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Original Article Ocular response analyser to assess hysteresis and corneal resistance factor in low tension, open angle glaucoma and ocular hypertension Sunil Shah FRCOphth, 1,2,3 Mohammad Laiquzzaman MBBS PhD, 1 Sanjay Mantry FRCS(Ed) 1,3 and Ian Cunliffe FRCOphth 1 1 Heart of England Foundation Trust, Solihull, 2 Ophthalmic Research Group, Aston University, and 3 Birmingham and Midland Eye Centre, Birmingham, UK ABSTRACT Purpose: The aim of this study is to compare the hysteresis and corneal resistance factor (CRF) in normal tension glaucoma (NTG), primary open angle glaucoma (POAG) and ocular hypertension (OHT) eyes measured by the ocular response analyser (ORA). Methods: This is a prospective, cross-sectional and compara- tive clinical trial.The setting was a teaching hospital in Birming- ham, England. Patients: 216 eyes with POAG, 68 eyes with NTG and 199 eyes with OHT. Observational procedures: Goldmann applanation tonometry and intraocular pressure (IOP), hysteresis and CRF measured by ORA and central corneal thickness (CCT) by ultrasonic pachymetery. The main outcome measures were IOP , CCT, hysteresis and CRF. Results: The hysteresis in NTG, POAG and OHT eyes was 9.0 1.9, 9.9 2.1 and 10.2 2.0 mmHg; CRF was 9.1 2.2, 10.6 2.0 and 12.0 2.0 mmHg; IOP by Goldmann applanation tonometry and ORA was 14.7 2.8 and 15.3 4.2 mmHg, 16.7 4.0 and 16.9 4.6 mmHg and 20.5 4.1 and 20.0 4.5 mmHg; CCT was 526. 5 42.2, 537.0 36.0 and 563.4 35.9 mm, respectively. The difference for CRF, IOP and CCT for NTG, POAG and OHT eyes was statistically significant. Conclusion: Hysteresis and CRF were highest in OHT eyes. These factors may prove to be useful measurements of ocular rigidity and may help to understand role of the corneal rigidity in monitoring the progress of conditions such as NTG,POAG and OHT. Key words: CCT, CRF, IOP, hysteresis. INTRODUCTION Goldmann applanation tonometry (GAT) is regarded as the gold standard for estimating intraocular pressure (IOP). The rigidity or elasticity of ocular tissue has been of great interest to ophthalmologists and eye care professionals when consid- ering the accuracy of IOP measurement with this and other instruments. It is now known that IOP measurement is influ- enced by the cornea and it can be reasonably assumed that ocular rigidity should be different in different individuals related to the corneal tissue structure. 1 Some of the variations in ocular rigidity are related to varying corneal thickness and it has also been shown that central corneal thickness (CCT) varies between different diagnostic groups: normal tension glaucoma (NTG), primary open angle glaucoma (POAG) and ocular hypertension (OHT). 2–14 The recent OHTS studies 15–16 have shown that CCT is a very important tool to be used as a prediction for glaucoma risk in OHT. There are also data showing that CCT affects IOP measurement and hence knowing the CCT can allow an estimate for the true IOP. 6–7 It is not clear whether the rela- tionship between CCT and measured IOP results from the cornea’s thickness per se or rigidity or other biomechanical properties. There is no easy method reported to determine the bio- mechanical properties of the cornea in vivo. To date, the only easy measure of ocular rigidity has been CCT. A recent addition to the armamentarium for assessing rigidity has been the ocular response analyser (ORA) (Reichert Oph- thalmic Instruments, Buffalo, NY, USA), which is an adapta- tion of their non-contact tonometer that allows measurement Correspondence: Dr Mohammad Laiquzzaman, Heart of England Foundation Trust, Lode Lane, Solihull, West Midlands B91 2JL, UK. Email: [email protected] Received 4 February 2008; accepted 23 June 2008. Clinical and Experimental Ophthalmology 2008; 36: 508–513 doi: 10.1111/j.1442-9071.2008.01828.x © 2008 The Authors Journal compilation © 2008 Royal Australian and New Zealand College of Ophthalmologists

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Original Article

Ocular response analyser to assess hysteresis and cornealresistance factor in low tension, open angle glaucoma andocular hypertensionSunil Shah FRCOphth,1,2,3 Mohammad Laiquzzaman MBBS PhD,1 Sanjay Mantry FRCS(Ed)1,3 andIan Cunliffe FRCOphth1

1Heart of England Foundation Trust, Solihull, 2Ophthalmic Research Group, Aston University, and 3Birmingham and Midland Eye Centre,Birmingham, UK

ABSTRACT

Purpose: The aim of this study is to compare the hysteresisand corneal resistance factor (CRF) in normal tensionglaucoma (NTG), primary open angle glaucoma (POAG)and ocular hypertension (OHT) eyes measured by theocular response analyser (ORA).

Methods: This is a prospective, cross-sectional and compara-tive clinical trial.The setting was a teaching hospital in Birming-ham, England. Patients: 216 eyes with POAG, 68 eyes withNTG and 199 eyes with OHT. Observational procedures:Goldmann applanation tonometry and intraocular pressure(IOP), hysteresis and CRF measured by ORA and centralcorneal thickness (CCT) by ultrasonic pachymetery. Themain outcome measures were IOP, CCT, hysteresis and CRF.

Results: The hysteresis in NTG, POAG and OHT eyeswas 9.0 � 1.9, 9.9 � 2.1 and 10.2 � 2.0 mmHg; CRF was9.1 � 2.2, 10.6 � 2.0 and 12.0 � 2.0 mmHg; IOP byGoldmann applanation tonometry and ORA was 14.7 � 2.8and 15.3 � 4.2 mmHg, 16.7 � 4.0 and 16.9 � 4.6 mmHgand 20.5 � 4.1 and 20.0 � 4.5 mmHg; CCT was 526.5 � 42.2, 537.0 � 36.0 and 563.4 � 35.9 mm, respectively.The difference for CRF, IOP and CCT for NTG, POAG andOHT eyes was statistically significant.

Conclusion: Hysteresis and CRF were highest in OHT eyes.These factors may prove to be useful measurements ofocular rigidity and may help to understand role of thecorneal rigidity in monitoring the progress of conditionssuch as NTG, POAG and OHT.

Key words: CCT, CRF, IOP, hysteresis.

INTRODUCTION

Goldmann applanation tonometry (GAT) is regarded as thegold standard for estimating intraocular pressure (IOP). Therigidity or elasticity of ocular tissue has been of great interestto ophthalmologists and eye care professionals when consid-ering the accuracy of IOP measurement with this and otherinstruments. It is now known that IOP measurement is influ-enced by the cornea and it can be reasonably assumed thatocular rigidity should be different in different individualsrelated to the corneal tissue structure.1 Some of the variationsin ocular rigidity are related to varying corneal thickness andit has also been shown that central corneal thickness (CCT)varies between different diagnostic groups: normal tensionglaucoma (NTG), primary open angle glaucoma (POAG)and ocular hypertension (OHT).2–14

The recent OHTS studies15–16 have shown that CCT is avery important tool to be used as a prediction for glaucomarisk in OHT. There are also data showing that CCT affectsIOP measurement and hence knowing the CCT can allow anestimate for the true IOP.6–7 It is not clear whether the rela-tionship between CCT and measured IOP results from thecornea’s thickness per se or rigidity or other biomechanicalproperties.

There is no easy method reported to determine the bio-mechanical properties of the cornea in vivo. To date, the onlyeasy measure of ocular rigidity has been CCT. A recentaddition to the armamentarium for assessing rigidity hasbeen the ocular response analyser (ORA) (Reichert Oph-thalmic Instruments, Buffalo, NY, USA), which is an adapta-tion of their non-contact tonometer that allows measurement

� Correspondence: Dr Mohammad Laiquzzaman, Heart of England Foundation Trust, Lode Lane, Solihull, West Midlands B91 2JL, UK. Email:

[email protected]

Received 4 February 2008; accepted 23 June 2008.

Clinical and Experimental Ophthalmology 2008; 36: 508–513doi: 10.1111/j.1442-9071.2008.01828.x

© 2008 The AuthorsJournal compilation © 2008 Royal Australian and New Zealand College of Ophthalmologists

of IOP as well as new measurements called hysteresis andcorneal resistance factor (CRF).

Hysteresis and CRF are determined by releasing an airpuff from the ORA that causes inward and then outwardcorneal motion, which in turn provides two applanationmeasurements during a single-measurement process (Fig. 1).Hysteresis is a measure of viscoelasticity owing to the com-bined effect of the corneal thickness and rigidity.17 Reichertsuggests that hysteresis may be a measurement that is theresult of the damping of the cornea because of its viscoelasticproperties and is derived from the difference of the twoapplanation measurements during the applanation process.Reichert believes that CRF is dominated by the elastic prop-erties of the cornea and appears to be an indicator of theoverall ‘resistance’ of the cornea.

This study compares ocular hysteresis and CRF betweeneyes with NTG, POAG and OHT and in addition looks atCCT and IOP in these groups.

METHODS

A total of 483 eyes (68 NTG eyes, 216 POAG eyes and 199of OHT eyes) were recruited at an outpatient clinic in theEye Department in a teaching hospital in Birmingham, UK.The mean age of patients of NTG eyes was 68.7 � 16.2 years (range 32–93 years), 19 women and 16 men; POAGeyes was 73.1 � 11.6 years (range 21–101 years), 75 womenand 37 men; and OHT eyes was 69.5 � 12.8 years (range38–89 years), 54 women and 53 men.

The clinical diagnosis of POAG was made on the basis ofmeasured IOP, evaluation of width of angle, glaucomatousnerve head damage and loss of field of vision. NTG wasdiagnosed on the basis of an IOP never more than21.0 mmHg on GAT (even with phasing), glaucomatousoptic disc damage, open angle on gonioscopy, visual fieldloss; Hymphrey’s vision field test (Carl Zeiss Corporation,Oberochen, Germany), and the OHT was diagnosed onthe basis of measured IOP more than 21.0 mmHg on twoconsecutive visits, absence of optic nerve head damage, agemore than 35 years. Patients suffering from diabetes, taking

cortisone either systemically or topically, previously under-gone eye surgery or suffered eye trauma, contact lens use, dryeye or corneal abnormality, which may affect measurementof IOP, were not included in this study. Other examinationssuch as refraction, visual acuity, slit-lamp examination of eyewere also performed. The diagnosis had been determined bya senior ophthalmologist (SS) at a previous visit. Ethicalapproval for the study was obtained from the Local ResearchEthics Committee.

The IOP was measured with the patient seated by GAT,after instillation of one drop of topical proxymethacaine0.5%, and fluorescein (Bausch & Lomb, Rochester, NY,USA). Non-contact IOP, hysteresis and CRF were measuredby ORA using a standard technique.18–19 The data wererecorded with generation 3 software of the ORA. CCT wasmeasured using a hand-held ultrasonic pachymeter (DGH–550, DGH Technology Inc., Exton, PA, USA). Three read-ings were taken and the mean value was used as the CCT.

There was at least 10 min interval between measurementof IOP by GAT and ORA. The measurements were alwaysrecorded in the same order.

Statistical analysis of data

Several computer packages were used to analyse the dataobtained. These include Excel (Microsoft Corporation,Romando, WA, USA) and Medcalc (Med Calc Software,Mariakerke, Belgium).

For general statistical reporting, the mean values fromeach dataset were calculated along with the standard devia-tion (SD). The distributions of values within each datasetwere evaluated graphically. The level of statistical signifi-cance was chosen at P < 0.05. All graphs were constructedusing Medcalc and Excel.

RESULTS

Table 1 shows the mean, SD and range of hysteresis, CRFand CCT. Table 2 shows mean � SD and range of IOP

Figure 1. Measurement of ocular hysteresis. 1, Convex cornea;2, flat cornea; 3, concave cornea; 4, flat cornea; 5, convex cornea.

Table 1. Mean � SD and range of hysteresis, CRF and CCT inthree groups of eyes

Eyes Hysteresis(mmHg)

CRF(mmHg)

CCT(mm)

Mean � SD Mean � SD Mean � SD(range) (range) (range)

NTG 9.0 � 1.9 9.1 � 2.2 526 � 42.2(4.2–14.1) (4.6–14.9) (419.0–613.0)

POAG 9.9 � 2.1 10.6 � 2.0 537.0 � 36.0(4.0–15.6) (5.4–16.7) (457.0–630.0)

OHT 10.2 � 2.0 12.0 � 2.0 563.4 � 35.9(5.1–15.3) (6.7–19.3) (463.0–655.0)

CCT, central corneal thickness; CRF, corneal resistance factor;NTG, normal tension glaucoma; OHT, ocular hypertension;POAG, primary open angle glaucoma; SD, standard deviation.

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measured by GAT (Goldmann tonometry) and ORA (non-contact tonometry); and Table 3 shows the P-values of hys-teresis, CRF and CCT in the three groups of eyes.

The box and whiskers plot (Fig. 2) shows the comparisonof hysteresis (median and interquartile ranges) in NTG,POAG and OHT eyes. The difference was statistically sig-nificant between NTG and OHT, and OHT and POAG eyes

(P < 0.0001 and P < 0.001, respectively) but it was not sig-nificant between POAG and NTG eyes (P > 0.1) using anunpaired t-test.

The box and whiskers plot (Fig. 3) shows the comparisonof CRF (median and interquartile ranges) in NTG, POAGand OHT eyes. The difference in CRF between all the threegroups was statistically significant (P < 0.0001; unpairedt-test).

The box and whiskers plot (Fig. 4) shows the comparisonof CCT (median and interquartile ranges) in NTG, POAGand OHT eyes. The difference in CCT between all the threegroups was statistically significant (NTG and POAG P <0.05; OHT and POAG and OHT and NTG P < 0.0001;unpaired t-test).

Table 2. Mean � SD and range of intraocular pressure measuredby GAT and NCT in three groups of eyes

Eyes IOP(GAT), mmHg

IOP(NCT), mmHg

Mean � SD Mean � SD(range) (range)

NTG 14.7 � 2.8 15.3 � 4.2(10.0–21.0) (9.6–27.4)

POAG 16.7 � 4.0 16.9 � 4.6(8.0–28.0) (7.6–35.2)

OHT 20.5 � 4.1 20.0 � 4.5(12.0–34.0) (11.5–34.0)

GAT, Goldmann applanation tonometry; IOP, intraocularpressure; NCT, non-contact tonometry; NTG, normal tensionglaucoma; OHT, ocular hypertension; POAG, primary open angleglaucoma; SD, standard deviation.

Table 3. P-values between the three groups of eyes

Eyes Hysteresis CRF CCT

NTG vs. OHT <0.0001 <0.0001 <0.0001OHT vs. POAG <0.001 <0.0001 <0.0001POAG vs. NTG >0.1 <0.0001 <0.05

CCT, central corneal thickness; CRF, corneal resistance factor;NTG, normal tension glaucoma; OHT, ocular hypertension;POAG, primary open angle glaucoma.

Figure 2. Box and whiskers plot (median and interquartile range)of hysteresis in normal tension glaucoma (NTG), primary openangle glaucoma (POAG) and ocular hypertension (OHT) eyes.

Figure 3. Box and whiskers plot (median and interquartile range)of central corneal thickness in normal tension glaucoma (NTG),primary open angle glaucoma (POAG) and ocular hypertension(OHT) eyes.

Figure 4. Box and whiskers plot (median and interquartile range)of corneal resistance factor in normal tension glaucoma (NTG),primary open angle glaucoma (POAG) and ocular hypertension(OHT) eyes.

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The difference in IOP measured by both GAT and NCTwas statistically significant between all the three groups ofeyes (P < 0.0001, unpaired t-test).

The scatter plots (Figs 5–7) show the relationshipsbetween CCT and hysteresis (r = 0.3, P < 0.0001), CCT andCRF (r = 0.4, P < 0.0001) and CRF and hysteresis, respec-tively (r = 0.6, P < 0.0001), are for all eyes together.

DISCUSSION

Experimental studies measuring IOP by applanation tono-metry and manometry have suggested that applanationtonometry may not be a true measurement of IOP.10 Otherstudies have concluded that the OHT eyes have thickercorneas2–6,10,11 and NTG eyes have thinner corneas.3–5 Morerecently, studies have shown that applanation tonometry

measurements after refractive surgery demonstrate a lowerIOP measurement than preoperatively.20–22

The above observations and others indicate that theapplanation pressure measurement is dependent on oculartissue rigidity as had been predicted by Goldmann andSchmidt themselves.23 The factors that influence and governIOP are of tremendous clinical significance. Ocular rigidityand its effect on IOP measurement may also be of greatimportance in the diagnosis of glaucoma after surgical pro-cedures such as refractive surgery. IOP is measured by apply-ing a force to cause a relative flattening or deformation of thecorneal surface.24 Goldmann and Schmidt23 were aware thatthe physical and physiological properties of the cornea mayaffect the measurement of IOP. They considered two factorsas possible source of error in evaluating IOP. First, the resis-tance provided by the corneal tissue and second, the resis-tance of the surface tension of the preocular tear film. Theyconcluded that for an applanation diameter of 3.06 mm, thecorneal tissue and tear film resistance will neutralize eachother for an average CCT of 520 mm. They were aware thatthis was an average measurement and expected some varia-tion around this value for different corneal thickness.

Consequently, knowledge regarding the structural andelastic properties of the corneal tissue has assumed a greatersignificance in the diagnosis and management of glaucomaand OHT. However, we are unable to directly measureocular rigidity.

Intraocular pressure has been reported to vary with theCCT and that the CCT has an influence on the measuredIOP, that is, for a thicker cornea the measured IOP will behigher and vice versa. However, IOP measurement is not onlydependent on the CCT but several other factors and theseinclude corneal structure, curvature, intraocular volume andhydration.9–11,12,25,26 It is important to emphasize that IOP isonly one factor in the diagnosis of glaucoma but is still veryimportant when assessing the response to therapy. Severalstudies have found that when the corneal tissue structure is

Figure 5. Scatter plot of relationship between hysteresis andcentral corneal thickness.

Figure 6. Scatter plot of relationship between corneal resistancefactor and central corneal thickness.

Figure 7. Scatter plot of relationship between hysteresis andcorneal resistance factor.

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altered owing to any reason, for example, owing to excimerlaser ablation in refractive surgery21 or owing to a diseaseprocess like keratoconus, the IOP showed lower readingsthan would be expected. This suggests that corneal tissuethickness or more probably rigidity plays an important partin IOP measurement.

The ORA is a new device developed by Reichert, which isa non-contact tonometer that measures IOP as well as newmetrics, hysteresis and CRF. The ORA is an attempt to makethe measurement of rigidity and elasticity easily accessible toclinicians for all patients.

Measuring corneal biomechanical properties by theapplanation of a force to the cornea requires a procedurecapable of separating the contributions of the corneal resis-tance and the IOP because the corneal resistance and trueIOP are basically independent. The ORA releases a preciselymetered air pulse which causes the cornea to move inwards.Thus, the cornea passes through applanation (inward appla-nation), and then to the past applanation phase where itsshape becomes slightly concave. Milliseconds after applana-tion, the air puff shuts off, resulting in a pressure decrease ina symmetrical fashion. During this phase, the cornea tries toregain its normal shape and again passes through an appla-nation phase (outward applanation). Theoretically, these twopressures should be the same but this is not the case. This isdescribed as the dynamic corneal response that is said to bethe resistance to applanation manifested by the corneal tissueowing to its viscoelastic properties. The difference betweenthe outward and inward pressures is termed hysteresis and ismeasured in mmHg. Hysteresis is said to be a measurementof viscous properties whereas the CRF is dominated byelastic properties of cornea and is an overall indicator of thecorneal resistance.

The cornea reacts to stress as a viscoelastic material, thatis, for a given stress, the resultant corneal strain is timedependent. The viscoelastic response consists of an immedi-ate deformation followed by a rather slow deformation.26

The immediate elastic response of the ocular tunics seems toreflect the immediate elastic properties of the collagen fibres;the steady-state elastic response reflects the properties of thecorneal matrix.26 The two applanation pressure readings –‘inward’ and ‘outward’ – are perhaps result of immediateelastic response and delayed or steady-state elastic response,respectively, of the corneal tissue.

Several studies in the past have been conducted tomeasure and establish ocular rigidity,24–28 but we do not havea simple technique that could be used for the day-to-daymeasurements. Hence we investigated the ORA, which maybe useful for this purpose.

The results in this study showed that the mean hysteresisin OHT eyes was higher compared with NTG eyes and thedifference was found to be statistically significant betweenthese two groups of eyes, but there was no statistically sig-nificant difference between hysteresis in POAG and NTGeyes (P > 0.1).

Analysis of a possible relationship between CCT andhysteresis was performed using the data from all the three

groups (Fig. 5). A simple regression line revealed a relation-ship showing a positive effect, that is, the higher the CCTthe higher the hysteresis and vice versa. Although the relation-ship was statistically significant the correlation coefficientwas not that strong (r = 0.3), implying that hysteresis andCCT are related but are not measurements of the same bio-mechanical parameter. In the absence of another reliablemeasure of viscoelasticity, it is difficult to assess to whatextent hysteresis values are thickness (CCT) dependentrather than viscoelastic dependent. It is, however, assumedthat hysteresis is primarily viscoelastic.

Differences in mean CRF values in NTG, POAG andOHT eyes, respectively, were statistically significantbetween all the three groups. Analysis of possible relation-ship between CRF and CCT (Fig. 6) and CRF and hysteresis(Fig. 7) were performed using the data from all the threegroups and simple regression line in the scatterplot revealedthat higher the CCT and hysteresis higher the CRF. Therelationship was significant statistically between both CRFand CCT and CRF and hysteresis (P < 0.0001), but the cor-relation coefficient was not as strong between CRF and CCT(r = 0.4) compared with CRF and hysteresis (r = 0.6). Thescatterplot of hysteresis and CRF suggest that they are notthe measurement of the same parameters. It may be, asReichert suggest, hysteresis may be a measurement ofviscoelastic properties and CRF measurement of elasticproperties.

The findings of this study are at first sight similar to otherstudies,29 where NTG, POAG and OHT eyes have differ-ences in their mean CCT but there is considerable overlap inthe CCT values. However, the correlation betweenhysteresis and CCT (r = 0.3) and CCT and CRF (r = 0.4) andhysteresis and CRF (r = 0.6) is not that strong. The dataimply that the new Reichert method measures some cornealproperties that would be affected by thickness but representmore than just corneal thickness, that is, hysteresis and CRFare different biomechanical values.

Wolfs et al.11 propose that a measurement error in appla-nation tonometry may be either due to the differences inCCT, a physiological effect on the IOP of corneal tissues, anincrease of collagen fibres or corneal stromal rigidity or itmay be due to all of the above-stated factors. Hysteresis andCRF may prove a helpful guide to measure this relationship.

The authors acknowledge that this study has some short-falls in terms of low numbers of NTG eyes in comparison tothe other two groups and patients not being age and sexmatched. Although both eyes of the patients were used inthis study for the purpose of graphical demonstration, nostatistical difference was found between the eyes. The inves-tigators were also not blind to the diagnosis. However, this isnot felt to detract from the findings.

The results of this study showed that hysteresis and CRFmeasured by the ORA have a positive but moderate correla-tion to CCT; the higher the CCT the higher the hysteresis(viscoelasticity) and CRF (elasticity).

It could be suggested that ORA may measure the cornealrigidity in vivo. The measurement of hysteresis and CRF is

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easy and can be performed by any trained technician.Hysteresis and CRF and CCT appear to be related but arenot measurements of the same physical/biomechanicalparameter. These measures may help to clarify the role ofocular rigidity (elasticity) in IOP measurement. ORA mea-surements hence may be helpful in the future for long-termmonitoring of IOP especially in eyes with an abnormalrigidity. It may provide additional factors over and aboveCCT and help with the assessment of accuracy of IOP (in themanner that CCT has been found to be in OHTS).15–16

Further studies are needed to be performed to establishthe relevance and usefulness of these measures.

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