Results show that ICP changes much more than IOP with body position, and thus ICP change drives TLP change to a greater degree than IOP. Hence, TLP changes much more than IOP with body position, and these changes occur very rapidly with body position change. The rapid changes in IOP and ICP with body position were about 2.7 and 2.5 seconds, respectively, for each body position. The HIP was located in the lower cervical/upper thoracic spine, 9.2 to 14.7 cm from the eyes toward the tail, consistent with prior human studies.
25
IOP is a primary risk factor for glaucoma and damage to the retinal ganglion cell axons is thought to occur at the ONH. ONH biomechanics have been hypothesized to play an important role in glaucoma pathophysiology, and yet IOP is not the only mechanical pressure affecting this region.
38–42 Cerebrospinal fluid pressure surrounding the retrobulbar optic nerve counteracts IOP, but only at the ONH, although both experimental studies and numerical simulations indicate this interplay is complex.
43–48 IOP acts on the entire corneoscleral shell and therefore IOP fluctuations can expand or contract the scleral canal, directly affecting the levels of in-plane mechanical stretch in the lamina cribrosa. CSFP however, only acts on the retrolaminar optic nerve and where the subarachnoid space abuts the peripapillary sclera.
39,43,45,47,49–51 Although IOP has been shown to be important in glaucoma, TLP may be the more relevant factor when considering biomechanical risk for the disease.
Eklund et al.’s
11 results on positional changes in humans showed that the largest calculated TLP change was observed when moving from the supine to the seated position. Similarly, Linden et al.
31 studied the changes of IOP and ICP in human patients with positional change and reported larger changes in ICP than IOP measurements. Both these studies showed that the calculated retrobulbar CSFP changed much more than IOP with body position change which agree with the results reported herein. The similarity in the direction and relative magnitudes of IOP, ICP, and TLP changes seen in this study and previous studies show that the NHP is an appropriate model for positional testing and changes in systemic pressure measurements.
The relative changes in IOP with body position are largely consistent with our previously published work, with one exception.
33 IOP changes in NHP 12.38 were not consistent with the other two animals, especially for the supine to inverted position (
Table 3), thus resulting in a large standard deviation of the mean across the three animals. It is possible that IOP measurements in this animal are erroneous and the error is related to implant failure that occurred shortly after these measurements were taken. That said, the IOP data from fellow eyes are consistent across all three body position trials and IOP calibration data from the sessions before and after the body position testing reported herein indicated proper IOP transducer function in this NHP. Hence, we elected to include the IOP measurements from this animal in the analysis despite the inconsistencies with the other NHPs and data from prior studies. There is no obvious explanation for these results.
It should also be noted that ICP is the best surrogate measure for both optic nerve subarachnoid space pressure and retrolaminar tissue pressure. However, it has been previously shown that ICP is likely affected by orbital tissue pressure and pia mater tension when ICP decreases below ∼3 mm Hg.
49 Therefore it can be assumed that the interaction between ICP and the orbital tissue pressure thus also affects the true TLP when ICP levels are very low in the sitting and standing positions. Due to this effect, it is reasonable to conclude that the relative change in ICP and TLP from the supine to the seated and standing positions we report ignore the interaction of with orbital tissue pressure, leading to an overstatement of true TLP change. That said, ICP tracks subarachnoid space pressure very well for ICP >3 mm Hg, so this effect would be limited to approximately 20% of the 15 and 13.5 mm Hg ICP changes we report for body position change from supine baseline to seated and standing positions, respectively. Also, it is unlikely that this previously reported phenomenon
49 would alter the reported increases in ICP and TLP in the inverted position.
The study is limited by the following considerations. First, the study was limited to a small sample size of three NHPs due to the preliminary nature of the investigation. Hence, the reported results may not translate to the larger population of Rhesus macaques, although the results showed significant differences between body positions and ICP and TLP, showing that the results were consistent between trials and across animals such that we had adequate statistical power to detect effects. Also, these results may not translate to the human population because of differences in eye and body size, although similar changes in IOP, ICP/CSFP and TLP with body position, and similar variability between subjects, have been reported in patients.
11,31 Similarly, the hydrostatic indifference point calculation was also limited in sample size, although the results are consistent with those of humans in terms of the location of the HIP between the lower cervical spine and the upper thoracic spine in both NHPs and humans.
25 Second, the adolescent age of the NHPs is a limiting factor, in that the reported results may not directly translate to older NHPs or humans in whom glaucoma would be prevalent. However, the magnitude of TLP change due to body position is much more likely to be driven by physics (cephalad fluid shifts) than any age-related physiological phenomenon. However, we report the time course and magnitude of TLP change with body position in adolescent NHPs, as well as the location of the HIP, and future positional studies should be performed in older NHPs. Third, the tilt table is unable to position animals in the upright (seated/standing) or inverted positions, so positional testing was done manually. However, the tilt table was used to accurately assess and measure the HIP of three animals, two of which were included in this body position study. A future study using precisely controlled angular tilt in a larger number of animals will be performed. Finally, the third NHP (NHP 150172) used for the HIP testing was not included in the body position analyses because he did not have a working IOP transducer. Similarly, NHP 12.38 was not used for HIP testing because his telemetry implant failed shortly after the body position testing was performed. There is no reason to suspect that this biased the reported results in any way.
Body position testing in NHPs showed that TLP change due to body position change is driven more by ICP/CSFP than IOP, suggesting that ICP/CSFP variability is an important driver of ONH and laminar biomechanics. Natural IOP, ICP, and TLP variability, coupled with telemetry, should allow us to test the hypotheses that IOP, ICP, or TLP fluctuations contribute independently to glaucoma onset or progression.