September 2008
Volume 49, Issue 9
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Physiology and Pharmacology  |   September 2008
Estimation of Ocular Rigidity Based on Measurement of Pulse Amplitude Using Pneumotonometry and Fundus Pulse Using Laser Interferometry in Glaucoma
Author Affiliations
  • Anton Hommer
    From the Departments of Clinical Pharmacology,
    Department of Ophthalmology, Sanatorium Hera, Vienna, Austria.
  • Gabriele Fuchsjäger-Mayrl
    From the Departments of Clinical Pharmacology,
    Ophthalmology, and
  • Hemma Resch
    From the Departments of Clinical Pharmacology,
  • Clemens Vass
    Ophthalmology, and
  • Gerhard Garhofer
    From the Departments of Clinical Pharmacology,
  • Leopold Schmetterer
    From the Departments of Clinical Pharmacology,
    Biomedical Engineering and Physics, Medical University of Vienna, Vienna, Austria; and the
Investigative Ophthalmology & Visual Science September 2008, Vol.49, 4046-4050. doi:10.1167/iovs.07-1342
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      Anton Hommer, Gabriele Fuchsjäger-Mayrl, Hemma Resch, Clemens Vass, Gerhard Garhofer, Leopold Schmetterer; Estimation of Ocular Rigidity Based on Measurement of Pulse Amplitude Using Pneumotonometry and Fundus Pulse Using Laser Interferometry in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2008;49(9):4046-4050. doi: 10.1167/iovs.07-1342.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

purpose. There is evidence from theoretical models and animal studies that the biomechanical properties of the optic nerve head and the sclera play a role in the pathophysiology of glaucoma. There are, however, only a few data available that demonstrate such biomechanical alterations in vivo. In this study, the hypothesis was that patients with primary open-angle glaucoma (POAG) have an abnormal ocular structural stiffness based on measurements of intraocular pressure amplitude and ocular fundus pulsation amplitude (FPA).

methods. Seventy patients with POAG and 70 healthy control subjects matched for age, sex, intraocular pressure and systemic blood pressure were included. The ocular PA and pulsatile ocular blood flow were assessed with pneumotonometry. The FPA was measured by using laser interferometry. Based on the Friedenwald equation, a coefficient of ocular rigidity (E1) was calculated relating PA to FPA.

results. There was no difference in systemic blood pressure, intraocular pressure, and ocular perfusion pressure (OPP) between the patients with glaucoma and the healthy control subjects. Both, FPA and PA were lower in the patients with glaucoma than in the control subjects. The calculated factor E1 was significantly higher in the patients with POAG (0.0454 ± 0.0085 AU) than in the control subjects (0.0427 ± 0.0058 AU, P = 0.03). Multiple regression analysis revealed that E1 was independent of age and sex, and correlated only slightly with OPP.

conclusions. The present study indicates increased ocular rigidity in patients with POAG. This is compatible with a number of previous animal experiments and supports the concepts that the biomechanical properties of ocular tissues play a role in the diseases process.

Increased intraocular pressure (IOP) is the most important risk factor for the development and progression of glaucomatous optic neuropathy. The mechanisms by which increased IOP predisposes the eye to loss of nerve fibers and the process leading to retinal ganglion cell axon damage and/or retinal ganglion cell death is not well understood. It has been hypothesized that the biomechanical properties of the optic nerve head and/or sclera play a role in this context. 1 2 3 4 5 6 To measure these elastic properties of the ocular surfaces in vivo, however, is difficult. 
One approach to gaining insight into the biomechanical properties of the eye is based on the Friedenwald equation 7 :  
\[E\ {=}\ (\mathrm{log\ IOP}_{1}\ {-}\ \mathrm{log\ IOP}_{2})/(V_{1}\ {-}\ V_{2}),\]
where E is ocular rigidity. When E increases, it suggests that the eye is stiffer; when E decreases, it suggests that the eye is less stiff. We use the term ocular rigidity to describe the combined structural stiffness of the sclera, choroid, Bruch’s membrane (BM), retina, and cornea. Structural stiffness is an engineering term that combines the separate components of a load-bearing structure, architecture, and material properties. Understood in this context, the ocular tissues can become stiffer, because they, together or individually, become more robust (thicker, for example) and/or their extracellular matrix changes in a way that they are individually or together stiffer, or less pliant. Although we believe that scleral structural stiffness is the principal component of ocular rigidity as it applies to the Friedenwald equation, for the purposes of this report, our measurements most directly relate to the combined behaviors of the sclera, choroid, BM, retina, and cornea, and cannot be attributed to any one of these structures alone. 
In the present study pulse-related changes in IOP were measured by using pneumotonometry. 8 Insight into ΔV was gained by measuring ocular fundus pulsation amplitude (FPA) with laser interferometry. 9 Based on these measurements, a factor related to overall ocular structural stiffness was calculated. In the present study, we tested the hypothesis that this factor may be altered in patients with primary open-angle glaucoma (POAG). 
Subjects and Methods
Patients
The present study adhered to the principles of the Declaration of Helsinki. After approval from the Ethics Committee of the Medical University of Vienna, 70 patients with POAG and 70 healthy subjects matched for age, sex, and systemic blood pressure were included. Matching for systemic blood pressure was based on a previous notion that the level of blood pressure may influence the relation between changes in ΔV and IOP. 10 11 The baseline characteristics of these patients are given in Table 1 . In the present study, patients with POAG independent of untreated IOP were included. The diagnosis of POAG was based on an abnormal optic nerve head appearance and the visual field criteria of the Ocular Hypertension Treatment Study. 12 An abnormal visual field was accordingly defined as having a glaucoma hemifield test result outside normal limits and/or a corrected pattern standard deviation (CPSD) with P < 0.05. All patients were treated with antiglaucoma drugs and had IOP levels <21 mm Hg at the time when they were studied. Any of the following excluded a patient from participation in this clinical trial: exfoliation glaucoma, pigmentary glaucoma, history of acute angle closure, standard deviation (mean deviation [MD]) of visual field testing (Humphrey 30-2 program; Carl Zeiss Meditec, Inc., Oberkochen, Germany) >10, history of intraocular glaucoma surgery or argon laser trabeculoplasty, and ocular inflammation or infection within the past 3 months. 
Blood Pressure and Pulse Rate
Systolic, diastolic, and mean blood pressures (SBP, DBP, MAP, respectively) were measured on the upper arm with an automated oscillometric device (HP-CMS patient monitor; Hewlett Packard, Palo Alto, CA). Pulse pressure amplitude (PPA) was measured as SBP minus DBP. Ocular perfusion was calculated as MAP minus IOP. The pulse rate was automatically recorded from a finger pulse-oximetric device (HP-CMS patient monitor; Hewlett-Packard). 
Fundus Pulsation
Synchronous pulsations of the eye fundus were assessed by laser interferometry on the subject’s right eye. The method is described in detail elsewhere. 13 14 Briefly, the eye is illuminated by the beam of a single-mode laser diode with a wavelength (λ) of 783 nm. The light is reflected at both the surface of the cornea and the retina. The two re-emitted waves produce interference fringes from which the distance changes between the cornea and retina during a cardiac cycle can be calculated. Distance changes between the cornea and retina lead to a corresponding variation of the interference order (ΔN(t)). This change in interference order can be evaluated by counting the fringes moving inward and outward during the cardiac cycle. Changes in optical distance (ΔL(t)), corresponding to the cornea–retina distance changes, can then be calculated by ΔL(t) = ΔN(t) · λ/2. The maximum distance change is called the FPA and estimates the local pulsatile blood flow. 13 14 FPA was calculated as the mean of measurements in at least five cardiac cycles. The short-term and day-to-day variability of the method is small. 15 To obtain information on the choroidal blood flow, the macula, where the retina lacks vasculature, was chosen for measurements. 
Pneumotonometric Measurement of Pulsatile Ocular Blood Flow
Pulsatile ocular blood flow (POBF) was determined with a commercially available blood flow measurement system (System 3000; OBF Laboratories, Malmesburry, UK). 8 By means of a pneumatic applanation tonometer, the system assesses changes in IOP that are caused by the rhythmic filling of the intraocular vessels. The maximum IOP change during the cardiac cycle is called pulse amplitude (PA). Based on a theoretical eye model, the POBF is calculated from the IOP variation over time. This hydrodynamic model is based on the assumption that venous outflow from the eye is nonpulsatile. Moreover, the ocular rigidity, which is used to derive ocular volume changes from changes in IOP, is assumed to be equal in all subjects. The calculation of POBF is automatically derived from the five pulses that are closest to each other in IOP beat-to-beat variation. 
Data Analysis
The IOP change during the cardiac cycle, called PA, is not directly a measure of volume flow. It rather reflects the pressure change that is associated with the volume flow. The point where scleral stiffness comes in is the calculation of POBF. This procedure has been formulated by Silver and Farrell. 8 A key point in this calculation is the transformation of PA into the associated volume change. Because this volume change is not directly measurable, Silver calculated it from PA by assuming a standard ocular rigidity. 8 In the approach presented in the present paper, this procedure was not applied. Instead, we assumed that the ocular volume change can be estimated based on measurement of FPA. Assuming that FPA is proportional to the change in ΔV during the cardiac cycle a factor E1 = (log IOP1 − log IOP2)/FPA was calculated as a measure of the mechanical properties of the eyeball based on the Friedenwald equation. IOP2 and IOP1 are the highest IOP during systole and the lowest IOP during diastole, respectively. This factor related to ocular rigidity was chosen as the main outcome variable and compared between the patients and control subjects. All outcome parameters are given in absolute values as the mean ± SD. The unpaired t-test was used to compare the outcome parameters between the two groups. Linear correlation analysis was used to investigate the association between FPA and the outcome parameters of pneumotonometry. Finally, a multiple regression model was used to investigate whether E1 is dependent on factors such as age, sex, systemic blood pressure, pulse rate, and ocular perfusion pressure (OPP). This analysis was performed separately in the patients and healthy control subjects. 
Results
The patients’ characteristics are presented in Table 1 . The two study groups did not differ with respect to age, sex, IOP, systemic hemodynamic parameters, and optic disc size. As expected, the vertical and horizontal cup-to-disc ratio was higher in the patients. 
Ocular hemodynamic parameters were lower in the patients than in the age-matched control subjects. In the group of patients with POAG, FPA was 3.21 ± 0.98 μm, whereas it was 3.99 ± 0.94 μm in the healthy control group (P < 0.001 between groups). Likewise, PA was lower in the patients than in the control subjects (POAG: 2.42 ± 0.66 mm Hg; healthy control: 2.88 ± 0.60 mm Hg; P < 0.001 between groups). The POBFs were also lower in the patients with POAG (879 ± 225 μL/min) than in the healthy control subjects (1045 ± 187 μL/min, P < 0.001 between groups). 
The data of the correlation analysis are presented in Figure 1 . In both study groups, the association between FPA and the parameters of pneumotonometry were significant (P < 0.001 each). As expected, correlation coefficients were higher for FPA versus PA analysis than for FPA versus POBF analysis. In addition, correlation coefficients were higher in the healthy subjects than in the patients. The factor of structural stiffness E1, as calculated from FPA and PA, was significantly higher in the patients with POAG (0.0454 ± 0.0085 AU) than in the healthy control subjects (0.0427 ± 0.0058 AU, P = 0.03). 
The result of the multiple regression analysis is presented in Table 2 . In healthy control subjects, a significant positive association of E1 was found with MAP and DBP. In both study groups E1 correlated positively with OPP, but independent of age, sex, SBP, PPA, and pulse rate. 
Discussion
The present study indicates an increased ocular rigidity in patients with POAG. This conclusion is based on an abnormally elevated factor E1 as calculated from laser interferometric and pneumotonometric measurements. The main limitation of this approach is whether FPA is an adequate measure of ΔV. There is evidence that the measure is indeed adequate. On the one hand, the association between FPA and PA in healthy subjects is high, 13 15 which was confirmed in the present study. On the other hand, FPA measurements provide a reasonable estimates of POBF when a theoretical model is applied. 16 Hence, E1 appears to represent a semiquantitative estimate of the rigidity of the eyeball. 
Alterations of the mechanical properties of ocular tissues in glaucoma have been proposed based on a variety of previous studies. Two different approaches for finite element modeling of the optic nerve head have provided theoretical evidence f a potential contributing role of optic nerve head and scleral elastic properties. Bellezza et al. 17 suggested that IOP-related stress and strain are dependent on scleral canal size and scleral thickness. More recently, an improved finite element model was presented 1 5 18 that imposed more realistic boundary conditions on the lamina cribrosa. This model shows that IOP-induced biomechanical effects in the lamina cribrosa are largely dependent on the rigidity of the sclera. Both analyses, however, clearly indicate that the mechanical properties of ocular tissues in an individual may contribute to the differences in susceptibility to IOP in different subjects. 
A large body of evidence for the involvement of biomechanical factors in the glaucomatous process arises from animal studies. These studies clearly indicate that the ONH deforms early after an experimental increase in IOP and that this effect is subject o a high-intraindividual variability. 19 20 When considering the data of the present study, it is important to notice that this IOP-induced deformation also includes the peripapillary sclera. In monkeys with early glaucomatous damage, induced by a short-term moderate IOP increase, the biomechanical properties of the peripapillary sclera were altered. 21 More specifically, an increased equilibrium modulus was found in these eyes compared with nonglaucomatous monkey eyes, indicating increased scleral stiffness in agreement with the results of the present study. This finding means that an increase in IOP is less counterregulated by an increase in ocular volume to reduce IOP. 
Our data are compatible with those in a previous in study in human postmortem donor eyes. 22 In these eyes, a momentary increase in IOP was used to inflate the globe. The motion of the optic nerve head relative to the adjacent sclera was investigated by using a laser Doppler velocimetry technique. The displacement of the optic nerve head was smaller the more advanced the disease. Since the present study represents a cross-sectional approach, we cannot answer whether changes in E1 are stage-dependent. In the present study the glaucoma population selected was as homogeneous as possible to increase the likelihood of detecting a significant difference compared with control subjects. Obviously, the major determinant of ocular rigidity estimated based on E1 is the rigidity of the sclera. 10 This increase in scleral rigidity may be related to increased scleral stiffness on the basis of the sclera’s becoming thicker, more rigid, or both. However, other factors such as the structural stiffness of the optic nerve head or the choroidal vasculature may contribute as well. In glaucoma, the changes in optic nerve head morphology may be directly linked to the geometry and extracellular matrix changes within the immediate peripapillary sclera, but it is less likely that they are directly linked to extracellular matrix changes in the more peripheral posterior, equatorial, and anterior sclera. Hence, an increase in the structural stiffness of the immediate peripapillary sclera seems to be closely related to the disease process and may be considered a consequence of glaucoma. Alternatively, one may also hypothesize that increased scleral stiffness is a principle risk factor for glaucoma. This hypothesis is difficult to test, however, and would require a longitudinal approach for investigating the incidence of glaucoma in association with E1 in a healthy population. 
Several experiments indicate that changes in the biomechanical properties of the lamina cribrosa are age-related. 23 24 25 26 27 28 Recently, it has been hypothesized that advanced glycation end products play a role in the process of stiffening, and experimental data from porcine lamina cribrosa and peripapillary sclera indicate that glyceraldehyde and methylglyoxal increase the stiffness of these tissues. 4 Further support for this hypothesis was gained by the recent observation that glaucomatous tissues show increased accumulation of advanced glycation end products. 29 In the present study, however, we did not observe an age dependence of E1. This may well be related to the relatively small age range of the included study population. Further studies are warranted to investigate whether E1 is age-dependent in a healthy population spanning over at least seven decades. 
In vivo data indicating altered biomechanical properties of ocular tissues in glaucoma are sparse. In patients with POAG, corneal hysteresis is significantly associated with progressive visual field worsening. 30 A connection between corneal thickness and the mechanical properties of the lamina cribrosa has been shown by Lesk et al. 31 In their study, they have shown that patients with POAG and ocular hypertension have an increased shallowing of the cup. Of interest, patients with thinner corneas also show a reduced blood flow increase at the neuroretinal rim after IOP reduction, providing a potential link between the biomechanical and the vascular hypothesis of blood flow. 
An additional result of the present study is that the patients with POAG showed reduced values of FPA and POBF than did the healthy age-matched control subjects. This result is in keeping with a variety of previously published studies. 32 33 34 Today, there are several lines of evidence that reduced ocular blood flow plays a causative role in patients with POAG 35 36 37 and pathophysiological concepts have been elaborated that contain ischemia as an important contributing factor in the disease process, 38 but a detailed discussion on this subjects is beyond the scope of the present paper. 
Regarding the results of the present study, several limitations should be considered. Most important, comparison of E1 between groups requires that they have equal IOPs, because the pressure–volume relationship is dependent on the absolute IOP. Hence, we selected patients who had pharmacologically controlled IOP when they were measured and cannot exclude that their topical medication influenced ocular rigidity. We deem this unlikely, however, because different classes of drugs were used in our study cohort. In addition, our healthy control group was matched in age, sex, and systemic blood pressure. The latter is important, because there is evidence that the pressure within the choroid is also a determinant of the pressure–volume relationship. 10 11 In the present study we observed only a weak association between DBP and E1 in the healthy subjects. The association with OPP in both groups is more likely related to the fact that calculation of OPP includes IOP. Finally, the present study did not test the reproducibility of E1 measurements. We have previously shown, however, that both PA and FPA show satisfactory reproducibility in healthy subjects. 39  
The results of the present study indicate that patients with glaucoma have increased ocular structural stiffness. This conclusion is based on pneumotonometric measurements of PA and laser interferometric measurement of FPA. Whether this is a primary contributing factor to glaucomatous damage of the retinal ganglion cell axons or is a secondary effect of this damage remains to be determined in future longitudinal studies. 
 
Table 1.
 
Characteristics of the Study Population
Table 1.
 
Characteristics of the Study Population
POAG Healthy Control P
Number 70 70
Age (y) 66.3 ± 9.2 67.1 ± 9.3 0.60
Male/female 35/35 36/34 0.99
Topical medication
 Timolol 28
 Levobunolol 1
 Metipranolol 1
 Latanoprost 11
 Bimatoprost 4
 Travoprost 3
 Dorzolamide 3
 Brinzolamide 1
 Timolol/dorzolamide 11
 Timolol/latanoprost 6
 Timolol/brimonidine 2
IOP (mm Hg) 16.1 ± 2.2 15.9 ± 2.1 0.59
SBP (mm Hg) 142.5 ± 11.6 140.2 ± 16.2 0.32
DBP (mm Hg) 76.4 ± 9.8 74.3 ± 9.8 0.20
MAP (mm Hg) 99.8 ± 10.8 98.2 ± 8.9 0.34
PPA (mm Hg) 66.1 ± 11.0 65.9 ± 15.7 0.92
OPP (mm Hg) 83.7 ± 11.5 82.3 ± 11.5 0.42
Pulse rate (min−1) 78.5 ± 12.2 77.4 ± 11.6 0.60
Optic disc size (mm−2) 2.37 ± 0.56 2.39 ± 0.46 0.77
Horizontal cup-to-disc ratio 0.71 ± 0.09 0.55 ± 0.11 <0.01
Vertical cup-to-disc ratio 0.75 ± 0.10 0.57 ± 0.11 <0.01
Mean deviation −3.8 ± 2.7
Figure 1.
 
Linear correlation between FPA and POBF (top) and between FPA and PA (bottom). Data are shown separately for the patients with POAG (right, n = 70) and the healthy control subjects (left, n = 70). Dashed lines: 95% confidence intervals.
Figure 1.
 
Linear correlation between FPA and POBF (top) and between FPA and PA (bottom). Data are shown separately for the patients with POAG (right, n = 70) and the healthy control subjects (left, n = 70). Dashed lines: 95% confidence intervals.
Table 2.
 
Results of Multiple Regression Analysis, Determinants of the Factor of Structural Stiffness E1, Calculated Separately in Patients with POAG and Healthy Control Subjects
Table 2.
 
Results of Multiple Regression Analysis, Determinants of the Factor of Structural Stiffness E1, Calculated Separately in Patients with POAG and Healthy Control Subjects
POAG Healthy Controls
Age (y) 0.529 0.892
Male/female 0.282 0.311
Systolic blood pressure (mm Hg) 0.438 0.122
Diastolic blood pressure (mm Hg) 0.151 0.034
Mean blood pressure (mm Hg) 0.098 0.040
Pulse pressure amplitude (mm Hg) 0.645 0.913
Ocular perfusion pressure (mm Hg) 0.014 0.002
Pulse rate (min−1) 0.355 0.230
Mean deviation 0.454
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Figure 1.
 
Linear correlation between FPA and POBF (top) and between FPA and PA (bottom). Data are shown separately for the patients with POAG (right, n = 70) and the healthy control subjects (left, n = 70). Dashed lines: 95% confidence intervals.
Figure 1.
 
Linear correlation between FPA and POBF (top) and between FPA and PA (bottom). Data are shown separately for the patients with POAG (right, n = 70) and the healthy control subjects (left, n = 70). Dashed lines: 95% confidence intervals.
Table 1.
 
Characteristics of the Study Population
Table 1.
 
Characteristics of the Study Population
POAG Healthy Control P
Number 70 70
Age (y) 66.3 ± 9.2 67.1 ± 9.3 0.60
Male/female 35/35 36/34 0.99
Topical medication
 Timolol 28
 Levobunolol 1
 Metipranolol 1
 Latanoprost 11
 Bimatoprost 4
 Travoprost 3
 Dorzolamide 3
 Brinzolamide 1
 Timolol/dorzolamide 11
 Timolol/latanoprost 6
 Timolol/brimonidine 2
IOP (mm Hg) 16.1 ± 2.2 15.9 ± 2.1 0.59
SBP (mm Hg) 142.5 ± 11.6 140.2 ± 16.2 0.32
DBP (mm Hg) 76.4 ± 9.8 74.3 ± 9.8 0.20
MAP (mm Hg) 99.8 ± 10.8 98.2 ± 8.9 0.34
PPA (mm Hg) 66.1 ± 11.0 65.9 ± 15.7 0.92
OPP (mm Hg) 83.7 ± 11.5 82.3 ± 11.5 0.42
Pulse rate (min−1) 78.5 ± 12.2 77.4 ± 11.6 0.60
Optic disc size (mm−2) 2.37 ± 0.56 2.39 ± 0.46 0.77
Horizontal cup-to-disc ratio 0.71 ± 0.09 0.55 ± 0.11 <0.01
Vertical cup-to-disc ratio 0.75 ± 0.10 0.57 ± 0.11 <0.01
Mean deviation −3.8 ± 2.7
Table 2.
 
Results of Multiple Regression Analysis, Determinants of the Factor of Structural Stiffness E1, Calculated Separately in Patients with POAG and Healthy Control Subjects
Table 2.
 
Results of Multiple Regression Analysis, Determinants of the Factor of Structural Stiffness E1, Calculated Separately in Patients with POAG and Healthy Control Subjects
POAG Healthy Controls
Age (y) 0.529 0.892
Male/female 0.282 0.311
Systolic blood pressure (mm Hg) 0.438 0.122
Diastolic blood pressure (mm Hg) 0.151 0.034
Mean blood pressure (mm Hg) 0.098 0.040
Pulse pressure amplitude (mm Hg) 0.645 0.913
Ocular perfusion pressure (mm Hg) 0.014 0.002
Pulse rate (min−1) 0.355 0.230
Mean deviation 0.454
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