Patterns of Optical Coherence Tomography Imaging in Preperimetric Open Angle Glaucoma: A Comparative Study With Young-Age-Onset and Old-Age-Onset Eyes : Journal of Glaucoma

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New Understandings of Glaucoma: Original Studies

Patterns of Optical Coherence Tomography Imaging in Preperimetric Open Angle Glaucoma: A Comparative Study With Young-Age-Onset and Old-Age-Onset Eyes

Bak, Eunoo MD*,†; Sun, Sukkyu PhD; Wy, Seoyoung MD†,§; Kim, Yong Woo MD, PhD†,§; Kim, Young Kook MD†,§; Park, Ki Ho MD, PhD†,§; Kim, Hee Chan PhD∥,¶; Jeoung, Jin Wook MD, PhD†,§

Author Information
doi: 10.1097/IJG.0000000000002104

Abstract

Of the current imaging devices, optical coherence tomography (OCT) obtains accurate, objective, and quantitative measurements of ocular structures in glaucoma.1,2 Spectral-domain OCT (SD-OCT) has been adopted widely in clinical practice, performing quantitative assessments of the optic nerve head (ONH) and retinal nerve fiber layer (RNFL) with long-term reproducibility.3–5 In addition to the ONH and RNFL, the inner layers of the glaucomatous macula were found to be comparable to those of the RNFL.6 Combining information from ONH and macular scan of ganglion cell-inner plexiform layer (GCIPL) has been reported to improve early glaucoma detection effectiveness.7 More advanced technology applied in diagnostic tests has enabled detection to be both earlier and more accurate, even at the preperimetric stage.8,9

Glaucoma can affect individuals of all ages. The prevalence and development of glaucoma increase with age, and the prevalence increases considerably after age 40.10,11 However, the mechanisms mainly involved in glaucoma and the underlying etiologies of age is not well understood. In previous studies, the increased prevalence of glaucoma in older patients did not seem to be explained solely by the increased prevalence of risk factors such as high intraocular pressure (IOP) with aging. It suggested that aging may increase the vulnerability of the optic nerve, resulting in loss of retinal ganglion cells.12–14 Interestingly, recent studies have also reported increases in the proportion of young adults in the glaucoma population, especially among individuals under 40 years.15,16 However, clinical studies to date have not adequately investigated the glaucomatous structural changes depending on the age of occurrence. In turn, knowledge of early structural changes according to age may help the understanding of the pathogenesis of glaucoma. Therefore, in this study, using OCT, we sought to investigate the structural topographic patterns and characteristics of RNFL and GCIPL thinning in young-age-onset (below 40) and old-age-onset (over 40) preperimetric open angle glaucoma (OAG) patients.

MATERIALS AND METHODS

Preperimetric OAG patients were consecutively enrolled from an ongoing study on a preperimetric OAG cohort at the Glaucoma Clinic of Seoul National University Hospital that was examined between January 2014 and December 2019. This study was approved by the Seoul National University Hospital Institutional Review Board. Informed consent was waived due to the study’s retrospective nature by the Institutional Review Board of Seoul National University Hospital. All of the specific investigations adhered to the tenets of the Declaration of Helsinki.

Study Subjects

This study included a total of 194 preperimetric OAG patients and 97 age-matched normal subjects. All subjects were over age 18, had best-corrected visual acuity of 20/30 or better, a spherical equivalent between –6.0 and +3.0 diopters and a cylinder correction within +3 diopters, good-quality OCT images, reliable VF testing results, and no history of IOP-lowering treatment. For the normal subjects, the following criteria had to be met: (1) baseline IOP <21 mmHg, with no history of elevated IOP; (2) normal optic disk and retina; (3) normal VF test result. Preperimetric OAG was defined as the presence of glaucomatous optic nerve damage (eg, the presence of focal thinning, notching, and RNFL defect), open angle confirmed by gonioscopy, and the absence of definite glaucomatous VF defect in SAP at 2 initial consecutive VF examinations.17,18 Glaucomatous VF defect was defined as (1) 3 or more abnormal points with a probability of P<0.05, of which at least 1 point had a pattern deviation of P<0.01, or (2) a pattern standard deviation of P<0.05, or (3) glaucoma hemifield test values outside the normal limits. The age at onset of preperimetric OAG was considered to be the age at which the first diagnosis had been made, as described elsewhere.18 All of the patients were divided into two groups based on age at onset: (1) young-age onset (age <40 y) and (2) old-age onset (age ≥40 y).

Patients were excluded for any of the following reasons: history of primary or secondary congenital glaucoma, secondary (eg, uveitic) glaucoma, history of intraocular surgery or laser treatment, any ophthalmic or neurological disease known to affect the ONH, macular structure, or VF examination results, segmentation failure in OCT scans of the RNFL or GCIPL in the optic disk or macular cube, low reliability of VF index (fixation loss >20%, false-positive errors >15%, false-negative errors >15%). The first VF available from each participant was excluded due to the possibility of a learning effect. If both eyes were qualified according to the inclusion criteria, 1 eye was randomly selected for further analysis.

Ophthalmic Examinations

All of the subjects underwent a full ophthalmic examination, including best-corrected visual acuity, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry (Haag-Streit, Koniz, Switzerland), dilated stereoscopic examination of optic disk, digital color stereo disk photography, red-free RNFL photography (TRC-50IX; Topcon Corporation, Tokyo, Japan), central corneal thickness measurement (Orbscan 73 II, Bausch & Lomb Surgical, Rochester, NY, USA), axial length measurement (IOL Master ver. 5, Carl-Zeiss Meditec, Dublin, CA, USA), Cirrus HD-OCT and central 24-2 full-threshold testing of the Humphrey visual field (HFA II; Humphrey Instruments, Dublin, CA, USA). All of the disk and RNFL photographs were taken with a simultaneous fundus camera after dilation of the pupil. Images were saved in a 1600×1216-pixel digital imaging format and stored in the picture-archiving communication system of Seoul National University Hospital. The Orbscan was used for corneal topography measurements with patients keeping both eyes open and focused on the light source in the center of the scan field. The measurements were obtained once correct alignment and focus of the eye had been achieved, and the central corneal thickness was recorded automatically. The axial length was measured, and optical A-scans were obtained along the visual axis.

Features associated with myopia, including ß-zone parapapillary atrophy (PPA) and disk tilt, were assessed. ß-zone PPA was defined as follows: an area adjacent to the disk margin with notable atrophy of the retinal pigment epithelium, visible sclera, and visible large choroidal vessels. The measurements were performed using ImageJ software (version 1.52; National Institutes of Health, Bethesda, MD, USA). Images were evaluated by two glaucoma specialists (EB, YWK) masked to all patients’ clinical information. The representative value was considered to be the average of the values measured by the two specialists. The extent of disk tilt was defined as the ratio between the longest and shortest diameters of the optic disk. The area was delineated using a mouse-driven cursor to trace the PPA and disk margins directly onto the disk photograph image. The structures for quantification were outlined on the inside edge in order that the trace thickness could be incorporated into the total delineated area. Instead of the β-zone PPA area, the β-zone PPA-to-disk-area ratio was used to minimize the effects of photographic-magnification error.

Assessment of SD-OCT

Spectral-domain OCT images were obtained using the Cirrus HD-OCT system (software version 9.5; Carl Zeiss Meditec). One macular (Macular Cube 200×200 protocol) and one optic disk (Optic Disc Cube 200×200 protocol) scan were acquired in each qualifying eye after pupil dilation. All of the OCT examinations were performed by the same well-trained technician. Satisfactory OCT quality was defined as (1) a well-focused image, (2) the presence of a centered circular ring around the optic disk, and (3) a signal strength of ≥6 (10=maximum). OCT scans with motion artifacts, misalignment, poor centration, or segmentation error were checked and discarded by the examiner, with rescanning being performed on the same visit.

An “optic disk cube” scan protocol was used to measure the RNFL thickness in a 6×6-mm2 area composed of 200×200 axial scans (pixels) in the optic disk region. The RNFL thickness at each pixel was measured, and a RNFL thickness map was generated. A built-in algorithm located the center of the optic disk, which was identified by finding a dark spot near the center of the scan that had a shape and size consistent with a range of optic disks. A calculation circle of 3.46 mm diameter consisting of 256 A-scans was then automatically positioned around optic disk, for calculation of the RNFL thickness. Any abnormal RNFL measurements in the 6×6-mm2 parapapillary area were analyzed and displayed on the RNFL thickness deviation map. The ONH parameters were measured automatically using a Carl Zeiss Meditec analysis algorithm that had been developed for Cirrus HD-OCT.

For the macular cube, a ganglion cell analysis algorithm was used by performing 200 horizontal B-scans, each comprising 200 A-scans within a 6-×6-×2-mm cube centered on the fovea. Full details on the mechanism of the ganglion cell analysis algorithm are available elsewhere.19,20 In brief, the annulus has inner vertical and horizontal diameters of 1 and 1.2 mm, respectively, and outer vertical and horizontal diameters of 4 and 4.8 mm, respectively. The desired boundaries are the outer boundaries of both the RNFL and the inner plexiform layer, and the difference between these yields the GCIPL thickness.

Patterns of RNFL Defect

The RNFL defects were visualized on the RNFL thickness deviation map, which was composed of 298×298 pixels. When the RNFL measurement was below the lower 95th or 99th centile range for that particular pixel, the pixel was coded in yellow or red, respectively. Only RNFL defects with an area of contiguous color-coded pixels ≥10 in size over a boundary 3 pixels away from the optic disk margin or the margin of PPA (if present) were analyzed. The size was arbitrarily selected as the minimal defect size so as to exclude potential nonspecific changes detected in the RNFL thickness deviation map.21 To evaluate the overall spatial distribution of RNFL defects, the areas with color-coded RNFL defects on the RNFL deviation maps were overlaid after aligning the optic disk centers, using a computer program written in the Python (version 3.6) OpenCV (version 4.1.1) framework, as performed by a masked observer (SS). The maps were aligned based on the right eye’s orientation. A total RNFL defect image—an RNFL deviation frequency map— from the young-age and old-age groups was obtained, respectively. The map was represented in the color-bar scale from blue to red. The red-colored region indicated RNFL defects detected at the highest frequency, whereas the blue-colored region indicated those detected at close-to-zero frequency (Supplementary Figure 1, Supplemental Digital Content 1, https://links.lww.com/IJG/A658).

The angular width and the size of RNFL defects in more than 50% and the maximum percentage of patients were assessed by pixel counting (Python). The size was evaluated by the areal proportion with RNFL measurements in the RNFL thickness deviation map. It was expressed as the proportion of RNFL defect area within the 6×6-mm2 parapapillary measurement region after excluding the optic disk and parapapillary atrophic areas (in percent): [area of pixels coded in yellow or red/(6×6 – optic disk and parapapillary atrophic area)].

Patterns of GCIPL Defect

An abnormal GCIPL measurement in the 6×6-mm2 macular area was analyzed by comparison with the built-in normative data, and the results were presented as the GCIPL thickness deviation map. This map comprised 298×298 pixels coded in yellow or red if the GCIPL measurement was less than the lower 95th or 99th centile range, respectively. The GCIPL defect was defined as ≥10 contiguous yellow or red pixels on the GCIPL thickness deviation map. The area was arbitrarily selected as the minimal defect size so as to exclude potential non-specific changes.22 To investigate the overall spatial distribution of GCIPL defects, the areas with color-coded GCIPL defects on the GCIPL deviation map were overlaid by a blinded observer (SS) after aligning at the fovea center using Python. A total GCIPL defect image—GCIPL deviation frequency map—from the young-age and old-age groups was obtained in the same manner as was the RNFL deviation frequency map.

The number and probability of GCIPL defects were determined within a 6×6-mm2 macular area at different circle diameters and 0.04-mm intervals. The location and size of GCIPL defects in >50% and the maximum percentage of patients were evaluated (Python). The size was evaluated by the areal proportion in the GCIPL thickness deviation map (in percent): [area of pixels coded in yellow or red/(6×6 area)]. Angle measurement was assessed in the clockwise direction with the temporal equator set at 0 degree, based on the right eye’s orientation. 12 o’clock corresponded to the superior region; 3 o’clock, the nasal region; 6 o’clock, the inferior region, and 9 o’clock, the temporal region.23

Data Analysis

The baseline characteristics were compared by independent Student t test for normally distributed data and analyzed by χ2 testing for categorical data. For validation of the inter-observer agreement on the measurements of the extent of disk tilt and β-zone-to-disk-area ratio, Kappa statistics (к) were assessed. The strength of agreement was categorized according to Landis and Koch’s classification24: 0=poor, 0–0.20=slight, 0.21–0.40=fair, 0.41–0.60=moderate, 0.61–0.80=substantial, and 0.81–1.00=almost perfect. To demonstrate the distribution of GCIPL defect areas, their areal proportion on the GCIPL deviation map was calculated. A comparative analysis of the areal proportions of GCIPL defects among the groups was performed by 1-way analysis of variance with Tukey post hoc test. All of the statistical analyses were performed with the commercially available statistics software SPSS version 21.0 (SPSS, Inc., Chicago, IL, USA). P values of 0.05 or less were considered statistically significant.

RESULTS

Initially, 198 eyes meeting the eligibility criteria of preperimetric OAG were enrolled. Among them, 4 were excluded because the OCT image was of poor quality; repeated segmentation failure caused by a low signal strength (three patients) and giant vitreous floaters (one patient). A total of 194 eyes of 194 patients (94 young-age-onset and 100 old-age-onset) with preperimetric OAG and 97 normal age-matched subjects (47 young-age-onset and 50 old-age-onset) were included. The patients’ demographics and clinical characteristics are summarized in Table 1.

TABLE 1 - Demographics and Clinical Characteristics of Normal Subjects and Preperimetric Open angle Glaucoma Patients
Normal (n=97) Preperimetric Open Angle Glaucoma (n=194)
Young-age (<40 y, n=47) Old-age (≥40 y, n=50) P Young-age Onset Glaucoma (<40 y, n=94) Old-age Onset Glaucoma (≥40 y, n=100) P
Demographic variables
 Age at diagnosis (yr) 30.9±5.6 52.1±6.8 <0.001 30.7±6.1 52.0±6.9 <0.001
 Male, n (%) 25 (53.2) 26 (52.0) 0.91 46 (48.9) 52 (52.0) 0.67
 Spherical equivalence (D) –3.0±2.9 –3.0±3.1 0.37 –3.1±1.9 –2.9±2.2 0.22
 Axial length (mm) 25.1±1.3 24.8±1.6 0.42 25.2±0.9 24.9±1.2 0.38
 Central corneal thickness (µm) 545.3±47.1 546.3±40.5 0.61 542.9±45.8 542.3±33.7 0.77
 Baseline IOP (mmHg) 13.4±2.9 13.7±2.8 0.27 14.8±3.1 14.1±2.8 0.35
 Hypertension, n (%) 3 (6.3) 5 (10.0) 0.52 7 (7.4) 12 (12.0) 0.36
 Diabetes mellitus, n (%) 1 (2.1) 5 (10.0) 0.11 0 (0.0) 4 (4.0) 0.12
 Family history of glaucoma, n (%) 2 (4.2) 3 (6.0) 0.69 11 (11.7) 11 (11.0) 0.14
 PPA, n (%) 34 (72.3) 36 (72.0) 0.84 85 (90.4) 85 (85.0) 0.21
Structural parameters
 PPA-to-disk area ratio 0.47±0.37 0.51±0.29 0.33 0.42±0.36 0.52±0.39 0.13
 Tilt ratio 0.84±0.18 0.84±0.15 0.48 0.85±0.10 0.87±0.18 0.27
 Vertical cup/disk ratio 0.60±0.13 0.61±0.16 0.51 0.65±0.10 0.64±0.15 0.65
 Rim area (mm2) 1.13±0.21 1.12±0.24 0.35 0.98±0.21 1.01±0.18 0.20
 Disk area (mm2) 2.01±0.43 2.02±0.43 0.72 1.98±0.46 1.99±0.45 0.71
 Baseline RNFL thickness (µm) 97.1±8.6 97.0±7.9 0.78 87.1±7.5 85.5±8.9 0.23
 Baseline GCIPL thickness (µm) 84.3±6.5 83.9±5.7 0.81 78.4±5.9 76.2±5.8 0.80
Functional parameters
 Baseline MD (dB) 0.10±1.75 0.08±1.29 0.27 0.09±1.31 0.02±1.36 0.10
 Baseline PSD (dB) 1.57±0.34 1.58±0.49 0.46 1.63±0.48 1.67±0.40 0.40
Values are mean±SD and n (%).
P values adjusted by Benjamini-Hochberg method to compensate for multiple comparison. Values with statistical significance are shown in bold.
D indicates diopters; dB, decibels; GCIPL, ganglion cell-inner plexiform layer; IOP, intraocular pressure; MD, mean deviation; PPA, parapapillary atrophy; PSD, pattern standard deviation; RNFL, retinal nerve fiber layer.

Distribution Patterns of RNFL Defects

The spatial distribution profiles of RNFL defects in the glaucoma and normal control groups are presented in Figure 1A. Distinct peaks of RNFL defects were located at the inferotemporal meridian at 284 degree in the young-age-onset glaucoma eyes, and at the inferotemporal meridian at 292 degree followed by the superotemporal meridian at 42 degree in the old-age-onset glaucoma eyes (Fig. 1B). Table 2 presents the angular location and areal proportion of RNFL defects detected in >50% and the maximum percentage of patients. The location of RNFL defects in more than half of the eyes in each group was located inferotemporally (264–296 degrees) in the young-age-onset patients, and superotemporally (33–67 degrees) and inferotemporally (266–294 degrees) in the old-age-onset patients. In both the young-age-onset and old-age-onset eyes, the maximum percentage of defects was located inferotemporally (274–289 and 287–292 degrees, respectively) with a comparable areal proportion (1.77 and 1.25%).

F1
FIGURE 1:
Spatial distribution profile of baseline RNFL defects in normal subjects and preperimetric OAG patients as displayed on RNFL deviation frequency map (A) and frequency distribution plot (B). The areas with yellow and red codes on the baseline RNFL thickness deviation map for all eyes were overlaid, thus generating an RNFL deviation frequency map. The maps were aligned to the disk center based on the right eye’s orientation. The temporal point of the line was set as 0 degree, and the location of angle was analyzed in a clockwise direction. The color bar indicates the frequency of defects. In the young-age-onset preperimetric OAG eyes, the RNFL defects were most frequently detected at the inferotemporal meridian at 284 degree (87.2%). In the old-age-onset preperimetric OAG eyes, the RNFL defects were most frequently detected at the inferotemporal meridian at 292 degree (85.0%), followed by the superotemporal meridian at 42 degree (64.2%). OAG indicates open angle glaucoma; RNFL, retinal nerve fiber layer.
TABLE 2 - Location and Proportion of Area of Retinal Nerve Fiber Layer Defects and Ganglion Cell-Inner Plexiform Layer Defects Detected in More than 50% and Maximum Percentage of Preperimetric Open Angle Glaucoma Patients
>50%* Maximum Percentage
Location, Degree Proportion of Area, % Location, Degree Proportion of Area, %
RNFL defects
 Young-age onset 264–296 7.21 274–289 1.77
 Old-age onset 33–67, 266–294 10.80 287–292 1.25
GCIPL defects
 Young-age onset 213–357 20.53 287–308 13.42
 Old-age onset 0–22, 206–360 26.00 243–330 3.94
The temporal point of the line was set as 0 degree, and the location of angle was analyzed in a clockwise direction for right eyes.
*Proportion of area detected in >50% of patients.
Proportion of area detected in the maximum percentage of patients (90%).
GCIPL indicates ganglion cell-inner plexiform layer; RNFL, retinal nerve fiber layer.

Distribution Pattern of GCIPL Defects

The spatial distribution profiles of baseline GCIPL defects in the glaucoma and normal control groups are presented in Figure 2A. Among the glaucoma eyes, the most frequent defects were found in the inferotemporal region (287–308 degrees) 3.84 mm from the fovea in the young-age-onset eyes, and in the inferotemporal region (243–330 degrees) 3.28–3.76 mm from the fovea in the old-age-onset eyes (Fig. 2B). The location and areal proportion of GCIPL defects detected in more than 50% and the maximum percentage of patients is presented in Table 2. The GCIPL defects of more than half of the eyes in each group were located in the inferior region (213–357°) in the young-age-onset patients, and in the superotemporal (0–22 degrees) and inferior (206–360 degrees) region in the old-age-onset patients. The maximum percentage of defects was located in the inferior region with the areal proportion larger in the young-age-onset patients than in the old-age-onset patients (287–308 vs. 243–330 degrees, 13.42 vs. 3.94%).

F2
FIGURE 2:
Spatial distribution of baseline GCIPL defects in normal subjects and preperimetric OAG patients as displayed on GCIPL deviation frequency map (A) and frequency distribution plot (B). The areas with yellow and red codes in the baseline GCIPL thickness deviation map for all eyes were overlaid after aligning to the fovea center. The maps were aligned based on the right eye’s orientation. The temporal point of the line was set as 0 degree, and the location of angle was analyzed in a clockwise direction. The color bar indicates the frequency of defects. In the young-age-onset preperimetric OAG eyes, the GCIPL defects were most frequently found inferotemporally (287–308°) 3.84 mm from the fovea (45.0%). In the old-age-onset preperimetric OAG eyes, the GCIPL defects were most frequently found inferotemporally (243–330°) 3.28–3.76 mm from the fovea (54.0%). GCIPL indicates ganglion cell-inner plexiform layer; OAG, open angle glaucoma.

OCT Measurements

The parameters of the RNFL and GCIPL thicknesses of the normal and preperimetric OAG eyes are presented in Table 3. Average RNFL thickness did not differ between young-age-onset and old-age-onset eyes (P=0.23). The superior and temporal quadrant was thinner in the old-age group than in the young-age-onset group (P=0.003 and P<0.001, respectively), while the inferior quadrant was thinner in the young-age-onset group (P=0.012). The average GCIPL thickness did not differ between the young-age-onset and old-age-onset eyes (P=0.80). The superotemporal and superior GCIPL was thinner in the old-age-onset group than in the young-age-onset group (P=0.001 and P=0.005, respectively), while the inferotemporal area was thinner in the young-age-onset group (P=0.016). No difference in RNFL or GCIPL thickness was detected between the young-age-onset and old-age normal eyes. The clock-hour sectoral RNFL thicknesses are presented in Table 4. The 6, 7, 8, 9, 10 and 11 o’clock RNFL sectors demonstrated significant differences between the 2 groups of preperimetric OAG: the young-age-onset eyes were thinner in the 6 and 7 o’clock sectors and the old-age-onset eyes were thinner in the 8–11 ‘clock sectors (all P<0.05, adjusted by Benjamini-Hochberg method). No difference was detected between the young-age and old-age normal eyes.

TABLE 3 - Peripapillary RNFL Thickness and Macular GCIPL Thickness Obtained by Cirrus OCT in Normal Subjects and Preperimetric OAG Patients
Normal (n=97) Preperimetric Open Angle Glaucoma (n=194)
Young-age (n=47) Old-age (n=50) P Young-age Onset Glaucoma (n=94) Old-age Onset Glaucoma (n=100) P
RNFL thickness parameters, µm
 Average 96.7±8.2 95.5±6.2 0.53 87.1±7.5 85.5±8.9 0.23
 Quadrant
 Superior 112.9±14.3 113.1±13.9 0.52 110.8±13.1 105.1±19.3 0.003
 Nasal 67.2±8.5 68.2±9.1 0.51 63.4±8.1 64.0±9.6 0.53
 Inferior 126.7±13.9 124.7±12.1 0.32 99.5±14.9 104.9±12.7 0.012
 Temporal 80.9±10.9 79.8±10.9 0.29 76.7±12.6 67.5±13.6 <0.001
GCIPL thickness parameters, µm
 Average 81.7±6.2 80.6±6.7 0.78 78.4±5.9 76.2±5.8 0.80
 Superotemporal 81.7±5.7 80.5±7.1 0.85 79.4±4.4 76.6±6.4 0.001
 Superior 82.6±7.4 82.5±6.8 0.80 80.6±6.7 78.3±5.4 0.005
 Superonasal 82.9±6.3 82.4±7.5 0.91 82.6±6.6 80.8±5.9 0.53
 Inferonasal 81.8±5.9 81.0±7.2 0.77 79.6±6.6 79.1±6.0 0.91
 Inferior 79.9±6.5 78.2±8.2 0.68 73.4±6.6 75.2±6.7 0.06
 Inferotemporal 82.2±6.9 81.8±6.1 0.69 74.2±8.2 76.9±8.4 0.016
Mean±SD.
P values adjusted by Benjamini-Hochberg method to compensate for multiple comparison. Values with statistical significance are shown in bold.
GCIPL indicates ganglion cell-inner plexiform layer; OAG, open angle glaucoma; OCD, osteochondritis dissecan; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer.

TABLE 4 - Clock-hour Sectoral RNFL Thicknesses Obtained by Cirrus OCT in Normal Subjects and Preperimetric OAG Patients
Normal (n=97) Preperimetric Open Angle Glaucoma (n=194)
Young-age (n=47) Old-age (n=50) P Young-age Onset Glaucoma (n=94) Old-age Onset Glaucoma (n=100) P
12 superior 119.0±25.5 118.2±27.9 0.66 102.2±21.2 103.5±24.8 0.67
1 107.4±19.1 109.4±17.7 0.63 97.8±17.8 94.2±20.1 0.32
2 80.2±16.5 81.3±12.9 0.49 73.0±11.1 74.3±14.1 0.42
3 nasal 58.2±9.1 57.3±8.9 0.72 55.5±8.7 57.1±9.9 0.31
4 61.2±12.0 60.4±11.1 0.38 58.6±9.6 60.6±10.1 0.51
5 86.7±15.8 88.6±16.2 0.47 81.6±13.5 82.4±14.7 0.81
6 inferior 134.5±22.1 132.7±24.3 0.55 100.3±23.5 106.2±19.4 0.021
7 137.2±18.3 136.2±17.5 0.61 116.2±30.3 125.3±24.7 0.041
8 81.1±20.7 80.0±14.6 0.53 80.9±20.5 73.0±16.2 0.011
9 temporal 60.1±10.8 60.9±11.8 0.82 61.3±9.4 54.4±10.6 <0.001
10 90.7±12.9 87.2±14.8 0.29 89.1±17.5 75.6±18.9 <0.001
11 126.7±25.2 123.8±23.5 0.33 131.5±18.6 114.8±25.9 <0.001
Mean±SD.
P values adjusted by Benjamini-Hochberg method to compensate for multiple comparison. Values with statistical significance are shown in bold.
OAG indicates open angle glaucoma; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer.

DISCUSSION

To our knowledge, this is the first study investigating the specific patterns of early structural changes in glaucomatous eyes based on age-of-onset. With detailed spatial analysis of the RNFL and GCIPL thickness deviation map constructed from the Cirrus HD-OCT, we characterized the structural topographic patterns in young-age-onset and old-age-onset preperimetric OAG eyes.

RNFL thickness is a sensitive indicator for assessment of glaucoma-related lesions. RNFL defects in glaucoma are most frequently found in the inferotemporal region, followed by the superotemporal region.21,25 However, little is known about age discrepancies in the patterns of RNFL thickness. Leung et al26 investigated age-related changes of RNFL thickness by SD-OCT in normal individuals aged over 40 (mean age: 56.43 y). In the cross-sectional analysis, the inferior and temporal RNFL thicknesses were found to have significant associations with age. Whereas in the longitudinal analysis, RNFL thickness reduction was evident in the superior and inferior quadrants. Rougier et al27 measured RNFL thickness by SD-OCT in elderly normal participants aged over 75, finding that the supero- and inferotemporal segments decreased with age, particularly the latter. In the present study, the old-age-onset eyes (range: 40–60, mean: 50.3 y) had significantly thinner RNFL in the superior region relative to the young-age-onset eyes (range: 18–39, mean: 30.7 y). However, the inferior RNFL region was greatly thinner in the young-age-onset group. We speculate that in old-age-onset eyes, the superior and inferior regions are vulnerable, whereas in young-age-onset eyes, the inferior region is most susceptible to glaucomatous damage.

The performance of macular GCIPL parameters in early glaucoma has shown promising results. There is evidence that the diagnostic utility of GCIPL measures are comparable to that of RNFL parameters,28–30 and that when they are added together, they can be used to improve diagnostic utility.29 The area of the macula most likely damaged by early glaucoma falls within the inferior retinal region. Likewise, in the current study, the maximum percentage of GCIPL defect was located in the inferior region. Topographically, GCIPL thinning occurs in the inferior portions of the macula in early glaucoma,31 which have been shown to be the most sensitive sectors.32 Approximately 50% of the RGCs are concentrated within a 4.5 mm area of the fovea,33 and notably, most of the RNFL bundles of the inferior macula enter the inferior quadrant of the disk, a region at high risk of glaucomatous damage. On the other hand, the RNFL bundles in the superior macula enter in the temporal quadrant of the disk, a region less at risk.

The discrepancy in the distribution of age-related patterns is likely attributable to age-associated ocular tissue stiffening. Extracellular matrix changes in natural aging generate a stiffer extracellular environment, which plays a major role in numerous ophthalmic pathologies including glaucoma.34 The ONH undergoes extensive extracellular matrix remodeling characterized by fibrotic changes that drive further tissue fibrosis and stiffening. A previous histologic study reported age-related changes in collagen composition within the lamina cribrosa (LC).35 In that case, the altered mechanical properties of the LC apparently resulted in a stiffer, less resilient structure with age. Another study, using a confocal scanning laser microscope to assess the shape and volume of the LC in cadaver eyes, determined that the mechanical compliance and resilience of the human LC decreases with age.36 Moreover, in vivo imaging studies have noted that the superior and inferior parts of the lamina relative to the nasal and temporal parts appear to contain larger pores and thinner connective-tissue support for the passage of nerve-fiber bundles.37 And notably, human LC thickness has been shown to increase with age. The alteration of the structural properties of the LC may affect its function, with regard to compliance and reversibility.38 Such changes in structure may contribute to increased susceptibility of regions to axonal damage in OAG.

Our study has some potential limitations. First, all of the patients were Korean; thus, studies with populations of other ethnicities will be necessary to validate our findings. In addition, with regard to the limitations of a cross-sectional study, we cannot exclude the possible effects of selection artifacts. Our study had a potential for referral bias as patients in tertiary medical centers may be considerably different from the general population. In future research, a population-based participant source should be considered. Second, the cohort of the current study had a mean refractive error considered to be representative of low-to-moderate myopia (–3.1 D in the young-age group; –2.9 D in the old-age group), and thus, caution should be exercised when interpreting our results. To overcome the limitations of our study, further studies enrolling a larger number of eyes representative of a wider spectrum of myopic degree also are warranted. Third, physiological age-related changes may have contributed to the pattern of RNFL and GCIPL thicknesses.26,39 Leung et al reported that significant negative correlations were found between age and average, inferior RNFL thicknesses. However interestingly in our study, the inferior RNFL thickness was thicker in the old-age-onset glaucoma group compared with the young-age-onset glaucoma group. This indicates difference in the characteristics of early glaucomatous damage between young-age-onset and old-age-onset. Moreover, to overcome the issue, we also included age-matched normal subjects of young-age and old-age. However, ultimately, a prospective, longitudinal analysis investigating the progressive change of RNFL and GCIPL thickness in young and old normal and glaucoma patients is warranted, to addresses the issue of differentiating physiological and pathologic changes.

In conclusion, young-age-onset and old-age-onset eyes of preperimetric OAG presented specific patterns of RNFL and GCIPL thinning on deviation frequency maps. The superior quadrant was thinner in old-age-onset eyes compared with the young-age-onset eyes, and the inferior quadrant was thinner in the young-age-onset eyes. Our study provides insights in understanding the characteristics of early structural damage based on age occurrence.

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Keywords:

preperimetric; open angle glaucoma; optical coherence tomography; retinal nerve fiber layer; ganglion cell-inner plexiform layer

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