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1 From the Lions Eye Institute, University of Western Australia, Perth, Australia; and the 2 Department of Ophthalmology, Dalhousie University, Halifax, Nova Scotia, Canada.
| Abstract |
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METHODS. The anterior chamber and lateral ventricles were cannulated in mixed-breed dogs (n = 8) to allow modulation and control of IOP and CSFP, respectively. Optic disc topography was determined after baseline (set at IOP 15 mm Hg and CSFP of 0 mm Hg) and with each step-wise increase in IOP (steps of 35 mm Hg up to an average of 32 mm Hg) with CSFP fixed at 0 mm Hg. After the pressure returned to baseline, images were obtained after each step-wise increase in CSFP (steps of 2 to 4 mm Hg up to an average of 12 mm Hg) with IOP fixed at 15 mm Hg. Data were analyzed by a new probabilistic method for CSLT and global parameters generated by the instrument software. The global parameter changes from baseline were analyzed as a function of the translaminar pressure difference (IOP minus CSFP).
RESULTS. Elevation in IOP resulted in significant posterior displacement of the disc surface, whereas elevation in CSFP resulted in significant anterior displacement. For a given degree of pressure change, an increase in CSFP resulted in larger changes than a corresponding increase in IOP. The deepest 5% of locations within the disc surface were displaced nonlinearly (with an inverse exponential function, r = 0.92) as a function of the difference in translaminar pressure. Most displacement occurred at low translaminar pressure differences, with little extra movement at differences higher than 15 mm Hg. The change in the volume subtended by the anterior lamina cribrosa showed a nonlinear relationship similar to the translaminar pressure difference (r = 0.98), with negligible volume change at high difference in pressures.
CONCLUSIONS. Most optic disc movement occurs with pressure changes in the low range of translaminar pressure differences. This is consistent with the mechanical properties of collagen.
| Introduction |
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Previous investigation of optic disc mechanics has examined the effect of IOP alone on axial displacement of the disc surface2 3 4 5 6 7 8 or lamina cribrosa.9 The neural tissue of the optic disc anterior to the lamina cribrosa is not subject to a pressure gradient, and its extravascular volume can therefore be assumed to remain constant during short-term IOP changes. Retinal arterial and venous diameters do not change significantly when IOP increases up to 40 mm Hg.10 It appears reasonable to assume that optic disc volume anterior to the lamina cribrosa remains constant with IOP changes below 40 mm Hg, and so the surface movement measured in these experiments most likely reflects underlying anterior laminar movement. A variety of techniques have been used for measuring the displacement of the whole or large parts of the disc with relatively large measurement error, constraining the experimental design to the use of large pressure steps. In vivo displacement measurements of the optic disc surface have been performed with optic disc imaging devices5 6 7 and histologic studies2 and by integrating the velocity of disc surface movement over time in response to changes in IOP.3 4 In vitro studies have also been performed,3 8 9 11 but they may have limitations due to postenucleation changes in the optic disc tissue. They report maximum posterior disc surface displacement of 28 to 60 µm with IOP increases from 35 to 60 mm Hg.3 4 7 9 A systematic evaluation of the effect of CSFP on optic disc mechanics has not yet been reported.
Of greater interest than the optic disc tissue movement in response to a single large pressure change is its behavior across a range of pressure differences. The major structural component of the optic disc is collagen, which has highly nonlinear stressstrain properties with decreasing relative strain as stress increases.12 If similar properties exist in lamina cribrosa collagen, then decreasing laminar displacement would be expected as IOP increases. The shape of the lamina cribrosa also influences its mechanical characteristics. Its approximation to a spherical surface and the use of LaPlaces tension relationship suggests the theoretical possibility that laminar displacement may increase with increasing IOP.13
Experimental measurements of optic disc and laminar displacement have been inconsistent to date. Disc surface displacement per unit change in IOP was found to either remain constant or increase with increasing IOP,3 whereas other evidence suggested that disc displacement decreased with increasing IOP.9 Recently, however, measurements with new imaging techniques suggest that disc displacement remains constant with increasing IOP.14
If disc displacement increases with increasing IOP, then more laminar movement and greater laminar distortion would be expected at high IOP. This would be consistent with Maumenees hypothesis that glaucoma is in part caused by laminar movement that kinks retinal ganglion cell axons.15 In addition, laminar movement may be important in determining the diameter and flow resistance of the central retinal vein, because the central retinal vein wall collagen merges with that of the lamina cribrosa16 transferring laminar tension to the vein wall.
We used confocal scanning laser tomography (CSLT), a technique that allows quantitative measurements of optic disc topography, to perform in vivo experiments to measure disc displacement and volume changes. Of critical importance in measuring laminar movement is the ability to control and monitor CSFP, which has been shown to determine retrolaminar tissue pressure.1 This, combined with IOP, determines the pressure difference that acts across the optic disc and lamina cribrosa. IOP changes from 10 to 32 mm Hg have been shown to cause no significant change in choroidal volume or blood flow,17 18 and therefore we planned our protocol to vary IOP within this range. The possibility that optic disc tissue may become compressed under raised IOP prompted us to measure volume change when the IOPCSFP difference was kept constant, while IOP was varied.
| Methods |
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Confocal Scanning Laser Tomography
CSLT was performed (Heidelberg Retina Tomograph; Heidelberg Engineering GmbH, Dossenheim, Germany) to measure relative height or depth of the optic disc surface. The instrument and its operation have been described elsewhere.19
Briefly however, the device measures the topographic height at 65,536 (256 x 256) discreet points on the imaged area by image processing of 32 confocal optical sections through the optic nerve and retina in a 10° x 10°, 15° x 15°, or 20° x 20° area. In each animal, the same scan angle was used for all conditions.
Experimental Protocol
Two measurement protocols were used: varying IOP at fixed CSFP and varying CSFP with fixed IOP. After each pressure adjustment, we waited 15 minutes before acquiring any images. With each protocol, a set of six baseline images were taken with the tomograph. Six images were also taken at each step after the 15-minute wait. For the analysis, three best-quality images were taken from the images obtained at each pressure setting. The criteria used for selecting these images were (1) satisfactory grade in the built-in image quality-control analysis; (2) SD, after alignment, of less than 10 µm; and (3) manual inspection of aligned images.
Data Analysis
We analyzed the change in optic disc topography by a method described recently.20
Essentially, the 256 x 256-pixel image matrix was divided into an array of 64 x 64 superpixels, so that each superpixel contained 16 (4 x 4) pixels.21
An analysis of variance technique to analyze the topographic difference between the two sets of three images under two conditions (e.g., baseline and follow-up) was used. The analyses provide a topographic difference map and the likelihood of these localized changes being within the normal corresponding testretest variability limits that are derived. The topography difference map is displayed as a pseudocolor image, with green representing anterior displacement and red representing posterior displacement. The corresponding probability values of these displacements are displayed on a gray-scale map.20
We also used the global indices provided by the tomograph. A circular contour line was placed 500 µm from the disc margin. This contour line was not used to define the optic disc margin, as in conventional clinical use. The reference height was always set at 300 µm below the average height of the reference ring, which is automatically placed in the periphery of the image (in the flat peripapillary retina) and used to align serial topography images. The absolute mean axial depth of the reference ring was noted for each image and pressure condition in the experimental protocol to determine whether there was a shift in the position of the peripapillary retina (due to axial movement of the retinal surface or choroidal compression with the IOP or CSFP modulation). All subsequent depth measurements including the reference height were made relative to the normalized reference ring depth after image alignment.
Maximum cup depth (MaxD) was defined as the mean depth of the deepest 5% of pixels within the circular contour line, representing the average depth of the deepest portion of the cup. These could be seen on the surface maps and were in the center of each optic disc. In this region, there is a minimum of tissue between the lamina cribrosa and the disc surface; therefore, movement of this region may be most representative of movement of the central lamina cribrosa. No laminar pores or other potentially confusing anatomic anomalies were seen in any of our animals.
Regarding volume measurements, the curved surface was used as the reference surface. The geometric center of the circular contour line was used as the curved surface center with surface lines radiating out to the contour line. The curved surface has an appearance similar to that of a circus tent roof. Volume below the curved surface (Fig. 1 ; VolC) was that bounded by the curved surface and the disc surface below the curved surface. Volume above the curved surface (Fig. 1 , VolAC) is that bounded by the curved surface and the neural tissue surface above the curved surface.
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From Figure 1
it can be seen that
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VolS) is determined by movement of the anterior lamina. Hence, VolC minus VolAC at two conditions would be equivalent to
VolS. Curve fitting was performed on computer (SigmaPlot; SPSS Science, Chicago, IL).
| Results |
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Probability Map Analysis
An example of the probability map analysis is shown in Figure 2 . When IOP was increased incrementally from 20 to 33 mm Hg at constant CSFP (0 mm Hg), the central disc surface moved posteriorly by up to 64 µm (Fig. 2B)
. The corresponding probability map confirmed that most of the movement occurred in the central disc region. When CSFP was increased incrementally from 0 to 10 mm Hg at constant IOP (17 mm Hg), large anterior movement occurred across the whole optic disc surface (Fig. 2D)
. Even a small increase in CSFP caused large and significant anterior disc displacement.
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MaxD and
VolS, respectively (Fig. 1)
, were calculated at each pressure setting and in each animal. For the results when the IOPCSFP difference was constant,
VolS was normalized to that at IOP of 24 mm Hg and CSFP of 10 mm Hg. For grouped analysis,
MaxD and
VolS were binned at pressure intervals of 3 to 5 mm Hg.
As the translaminar pressure increased,
MaxD increased nonlinearly and then reached an asymptote (Fig. 3)
. The maximum depth increased by 80 µm as the pressure difference increased from 3 to 20 mm Hg. The relationship is described by the following function with r = 0.92
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VolS increased nonlinearly (Fig. 4A)
. The relationship was described by the following function with r = 0.98
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VolS was found when IOP was elevated from 14 to 32 mm Hg, maintaining the IOPCSFP difference at 14 mm Hg (Fig. 4B)
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| Discussion |
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Large movements of the central and deepest parts of the lamina cribrosa were seen with some small areas moving more than 128 µm with an increase in CSFP of only 2 mm Hg, or a decrease in IOP of only 5 mm Hg. Larger areas moved up to 80 µm with a translaminar pressure difference (IOP minus CSFP) of 20 mm Hg. These measurements are larger than the 32-µm posterior displacement recorded by Levy and Crapps11 when IOP was elevated from 10 to 70 mm Hg in human cadaveric eyes. That our measurements were in vivo rather than postmortem with attendant temperature changes may explain some of this difference. Small increases in CSFP had a much greater effect than equivalent increases in IOP, suggesting that greater movement occurred at lower translaminar pressure differences. This nonlinearity was suggested by the previous work of Levy, who noted that 53% of the movement occurred during the first 15-mm Hg IOP increase.11
We also found that
MaxD was nonlinearly related to the translaminar pressure difference (Fig. 3)
. The curve of best fit was a logarithmic increase to a maximum. This maximum displacement was stable at translaminar pressure differences greater than 15 mm Hg. This would suggest that at pressure differences of more than 15 mm Hg, almost no further posterior laminar movement occurred (Fig. 3)
. However, at pressure differences of less than 15 mm Hg, relatively large displacements occurred. Similarly, the
VolS with translaminar pressure difference was nonlinear (Fig. 4) .
VolS was greatest at translaminar pressure differences of less than 15 mm Hg and lowest at higher pressure differences, although, unlike changes in the maximum displacement of the cup, volume change was not asymptotic. These observations suggest that the increase in cup volume at high translaminar pressure differences is due to peripheral laminar displacement and not to a further increase in cup depth at the most cupped locations. This nonlinearity is consistent with the known nonlinear stressstrain relation of collagen, whereby the change in strain decreases with increasing stress.
It is interesting to note that the in vitro compliance of the human eyeball is approximated by the following formula22
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Currently, imaging techniques are used to measure changes in optic disc neural tissue, with increasing cup volumes usually being interpreted as due to the loss of axons, and worsening glaucoma. The results in this study raise the possibility that changes in IOP and CSFP between imaging sessions may induce changes in volume that are not related to the loss of neural tissue. Clinical studies with CSLT have shown changes in disc topography with pharmacologically23 24 and surgically25 26 induced changes in IOP. Another study has shown spontaneous variations in disc topography in patients with untreated idiopathic intracranial hypertension27 who have large variations in CSFP.28
In summary, with a given change in either IOP or CSFP, there is relatively greater optic disc movement across lower translaminar pressure ranges than across higher ranges. This may have implications regarding the vulnerability of vital structures, such as ganglion cell axons and blood vessels in the optic disc.
| Footnotes |
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Submitted for publication November 1, 2001; revised April 8, 2002; accepted May 30, 2002.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C.
1734 solely to indicate this fact.
Corresponding author: William H. Morgan, Lions Eye Institute, University of Western Australia, 2 Verdun Street, Nedlands, WA 6009, Australia; whmorgan{at}cyllene.uwa.edu.au.
| References |
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