of change using a dynamic range–based normal- larger baseline circumpapillary RNFL and macular GCIPL ized coefficient: percent of dynamic range change ¼ [(visit thickness for all sectors when compared with glaucoma value floor value)/dynamic range] 3 100/year. The eyes. Early glaucoma eyes had larger baseline circumpapil- dynamic range was estimated by calculating the means of lary RNFL and macular GCIPL thickness for all sectors the top and bottom 3% of eyes of unique patients. when compared with moderate and severe glaucoma eyes. Because the sectors of macular GCIPL thickness mea- Rates of global and sectoral circumpapillary RNFL and surements are generally topographically related to specific macular GCIPL thickness loss and normalized loss in circumpapillary RNFL sectors,33 we analyzed the strength healthy and glaucoma eyes are presented in Tables 3 and of the associations among sectors by calculating the corre- 4, respectively. In healthy eyes, the rate of normalized lation coefficient for all combinations of circumpapillary circumpapillary RNFL change was significantly different RNFL and macular GCIPL sectors using Spearman correla- from zero globally and in the inferior quadrant, whereas tion coefficients. the rate of normalized macular GCIPL change was not A P value less than .05 was considered statistically signif- significantly different from zero in any sector. In glaucoma icant. Statistical analyses were performed using SAS eyes, rates of normalized circumpapillary RNFL and macu- software version 9.3 (SAS Institute, Cary, North Carolina, lar GCIPL change were significantly different from zero USA). globally and in all quadrants/sectors. Rates of normalized change by sector are presented in Figures 1 and 2. The distributions of the rates of global circumpapillary RNFL and average macular GCIPL percent loss for healthy RESULTS and glaucoma eyes are presented in Figures 3 and 4, respectively. In healthy eyes, mean global circumpapillary RNFL FIFTY-SIX EYES OF 28 HEALTHY SUBJECTS AND 176 EYES OF 97 normalized change was 1.4 times faster than mean average glaucoma subjects were included in this study (135 eyes of macular GCIPL percent change; however, this difference 70 early, 21 eyes of 16 moderate, 20 eyes of 11 severe did not reach statistical significance (0.61%/year

40 AMERICAN JOURNAL OF OPHTHALMOLOGY JUNE 2017 TABLE 1. Diagnostic Innovation in Glaucoma Study (DIGS): Baseline Demographics and Ocular Characteristics by Groupa

Glaucoma

Healthy Early Moderate Severe Total By Subject N ¼ 28 N ¼ 70 N ¼ 16 N ¼ 11 N ¼ 97 P Valueb P Valuec

Mean age at baseline (y) 47 6 11 68 611 71 6 11 66 6 12 68 6 11 .150 <.001* Sex, female (%) 21 (75%) 37 (53%) 4 (25%) 7 (64%) 48 (50%) .020* .001* Race .362 European descent 17 (61%) 65 (67%) African descent 8 (29%) 19 (20%) Other 3 (10%) 13 (13%)

By Eye N ¼ 56 N ¼ 135 N ¼ 21 N ¼ 20 N ¼ 176

Mean IOP during follow-up (mm Hg) 14.1 6 1.8 15.2 6 2.9 12 6 2.8 11.5 6 4.0 14.4 6 3.4 .010* .547 CCT (mm) 563 6 33 549 6 43 534 6 43 531 6 47 545 6 44 .002* .005* Disc area (mm2) 1.94 6 0.47 1.87 6 0.43 1.92 6 0.49 1.79 6 0.42 2.06 6 0.54 .350 .122 Baseline MD (dB) 0.1 6 1.8 1.6 6 1.9 8.8 6 1.3 17.8 6 5.0 4.3 6 5.9 <.001* <.001* Median no. of Cirrus visits (IQR) 6 (4–7) 7 (5–10) 6 (4–11) 5 (4–7) 7 (5–9) .014* .005* Median follow-up (y) (IQR) 1.7 (1.4–2.0) 3.2 (2.2–3.6) 3.2 (1.4–3.4) 1.8 (1.4–2.6) 3.2 (1.9–3.5) .001* <.001*

CCT ¼ central corneal thickness; IOP ¼ intraocular pressure; IQR ¼ interquartile range; MD ¼ mean deviation. Statistically signiﬁcant P values are denoted by asterisk. aData are presented as mean 6 SD unless otherwise indicated. bP value between different glaucoma groups. cP value healthy and glaucoma.

TABLE 2. Diagnostic Innovation in Glaucoma Study (DIGS): Baseline Global and Sectoral Circumpapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell–Inner Plexiform Layer Measurements by Diagnostic Group

Glaucoma Eyes

Healthy Eyes Early Moderate Severe Total Difference Sector N ¼ 56 N ¼ 135 N ¼ 21 N ¼ 20 N ¼ 176 P Valuea P Valueb

Circumpapillary retinal nerve ﬁber layer sector Global 97.3 6 9.5 77.0 6 11.7 66.6 6 12.4 60.8 6 9.1 73.9 6 12.9 <.001* <.001* Superior 123.7 6 14.5 92.1 6 17.9 75.3 6 16.6 72.1 6 16.8 75.0 6 16.7 <.001* <.001* Inferior 127.0 6 17.9 92.6 6 21.7 75.6 6 19.5 58.8 6 6.6 86.7 6 23.3 <.001* <.001* Nasal 76.2 6 12.5 66.4 6 10.43 68.5 6 11.6 61.8 6 10.0 66.1 6 10.6 .47 <.001* Temporal 62.5 6 10.8 57.1 6 13.2 47.6 6 12.0 50.8 6 14.0 55.3 6 13.5 .21 .014* Macular ganglion cell–inner plexiform layer sector Average 83.2 6 6.1 71.6 6 9.7 62.0 6 8.9 62.76 8.9 69.4 6 10.2 <.001* <.001* Minimum 81.2 6 6.0 65.3 6 12.3 55.0 6 8.2 51.5 6 6.6 62.5 6 12.5 <.001* <.001* Temporal superior 81.6 6 6.0 71.9 6 9.0 62.0 6 10.4 64.7 6 13.3 69.9 6 10.3 <.001* <.001* Superior 83.6 6 6.5 72.6 6 10.7 62.9 6 11.4 68.1 6 16.1 70.9 6 11.9 <.001* <.001* Nasal superior 85.1 6 6.4 74.2 6 11.6 64.5 6 11.5 67.3 6 10.8 72.2 6 12.0 <.001* <.001* Nasal inferior 83.4 6 6.6 72.0 6 12.3 61.7 6 11.5 62.6 6 8.1 69.7 6 12.5 <.001* <.001* Inferior 82.1 6 6.8 68.3 6 13.2 59.7 6 9.1 57.6 6 7.4 66.0 6 12.1 <.001* <.001* Temporal inferior 83.6 6 5.8 70.6 6 11.0 61.5 6 8.6 57.6 6 7.4 67.9 6 11.6 <.001* <.001*

Data are presented in mmasmean6 SD. Statistically signiﬁcant P values are denoted by asterisk. aP value: Difference between different glaucoma severity groups. bP value: Difference between healthy and glaucoma eyes.

VOL. 178 RATES OF CIRCUMPAPILLARY AND MACULAR LOSS IN GLAUCOMA EYES 41 42

TABLE 3. Diagnostic Innovation in Glaucoma Study (DIGS): Age-adjusted Rates of Global and Sectoral Circumpapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell–Inner a Plexiform Layer Thickness Loss by Diagnostic Group, Mean (95% CI) Rate of Change (mm/Year)

Glaucoma Eyes

Healthy Eyes Early Moderate Severe Total Difference b c Sector N ¼ 56 N ¼ 135 N ¼ 21 N ¼ 20 N ¼ 176 P Value P Value

Circumpapillary retinal nerve ﬁber layer sector Global 0.48 (0.95, 0.02) 1.02 (1.27, 0.78) 1.07 (1.85, 0.29) 0.62 (1.38, 0.15) 0.98 (1.20, 0.76) .080 .060 P ¼ .045 P < .001 P ¼ .007 P ¼ .113 P < .001 Superior 0.38 (1.43, 0.53) 1.13 (1.58, 0.69) 1.34 (2.39, 0.30) 0.44 (1.33, 2.21) 1.04 (1.45, 0.62) .470 .050 P ¼ .375 P < .001 P ¼ .012 P ¼ .623 P < .001

A Inferior 0.99 (1.8, 0.11) 1.44 (1.87, 1.02) 1.28 (2.73, 0.18) 1.12 (2.09, 0.15) 1.35 (1.73, 0.96) .090 .080 MERICAN P ¼ .120 P < .001 P ¼ .015 P ¼ .024 P < .001 Nasal 0.24 (0.53, 0.04) 0.89 (1.18, 0.6) 0.90 (1.78, 0.01) 0.87 (1.89, 0.15) 0.89 (1.15, 0.64) .480 .009 P ¼ .097 P < .001 P ¼ .048 P ¼ .095 P < .001 J UNLOF OURNAL Temporal 0.16 (0.6, 0.30) 0.62 (0.84, 0.41) 0.05 (0.16, 0.26) 0.06 (1.3, 0.02) 0.65 (0.84, 0.47) .133 .024 P ¼ .501 P < .001 P ¼ .460 P ¼ .025 P < .001 Macular ganglion cell–inner plexiform layer sector Average 0.14 (0.57, 0.34) 0.55 (0.72, 0.38) 0.77 (1.44, 0.10) 0.79 (1.57, 0.01) 0.57 (0.73, 0.41) .070 .059 O P ¼ .605 P < .001 P ¼ .024 P ¼ .019 P < .001 PHTHALMOLOGY Minimum 0.25 (0.96, 0.46) 0.73 (1.01, 0.45) 0.87 (1.65, 0.08) 1.02 (1.96, 0.08) 0.73 (0.98, 0.48) .006 .212 P ¼ .484 P < .001 P ¼ .031 P ¼ .033 P < .001 Temporal superior 0.03 (0.56, 0.62) 0.56 (0.79, 0.33) 0.72 (1.52, 0.08) 0.8 (2.15, 0.56) 0.55 (0.78, 0.33) .153 .061 P ¼ .915 P < .001 P ¼ .018 P ¼ .250 P ¼ .001 Superior 0.10 (0.68, 0.48) 0.61 (0.82, 0.40) 0.98 (1.88, 0.08) 0.87 (2.26, 0.05) 0.62 (0.85, 0.40) .026 .093 P ¼ .730 P < .001 P ¼ .033 P ¼ .011 P < .001 Nasal superior 0.25 (0.85, 0.35) 0.59 (0.82, 0.37) 0.77 (1.68, 0.13) 0.87 (1.73, 0.06) 0.59 (0.81, 0.37) .018 .292 P ¼ .406 P < .001 P ¼ .094 P ¼ .034 P < .001 Nasal inferior 0.25 (0.84, 0.35) 0.68 (0.93, 0.43) 0.84 (1.5, 0.16) 0.85 (1.87, 0.09) 0.67 (0.91, 0.43) .034 .196 P ¼ .413 P < .001 P ¼ .015 P ¼ .049 P ¼ .001 Inferior 0.10 (0.67, 0.47) 0.49 (0.73, 0.24) 0.9 (1.57, 0.23) 0.81 (1.34, 0.27) 0.55 (0.77, 0.33) .011 .113 P ¼ .726 P < .001 P ¼ .009 P ¼ .003 P ¼ .001 Temporal inferior 0.10 (0.62, 0.42) 0.56 (0.8, 0.31) 0.56 (1.15, 0.04) 0.65 (1.22, 0.07) 0.56 (0.78, 0.34) .147 .110 P ¼ .709 P < .001 P ¼ .068 P ¼ .027 P < .001

a Results are presented as mean, (low and high 95% CI), P value. b P value between different glaucoma groups. cP J value between healthy and glaucoma groups. N 2017 UNE V OL . 178

TABLE 4. Diagnostic Innovation in Glaucoma Study (DIGS): Normalized Age-adjusted Rates of Global and Sectoral Circumpapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell– a Inner Plexiform Layer Thickness Loss by Diagnostic Group, Presented as Normalized Change From Baseline (%/Year)

Healthy Eyes Glaucoma Eyes

Early Moderate Severe Total Difference b c Sector N ¼ 56 N ¼ 135 N ¼ 21 N ¼ 20 N ¼ 176 P Value P Value

Circumpapillary retinal nerve ﬁber layer sector R

TSOF ATES Global 0.61 (1.2, 0.001) 1.7 (2.2, 1.3) 1.8 (3.2, 0.5) 1.1 (2.4, 0.3) 1.7 (2.1, 1.3) .080 .060 P ¼ .006 P < .001 P ¼ .007 P ¼ .113 P < .001 Superior 0.43 (1.7, 0.56) 1.3 (1.8, 0.8) 1.5 (2.8, 0.3) 0.5 (1.2, 0.3) 1.2 (1.7, 0.7) .470 .050 C P ¼ .375 P < .001 P ¼ .012 P ¼ .623 P < .001 RUPPLAYAND IRCUMPAPILLARY Inferior 0.93 (1.1, 0.005) 1.5 (1.9, 1.1) 1.3 (2.8, 0.2) 1.2 (2.2, 0.2) 1.4 (1.8, 1.0) .090 .080 P ¼ .120 P < .001 P ¼ .015 P ¼ .024 P < .001 Nasal 0.5 (1.1, 0.09) 1.9 (2.5, 1.2) 1.9 (3.7, 0.02) 1.8 (3.9, 0.3) 1.8 (2.4, 1.3) .480 .009 P ¼ .097 P < .001 P ¼ .048 P ¼ .095 P < .001 Temporal 0.29 (1.1, 0.56) 1.1 (1.5, 0.7) 1.2 (2.1, 0.3) (0.7 3.3, 0.2) 1.2 (1.5, 0.8) .133 .024 P ¼ .501 P < .001 P ¼ .046 P ¼ .025 P < .001 Macular ganglion cell–inner plexiform layer sector M ACULAR Average 0.43 ( 1.1, 0.27) 1.3 ( 2.0, 0.9) 1.8 ( 3.3, 0.2) 1.8 ( 3.6, 0.01) 1.3 ( 1.7, 0.9) .070 .059 P ¼ .605 P < .001 P ¼ .024 P ¼ .019 P < .001 Minimum 0.7 (2.2, 0.8) 1.0 (1.5, 0.4) 1.9 (2.6, 0.8) 2.0 (3.8, 0.2) 1.4 (1.9, 0.9) .006 .212

L P ¼ .484 P < .001 P ¼ .031 P ¼ .033 P < .001 S IN OSS Temporal superior 0.51 (0.13, 1.16) 1.4 (1.9, 0.7) 1.6 (3.4, 0.2) 1.8 (4.9, 1.3) 1.3 (1.7, 0.7) .153 .061 P ¼ .120 P < .001 P ¼ .018 P ¼ .250 P < .001 G Superior 0.18 (0.9, 0.05) 1.2 (1.6, 0.8) 2.0 (3.8, 0.2) 1.7 (4.5, 0.1) 1.2 (1.7, 0.8) .026 .093 LAUCOMA P ¼ .730 P < .001 P ¼ .033 P ¼ .011 P < .001 Nasal superior 0.70 (1.9, 0.49) 1.2 (1.6, 0.7) 1.3 (3.6, 0.2) 1.4 (3.5, 0.1) 1.2 (1.6, 0.7) .018 .292 P ¼ .406 P < .001 P ¼ .094 P ¼ .034 P < .001

YES Nasal inferior 0.78 ( 2.0, 0.04) 1.4 ( 1.9, 0.9) 1.7 ( 3.0, 0.3) 2.0 ( 3.7, 0.2) 1.3 ( 1.8, 0.9) .034 .196 P ¼ .413 P < .001 P ¼ .015 P ¼ .049 P < .001 Inferior 0.49 (1.2, 0.24) 1.0 (1.6, 0.5) 1.9 (3.3, 0.5) 1.9 (2.8, 0.6) 1.2 (1.6, 0.7) .011 .113 P ¼ .726 P < .001 P ¼ .009 P ¼ .003 P < .001 Temporal inferior 0.48 (0.93, 0.14) 1.2 (1.7, 0.6) 1.2 (2.4, 0.1) 1.6 (1.8, 0.07) 1.4 (2.5, 0.2) .147 .110 P ¼ .709 P < .001 P ¼ .068 P ¼ .027 P < .001

a Results are presented as mean, (low and high 95% CI), P value. b P value between different glaucoma groups. c P value between healthy and glaucoma groups. 43 FIGURE 1. Sectoral rates of normalized change from baseline of macular ganglion cell–inner plexiform layer (GCIPL) thickness (Left) and circumpapillary retinal nerve ﬁber layer (RNFL) thickness (Right) in glaucoma eyes.

FIGURE 2. Sectoral rates of normalized change from baseline of macular ganglion cell–inner plexiform layer (GCIPL) thickness (Left) and circumpapillary retinal nerve ﬁber layer (RNFL) thickness (Right) in healthy eyes.

44 AMERICAN JOURNAL OF OPHTHALMOLOGY JUNE 2017 FIGURE 3. Distribution of the rates of normalized change from baseline of macular ganglion cell–inner plexiform layer (GCIPL) thickness and circumpapillary retinal nerve ﬁber layer (RNFL) thickness in healthy eyes. Mean circumpapillary RNFL normalized change was faster than the rate of percent macular GCIPL change, but the difference did not reach statistical signiﬁcance (L0.61%/ year and L0.43%/year, respectively, P [ .661).

FIGURE 4. Distribution of the rates of normalized change from baseline of macular ganglion cell–inner plexiform layer (GCIPL) thickness and circumpapillary retinal nerve ﬁber layer (RNFL) thickness in glaucoma eyes. Mean circumpapillary RNFL normalized change was 1.3 times faster than rate of percent macular GCIPL change (L1.7%/year and L1.3%/year, respectively, P < .001).

and 0.43%/year, respectively, P ¼ .661, Figure 3). In glau- mm/year and normalized (%/year), were both faster in coma eyes, mean global circumpapillary RNFL normalized glaucoma eyes compared with healthy eyes in all sectors. change was signiﬁcantly faster (1.3 times faster) than mean These differences reached statistical signiﬁcance in the average macular GCIPL percent change (1.7%/year nasal and temporal circumpapillary RNFL quadrants and 1.3%/year, respectively, P < .001, Figure 4). only. The mean rate of global circumpapillary RNFL loss Age-adjusted mean rates of circumpapillary RNFL and in glaucoma eyes was 2 times faster than in healthy eyes macular GCIPL thickness loss over time, measured in (0.98 mm/year and 0.48 mm/year, respectively,

VOL. 178 RATES OF CIRCUMPAPILLARY AND MACULAR LOSS IN GLAUCOMA EYES 45 TABLE 5. Diagnostic Innovation in Glaucoma Study (DIGS): Correlation Between the Rates of Change of Circumpapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell–Inner Plexiform Layer in Healthy and Glaucoma Eyes

Circumpapillary RNFL

Glaucoma Eyes Healthy Eyes

Global Superior Inferior Global Superior Inferior

Macular GCIPL Average 0.12 (.060) 0.002 (.977) 0.20 (.006) 0.01 (.910) 0.17 (.900) 0.081 (.550) Superior 0.05 (.440) 0.052 (.490) 0.135 (.073) 0.20 (.140) 0.089 (.518) 0.05 (.710) Inferior 0.16 (.032) 0.044 (.556) 0.23 (.002) 0.10 (.440) 0.157 (.255) 0.171 (.874)

GCIPL ¼ ganglion cell–inner plexiform layer; RNFL ¼ retinal nerve ﬁber layer. Results are presented as Spearman correlation coefﬁcient (P value).

TABLE 6. Diagnostic Innovation in Glaucoma Study (DIGS): Scatterplots of the Rates of Change of Circumpapillary Retinal Nerve Fiber Layer and Macular Ganglion Cell–Inner Plexiform Layer in Glaucoma Eyes

Circumpapillary RNFL

Global Superior Inferior

Macular GCIPL Average

Superior

Inferior

GCIPL ¼ ganglion cell–inner plexiform layer; RNFL ¼ retinal nerve ﬁber layer.

P ¼ .060). Mean rate of global normalized circumpapillary with early glaucoma eyes in the superior, nasal-superior, RNFL loss was 2.8 times faster than in healthy eyes nasal inferior, inferior, and minimum macular GCIPL. (1.7%/year and 0.61%/year, respectively, P ¼ .060). To examine the topographic relationship between Age-adjusted mean rates of circumpapillary RNFL loss macular and RNFL changes, correlations (Table 5) and over time tended to be faster in moderate and early scatterplots (Table 6) among the average, superior, and compared with severe glaucoma eyes. However, these dif- inferior sectors of macular GCIPL and circumpapillary ferences did not reach statistical significance. Rates of mac- RNFL rates of normalized change from baseline are ular GCIPL thickness loss over time were significantly presented. In glaucoma eyes, we found weak but statisti- faster in moderate and severe glaucoma eyes compared cally significant correlations between the rates of average

46 AMERICAN JOURNAL OF OPHTHALMOLOGY JUNE 2017 macular GCIPL normalized change and inferior circumpa- rates of normalized circumpapillary RNFL loss were faster pillary RNFL normalized change and between the rates of than rates of normalized macular GCIPL loss in both inferior macular GCIPL normalized change and both healthy and glaucoma eyes, but the difference was statisti- global and inferior circumpapillary RNFL normalized cally significant for glaucoma eyes only. The lack of change. For healthy eyes, no correlation was found between significant differences between circumpapillary RNFL and average or sectoral macular GCIPL and global or sectoral macular GCIPL loss in healthy eyes may be owing to the circumpapillary RNFL normalized change. smaller sample size. Alternatively, these results may suggest that aging changes are similar in the RNFL and GCIPL, but that glaucomatous changes tend to be faster in the RNFL. The Cirrus HD-OCT macular GCIPL thickness map is DISCUSSION derived from an annulus with an outer diameter of 4 mm vertically and 4.8 mm horizontally. These dimensions IN THIS STUDY, WE FOUND THAT IN GLAUCOMA EYES, THE were selected based on analysis using macular GCIPL rate of global circumpapillary RNFL loss, as measured using maps of healthy eyes to include the area wherein the mac- Cirrus HD-OCT, was significantly faster than macular ular GCIPL is thickest in a normal eye.38 As described by GCIPL loss. In healthy eyes with a shorter mean follow- Hood and associates12 in a model describing the topo- up time and smaller sample size, the normalized global graphic relationship between macular and optic nerve circumpapillary RNFL loss also tended to be faster than head damage in glaucoma, the temporal quadrant of the normalized global macular GCIPL loss, but the difference disc predominantly contains the axons from RGCs of the in rates did not reach statistical significance. superior macula with some of the RGCs of the inferior mac- Our study is one of the few to directly compare the rates ula. Most of the inferior RGCs’ axons project largely to the and of circumpapillary RNFL and macular GCIPL loss over inferior quadrant of the disc (see Figure 1 in ref 12). None- time in the same eyes. Leung and associates25 also reported a theless, there are individual differences in the mapping of faster rate of global circumpapillary RNFL thinning RGCs to the optic disc, and any model represents the compared to macular GCIPL thinning in a cohort of average relationship.39 Because our objective is to help cli- 150 glaucoma eyes (1.53 mm/year and 0.81 mm/year, nicians better interpret the output provided by the instru- respectively). In 2 separate reports, Leung and associates ment, we decided to include all sectors as calculated by reported a mean rate of 0.52 mm/year loss of global the Cirrus HD-OCT in our analysis. Our longitudinal find- circumpapillary RNFL in a cohort of 35 healthy eyes, and ings in healthy and glaucoma eyes are generally consistent a mean rate of 0.32 mm/year of average macular GCIPL with the cross-sectional model suggested by Hood and asso- loss in a cohort of 72 healthy eyes, measured by Cirrus ciates.12 However, the current analysis is not intended to HD-OCT.25 Na and associates29 reported a rate verify or contradict previous work, but rather to examine of 0.64 mm/year global circumpapillary RNFL loss in a the temporal relationship of circumpapillary RNFL and retrospective cohort of glaucoma eyes using Cirrus HD- macular GCIPL changes in glaucoma and healthy eyes. OCT. Alencar and associates37 reported a rate Several recent studies have reported that minimum mac- of 0.65 mm/year loss in circumpapillary RNFL thickness ular GCIPL measurements have the best diagnostic perfor- in progressing glaucoma eyes and 0.11 mm/year in mance in detection of glaucoma among macular GCIPL nonprogressing glaucoma eyes in a DIGS/ADAGES cohort parameters, comparable to that of circumpapillary RNFL using GDx VCC. These results are consistent with our measurements, even in early stages of the disease.40,41 results (mean circumpapillary RNFL loss 0.48 mm/year However, our results suggest that the minimum macular and 0.98 mm/year for healthy and glaucoma eyes, respec- GCIPL may not be the best parameter for estimating the tively; mean macular GCIPL loss 0.14 mm/year rate of change. This is likely owing in part to the fact and 0.57 mm/year, healthy and glaucoma eyes, respec- that the location of minimum macular GCIPL varies tively). Differences in the magnitude of the rate of change among subjects and varies in the same subject over time. among the different studies may be explained by differences Further investigation is warranted regarding the role of in study population, severity of disease, sample size, and minimum macular GCIPL measurements in the long- length of follow-up. Our goal was to compare the rates of term follow-up and management of glaucoma. circumpapillary RNFL and macular GCIPL loss within In addition, we found that in glaucoma eyes the rates of the same group of eyes using the same visit dates. Because both global circumpapillary RNFL and average macular the measurements of circumpapillary RNFL and macular GCIPL normalized change were all significantly different GCIPL differ in magnitude and range, a comparison of from zero. When we stratified to subgroups based on disease the rates of change in mm/year would be inappropriate. In severity, in early and moderate glaucoma eyes rates of both order to compare the rates of loss, we calculated the rates global circumpapillary RNFL and average macular GCIPL of loss using a dynamic range–based normalized coefficient normalized change were all significantly different from (percent of dynamic range change ¼ [(visit value floor zero. In the severe glaucoma group, only rates of normalized value)/dynamic range] 3 100/year) and showed that the average macular GCIPL change and in all sectors except

VOL. 178 RATES OF CIRCUMPAPILLARY AND MACULAR LOSS IN GLAUCOMA EYES 47 temporal superior, were statistically different from zero, small sample size in the moderate and severe glaucoma suggesting that structural changes in the macula can be groups makes the comparison difficult. Although the detected in advanced disease.42 In severe glaucoma eyes, participants in the healthy group were significantly younger significant rates of RNFL loss were found in the inferior than those in the glaucoma group, our primary objective and temporal sectors only. This may be explained in part was to compare circumpapillary RNFL and macular GCIPL by the fact that these patients were treated for their glau- within each group, and the comparison between the rates of coma during the study period, and patients’ treatment glaucoma and healthy eyes was adjusted for age. The differ- may be intensified with advancing disease. The small sam- ence in superior and inferior circumpapillary RNFL rates of ple size in these 2 subgroups (21 moderate and 20 severe change between healthy and glaucoma eyes were not statis- glaucoma eyes) may also explain the lack of detectable sig- tically significant (borderline P values .050 and .080), nificance in some sectors/quadrants. A cohort including a which might be explained by the fact that the glaucoma larger number of moderate and severe glaucoma eyes will group includes eyes in various disease stages, as well as by provide a more robust estimation of the differences in rates the short follow-up time of the healthy eyes, which in- of change in different stages of the disease. In healthy eyes, creases the variability (average of 1.7 years). Moreover, only the rates of global and inferior circumpapillary RNFL the rate of changes in healthy eyes for both superior and normalized change were significantly different from zero. inferior were not significantly different from zero (P value One possible reason for the lack of detectable statistically .375 and .120). significant age-related loss in healthy eyes is the relatively The Cirrus HD-OCT macular GCIPL thickness map is short follow-up time of this cohort. Continued follow-up of derived from an annulus with an outer diameter of 4 mm this cohort will provide more robust estimates of age- vertically and 4.8 mm horizontally. These dimensions related loss of circumpapillary RNFL and macular GCIPL were selected, based on analysis using macular GCIPL thickness. maps of healthy eyes, to include the area wherein the mac- We compared rates of circumpapillary RNFL and macu- ular GCIPL is thickest in a normal eye.38 It is known that lar GCIPL change over a given period of time. As the path- the superior and inferior poles of the optic disc are particu- ophysiology of glaucoma is not fully understood, it is larly vulnerable to glaucomatous damage.1 Accordingly, difficult to determine whether loss of RGCs and their axons glaucomatous circumpapillary RNFL damage is uncommon occurs simultaneously or if perhaps one event precedes the at the nasal and temporal sectors.43 Because the macular other. It is thought that in some patients the initial glau- scan is limited to the annulus described above, measure- comatous insult is pressure-related lamina cribrosa and ments of macular GCIPL in regions of RGCs whose axons axonal deformation, leading to blockade of retrograde comprise the superior and some of the inferior circumpapil- axonal transport, resulting in RGC death. Other proposed lary RNFL quadrants are probably underrepresented in the mechanisms suggest the initial insult is retinal (ischemic- macular GCIPL scan. The absence of these measurements hypoxic or other), leading to death of RGCs and their limits our ability to compare the rates of macular GCIPL axons.1 It is possible that in glaucoma eyes thinning of and circumpapillary RNFL thinning in glaucoma eyes. circumpapillary RNFL and macular GCIPL occur at Wide-angle scans allow imaging of the macula and optic different times during the course of the disease. Moreover, nerve head in a single scan.41 The use of wide-angle scans it is possible that the initial insult varies, so that in some may potentially provide a better understanding of the rela- eyes the first detectable sign of glaucomatous structural tionship between glaucomatous damage in the macular re- damage will be ganglion cell loss in the macula, while in gion and the optic nerve head, by providing information others the first detectable sign is in the peripapillary from a larger area of RGCs and by enabling analysis of RNFL. Our findings of weak but statistically significant cor- RGC axons continuously along their course from the pos- relations between the rates of inferior macular GCIPL terior pole to the optic nerve head. normalized change and both global and inferior circumpa- In summary, in glaucoma eyes the overall rate of pillary RNFL normalized change are consistent with the circumpapillary RNFL loss is 1.3 times faster compared possibility that there is considerable individual variability with macular GCIPL loss. In healthy eyes, the rate of in the temporal relationship between loss of RGCs and circumpapillary RNFL loss also tended to be faster than their axons. macular GCIPL loss, but the difference did not reach statis- There are several limitations to this study, including the tical significance. These results suggest that the establish- relatively small sample size (56 eyes) and short follow-up ment of longitudinal reference databases of healthy eyes time in healthy eyes (median 1.7 years) and the relatively can help improve the clinician’s ability to differentiate short follow-up time of glaucoma eyes (median 3.2 years). between macular GCIPL and circumpapillary RNFL The wide range of disease severity among glaucoma eyes age-related loss and disease progression. Moreover, as sig- (baseline SAP-SITA MD mean 4.3 dB, range 24.9 to nificant change in macular GCIPL was detectable in severe 1.9 dB) may also explain the relatively wide distribution glaucoma eyes, imaging may provide important informa- of the rate of circumpapillary RNFL and macular GCIPL tion on whether a patient is progressing at all stages of glau- loss. However, despite a total of 176 glaucoma eyes, the coma, including advanced disease.

48 AMERICAN JOURNAL OF OPHTHALMOLOGY JUNE 2017 FUNDING/SUPPORT: EY11008; U10EY14267; EY019869; EY021818; P30EY022589, GENENTECH INC, SAN FRANCISCO, CALIFORNIA, USA, and participant retention incentive grants in the form of glaucoma medication at no cost from Alcon Laboratories Inc, Fort Worth, Texas, USA; Allergan Inc, Dublin, Ireland; Pﬁzer Inc, New York, New York, USA; and Santen Pharmaceutical Co Ltd, Osaka, Japan; unrestricted grant from Research to Prevent Blindness, New York, New York. Financial Disclosures: Robert N. Weinreb: Alcon Laboratories Inc, Fort Worth, Texas, USA; Allergan Inc, Dublin, Ireland; BauschþLomb Inc, Bridgewater, New Jersey, USA; Carl-Zeiss Meditec Inc, Dublin, California, USA; Topcon Medical Systems Inc, Tokyo, Japan; Heidelberg Engineering GmbH, Heidelberg, Germany; Genentech Inc, San Francisco, California, USA; Optovue Inc, Fremont, California, USA. Felipe A. Medeiros: Carl-Zeiss Meditec Inc, Dublin, California, USA; Heidelberg Engineering GmbH, Heidelberg, Germany; Topcon Medical Systems Inc, Tokyo, Japan; Ametek Inc, Berwyn, Pennsylvania, USA; BauschþLomb Inc. Bridgewater, New Jersey, USA; Allergan Inc, Dublin, Ireland; Sensimed AG, Lausanne, Switzerland; Alcon Laboratories Inc, Fort Worth, Texas, USA. Linda M. Zangwill: Carl Zeiss Meditec Inc, Dublin, California, USA; Hei- delberg Engineering GmbH, Heidelberg, Germany; Optovue Inc, Fremont, California, USA; Topcon Medical Systems Inc, Tokyo, Japan; Quark Pharma- ceuticals Inc, Fremont, California, USA. The following authors have no ﬁnancial disclosures: Naama Hammel, Akram Belghith, and Nadia Mendoza. All authors attest that they meet the current ICMJE criteria for authorship.

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