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1From the Optic Nerve Head Research Laboratory and the 2Ocular Biomechanics Laboratory, Devers Eye Institute, Legacy Health System, Portland, Oregon; and the 3Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana.
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Abstract |
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METHODS. Trephinated ONH and peripapillary sclera from both eyes of six normal monkeys were serial sectioned, 3-D reconstructed, 3-D delineated, and parameterized. For each normal animal and each parameter, PID was calculated (both overall and regionally) by converting all left eye data to the right eye configuration and subtracting the right eye value from that of the left eye. Physiologic intereye percent difference (PIPD) was calculated as the PID divided by the measurement mean of the two eyes. For each EEG monkey, intereye (EEG minus normal) differences and percent differences for each parameter overall and regionally were compared to the PID and PIPD maximums.
RESULTS. For all parameters the PID maximums were relatively small overall. Compared to overall PID maximums, overall intereye differences in EEG monkeys were greatest for laminar deformation and thickening, posterior scleral canal enlargement, cupping, and prelaminar neural tissue thickening. Compared with the regional PID maximums, the lamina cribrosa was posteriorly deformed centrally, inferiorly, inferonasally, and superiorly and was thickened centrally. The prelaminar neural tissues were thickened inferiorly, inferonasally, and superiorly.
CONCLUSIONS. These data provide the first characterization of PID and PIPD maximums for ONH neural and connective tissue parameters in normal monkeys and serve to further clarify the location and character of early ONH change in experimental glaucoma. However, because of the species differences, the findings in EEG should be confirmed in EEG rhesus monkey eyes.
We recently introduced our method for three dimensional (3-D) delineation of 13 optic nerve head (ONH) and peripapillary sclera landmarks and used it to quantify enlargement and elongation of the neural canal at the onset of CSLT-detected ONH surface change in three monkeys with early experimental glaucoma (EEG) that occurred after moderate levels of IOP elevation in one eye.11 In a second report,12 we described our method for continuously mapping position and thickness of the lamina cribrosa, scleral flange, and peripapillary sclera and used it to report significant posterior deformation and thickening of the lamina cribrosa accompanied by mild posterior deformation of the scleral flange and peripapillary sclera in the same EEG eyes. In a third report,13 we introduced our concept of prelaminar and laminar cupping, and used four new postmortem 3-D histomorphometric parameters to report that clinical cupping in early glaucoma is primarily due to fixed permanent posterior deformation of the ONH connective tissues and occurs in the setting of prelaminar tissues that are thickened.
The purpose of the present study was to characterize the upper range of physiologic intereye differences (PIDs) and physiologic intereye percent differences (PIPDs) in ONH neural and connective tissue architecture in six normal monkeys and compare them with intereye differences in the three previously reported monkeys with EEG in one eye,11 12 13 to clarify the most important optic nerve head changes in early experimental glaucoma. Once clarified by region and character and confirmed in a larger number of EEG eyes (manuscripts in preparation), these changes should become important imaging targets in patients with moderate levels of ocular hypertension.
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Materials and Methods |
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ONH Surface Compliance Testing and Early Glaucoma
We have described our confocal scanning laser tomography (CSLT)-based ONH surface compliance testing strategy (Laser Diagnostic Technologies; LDT, San Diego, CA) and how we use it to detect the onset of EEG.14 15 Briefly, for each compliance test, the animals were initially anesthetized with a combination of 7 mg/kg ketamine and 1 mg/kg xylazine given intramuscularly, IOP was measured (Tono-Pen XL; Bio-Rad, Glendale, CA) three times in each eye, and a contact lens was placed to maintain the corneal surface for CSLT imaging.
In all normal monkeys, both eyes were compliance tested on three to five separate occasions before euthanatization under pentobarbital anesthesia. In the early glaucoma monkeys, both eyes of each monkey were imaged on three separate occasions while normal, and then lasering of the trabecular meshwork was begun in one eye of each animal to elevate IOP. CSLT imaging was continued at 2-week intervals until the onset of significant permanent posterior deformation of the ONH surface in the lasered eye (the EEG eye), compared to the contralateral eye (the normal eye) using the CSLT-based parameter mean position of the disc.14 See Table 1 and Figure 1 in our previous publication regarding the magnitude and duration of IOP elevation experienced by each animal.14 Briefly EEG monkeys 2 and 3 were euthanatized 3 weeks and monkey 1 six weeks after CSLT detection of ONH surface change. In EEG monkey 1, detected IOP elevation occurred approximately 1 week before death with the maximum 26 mm Hg (average postlaser IOP 13 mm Hg, IOP not recorded on the day of death). In EEG monkey 2, detected IOP elevation occurred approximately 3 weeks before death, with the IOP maximum of 37 mm Hg recorded on the day of death (average post-laser IOP of 19 mm Hg). No IOP elevation was detected in EEG monkey 3 (average postlaser IOP 13 mm Hg, 18 mm Hg on the day of death). Axon counts in each EEG eye ranged from 16% to 30%, as previously reported.13
Monkey Euthanatization and Perfusion Fixation at Prescribed IOP
Under deep pentobarbital anesthesia, both eyes of each monkey were cannulated with a 27-gauge needle and the IOP was set to 10 mm Hg with an adjustable saline reservoir. After a minimum of 30 minutes, the monkey was perfusion fixed via the descending aorta with 1 L of 4% buffered hypertonic paraformaldehyde solution followed by 6 L of 5% buffered hypertonic glutaraldehyde solution.14 After perfusion fixation, IOP was maintained for 1 hour, each eye was enucleated, all extraorbital tissues were trimmed, and the anterior chamber was removed 2 to 3 mm posterior to the limbus. By gross inspection, perfusion was excellent for all 12 eyes. The posterior scleral shell with intact ONH, choroid and retina were placed in 5% glutaraldehyde solution for storage.
Generation of the Aligned Serial Section Images for Each ONH and 3-D ONH Reconstruction
These steps have been described in detail in our previous reports.11 14 For this study, all 12 eyes were reconstructed in an enhanced protocol that increases axial and transverse image resolution. Briefly, the ONH and peripapillary sclera were trephinated (6 mm diameter), embedded in paraffin, and mounted on a microtome with the ONH facing out. The fresh block surface was stained with a 1:1 (vol/vol) mixture of ponceau S and acid fuchsin stains, imaged at a transverse resolution of 1.5 x 1.5 µm per pixel and serial sectioned at 1.5-µm increments. Imaging of the stained embedded tissue block surface started at the vitreoretinal interface and ended 200 µm into the retrolaminar orbital optic nerve. The position of the tissue block and camera were recorded by laser displacement sensors (Keyence Corp., Woodcliff Lake, NJ) at each serial section. All acquired images were then stacked and aligned using the laser position data into a digital 3-D reconstruction consisting of approximately 3400 (width) x 3200 (height) x 500 (depth) voxels (depth range, 342–665), each 1.5 x 1.5 x 1.5 µm in size.
3-D Delineation of ONH and Peripapillary Scleral Landmark Points
Our 3-D delineation technique has been described in detail in previous reports.11 12 13 Briefly, using custom software (based on the Visualization Toolkit [VTK], Clifton Park, NY), the 3-D ONH reconstruction was loaded and the delineator assigned the approximate center of the neural canal as the center of rotation, around which 40, 7-voxel-thick, digital radial sagittal slices of the digital 3-D reconstruction were serially served at 4.5° intervals to the delineator’s workstation (Fig. 1A) .
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While marking in the sagittal section view window, the delineator simultaneously viewed a slaved window showing the cursor’s 3-D location within a digital transverse section image (Fig. 1C) . The 3-D Cartesian coordinates and category number for each mark were saved, generating a 3-D point cloud that represented each of the marked structures (Fig. 1D) .
Clinical Alignment of the 3-D Reconstruction
For each ONH, a high-resolution reconstruction of the central retinal vessels was performed and three dimensionally overlaid onto a predeath clinical photograph using the best match of the ONH and retinal vessels. Once preliminarily aligned (using the vessels only) the vessels and BMO points were covisualized to assess the relationship of the clinically visible optic disc margin to the delineated BMO points. A final 3-D adjustment was then performed to best match BMO to the disc margin while maintaining best vessel alignment.
BMO Zero Reference Plane
For each 3-D ONH reconstruction, a least-squares ellipse was fit to the 80 marks defining BMO, creating a BMO zero reference plane.11 The centroid of the BMO ellipse established the center point for all measurements. All quantification of neural canal offset, depth, anterior laminar/scleral position, post-BMO cup volume, and post-BMO total prelaminar volume were made relative to this plane.
Parameterization
The definitions and calculation methods of these parameters have been described in detail in our previous reports.11 12 13 In this report, we have included overall and regional quantification of neural canal offset and depth (Fig. 1E) , lamina cribrosa position (Fig. 1F) and thickness (Fig. 1G) , scleral flange thickness (Fig. 1H) , peripapillary scleral position and thickness, prelaminar tissue thickness (Fig. 1K) and volume (Fig. 1J) , post-BMO cup volume (Fig. 1L) , and post-BMO total prelaminar volume (Fig. 1I) . Scleral position and thickness were calculated in a similar way as lamina cribrosa position and thickness.
Parameter Regionalization and Difference Map Generation
Neural canal landmark offset and depth data were pooled for the eight clinical regions demonstrated in Figures 2A and 2B , respectively. The S, N, I, and T (superior, nasal, inferior, temporal) regions contain all marks within 60° of the ONH centered about the S–I and N–T clinical axes, and the SN, IN, IT, and ST regions contain all marks in 30° radial sections of the ONH centered about the SN–IT and IN–ST axes, as shown in Figure 2 .
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Post-BMO cup volume, post-BMO total prelaminar volume, and prelaminar tissue volume were divided into 24, 15° radial regions by using the BMO centroid as the center and BMO normal sections as cutting planes as shown in Figure 2C .
PID (PIPD) Range and Maximum in the Six Normal Monkeys
Overall and regional values were calculated for each parameter in each eye. For each animal, PID was calculated for each parameter (both overall and regionally) by converting all left eye data to right eye configuration, subtracting the right eye value from the left eye value and taking the absolute value. PIPD was calculated for each parameter as the PID divided by the absolute mean of the measurements of the two eyes. For all six animals, the measurement mean (both overall and regionally) for each parameter was calculated as the mean value of all six right eyes. The PID range was the range of PID values and the PID maximum was the largest PID (the upper range) among the six animals. The PIPD range was the range of PIPD values and the PIPD maximum was the largest PIPD (the upper range) among the six animals.
EEG Animal Intereye Differences and Comparison to the PID and PIPD Maximum
EEG minus normal eye differences and percent differences (the intereye difference divided by the normal eye value) for each parameter overall and regionally were calculated for each previously reported EEG monkey and compared to the PID/PIPD maximums established by the six normal animals. Parameter change for each EEG animal required the intereye difference and percent difference (overall or regionally) to exceed the PID and PIPD maximum for that parameter.
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Qualitative Inspection of Quantitative 3-D Neural Canal Size and Shape Data by Monkey
The size and shape of the clinical disc as defined by BMO and the neural canal landmark points of both eyes of each monkey were overlaid and presented in right eye configuration in Supplementary Figure S1, http://www.iovs.org/cgi/content/full/50/1/224/DC1. For all six animals, the two eyes demonstrated remarkably similar neural canal size, shape, enlargement (the degree to which the PSCO is bigger than the BMO) and obliqueness (the degree to which the PSCO is off center relative to BMO). However, there were clear differences in the size and shape of the anteriormost aspect of the subarachnoid space in three of the monkeys, especially in the inferior and inferior–nasal regions.
Qualitatively, BMO in the two eyes of each monkey was almost identical (Supplementary Fig. S1) and in each eye BMO closely colocalized to the clinically visible optic disc margin when the retinal and ONH vessels were used to maximize the colocalization (Supplementary Figs. S2 and S3, http://www.iovs.org/cgi/content/full/50/1/224/DC1).
Overall Measurement Mean and Range of Each Parameter
The measurement mean and range (for six right eyes of six animals) for each parameter are listed in Table 2 .
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Regional Measurement Means
The measurement mean (for six right eyes of six animals) and the PID and PIPD maximum (for six animals) are reported for all regional parameters in Figures 3 to 9 .
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Regional Lamina Cribrosa Position and Thickness Measurement Means and PID Maximums
The PID maximum varied from 7 to 42 µm for laminar position and 9 to 36 µm for laminar thickness (Fig. 4) . In general, regional PID maximums for laminar position were greatest centrally and inferonasally, whereas laminar thickness PID maximums were greatest in the peripheral regions.
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Comparison of Overall PID and PIPD Maximums to Overall Intereye Differences in the Three Previously Reported EEG Animals
Data to make these comparisons are reported in Table 3 . Whereas overall laminar thickness differences exceeded the PID maximum in all three EEG monkeys, their percent differences exceeded the PIPD maximum in only monkeys 1 and 3 (equaling but not exceeding the PIPD maximum in monkey 2). EEG to normal eye differences exceeded the overall PID and PIPD maximums in all three EEG monkeys for parameters related to laminar deformation, posterior scleral canal enlargement, cupping, and prelaminar neural tissue thickening.
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Discussion |
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That our overall PID and PIPD maximum data focuses attention on the parameters related to laminar deformation, posterior scleral canal enlargement, cupping, and prelaminar neural tissue thickening in EEG is important for two reasons. First, it establishes that at least for these three EEG monkeys relative to the six bilaterally normal monkeys, the model and our methods were sensitive enough to detect similar forms of early damage in all three EEG eyes. Second, it suggests that these processes may not just be the most detectable in our model/method system, but rather that they may be the most consistent early processes in experimental glaucomatous damage to the monkey ONH that occurs at moderate levels of IOP elevation.
Our regional PID maximums create a more conservative benchmark for the detection of early glaucomatous damage and further clarify that in these three EEG animals the earliest changes were laminar deformation and thickening in the central region and laminar deformation and prelaminar neural tissue thickening in the inferior, inferonasal, and superior regions. Although the human and monkey optic nerve heads may fundamentally differ in their clinical behavior, we propose that these changes, (now clarified by region and character), suggest important new imaging targets for patients with moderate levels of ocular hypertension. A study assessing these findings in a larger group of EEG monkeys is nearing completion and will be the subject of a future report.
Apart from our principal findings, several additional points bear discussing. First, while we report both the PID and PIPD maximums for each overall and regional parameter, we emphasize the PID maximum without extensively discussing it as a percentage difference (PIPD). We believe that the PID value alone is most relevant to the monkey experimental glaucoma model for cross-sectional detection of change in one eye compared with its contralateral normal control. Whereas PID estimates show the variability inherent in our method, PID data are not variability data alone but rather are estimates of the biological difference between the two normal eyes of an animal. Because our method achieves 1.5-µm voxel resolution, its accuracy is adequate to detect that the intereye differences among bilaterally normal eyes are different from the intereye differences of monkeys with experimental glaucoma in one eye. As such, we propose that requiring that the intereye difference in a given parameter exceed the upper range of its PID is a valid benchmark for change detection in the early glaucomatous eye of an animal, whether it is 0.1% or 50% of the measurement value in the contralateral normal eye.
However, we have included PIPD data (and used it as a criteria for change that is likely to be important), because in so doing, the data we report may be more applicable to similar measurements made with a clinical instrument in which the exact scale of the measurement cannot be certain. In the case of laminar position as measured by clinical Spectral Domain Optical Coherence Tomography (SD-OCT) in both eyes of an animal, the PIPD maximum for overall or regional laminar position conservatively estimates the percentage difference (between the treated and contralateral normal eye of a study animal) required to exceed the highest percent difference that occurred among these six pairs of bilaterally normal eyes.
Although we report measurement means and their range for each parameter, we do not extensively discuss their significance, as these data will soon be supplemented by the report of measurement means, 95% CI, and upper and lower range for each parameter in 41 normal eyes of 41 monkeys, ranging from 2 to 31 years of age, all perfusion fixed at 10 mm Hg IOP. These data will form the most comprehensive characterization of normal monkey ONH neural and connective tissue architecture to date and provide the source dimensions for parameterized finite element models, which will characterize the most important determinants of IOP-related stress and strain at all levels of IOP.16 17 18 19 20
Our report should be considered in the context of the following limitations. First, the true range of physiologic intereye variation would be best characterized in hundreds of pairs of normal eyes and include groups designed to assess the effects of species, age, and asymmetries in ocular dimensions and refractive errors. Although we did not preselect these animals, that we happened to study six rhesus monkeys in which the eyes of each animal were very similar does not mean that more marked intereye differences are not present in some or even most normal rhesus monkeys. We therefore view our report as preliminary and hope to gradually add to these data through additional postmortem 3-D histomorphometric reconstruction of dedicated bilaterally normal animals as well as clinical SD-OCT ONH reconstructions21 of bilaterally normal monkeys before their inclusion in our longitudinal studies of experimental glaucoma.
Because of circumstances beyond our control, we were forced to establish PID and PIPD maximums in rhesus monkeys that may not directly apply to the three cynomolgus EEG monkeys in our previous reports.11 12 13 Although there may be differences in measurement means between the species, we believe that important species differences in PID and PIPD maximum are unlikely. By gross comparison, the right eye measurement ranges of all parameters for the six rhesus monkeys (Table 2) are very similar to the normal eye ranges of the three cynomolgus EEG monkeys (Table 3) . However, without having studied a large population of animals, the species difference between our normal and EEG groups add to the preliminary nature of our findings.
The measurement means and PID values reported herein are not the actual physiologic dimensions of the living monkey before death, because of uncharacterized tissue shrinkage effects (from both fixation and embedding) associated with our 3-D histomorphometric technique. However, since both eyes of each animal were treated identically (i.e., at the same time and in the same dehydration solutions), comparisons between the two eyes of each monkey should still be valid. It is within this context that the PIPD maximum we report may have the greatest relevance to any future study in which a consistent but uncertain shrinkage or measurement artifact is present.
It is possible that lowering IOP to 10 mm Hg 30 minutes before perfusion fixation induced the prelaminar tissue thickening seen in all three EEG eyes. However, we think this is unlikely for the following reasons. First, IOP was lowered to 10 mm Hg slowly (over 1–2 minutes), and second, in those eyes in which it was measured, IOP was not that high on the day of death: 37 mm Hg in the EEG eye of monkey 2, 18 mm Hg in the EEG eye of monkey 3, and not measured in the EEG eye of monkey 1 (but the maximum IOP ever detected in that monkey was 26 mm Hg and IOP was 22 mm Hg 4 days before death). Although it is possible that the change from 37 to 10 mm Hg caused the prelaminar thickening in EEG monkey 2, we doubt that the IOP change in EEG monkeys 1 and 3 accounts for this finding. It should also be noted that when we discussed these same data in our previous publication13 we erroneously reported which animal had no IOP data on the day of death (monkey 3 instead of monkey 1) and the highest IOP recorded (32 mm Hg instead of 37 mm Hg). However, our interpretation of these data remains unchanged from that report.13 We predict that longitudinal SD-OCT imaging of prelaminar tissue volume and thickness (once clinically available), will confirm this finding in hypertensive human and monkey eyes.
Finally, previous studies have demonstrated that IOPs in ketamine-anesthetized normal monkeys (mean ± SD, 14.9 ± 2.1 mm Hg)22 are similar to those in normal humans (mean ± SD, 15.5 ± 2.6 mm Hg).23 However, our IOP measurements in these normal animals were made after administration of a combination of intramuscular ketamine and xylazine, and the IOP in our animals (range, 8–14 mm Hg) are overall slightly lower than the mean IOP in monkeys.22 There are two possible reasons for the lower IOP measurements: (1) the effects of ketamine can be time dependent24 25 26 ; thus, IOP may have become more variable and lower than actual pressures in both the normal and glaucomatous monkey eye in our experimental settings; and (2) xylazine may have an additional pressure-lowering effect, which has been reported to significantly reduce IOP in rabbits, cats, and monkeys.27
In conclusion, we have rigorously characterized the range of PID and PIPD maximums in ONH neural and connective tissue architecture in six normal rhesus monkeys. The PID and PIPD maximums of this report serve to clarify our previous studies in early experimental glaucoma and will now be used as reference values for a series of articles on intereye differences in ONH architecture in bilaterally normal monkeys as well as those with early, moderate, and severe EG, perfusion fixed with each eye at either identical or different levels of IOP.
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Acknowledgements |
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Footnotes |
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Supported in part by National Eye Institute Grant R01EY011610 (CFB); a grant from the American Health Assistance Foundation, Rockville, Maryland (CFB); a grant from The Whitaker Foundation, Arlington, Virginia (CFB); a Career Development Award (CFB); The Legacy Good Samaritan Foundation, Portland, Oregon; and the Sears Trust for Biomedical Research, Mexico, and Missouri.
Submitted for publication June 20, 2008; revised August 17, 2008; accepted November 17, 2008.
Disclosure: H. Yang, None; J.C. Downs, None; C.F. Burgoyne, None
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: Claude F. Burgoyne, Optic Nerve Head Research Laboratory, Devers Eye Institute, 1225 NE 2nd Avenue, PO Box 3950, Portland OR 97208-3950; cfburgoyne{at}deverseye.org.
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