Difference in the Properties of Retinal Nerve Fiber Layer Defect Between Superior and Inferior Visual Field Loss in Glaucoma

Abstract

Purpose.: To investigate the patterns of retinal nerve fiber layer (RNFL) defects in mean deviation-matched early glaucomatous eyes with either superior or inferior visual hemifield loss.

Methods.: Seventy-five open-angle glaucoma patients with isolated parafoveal scotoma (PFS) within a central 10° of fixation, and 62 patients with isolated peripheral nasal scotoma (PNS) in the nasal periphery outside 10° of fixation were enrolled if the scotoma involved only one hemifield. The relationship between the mean threshold sensitivity (MS) of each corresponding VF sector and optical coherence tomography–measured RNFL thickness was assessed by logarithmic regression analysis. The angular widths and locations of the RNFL defects were measured from red-free fundus photographs.

Results.: Eyes with superior PFS showed a significant relationship between RNFL thickness and corresponding MS at clock-hours 7 and 8 while eyes with inferior PFS had significant relationship at clock-hours 9, 10, and 11. Eyes with superior PNS displayed a significant relationship between RNFL thickness and MS at clock-hour 7 while eyes with inferior PNS showed significant relationship at clock-hours 11 and 12. Overall, fundus photographs–measured RNFL defect associated with inferior hemifield loss (inferior PFS + PNS) was significantly wider and closer to the horizontal meridian than those with superior hemifield loss (superior PFS + PNS) (P = 0.032 and 0.009, angular width and location, respectively).

Conclusions.: A superior RNFL defect associated with inferior hemifield loss was wider and was located closer to the horizontal meridian of the optic disc than an inferior defect with superior field loss, particularly in patients with central VF loss.

Introduction

The glaucoma hemifield test, which measures the disparity in retinal sensitivity between the superior and inferior hemifields, provides a useful tool for the detection of early glaucomatous damage. It is helpful because visual field (VF) damage often originates in only one hemifield. ^1,2 A previous report showed that the location and progression pattern of VF damage in the superior and inferior hemifields are different. ³ The superior VF is known to be more frequently involved than the inferior VF in the early stages of glaucoma. ^4,5 Leung et al. ⁶ reported that the inferotemporal side (324–336°) was the most common location for progressive changes in the retinal nerve fiber layer (RNFL) detected by optical coherence tomography (OCT). Additionally, RNFL damage occurs closer to the fixation point in the superior retina, which is farther from the fixation in the inferior retina. ⁷ Superior VF defects tend to progress more rapidly than inferior VF defects. ⁸ Therefore, it is postulated that the RNFL of the corresponding superior or inferior VF may exhibit different characteristics. However, the mechanism underlying this disparity in superior and inferior RNFLs is not well understood. 

In the retina, the ganglion cell axons traverse the nerve fiber layer in a characteristic pattern. While axons from the superior, inferior, and nasal retina take a relatively straight path to the optic nerve head, those from the temporal periphery take an arcuate course, originating on either side of the median raphe and arch above or below the fovea, passing through the optic nerve head. ⁹ In a healthy population, the optic nerve head is positioned above the fovea, which causes distinct asymmetry in the distribution of the RNFL between the superior and inferior retina, particularly in the papillomacular bundle fibers, which originate from the central retina. ^10,11 More temporally originating nerve fibers outside the macular region display lesser asymmetry between the superior and inferior retina when compared with papillomacular bundle fibers. 

In relation to this finding, previous reports showed that the involvement of the superior and inferior hemifields is significantly different between parafoveal scotoma (PFS) and peripheral nasal step scotoma (PNS). There are significantly more frequent superior VF defects in PFS; however, similar or more inferior VF defects occur in PNS. ^12,13 The reason for the predominant VF defects in the superior central region remains unclear. By analyzing the characteristics of RNFL in patients with superior or inferior visual hemifield loss, we may obtain insight into the reason for the different clinical presentations of superior and inferior glaucomatous damage. 

In the present study, we investigated the patterns of RNFL defects in mean deviation-matched early glaucomatous eyes with superior or inferior visual hemifield loss according to parafoveal or peripheral nasal scotoma. 

Patients and Methods

Study Samples

The medical records of all consecutive patients with early-stage open angle glaucoma and an isolated superior or inferior hemifield defect examined by a glaucoma specialist (CKP) between August 2010 and July 2011 at the glaucoma clinic of Seoul St. Mary's Hospital (Seoul, Korea) were reviewed retrospectively. Patients with PFS or PNS in either hemifield were considered for enrollment into this retrospective study. 

When both eyes of a patient met the inclusion criteria, one eye was randomly selected. 

The initial visit consisted of a review of the patient's medical history, measurement of the best-corrected visual acuity, refraction, slit-lamp biomicroscopy, gonioscopy, Goldmann applanation tonometry, dilated stereoscopic examination of the optic disc, disc and red-free fundus photography (Canon, Tokyo, Japan), standard perimetry (24-2 Swedish Interactive Threshold Algorithm SAP, Humphrey Field Analyzer II; Carl Zeiss Meditec, Inc., Dublin, CA), and OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Inc.). Patients were then reexamined using the same tests, usually at a 6- to 12-month interval. This study was performed according to the tenets of the Declaration of Helsinki after approval by our institutional review board. 

All included subjects had a best-corrected visual acuity of 20/40 or better, a spherical refraction within ±6.0 diopters, a cylinder correction within ±3.0 diopters, and an open and normal anterior chamber angle by gonioscopy, a presence of RNFL defect on red-free fundus photographs consistent with the glaucomatous optic disc damage (diffuse or localized rim thinning on stereoscopic color fundus photographs), and typical VF defect results on two consecutive and reliable standard automated perimetric examinations. 

A glaucomatous VF change was defined as the consistent presence of a cluster of three or more points on the pattern deviation plot with a probability of occurring in fewer than 5% of the normal population or with one point having a probability of occurring in fewer than 1% of the normal population, and glaucoma hemifield test results outside normal limits or a pattern SD with P less than 5%. 

Patients with 2 or more years of follow-up and three or more consecutive VF tests were chosen. Patients with neurological or intraocular diseases that could cause VF loss were excluded. Eyes with consistently unreliable VF results (defined as >25% false-negative results, >25% false-positive results, or >20% fixation losses) were also excluded. 

Analysis of VF Loss

The classification of VFs was based on the pattern SD plot described by Keltner et al. ¹⁴ First, patients with an isolated superior or inferior hemifield defects were reviewed. Among them, patients with PFS or PNS in one hemifield were selected. PFS and PNS were defined as described previously, with some modifications. ^12,13 PFS was defined as glaucomatous VF loss within a central 10° fixation in one hemifield and no VF abnormality outside of the central 10°. PNS was defined as a glaucomatous VF loss in one hemifield adjacent to the nasal periphery that included at least one abnormal point at or outside of 15° on the nasal periphery and no abnormalities within the central 5° fixation. Additionally, subjects with superior or inferior paracentral scotoma that exist outside a central 10° of fixation, yet are not adjacent to the nasal periphery, were included to investigate the differences of RNFLs that are located more superior or more inferior and hence farther from the raphe. Patients with a VF loss in both the superior and inferior hemifields or in both the nasal and central VFs were excluded from the study. 

To minimize false-positive results, a consistent VF loss on at least two consecutive examinations was required for inclusion. Based on these definitions, patients were assigned to one of four study groups: superior PFS, inferior PFS, superior PNS, and inferior PNS. 

Regional Structure-Function Relationship in Each Group

We evaluated the regional structure-function relationship in each group. The corresponding VF sectors for superior or inferior PFS were defined as the superior or inferior central six points, respectively, within a central 10° of fixation. The corresponding VF sectors for superior or inferior PNS were defined as the superior or inferior five points, respectively, adjacent to the nasal periphery (Fig. 1). The mean threshold sensitivity (MS) of the corresponding VF sector in each group was calculated as follows. First, the threshold sensitivity of each point in decibels was converted into a linear scale by unlogging each point and, subsequently, averaging them according to their visual field sector. Second, the average sensitivity value for each sector was transformed back into logarithmic scale (dB). 

Figure 1

 

Cases of the four study groups based on pattern deviation plot of 24-2 Swedish Interactive Threshold Algorithm standard automated perimetry. (A) A superior PFS with glaucomatous VF loss within a central 10 degrees of fixation in superior hemifield. (B) An inferior PFS with VF loss in the inferior hemifield. (C) A superior PNS with glaucomatous VF loss in superior hemifield adjacent to the nasal periphery, including at least one abnormal point at or outside 15 degrees on the nasal periphery and no abnormalities within central 5 degrees of fixation. (D) Inferior PNS with VF loss in the inferior hemifield. The corresponding VF sectors in each group are shown in the lower panel.

Spectral-domain OCT imaging was performed using an optic cube scan consisting of 200 × 200 axial scans (pixels) of the optic nerve region. Image quality was assessed by an experienced examiner blinded to the patient's identity and other test results. Only well-focused, well-centered images without eye movement and with a signal strength of 7/10 or greater were used. The average and mean RNFL thicknesses in each of the twelve 30° clock-hour segments were determined for all patients and used in the analysis. Right eye orientation was used for the documentation of clock-hour measurements. The 12:00 position represented the superior side of the optic disc, 3:00 the nasal side, 6:00 the inferior side, and 9:00 the temporal side for the right and left eyes. 

The structure-function relationship between the clock-hour–based RNFL thickness and the mean threshold sensitivity at the corresponding VF area, expressed in decibels (defined in Fig. 1), was assessed by logarithmic (y = a + b ln[x]) regression analyses in each group. The results are reported as R ². 

We also recorded the OCT-determined RNFL defects, defined as a deviation from the normal limits of RNFL thickness for each clock-hour, indicating a yellow area as outside of the 95% normal limit and a red area as outside of the 99% normal limits. 

Measurement of the Angular Locations and Widths of the RNFL Defects

Color disc and red-free fundus photographs were obtained using standardized settings on a nonmydriatic retinal camera (Nonmyd 7; Kowa, Tokyo, Japan). Fifty-degree views of the optic disc head and RNFL photography were reviewed on an LCD monitor. The color disc photographs and red-free RNFL images were evaluated independently in a random order and blinded fashion, without knowledge of the clinical information, by two of the authors (JAC, HYP). A diagnosis of localized RNFL defects was made when the width of the defect at one disc diameter distance from the edge of the disc was larger than a major retinal vessel, diverged in an arcuate or wedge shape, and reached the edge of the disc. ¹⁵ The angular locations and widths of the RNFL defects were measured from the fundus photographs using National Institutes of Health image analysis software (ImageJ version 1.40, available at http://rsb.info.nih.gov/ij/index.html; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD), as described previously. ^15–17 A circle of diameter 3.46 mm was placed around the optic nerve head. For the analysis of the angular locations of RNFL defect, two reference lines were used. First, a horizontal reference line was drawn horizontally through the center of the circle on the red-free photographs and designated as a horizontal meridian. The temporal meeting point of the line with the circle which corresponds to was set at 0° to correspond to the OCT line graph (Fig. 2A). Next, a reference line was drawn from the center of the optic disc to the foveal center on the red-free photograph (Fig. 2B). To define the borders of an RNFL defect, lines were drawn from the center of the optic disc to the points where the borders of the RNFL defect intersected with the circle. The angular width was the angle between the proximal and distal border lines of the RNFL defect. The angular location of an RNFL defect was defined as the angle formed by each reference line and proximal border of the RNFL defect. The average values of two authors were used. The angular width and locations of an RNFL defect from each reference line were compared between superior and inferior PFS group and between superior and inferior PNS group. Next, in total eyes with a superior or inferior hemifield defects (superior PFS + superior PNS versus inferior PFS + inferior PNS), the overall patterns of RNFL defects were analyzed. Additionally, the angular width and locations of RNFL defects were also compared between subjects with superior versus inferior paracentral scotoma that exist outside a central 10°. 

Figure 2

 

Measurement of the angular width and location of RNFL defects from a horizontal meridian and a line connecting the optic disc and the fovea in red-free fundus photographs. The white circle is centered on the optic disc with a 3.46-mm diameter. For the analysis of the angular locations of RNFL defect, two reference lines were used. (A) A horizontal reference line (horizontal meridian) was drawn through the center of the circle. The temporal meeting point of the line with the circle was set at 0°. (B) A reference line was drawn from the center of the optic disc to the foveal center on the red-free photograph. To define the borders of an RNFL defect, lines were drawn from the center of the optic disc to the points where the borders of the RNFL defect intersected with the circle. The angular location was defined as the angle between each reference line and the border line of the RNFL defect proximal to the reference line (white double-headed arc arrow) and the angular width as the angle between the two border lines of the RNFL defect (black double-headed arc arrow).

Data Analysis

Independent Student's t-tests and χ² test were used to compare the means and percentages between groups. Multiple comparisons among the groups were conducted using one-way ANOVA and Tukey's test. All analyses were performed using SPSS for Windows Version 14.0 (SPSS Inc., Chicago, IL). P values less than 0.05 were considered to indicate statistical significance. 

Results

Subject Baseline Characteristics

According to our classification criteria, 50 patients (50 eyes) with superior PFS, 25 patients (25 eyes) with inferior PFS, 27 patients (27 eyes) with superior PNS, and 35 patients (35 eyes) with inferior PNS were included in the study. The mean follow-up period was 5.75 ± 4.46 years for all subjects, 6.06 ± 4.61 years for the superior PFS group, 6.85 ± 4.76 years for the inferior PFS group, 3.71 ± 4.15 years for the superior PNS group, and 5.32 ± 4.20 years for the inferior PNS group. The follow-up period did not differ significantly between superior versus inferior PFS and superior versus inferior PNS groups (P = 0.457 and 0.417, respectively; Table 1). The mean age at the initial visit was not significantly different between superior versus inferior PFS and superior versus inferior PNS groups (P = 0.540 and 0.124, respectively). Sex, spherical equivalent, and baseline IOP without antiglaucoma medication were similar between superior and inferior PFS and PNS groups. For the perimetry parameters, the VF mean deviations were −2.77 ± 1.92 dB and −3.03 ± 1.68 dB for superior and inferior PFS groups (P = 0.544); −3.16 ± 1.75 dB and −3.27 ± 1.76 dB for superior and inferior PNS groups (P = 0.971). The pattern SDs were 4.50 ± 2.44 dB and 4.09 ± 2.86 dB for superior and inferior PFS groups (P = 0.587); and 4.46 ± 2.48 dB and 4.85 ± 2.60 dB for superior and inferior PNS groups (P = 0.745). The average RNFL thickness was also similar among the groups (P = 0.685 and 0.717 between superior versus inferior PFS and superior versus inferior PNS, respectively). The demographics and clinical characteristics of subjects with paracentral scotoma outside a central 10° were also similar between subjects with superior versus inferior scotoma group (see Supplementary Table S1). 

Table 1

 

Demographic and Clinical Characteristics of Glaucomatous Eyes With Each VF Pattern

	PFS		P	PNS		P
	Group A: Superior PFS, n = 50	Group B: Inferior PFS, n = 25		Group C: Superior PNS, n = 27	Group D: Inferior PNS, n = 35
Follow-up, y	6.1 ± 4.6	6.9 ± 4.8	0.457	3.7 ± 4.2	5.3 ± 4.2	0.417
Age, y	55 ± 13	58 ± 14	0.540	51 ± 13	56 ± 13	0.124
Sex, % female	60.0	56.0	0.466	37.0	42.8	0.795
Spherical equivalent, Diopters	−1.57 ± 2.18	−1.31 ± 2.43	0.763	−2.76 ± 3.72	−1.60 ± 2.83	0.185
IOP, mm Hg	15.7 ± 4.1	15.1 ± 3.3	0.660	15.3 ± 2.5	16.1 ± 2.8	0.462
MD, dB	−2.77 ± 1.92	−3.03 ± 1.68	0.544	−3.16 ± 1.75	−3.27 ± 1.76	0.971
PSD, dB	4.50 ± 2.44	4.09 ± 2.86	0.587	4.46 ± 2.48	4.85 ± 2.60	0.745
Average RNFL thickness, μm	76.08 ± 9.94	74.44 ± 10.75	0.685	75.77 ± 8.74	73.94 ± 9.10	0.717

 Values are mean ± SD.

 MD, mean deviation of perimetry; PSD, pattern standard deviation of perimetry.

*  Comparison among study groups by Student's t-test.

Regional Structure-Function Relationships

The regional structural and functional regression parameters of the superior and inferior hemifield defects in an analysis of the PFS and PNS groups are presented in Figure 3 and Table 2. In the superior PFS group, the corresponding MS had significant relationships with RNFL thickness at clock-hours 7 and 8 (inferotemporal: R ² = 0.092, P = 0.037 for clock-hour 7; R ² = 0.220, P = 0.001 for clock-hour 8) using logarithmic regression analyses. In the inferior PFS group, the area with significant relationships between RFNL thickness and MS was wider and included clock-hours 9 to 11 (temporal to superotemporal: R ² = 0.236, P = 0.014 for clock-hour 9; R ² = 0.345, P = 0.002 for clock-hour 10; R ² = 0.240, P = 0.013 for clock-hour 11) using logarithmic regression analyses. This trend was also observed in the PNS groups, where the superior PNS group showed a significant relationship between RNFL thickness and MS only for clock-hour 7 (inferotemporal: R ² = 0.210, P = 0.042), while in the inferior PNS group the relationship was significant for clock-hours 11 and 12 (superotemporal: R ² = 0.220, P = 0.007 for clock-hour 11; R ² = 0.312, P = 0.001 for clock-hour 12). The strength (R ²) of structure-function relationships for the superior PFS group (R ² = 0.092 at clock-hour 7, 0.220 at clock-hour 8) and superior PNS group (R ² = 0.210 at clock-hour 7) were relatively weaker than those for the inferior PFS group (R ² = 0.240 at clock-hour 11, 0.345 at clock-hour 10, and 0.236 at clock-hour 9) and the inferior PNS group (R ² = 0.220 at clock-hour 11 and 0.312 at clock-hour 12) by logarithmic regression analysis (Table 2). 

Figure 3

 

Regional structure-function relationships in glaucomatous eyes with hemifield patterns. (A) Superior PFS, (B) inferior PFS, (C) superior PNS, (D) inferior PNS. The corresponding VF sectors in each group are shown. In the superior PFS group, the MS of the corresponding VF sectors had a significant relationship with RNFL thickness at clock-hours 7 and 8 (inferotemporal) by logarithmic regression analyses. In the inferior PFS group, the area with a significant relationship between RFNL thickness and MS of the corresponding VF sectors was wider and included clock-hours 9 to 11 (temporal to superotemporal). This trend was also observed in the PNS groups, where the superior PNS group showed a significant relationship between RNFL thickness and MS only for clock-hour 7 (inferotemporal), whereas the relationships were significant for clock-hours 11 and 12 (superotemporal) in the inferior PNS group.

Table 2. 

 

Regional Structure-Function Relationships in Glaucomatous Eyes With Superior or Inferior Hemifield VF Loss According to PFS or PNS

	MS in VF Sector vs. RNFL Thickness in Clock-Hour Map
	PFS					PNS
	Group A: Superior PFS		Group B: Inferior PFS			Group C: Superior PNS		Group D: Inferior PNS
	R 2	P		R 2	P	R 2	P		R 2	P
Clock-hour 4	0.016	0.388	Clock-hour 2	0.028	0.424	0.002	0.828	Clock-hour 2	0.000	0.947
Clock-hour 5	0.007	0.574	Clock-hour 1	0.026	0.438	0.137	0.189	Clock-hour 1	0.050	0.219
Clock-hour 6	0.026	0.273	Clock-hour 12	0.018	0.525	0.007	0.721	Clock-hour 12	0.312	0.001
Clock-hour 7	0.092	0.037	Clock-hour 11	0.240	0.013	0.210	0.042	Clock-hour 11	0.220	0.007
Clock-hour 8	0.220	0.001	Clock-hour 10	0.345	0.002	0.121	0.134	Clock-hour 10	0.001	0.868
Clock-hour 9	0.017	0.371	Clock-hour 9	0.236	0.014	0.073	0.250	Clock-hour 9	0.028	0.360

Distribution of Cirrus-OCT Determined RNFL Defects in Each Group

The distribution of the RNFL defects determined by Cirrus HD-OCT is presented in Figure 4. In the superior PFS group, a high proportion of the RNFL defects below the 95th percentile range (yellow + red area) occurred in a narrow area; this was also true in the superior PNS group, where a high proportion of RNFL defects were found in clock-hours 6 and 7. However, in the inferior PFS group, the RNFL defects were diffusely distributed, with a relatively low proportion of RNFL defects below the 99th percentile (red-area) compared with the superior PFS group. Similarly, the RNFL defects in the inferior PNS group were more diffusely distributed than those in the superior PNS group. 

Figure 4

 

Distribution profile of RNFL defects identified by Cirrus HD-OCT. (A) Superior PFS, (B) inferior PFS, (C) superior PNS, (D) inferior PNS. The corresponding VF sectors in each group are shown. Proportions (%) of eyes with an RNFL measurement below the 99th or 95th percentile range are indicated in black and gray in each clock-hour, respectively. In the superior PFS group, a high proportion of OCT-determined RNFL defects occurred in a narrow area; this was also true in the superior PNS group, where a high proportion of RNFL defects were found in clock-hours 6 and 7. However, in the inferior PFS group, the RNFL defects were diffusely distributed, with a relatively lower proportion of RNFL defects below the 99th percentile range, compared with the superior PFS group. Similarly, the RNFL defects in the inferior PNS group were more diffusely distributed than those in the superior PNS group.

Angular Width and Locations of RNFL Defects in Red-Free Fundus Photographs

Table 3 shows the angular width and locations of corresponding RNFL defects either from the horizontal meridian or from a line connecting the disc center and the fovea. In terms of the angular width of RNFL defect, the mean angular width was significantly greater in the inferior PNS group than in the superior PNS group (P = 0.002), whereas there was no significant difference in angular width between superior and inferior PFS groups (P = 0.921). The angular location of RNFL defects in the inferior PNS group was significantly closer to the horizontal meridian than in the superior PNS group (P < 0.001), whereas there was no significant difference in defect locations between superior versus inferior PFS groups (P = 0.503). However, the relative locations of RNFL defects were changed when a line connecting the disc center and the fovea was used as a reference line. In the PNS group, the superior and inferior RNFL defects were equidistant from a line connecting the fovea and the disc center (P = 0.878), whereas the inferior RNFL defects were significantly closer to the line compared with superior RNFL defects in the PFS group (P < 0.001). 

Table 3

 

Comparison of the Angular Width and Locations of RNFL Defects in Red-Free RNFL Photographs Among Glaucomatous Eyes With Superior or Inferior Hemifield VF Loss

	PFS		PNS
	Group A: Superior PFS	Group B: Inferior PFS	Group C: Superior PNS	Group D: Inferior PNS
Angular width of corresponding RNFL defects, deg	30 ± 9	30 ± 14	26 ± 12	37 ± 14
P value	0.921		0.002
Angular location of corresponding RNFL defects from the horizontal meridian, deg	41 ± 9	39 ± 17	50 ± 11	38 ± 9
P value	0.503		<0.001
Angular location of corresponding RNFL defects from a line connecting the disc center and the fovea, deg	32 ± 9	45 ± 16	44 ± 12	44 ± 9
P value	<0.001		0.878

*  Comparison between two groups by Student's t-test.

The overall patterns of RNFL defects in total eyes with a superior or inferior hemifield defect are shown in Figure 5. The corresponding RNFL defects in inferior hemifield defect group was wider and closer to the horizontal meridian than in the superior hemifield group (P = 0.032 and 0.009, angular width and location, respectively). Based on a line connecting the disc center and the fovea, the corresponding RNFL defects in the superior hemifield defect group (37 ± 12°) was significantly closer to the line than in the inferior hemifield defect group (45 ± 13°; P < 0.001). 

Figure 5

 

Comparisons of the angular width and locations of RNFL defects in red-free fundus photographs among glaucomatous eyes with superior or inferior hemifield VF loss. Significantly wider RNFL defects closer to the horizontal meridian were observed in the inferior hemifield defect group compared with the superior hemifield group (P = 0.032 and 0.009, angular width and location, respectively). Asterisks indicate that the differences are statistically significant (P < 0.05).

In subjects with paracentral scotoma outside a central 10°, the angular width of RNFL defects was also significantly wider in the inferior hemifield group than in the superior hemifield group (P < 0.001, see Supplementary Table S1). However, no differences were noted in angular locations of RNFL defects between superior and inferior hemifield groups (P = 0.845 and 0.682, from the horizontal meridian and from a line connecting the disc center and the fovea, respectively). 

Discussion

In the present study, we characterized the patterns of circumpapillary RNFL defects in mean deviation-matched early glaucomatous eyes with different initial locations of VF loss. The RNFL defects in the superior and inferior hemifields occurred asymmetrically in both PFS and PNS groups. As shown in representative cases in Figure 6, RNFL defects in the superior retina that corresponded to an inferior VF loss were wider than those in the inferior retina with superior VF loss in early-stage glaucoma. The orientation of RNFL defects in each hemifield loss was also asymmetric. Patients with inferior hemifield defect showed an RNFL defect closer to the horizontal meridian, compared with those with superior hemifield defect. 

Figure 6

 

Representative cases showing the patterns of RNFL defects with different initial locations of VF loss. (A) Images from a 39-year-old female with superior PFS. A narrow RNFL defect at clock-hour 7 in the red-free photograph and HD-OCT clock-hour map is seen. (B) Images from a 63-year-old male with inferior PFS. RNFL defects of less than 1% of the normal limit are seen in a broader area at clock-hours 10 and 11. (C) Images from a 41-year-old male with superior PNS. Narrow RNFL defects at clock-hour 7 are shown. (D) Images from a 74-year-old female with inferior PNS. Relatively broader RNFL defects from clock-hours 11 and 12 are seen. An RNFL defect in the superior retina that corresponded to an inferior VF loss appeared to be wider than those in the inferior retina with superior VF loss in early-stage open-angle glaucoma. In addition, the RNFL defects associated with inferior PFS were closer to the horizontal meridian of the optic disc than the defects associated with superior PFS.

It is important for clinicians to understand the patterns of RNFL defects according to VF loss because the assessment of RNFL is a crucial element in the initial diagnosis and follow-up of glaucomatous patients. ^18–20 To our knowledge, this is the first study to statistically evaluate the differences in the properties of RNFL defects between superior and inferior hemifield loss based on central and peripheral VF loss. 

In this study, we grouped our study eyes into parafoveal scotoma and nasal step VF defects, which represent central and peripheral VF loss, respectively. Among glaucomatous patterns of loss, paracentral and nasal step defects are known to be major patterns of VF defects in the ocular hypertension treatment study. ¹⁴ Among the glaucoma patients with VF defects in the central region, we included eyes with parafoveal scotomas within the central 10° of fixation, because we focused on the effect of the asymmetrical anatomy of the papillomacular bundle on the location of RNFL defects and its consequences for the VF. 

In terms of the width of RNFL defect, the superior hemifield defect group was involved with narrower RNFL area, compared with the inferior defect group (Table 3). This was also observed in subgroup analysis of patients with paracentral scotoma outside a central 10° of fixation (Supplementary Table S1). In OCT-based analysis, the superior PFS group was associated with a 2 clock-hour RNFL defect (clock-hours 7 to 8), whereas the inferior PFS group was associated with a 3 clock-hour RNFL defect (clock-hours 9 to 11). The superior PNS group was also involved with a 1 clock-hour RNFL defect (clock-hours 7), whereas the inferior PNS group was involved with a 2 clock-hour RNFL defect (clock-hours 11 to 12) (Fig. 3, Table 2). The distribution of the OCT-determined RNFL defect also had similar results, showing a diffusely distributed RNFL defect, with a relatively low proportion of RNFL defect below the 99th percentile in eyes with inferior hemifield loss, compared with those with superior hemifield loss (Fig. 4). The differences in pattern of an RNFL defect between the superior and inferior retina suggest that the degree of the RNFL defect differs according to the location of the initial VF loss, providing indirect evidence of the relatively greater vulnerability of the inferior RNFL compared with the superior RNFL. In accordance with these results, the rate of VF loss progression was reported to be more rapid in the superior VF compared with the inferior VF. ^21,22  

The reason for the narrower defect width of the inferior RNFL compared with the superior RNFL under equivalent VF loss may be related to the regional fragility of the inferior lamina cribrosa and density of ganglion cell axons in the inferior retina. The lamina cribrosa is known to be the principal region of ganglion cell death in glaucoma. ^23–25 Larger pores and thinner supporting connective tissue in the superior and inferior areas of the lamina cribrosa may be associated with greater susceptibility to damage of the nerve fibers passing through these regions. ⁴ In particular, the inferior temporal lamina cribrosa is known to have larger single pore sizes and the least supporting connective tissue, ^26–28 which may be related to the dense distribution of the RNFL in the inferior retina. 

In this study, the angular location of the corresponding RNFL defect was closer to the horizontal meridian in the superior hemifield defect group compared with the inferior hemifield defect group in both OCT-measured RNFL thickness and red-free RNFL photograph data (Figs. 3, 5). This pattern was clearly seen in PFS, where the related regions of inferior PFS patients were more temporally located compared with superior PFS patients in OCT analysis (Fig. 3, Table 2). This asymmetrical location of RNFL defect is because circumpapillary OCT parameters are based on the optic nerve head, whereas the optic nerve is located relatively superiorly to the fovea and median raphe in healthy populations. ^10,11 Consistent with this notion, the relative locations of each RNFL defect corresponding to superior and inferior hemifield losses were changed according to the reference line (Table 3). When a line connecting the disc center and the fovea was used as a reference line, the related regions in superior and inferior PNS patients were equidistant from the reference line, whereas the angular location of RNFL defects in superior PFS patients was significantly closer to the reference line than in inferior PFS patients, which may be related to the asymmetric RNFL distribution between the superior and inferior retina, particularly in the papillomacular bundle fibers. More temporally originating nerve fibers outside the macular region display lesser asymmetry between the superior and inferior retina when compared with papillomacular bundle fibers, which may explain the equidistant RNFL defects from a line connecting the disc center and the fovea in the PNS group. The position of the optic disc in relation to the fovea is known to be one source of variability in the structure-function relationship. ²⁹ These results suggest that the relative location of the fovea should be considered when interpreting RNFL parameters in association with VF results. 

Parafoveal VF loss has been reported to occur predominantly in the superior hemifield; a previous study reported a 6:1 prevalence of superior over inferior parafoveal VF loss. ^{11 -13} Therefore, it is speculated that the RNFL area corresponding to inferior parafoveal VF loss is underestimated in most of the previous studies. The low frequency of inferior PFS may be explained by the wide distribution and relatively temporal position of the corresponding RNFL (clock-hours 9, 10, and 11) in inferior PFS (Fig. 3, Table 2). According to the crowding hypothesis proposed by Hood et al., ²⁸ the probability of glaucomatous damage at any given point of the optic disc is proportional to the axonal density at that point. In this regard, the relatively wider distribution of RNFL that corresponds to inferior central VF area may lead to a lower probability of axonal damage, compared with those of superior central VF area. In addition, the temporal side lamina cribrosa is less vulnerable to glaucomatous damage than the inferior and superior laminae. ^26,27  

Our study has limitations. First, the relatively small subgroup sizes and referral nature of the practice were limitations in this study. Next, we compared the pattern of RNFL defects among mean deviation-matched study groups. However, the high test-retest variability of the VF test must be considered, because it may lead to misclassification of the study groups and the inaccurate assessment of disease severity based on the mean deviation of perimetry. In this study, we used a cross-sectional study design to characterize the patterns of RNFL defects in the superior and inferior retina under equivalent VF loss at a single point in time. To confirm the increased vulnerability of the inferior RNFL, however, additional longitudinal studies will be necessary. 

In conclusion, we observed distinct characteristics of the RNFL defects in patients with superior or inferior hemifield loss, in terms of width and orientation of the involved area. A superior RNFL defect associated with inferior hemifield loss was wider and was located closer to the horizontal meridian of the optic disc than an inferior defect with superior field loss, particularly in patients with central VF loss. Knowledge of the differences in properties of RNFL defects between the superior and inferior retina will not only aid in the initial assessment of disease severity, but will also contribute to a better understanding of the pathophysiological mechanisms of glaucoma. 

Supplementary Materials

pdf S1 

Acknowledgments

Disclosure: J.A Choi, None; H.-Y.L. Park, None; K.-I. Jung, None; K.H. Hong, None; C.K. Park, None