Torsion of the Optic Nerve Head Is a Prominent Feature of Normal-Tension Glaucoma

Abstract

Purpose.: To compare optic nerve head (ONH) morphology between eyes with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG).

Methods.: Seventy-eight NTG patients and 78 POAG patients matched according to age and axial length were analyzed. Optic nerve head tilt and torsion were identified from cross-sectional images of optical coherence tomography. The degree of horizontal, vertical, and maximum ONH tilt and torsion was compared between NTG and POAG eyes, and additional comparisons were based on the presence of myopia and the location of the visual field defect. Logistic regression analysis was used to determine the factors related to the degree of ONH torsion.

Results.: Vertical (P = 0.610) and horizontal tilt degree (P = 0.746) did not differ between NTG and POAG eyes. However, torsion degree (P = 0.022) differed significantly between NTG and POAG eyes. Direction of vertical tilt (P = 0.040) and torsion (P < 0.001) showed more prevalent superior tilt and torsion in NTG eyes (21.8% and 33.3%, respectively) compared to POAG eyes (10.3% and 10.3%, respectively). Myopic NTG eyes showed greater torsion degree (P = 0.014) than nonmyopic NTG eyes, which was not observed in the comparison between myopic and nonmyopic POAG eyes. Only NTG eyes showed a significant difference in the degree of maximum tilt (P < 0.001) and torsion (P < 0.001) and the direction of vertical tilt (P < 0.001) and torsion (P = 0.010) by the location of visual field defect. Longer axial length, maximum tilt degree, and diagnosis of NTG were the factors related to the degree of ONH torsion.

Conclusions.: Normal-tension glaucoma eyes had a greater ONH torsion compared to POAG eyes with matched axial length. The direction of the ONH tilt and torsion was related to the location of the visual field defect only in NTG eyes.

Recent reports show that optic disc changes secondary to myopia, such as disc tilting and the development of peripapillary atrophy (PPA), may stretch and distort the optic nerve fibers, leading to damage of the axons of the retinal ganglion cells.^1–4 Our group has reported that the direction of disc tilt and torsion could predict the location of glaucomatous damage in eyes with myopic normal-tension glaucoma (NTG).^5,6 Inferior disc tilt and torsion could place stress on the inferior nerve axons, resulting in initial damage to the inferior nerve fiber bundle, and present as a superior visual field defect. Asymmetric posterior sclera expansion, in either the superior or the inferior region relative to the optic disc, may result in superior or inferior disc torsion as myopia develops. Current evidence suggests that the optic disc changes may originate from changes of the peripapillary sclera as myopia develops and are important in the pathogenesis of glaucoma in myopia.^7–9 

Central corneal thickness, anterior scleral thickness, and laminar thickness are reported to be thinner in NTG.^10–12 Posterior scleral thickness in the subfoveal region was thinner in myopic NTG eyes compared to myopic primary open-angle glaucoma (POAG) eyes.¹³ These studies suggest that NTG eyes may have a thinner outer coat. We hypothesized that if the outer coat of the eye is thinner and weaker, optic disc changes due to postnatal scleral changes by eyeball growth may be aggravated in NTG eyes. 

Since recent investigations have shown that photographically identified optic disc margins lack a solid anatomic foundation,^14–16 we analyzed ONH morphology with spectral-domain optical coherence tomography (SD-OCT) using the termination of Bruch's membrane opening (BMO) to define ONH tilt and torsion. By comparing features of the optic nerve head (ONH) morphology between NTG and POAG, matched according to age and axial length by propensity score, this study aimed to identify morphological characteristics of the ONH in NTG eyes. 

Methods

Subjects

We retrospectively reviewed the medical records of 125 consecutive patients with POAG and 156 patients with NTG seen by a glaucoma specialist (CKP) between March 2009 and January 2014 at the glaucoma clinic of Seoul St. Mary's Hospital. At the initial workup, each patient received a complete ophthalmologic examination, including a review of the medical history; measurement of best-corrected visual acuity (BCVA); refraction; slit-lamp biomicroscopy; gonioscopy; Goldmann applanation tonometry; dilated stereoscopic examination of the optic disc; disc and red-free fundus photography (Canon, Tokyo, Japan); and Humphrey visual field (VF) examination using the Swedish Interactive Threshold Algorithm (SITA) standard 24-2 test (Carl Zeiss Meditec, Dublin, CA, USA). Central corneal thickness (CCT) and axial length in each patient were also measured during the initial presentation using ultrasound pachymetry (Tomey Corporation, Nagoya, Japan) and ocular biometry (IOL Master; Carl Zeiss Meditec). All patients underwent detailed ONH examinations using the Heidelberg Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). 

For NTG diagnosis, patients had to fulfill the following criteria: glaucomatous optic disc changes (such as diffuse or localized rim thinning, disc hemorrhage, a notch in the rim, and a vertical cup-to-disc ratio higher than that of the other eye by more than 0.2) and glaucomatous VF loss (defined as a pattern standard deviation [P < 0.05] or glaucoma hemifield test results [P < 0.01] outside normal limits in a consistent pattern in the Bjerrum area on both qualifying VFs), confirmed and agreed on by two glaucoma specialists (H-YLP, CKP); BCVA better than 20/30; maximum intraocular pressure (IOP) less than 22 mm Hg (without glaucoma medications) during repeated measurements obtained on different days; and an open angle on gonioscopic examination. For POAG diagnosis, patients had to fulfill the NTG criteria with the exception of an IOP of more than 21 mm Hg (without glaucoma medications) even just once during repeated measurements obtained on different days. 

All patients had to meet the following additional inclusion criteria to be entered into the study: newly diagnosed glaucoma without previous treatment, consistently reliable VFs (defined as false negative < 15%, false positive < 15%, and fixation losses < 20%), and mean deviation (MD) better than −20.00 dB. Patients were excluded on the basis of any of the following criteria: a history of any retinal disease, including diabetic or hypertensive retinopathy; a history of eye trauma or surgery, with the exception of uncomplicated cataract surgery; other optic nerve diseases except for glaucoma; a history of systemic or neurologic diseases that might affect the VF; and axial length longer than 30 mm. If both eyes of a patient met the inclusion and exclusion criteria, one eye was randomly chosen for the study. 

The Institutional Review Board from Seoul St. Mary's Hospital approved the study, and the study adhered to the principles of the Declaration of Helsinki. 

Optical Coherence Tomography Imaging and Disc Analysis

A radial scanning pattern comprising forty-eight 3.758° angularly equidistant high-resolution B-scans was used. The scan pattern was centered on the clinical optic disc, and each B-scan was averaged for 35 single images with 768 A-scans per B-scan. With each technique, the operator checked for image quality, including SD-OCT proper B-scan positioning in the image frame centering on the ONH and a quality score > 20. When necessary, the images were reacquired. 

Two trained observers (K-IL and KL) performed the ONH analysis while blinded to the information of the patients and blinded to each other. Four parameters of ONH morphology were measured from the images: vertical tilt degree, horizontal tilt degree, maximum tilt degree, and torsion degree. Each degree was measured using the National Institutes of Health image analysis software (ImageJ 1.40; http://rsb.info.nih.gov/ij/index.html [in the public domain]; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD, USA). From six horizontal cross-sectional B-scan images from ONH radial scans at each clock-hour sector in right eye format, ONH tilt degree was measured according to a modified method proposed previously.^6,17,18 A line was drawn between inner tips of the RPE borders/Bruch's membrane (green line and points in Fig. 1). An additional line connecting two points in an arbitrary chosen distance of 2000 μm (measured with the built-in measurement tool) from the end of RPE borders/Bruch's membrane was drawn (red lines in Fig. 1). The line connecting the end of RPE borders/Bruch's membrane was then shifted toward the additional line (yellow arrows) to measure the angle of ONH tilt (yellow angle). The ONH vertical tilt was measured from a B-scan passing through the 6 and 12 o'clock positions. The ONH horizontal tilt was measured from a B-scan passing through the 3 and 9 o'clock positions. The maximum tilt was defined as the maximum tilt degree measured from six radial B-scans. 

Figure 1

 

Measurement of optic nerve head (ONH) tilt as tilt degree from cross-sectional images of the ONH by spectral-domain optical coherence tomography (SD-OCT). Six-millimeter radial scans comprised at forty-eight 3.75° apart were obtained centered on the clinical optic disc. From six horizontal cross-sectional B-scan images from ONH radial scans at each clock-hour sector in right eye format, ONH tilt degree was measured. Two points at the end of the Bruch's membrane/retinal pigment epithelium (RPE) were marked (green dot) and connected (green line) from each cross-sectional image. An additional line connecting two points at an arbitrarily chosen distance of 2000 μm (measured with the built-in measurement tool) from the end of RPE borders/Bruch's membrane was drawn (red lines). The line connecting the end of RPE borders/Bruch's membrane was then shifted toward the additional line (yellow arrows) to measure the angle of ONH tilt (yellow angle). The ONH vertical tilt was measured from a B-scan passing through the 6 and 12 o'clock positions. The ONH horizontal tilt was measured from a B-scan passing through the 3 and 9 o'clock positions. The maximum tilt was defined as the maximum tilt degree measured from six radial B-scans.

In each B-scan from the 48 radial scans of the ONH, the termination of the BMO on each side of the ONH was marked on the cross-sectional B-scans (Fig. 2, red and blue lines). The software then automatically identified the BMO points on the confocal scanning laser ophthalmoscopic image of the optic disc (Fig. 2, yellow outlines). Forty-eight BMO points marked on the confocal scanning laser ophthalmoscopic image of the optic disc were connected, and the ONH disc margin was delineated by SD-OCT using commercial software (Adobe Photoshop CS3; Adobe Systems, San Jose, CA, USA). This image was overlaid with the fundus photograph, which was converted into grayscale image by Photoshop (Fig. 2). The degree of ONH torsion (Fig. 2, blue angle) was measured between the vertical meridian of the line connecting the center of the BMO opening and fovea (Fig. 2, red lines) and the longest diameter of the BMO-delineated ONH margin defined by SD-OCT (Fig. 2, yellow outlines). 

Figure 2

 

Measurement of optic nerve head (ONH) torsion degree using Bruch's membrane opening (BMO)–foveal axis as reference by spectral-domain optical coherence tomography (SD-OCT). A radial scanning pattern comprising forty-eight 3.75° angularly equidistant B-scans was used (left). In each B-scan from the radial scans of the ONH, the termination of the BMO on each side of the ONH was marked on the cross-sectional B-scans (red and blue lines in middle). The software then automatically identified the BMO points on the en face image of the optic disc (yellow dots, left). The degree of ONH torsion was measured between the vertical meridian (red lines, right) and longest diameter of the BMO-delineated ONH margin (yellow line, right).

The β-zone PPA (an inner crescent of chorioretinal atrophy with visible sclera and choroidal vessels) was plotted using a mouse-driven cursor to trace the disc and PPA margins directly onto the image. The pixel areas of the β-zone PPA were calculated using ImageJ software. 

Measurement Reproducibility

To evaluate the intraobserver and interobserver reproducibility of our measuring method, 30 randomly selected eyes were evaluated. Analysis was based on five independent series of re-evaluations performed by the examiners. The absolute agreement of a single observer's measurement and the mean of all five measurements conducted by each observer was calculated with the intraclass correlation coefficient (ICC) from a two-way mixed effects model. To indicate the value of the averaged measurements obtained by each observer, the averaged measures of the ICC values were calculated using the Spearman–Brown prophecy formula,¹⁹ which gives the expected absolute agreement between the observers. According to Fleiss,²⁰ ICC scores ≥ 0.75, 0.40 to 0.75, and ≤ 0.4 are considered to be excellent, moderate, and poor, respectively. Test–retest variability was calculated using the repeated measures values (i.e., largest value minus smallest value for each measure). 

Identification of the Visual Field Defect Locations

Visual field examination using the SITA standard 24-2 test was reviewed to identify the location of the VF defects that occurred in less than 5% of age-matched controls in the pattern deviation map. Eyes showing defects within the 26 points of the superior hemifield were classified as the superior VF defect group. Eyes with defects within the 26 points of the inferior hemifield were classified as the inferior VF defect group. Eyes with defects involving both the superior and inferior hemifields were excluded from this analysis. 

Statistical Analysis

To match patients between the POAG and the NTG group according to age and axial length, propensity score analysis was performed. The propensity scores were estimated using multiple logistic regression analysis.²¹ A propensity score was calculated using the logistic equation for each patient; age and axial length were the explanatory variables. Using predicted probabilities, we sought to match an individual in the POAG group with the closest individual in the NTG group using propensity score values. Using the Greedy 5→1 digit match²² algorithm, we created propensity score-matched pairs without replacement (a 1:1 match). Specifically, we sought to match each patient with a propensity score that was identical to five digits. If this could not be done, the algorithm proceeded sequentially to the next highest digit match (four-, three-, two-, or one-digit match) until no further matches were possible. From the initial 125 eyes with POAG and 156 eyes with NTG, we were able to match 78 eyes from the POAG group with 78 eyes from the NTG group. 

The independent t-test and χ² test for independent samples were used to assess the differences between the two groups. To determine the factors related to the degree of ONH torsion, univariate and multivariate linear regression analyses were performed. The dependent variable was the degree of ONH torsion by OCT measurements. The independent variables were age, axial length, MD of the VF, vertical tilt degree, horizontal tilt degree, maximum tilt degree, PPA area, CCT, and diagnosis. Because the diagnosis was nominal in scale, it was investigated as an independent factor using a regression model, and dummy variables were performed using the POAG group as the standard. The variables that retained significance at P < 0.10 in the univariate analysis were included in the multivariate model. A probability value of P < 0.05 was considered statistically significant. SPSS for Windows (ver. 16.0.0; SPSS, Inc., Chicago, IL, USA) was used for the statistical analyses. 

Results

In total, 156 eyes were analyzed (78 NTG and 78 POAG patients). Among them, 40 eyes (51.3%) had myopia (spherical equivalent greater than −2.00 diopters or axial length longer than 24 mm) in each group. The NTG group had a significantly thinner CCT (537.54 ± 37.36 μm) than the POAG group (545.20 ± 34.33 μm; P < 0.001). Intraocular pressure was significantly higher in the POAG group (26.42 ± 4.15 mm Hg) than in the NTG group (16.24 ± 3.01 mm Hg; P < 0.001). The VF MD and pattern standard deviation were similar between the NTG and POAG groups (P = 0.126 and P = 0.501, respectively) (Table 1). 

Table 1

 

Demographic Data of Normal-Tension Glaucoma and Primary Open-Angle Glaucoma Patients Matched According to Age and Axial Length by Propensity Score

 

The ONH morphology measurements using SD-OCT by the two observers showed excellent reproducibility (ICC of 0.946–0.964 for ONH tilt and 0.939–0.966 for ONH torsion). The test–retest variability was 1.07 for ONH tilt and 3.26° for ONH torsion. 

The horizontal (P = 0.746) and vertical tilt degree (P = 0.610) were not different between the NTG and POAG groups. However, torsion degree (P = 0.022) was significantly different between the NTG and POAG groups, showing more optic disc torsion in the NTG group. The direction of optic disc tilt was mainly temporal and inferior. However, superior disc tilt was significantly more frequent in the NTG group (21.8%) compared to the POAG group (10.3%, P = 0.040). Disc torsion was mainly inferior in both groups; however, superior torsion was significantly more frequent in the NTG group (33.3%) compared to the POAG group (10.3%, P < 0.001; Table 2). Two eyes in each group had disc torsion that was over 45°, which means that the long axis of the BMO-delineated ONH margin lay near the horizontal axis of the eye rather than the vertical axis. 

Table 2

 

The Degree of Optic Nerve Head Tilt, Torsion, and Peripapillary Atrophy Area of Normal-Tension Glaucoma and Primary Open-Angle Glaucoma Patients

 

Each group was subdivided into myopic and nonmyopic groups. The myopic POAG group had significantly greater horizontal (P = 0.022) and vertical disc tilt (P = 0.030) and PPA area (P = 0.003) than did the nonmyopic POAG group. However, the degree of disc torsion was not significantly different between the groups (P = 0.313). In the NTG group, myopic eyes had significantly greater horizontal (P = 0.037) and vertical disc tilt (P = 0.049) and PPA area (P = 0.010) than did nonmyopic NTG eyes. In contrast to the POAG group, however, the degree of torsion (P = 0.014) and maximum tilt degree (P = 0.032) were significantly greater in the myopic eyes than in the nonmyopic eyes in the NTG group (Table 3). 

Table 3

 

Demographic Data and the Degree of Optic Nerve Head Tilt, Torsion, and Peripapillary Atrophy Area of Normal-Tension Glaucoma and Primary Open-Angle Glaucoma Patients With or Without Myopia

 

Among the 78 eyes in each group, 40 eyes in the POAG group and 49 eyes in the NTG group had VF defects in either the superior or inferior hemifield. Further results from analysis of these eyes are shown in Table 4. Comparison between the superior and inferior VF defect groups showed no significant difference in the vertical tilt degree, horizontal tilt degree, and PPA area in the both the NTG and POAG groups. However, the direction of vertical disc tilt (P < 0.001), maximum tilt degree (P < 0.001) and mean clock hour of maximum tilt (P < 0.001), disc torsion degree (P < 0.001), and direction of torsion (P = 0.010) were significantly different between the superior and inferior VF defect groups only in the NTG group. 

Table 4

 

Optic Nerve Head Tilt, Torsion, and Peripapillary Atrophy Area of Normal-Tension Glaucoma and Primary Open-Angle Glaucoma Patients by the Location of Visual Field Defect

 

To determine the factors related to the degree of ONH torsion, univariate and multivariate linear regression analyses were performed. The axial length (P < 0.001), horizontal tilt degree (P = 0.050), vertical tilt degree (P = 0.036), maximum tilt degree (P = 0.032), and diagnosis of NTG (P = 0.010) showed significant relationships with ONH torsion by univariate regression analysis. A higher axial length (P = 0.038), maximum tilt degree (P = 0.042), and diagnosis of NTG (P = 0.040) were the related factors in the multivariate regression analysis (Table 5). 

Table 5

 

Linear Regression Analysis With the Dependent Variable Being the Degree of Optic Nerve Head Torsion (Independent Variables Were Age, Axial Length, Mean Deviation of Visual Field, Tilt Degree, Peripapillary Atrophy Area, Central Corneal Thickness, and Diagnosis)

 

Discussion

In this study, we compared the ONH morphology between age- and axial length–matched NTG and POAG eyes. Normal-tension glaucoma eyes had thinner CCT and more frequent accompanying ONH changes, such as superior ONH tilt and torsion. Only in the NTG eyes was ONH torsion related to the location of the VF defect. 

In a recent review of the Ocular Hypertension Treatment Study, the most significant risk factor for the development of glaucoma included thin CCT, and it was an important predictor in both univariate and multivariate analyses.²³ This finding has generated increased interest in the biomechanical properties of the ocular coat and its role in the pathophysiology of glaucoma. Normal-tension glaucoma eyes are reported to have thinner CCT, thinner anterior scleral thickness, and thinner laminar thickness than POAG eyes.^10–12 In a recent study by our group, myopic NTG eyes had thinner posterior subfoveal scleral thickness compared to POAG eyes.¹³ This may indicate that NTG eyes have a thinner and weaker external coat in both the anterior and the posterior sections of the eyeball compared with POAG eyes. With similar axial elongation of the eyeball during postnatal development, eyes with thinner sclera and lamina cribrosa may have more prominent changes in the ONH morphology.^4,9,24 This effect is usually observed in myopic eyes, which have thinner posterior sclera and lamina cribrosa. In this study, NTG eyes showed more frequent superior ONH tilt and torsion than did POAG eyes with a matched axial length. Comparison between myopic and nonmyopic eyes also showed different features between NTG and POAG eyes. Myopic POAG eyes showed more frequent ONH tilt but not ONH torsion. However, not only the ONH tilt and the PPA area, but also the torsion degree differed between the myopic NTG and the nonmyopic NTG eyes. This may suggest that NTG eyes with thinner sclera and lamina cribrosa acquire more prominent changes in the ONH morphology during postnatal development. 

Our previous study showed that the direction of optic disc torsion was related to the location of the VF defect in myopic NTG.⁵ A study by Ohno-Matsui et al.² showed that the development of significant VF defects in highly myopic eyes was related to abrupt changes of the sclera curvature. It is possible that the location of the abrupt change of the sclera, by the direction of the ONH torsion, determines where the stretching and distortion of the optic nerve fibers occur. Analysis of the factors related to the presence of ONH torsion shows that axial length and diagnosis of NTG are significant factors in both univariate and multivariate regression analysis. This may suggest that the scleral deformity, by either myopia or NTG itself, leads to changes of the ONH morphology, especially ONH torsion. The ONH torsion determines the location of optic nerve fiber damage and VF defect in NTG eyes. However, this relationship was not observed in POAG eyes. The difference in ONH tilt and torsion between NTG and POAG may require further investigation to reveal its clinical significance. 

Optic nerve head morphology was assessed by the tilt degree and torsion degree using the BMO as reference by SD-OCT. Advances in SD-OCT have offered a more precise evaluation of ONH tilt as tilt degree by SD-OCT.^18,25 We added evaluation of ONH torsion also using BMO by SD-OCT. The ending of the RPE/Bruch's membrane may not be identical with the clinically identified disc margin.^16,26 Using BMO as the reference for both ONH tilt and torsion on SD-OCT images may provide a more precise and reproducible method to be used further in other studies. However, ONH tilt and torsion may be a part of defining the ONH morphology. Other factors, such as peripapillary scleral bowing, scleral canal obliqueness, laminar insertion anatomy, and border tissue configurations, may all contribute to ONH morphological features. However, measurement of these is currently limited, and they may need further investigations. Additionally, two eyes in each group had disc torsion over 45°, which means that the BMO-delineated ONH margin was horizontally oval and that the longest axis of the ONH margin lay horizontally. All of these eyes had axial length over 27 mm and high myopia. Rather than real torsion of the disc, these eyes may have a temporally dragged BMO due to stretching during eyeball elongation by myopia.^27,28 However, we did not longitudinally observe the change in the BMO-delineated ONH margin, and it is difficult at present to conclude that this finding is from myopic ONH changes. Further longitudinal investigation is needed in order to conclude its significance and implication. 

The present study has some limitations. The subjects of our study were identified in a referral clinic-based practice. Glaucoma in patients with tilted discs is more difficult to evaluate than in patients without tilted discs, and patients with tilted discs may have been more frequently referred to our hospital. Thus, referral bias may have influenced our results. In addition, only one ethnic group of patients was enrolled, and they may represent a subgroup of Korean individuals who do not reflect the characteristics of individuals in other populations. This was a cross-sectional study, and longitudinal observation was not performed. The scleral changes that we assumed to be the underlying cause for ONH morphologic changes were not observed directly. However, we used the propensity score to match axial length between NTG and POAG eyes. Using this process, we sought to identify the difference in ONH morphology between eyes with different thicknesses of sclera and lamina cribrosa, apart from the effect of myopia, which may also cause a difference in the thickness of the sclera and the lamina cribrosa. Age could have affected the material properties of the sclera and the lamina cribrosa other than thickness. This may be another important factor resulting in changes in the ONH morphology, so age matching was also performed. Direct visualization of the sclera in the posterior segment or peripapillary region around the ONH in the NTG eyes and comparison with POAG eyes should be further evaluated. There are machines that are able to image the posterior sclera; however, they are not yet commercially available.^29,30 Our evaluation of ONH tilt and torsion is an indirect approach. More precise measures with three-dimensional characterization of the ONH by more advanced techniques may be needed to confirm our findings. We included only patients with typical VF defects located in Bjerrum's area. All temporal field loss that was not typical of glaucoma was excluded. However, it is known that tilted discs result in a variety of stationary field defects other than temporal field loss, and the potential for misclassification must thus be considered. 

In summary, NTG eyes had a high frequency of superior ONH tilt and torsion as compared to POAG eyes with matched axial length. The presence of ONH torsion was related to the axial length and the diagnosis of NTG. The direction of the ONH torsion was related to the location of the VF defect only in NTG eyes. These data suggest that NTG is more prominently associated with ONH torsion compared to POAG with similar axial length. 

Acknowledgments

Supported by Research Fund of Seoul St. Mary's Hospital, The Catholic University of Korea. 

Disclosure: H.-Y.L. Park, None; K.-I. Lee, None; K. Lee, None; H.Y. Shin, None; C.K. Park, None