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Diurnal variation of ocular hysteresis in normal subjects:relevance in clinical context

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Mohammad Laiquzzaman PhD,1 Rajan Bhojwani FRCOphth,1,2 Ian Cunliffe FRCOphth1 and Sunil Shah FRCOphth1,2,3
1 Birmingham Heartlands and Solihull NHS Trust, Solihull, 2Birmingham and Midland Eye Centre, and 3Anterior Eye Group, eurosciences Research Institute, Aston University, Birmingham, UK

ABSTRACT

Background:
This study was conducted to assess the diurnal variation in ocular hysteresis, as measured by the Ocular Response Analyser to establish a relationship between diurnal hysteresis variation and diurnal intraocular pressure (IOP) variation.

Methods:
Forty-two normal eyes of 21 colleagues and staff in a teaching hospital in Birmingham, UK, were recruited. The IOP and hysteresis were measured by the Ocular Response Analyser. The central corneal thickness (CCT) was measured using a hand-held ultrasonic pachymeter in the mid-pupillary axis.

Results: The mean ocular hysteresis at 8 AM was 12.7 ± 2.3 mmHg, at 11 AM was 12.2 ± 2.0 mmHg, at 2 PM was 12.7 ± 2.1 mmHg and at 5 PM was 12.7 ± 1.7 mmHg; the difference between the values at any time of measurement was not statistically significant (P > 0.9, repeated measures). IOP as measured by non-contact tonometry was 18.4 ± 2.8 mmHg, 17.9 ± 3.3 mmHg, 16.9 ± 3.1 mmHg and 16.8 ± 3.2 mmHg, respectively, for the same time period; the difference between the values in the morning and afternoon was statistically significant (P < 0.0001, repeated measures). The CCT was 548.8 ± 29.5 m, 547.0 ± 31.4 m, 548.2 ± 29.6 m and 548.6 ± 29.4 m, respectively; the difference between the values was not statistically significant at any time points. Multiple regression analysis showed the relationship between IOP and hysteresis was not statistically significant (P = 0.9).

Conclusion: The ocular hysteresis reading was almost constant throughout the day, whereas the IOP readings showed highest values in the morning with a reducing trend being lowest in the afternoon. The CCT values were almost stable throughout the day. IOP appears to vary independently of a variation in hysteresis or CCT. Key words: hysteresis, intraocular pressure, central corneal thickness.

INTRODUCTION
The cornea has been a subject of interest to ophthalmologist and other eye carers because of its maintenance of transparency, refractive power, shape and structural stability. Although studies have been carried out previously to determine ocular rigidity/elasticity, to the authors’ knowledge, no study has been performed to determine the diurnal variation of ocular rigidity.

To date, there has been no easy method reported to determine the biomechanical properties of the cornea in vivo. The only easy measure of ocular rigidity has been central corneal thickness (CCT). A recent addition to the armamentarium for assessing rigidity has been the Ocular Response Analyser (ORA) (Reichert Ophthalmic Instruments, Buffalo, NY, USA) that, in addition to being a non-contact tonometer (NCT), measures new metrics referred to as ‘hysteresis’ that is said to be a measure of the viscoelastic properties of the eye.1

The hysteresis is the difference between the inward and outward applanation pressure on the NCT. The air pressure that hits the corneal surface is a precisely metered ramp of air. It would be expected that the cornea would applanate at the same pressure on the way and in and out; however, because of the viscoelastic properties of the cornea, two different applanation pressures are noted. A viscoelastic tissue differs from elastic material in that it does not return energy in a predictable manner. The hysteresis is described as the unexpected loss or delay of energy due to resistance of the cornea to the tonometer.1
The aim of this study was to assess the variation in ocular hysteresis during normal working hours using the ORA and to assess the relationship to variation in CCT and intraocular pressure (IOP).

METHODS

Forty-two eyes of 21 normal volunteers (7 men and 14 women), mean age 39.8 ± 12.2 years standard deviation (SD) (range 21.0–65.0 years), who were colleagues and staff in a teaching hospital, Birmingham, UK, were recruited. All the subjects had no ocular pathology. There was no history of previous ocular injury. None of these volunteers had undergone any anterior ocular surgery or were contact lens wearers. A full ocular examination was performed. Institutional Review Board approval was obtained from the Local Research Ethics Committee.

A power calculation had confirmed that to have a 95% probability of identifying a difference in hysteresis of 1.5 mmHg, the study required 21 eyes. For a 1 mmHg difference, this rose to 46 eyes (based on a population with a SD of 1.87 mmHg). For a study with 80% power, these figures were 13 eyes and 28 eyes, respectively. Intraocular pressure, hysteresis and CCT readings were taken at intervals of 3 h (during the normal hospital working hours) between 8 AM and 5 PM; at 8 AM, 11 AM, 2 PM and 5 PM.

Non-contact tonometer IOP and hysteresis were measured using the ORA. The patient was asked to fixate at the target in the instrument (red blinking light) and the ORA was activated by pressing a button attached to the computer. A non-contact probe scanned the central area of the eye and released an air puff and then sent a signal to the ORA. The ORA then displayed the IOP and hysteresis on the monitor of the computer attached to the ORA.

Central corneal thickness was measured using a handheld ultrasonic pachymeter (DGH-550, DGH Technology, Exton, PA, USA) after instilling a drop of the topical anaesthetic Proxymethacaine (Bausch & Lomb, Rochester, New York, USA) in the eye before performing pachymetry. The patient was asked to fixate at a target in order to minimize any eye movement, in order to avoid damage to the corneal epithelium. The pachymeter probe was gently placed onto the mid-pupillary axis in a perpendicular orientation. Upon contact with the corneal surface, the CCT value was displayed on the monitor attached to the probe. Three readings were taken and the mean value was used as the CCT. These measurements were carried out in the same order to avoid any bias in the data collection.

Several computer packages were used to analyse and present the data obtained. These included Excel (Microsoft Corporation, Romando, WA, USA) and Medcalc (Medical Calc Software, Mariakerke, Belgium).

For general statistical reporting, the mean values from each data set were calculated along with the SD. The distributions of values within each data set were evaluated graphically. The level of statistical significance was chosen at P < 0.05. All figures were constructed using Medcalc and Excel.

RESULTS

The mean ocular hysteresis at 8 AM was 12.7 ± 2.3 mmHg, at 11 AM 12.2 ± 2.0 mmHg, at 2 PM 12.7 ± 2.1 mmHg and at 5 PM 12.7 ± 1.7 mmHg; the difference between the values at any time were not statistically significant (P > 0.9, repeated measures). IOP as measured by the NCT on the ORA was 18.4 ± 2.8 mmHg, 17.9 ± 3.3 mmHg, 16.9 ± 3.1 mmHg and 16.8 ± 3.2 mmHg, respectively, the difference between the values at 8 AM and 5 PM, 8 AM and 2 PM, 11 AM and 2 PM and 11 AM and 5 PM were statistically significant (P < 0.001, 0.002, 0.01, 0.02, paired t-test). The CCT was 548.8 ± 29.5 µm 547.0 ± 31.4 µm, 548.2 ± 29.6 µm and 548.6 ± 29.4 µm, respectively, at the same time periods; the difference between the values was not statistically significant for any time period.

The data were further analysed separately for the right and left eyes. In the right eye the hysteresis was 12.6 ± 2.6 mmHg, 12.2 ± 2.3 mmHg, 13.1 ± 1.9 mmHg and 13.0 ± 1.8 mmHg at 8 AM, 11 AM, 2 PM and 5 PM, respectively; the IOP was 18.7 ± 3.0 mmHg, 18.0 ± 3.6 mmHg, 16.7 ± 3.0 mmHg and 16.3 ± 3.5 mmHg; and the CCT was 547.1 ± 30.5 µm, 545.2 ± 32.1 µm, 547.3 ± 30.7 µm and 545.8 ± 28.6 µm, respectively.

In the left eye hysteresis was 12.8 + 2.1 mmHg, 12.3 ± 1.8 mmHg, 12.1 ± 2.2 mmHg and 12.3 ± 1.5 mmHg; the IOP was 18.2 ± 2.5 mmHg, 17.7 ± 3.0 mmHg, 17.1 ± 3.3 mmHg and 17.2 ± 2.7 mmHg; and the CCT was 550.5 ± 29.2 µm, 548.8 ± 31.5 µm, 549.1 ± 29.2 µm and 551.5 ± 29.1 µm, respectively. The difference between hysteresis of the right and left eyes and IOP of right and left eyes was not statistically significant (P > 0.08 and >0.7, respectively; paired t-test).

Statistical analysis revealed no difference between hysteresis, IOP or CCT of right and left eyes. Multiple regression analysis showed the relationship between IOP and hysteresis was not significant (P = 0.9).

The range and mean values of hysteresis, CCT and IOP are summarized in the Tables 1 and 2. Figures 1 and 2 show the mean and range of SD of hysteresis and IOP, respectively.

DISCUSSION

The factors that contribute to the distensibility and hence rigidity of a membrane are tissue mass (corneal thickness), its elastic properties and mechanical forces acting at it (IOP).2 However, the exact mechanism responsible for the maintenance of the corneal shape is not known. Perhaps the normal corneal shape may be due to distension of the corneal tissue exerted by IOP.

Several studies have been conducted to measure and establish ocular rigidity,2–10 but all these studies have used complicated mathematical formulae that are not practical for clinical ophthalmologists who are looking for a measure of ocular rigidity.

Corneal thickness has been suggested to be an important contributing factor for corneal rigidity among other factors. 11 The individual variation in the corneal rigidity has been suggested to be related to the physical dimensions of the tissue especially its thickness.11 Thus, CCT could be regarded as an indirect measurement of corneal rigidity.

The ORA is a new device developed by Reichert Ophthalmic Instruments that is a NCT and measures the IOP as well as new metrics: hysteresis. Measuring corneal biomechanical properties by the applanation of a force to the cornea requires a procedure capable of separating the contributions of the corneal resistance and the IOP because the corneal resistance and true IOP are independent.

The ORA releases a precisely metered air pulse that causes the cornea to move inwards. Thus, the cornea passes through applanation – inward applanation, then the past applanation phase where its shape becomes slightly concave. Milliseconds after applanation, the air puff shuts off resulting in pressure decrease in a symmetrical fashion; during this phase the corneal shape tries to gain its normal shape. During this process the cornea again passes through an applanation phase – outward applanation. Theoretically, these two pressures should be the same but this is not the case and this is described as the dynamic corneal response that is said to be the resistance to applanation manifested by the corneal tissue due to its viscoelastic properties. The difference between the outward and inward pressures is termed hysteresis and is measured in mmHg.

Figure 1. Mean hysteresis and standard deviation over time (mmHg).

Table 1. The mean ± SD and range of hysteresis, central corneal thickness (CCT) and intraocular pressure (IOP) readings of both eyes












Time (h)

Hysteresis (mmHg)
Mean ± SD(range)
CCT (µm)
Mean ± SD(range)
IOP (mmHg)
Mean ± SD (range)
8 AM 12.7 ± 2.3
(8.9–18.4)
548.8 ± 29.5
(495.0–613.0)
18.4 ± 2.8
(13.7–26.1)
11 AM 12.2 ± 2.0
(6.7–16.7)
547.0 ± 31.4
(458.0–617.0)
17.9 ± 3.3
(11.3–26.7)
2 AM 12.7 ± 2.1
(7.8–17.2)
548.2 ± 29.6
(492.0–616.0)
16.9 ± 3.1
(11.9–24.3)
5 AM 12.7 ± 1.7
(10.1–16.5)
548.6 ± 29.4
(494.0–617.0)
16.8 ± 3.2
(11.3–25.7)

The cornea reacts to stress as a viscoelastic material – for a given stress the resultant corneal strain is time dependent. The viscoelastic response consists of immediate deformation followed by a rather slow deformation.3 The immediate elastic response of the ocular tunic seems to reflect the immediate elastic properties of collagen fibres; the steadystate elastic response reflects the properties of the corneal matrix.3 The two applanation pressure readings – ‘inward’ and ‘outward applanation’ – are perhaps the result of immediate elastic response and delayed or steady-state elastic response, respectively, of the corneal tissue.

Figure 2. Mean intraocular pressure and standard deviation over time (mmHg).

Table 2. The mean ± SD and range of hysteresis, central corneal thickness (CCT) and intraocular pressure (IOP) readings of right and left eyes









Time (h)

Hysteresis (mmHg)
Mean ± SD(range)
CCT (µm)
Mean ± SD(range)
IOP (mmHg)
Mean ± SD (range)
8 AM
Right eyes

Left eyes

12.6 ± 2.6
(8.9–18.4)
12.8 ± 2.1
(10.1–17.9)

547.1 ± 30.5
(495.0–613.0)
550.5 ± 29.2
(492.0–609.0)

18.7 ± 3.0
(17.7–26.1)
18.2 ± 2.5
(13.7–22.7)
11 AM
Right eyes

Left eyes


12.2 ± 2.3
(6.7–16.7)
12.3 ± 1.8
(8.5–15.7)


545.2 ± 32.1
(493.0–617.0)
548.8 ± 31.5
(492.0–608.0)

18.0 ± 3.6
(11.3–26.7)
17.7 ± 3.0
(13.1–22.5)
2 AM
Right eyes

Left eyes


13.1 ± 1.9
(9.7–16.6)
12.1 ± 2.2
(7.8–17.2)


547.3 ± 30.7
(492.0–616.0)
549.1 ± 29.2
(495.0–611.0)

16.7 ± 3.0
(12.2–24.3)
17.1 ± 3.3
(11.9–24.2)
5 AM
Right eyes

Left eyes

13.1 ± 1.8
(10.7–16.4)
12.3 ± 1.5
(10.1–15.7)

545.8 ± 28.6
(496.0–611.0)
551.5 ± 29.1
(494.0–617.0)

16.3 ± 3.5
(11.3–25.7)
17.2 ± 2.7
(11.6–23.1)
Most ophthalmological measurements are carried out during hospital or clinic consulting hours, between 8 AM and 5 PM.12 This study was performed to examine the variation in the hysteresis, IOP and CCT during these hours to see whether they are constant or had any other relationship.

The results of this study showed hysteresis to have great individual variation but all the values were within the normal range.1 The mean hysteresis values were almost constant throughout the day. The difference in mean hysteresis readings at any of measurement time (between 8 AM and 5 PM) was not statistically significant (P > 0.9, repeated analysis). However, the mean hysteresis reading at 11 AM showed a little lower value (12.2 mmHg).

The ocular hysteresis values in the right and left eyes were almost the same, the mean difference between the hysteresis of the right and left eye was 0.4 mmHg, it was higher in the right eyes but this difference was not statistically significant (P > 0.08; paired t-test).

Various investigators have established the diurnal variation of CCT.13–19 Previous studies have reported CCT to be highest in the morning immediately after wakening and then to stabilize after 1 h.13 The result of this study also showed that the mean CCT value was higher in the morning (8 AM) and then the readings were almost stable. The difference between CCT values at any time was not statistically significant in this study. The mean CCT of the left eyes showed a higher value of 3.6 µm than right.

Shah et al. in their study conducted on suspected glaucoma patients reported that diurnal variation of IOP is independent of diurnal variation of CCT.18 The results of this study also confirmed the constant mean CCT readings over the day whereas the readings for hysteresis and IOP varied. Diurnal phasic variation in IOP in human eyes is well recognized.20,21 Studies conducted previously by various workers have reported IOP readings to be higher in the early morning and lower in the late afternoon.12,20,22 In normal human eyes the fluctuation in the measured IOP up to 5 mmHg has been suggested.12

This study showed a difference between the mean measured IOP in the morning (8 AM) and late afternoon (5 PM) was 1.6 mmHg. Figure 2 shows the mean and SD that showed the trend of reducing IOP readings. The difference between the mean IOP values in the early morning (8 AM) and late afternoon (5 PM) was statistically significant. It has been reported that in a group of normal patients, 63% of patients showed a peak in their IOP before 11 AM and 44% patient showed lowest IOP in the afternoon.22 The result of this study is in agreement with previously reported findings.

Although all measurements (IOP, hysteresis and CCT) were taken by the same examiner, operator bias as a result of human error cannot be excluded. It would not be possible for the CCT to be measured in exactly the centre and at the same location every time because the location is arbitrary. It is, however, doubtful whether this would produce any significant bias as multiple readings were taken each time.23,24

Our study has some limitations. The limitations include small number of volunteers, that the sex and age group were not matched and that this study was performed only in healthy volunteers. Further works need to be performed to assess the relationships between hysteresis and ocular rigidity and the measurement of IOP.

In this study, the diurnal variability of both ocular hysteresis and CCT were small and were not significantly correlated. IOP appears to vary independently of a variation in hysteresis or CCT.

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