Diurnal Variation of Corneal Hysteresis in Patients With Untreated Primary Open Angle Glaucoma and Normal Individuals : Journal of Glaucoma

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New Understandings of Glaucoma: Original Studies

Diurnal Variation of Corneal Hysteresis in Patients With Untreated Primary Open Angle Glaucoma and Normal Individuals

Okayama, Masahiko MD; Tsuchiya, Shunsuke MD, PhD; Higashide, Tomomi MD, PhD; Udagawa, Sachiko CO, PhD; Yamashita, Yoko MD, PhD; Shioya, Satomi MD, PhD; Takemori, Hayato MD; Nakazawa, Kazuki MD; Manbo, Yuki MD; Sugiyama, Kazuhisa MD, PhD

Author Information
doi: 10.1097/IJG.0000000000002112

Abstract

Glaucoma is a disease characterized by progressive optic nerve damage accompanied by corresponding visual field (VF) loss over time. Elevated intraocular pressure (IOP) is the most significant risk factor for glaucoma onset and progression.1 However, according to 1 systematic review, other factors, including age and optic disk hemorrhage, are also definite or probable prognostic factors for the progression of glaucoma.2 Among them, central corneal thickness (CCT) has gained attention because a smaller CCT is a significant risk factor for the development of open angle glaucoma from ocular hypertension in the Ocular Hypertension Treatment Study.3

More recently, corneal hysteresis (CH), another corneal biomarker, was reported to be more strongly associated with the progression of glaucoma than CCT.4–6 A low CH was more strongly associated with worse eyes in asymmetric primary open angle glaucoma (POAG) than CCT or IOP measured by Goldmann applanation tonometry (GAT IOP).7 CH is a corneal viscoelasticity-related parameter determined by the ocular response analyzer (ORA), and is derived from the pressure difference between the inward and outward applanation states after a rapid air impulse.8 According to a large-scale database of the UK Biobank, the mean CH of over 90,000 eyes was 10.6 mm Hg9 and was lower in eyes with glaucoma than in nonglaucomatous eyes.9–11 CH values were significantly associated with many factors, including age,9,12 sex,9 ethnicity,9 GAT IOP,13,14 CCT,4–6,10–12,15–19 corneal curvature,15 refractive errors,9 axial length,20 smoking,9 and diabetes,9 although negative results have also been reported for several factors, including age,11,15 GAT IOP,6,12,21 and axial length.4

IOP and CCT show significant variations over a 24-hour period in both normal and glaucomatous eyes.14,17–28 As such, CH that reflects corneal viscoelastic properties, can also be expected to show 24-hour variation. However, previous reports that explored the diurnal variation of CH in normal eyes showed that CH is stable throughout the day14,17–19,21,26 except for 1 report that showed a small but significant overnight increase of 0.4 mm Hg from 23:00 to 7:00.27 Only 1 study examined diurnal CH variations in eyes with glaucoma every 2 hours from 9:00 to 17:00 and found no evidence of variation with measurement time.14 However, changes in CH during the night have not yet been explored in eyes with glaucoma. Given the larger diurnal IOP fluctuations in patients with glaucoma than in normal individuals,28 CH may show larger variations over a 24-hour period in glaucomatous eyes than in normal eyes. Thus, the purpose of this study was to investigate the diurnal variations of CH in untreated patients with POAG in comparison with those in normal individuals and to identify the factors associated with CH variation.

MATERIALS AND METHODS

This prospective study was performed in accordance with the tenets of the Declaration of Helsinki and approved by the ethics committee of Kanazawa University Hospital, Japan. Written informed consent was obtained from all participants enrolled at Kanazawa University Hospital between February 2016 and June 2021.

Ophthalmic Examinations

All participants underwent the following ophthalmologic examinations: measurements with an auto refractometer (KR-800; Topcon Corporation, Tokyo, Japan), evaluation of CCT and anterior chamber parameters (Pentacam; Oculus GmbH, Wetzlar, Germany), axial length measurements (OA-2000; TOMEY, Tokyo, Japan), slit-lamp examination, gonioscopy, dilated fundus examination, and standard automated perimetry (SAP; Swedish Interactive Threshold Algorithm standard 24-2, Humphrey Field Analyzer II; Humphrey-Zeiss Instruments, Dublin, CA).

Glaucoma Diagnosis and Criteria for Study Participants

POAG was diagnosed based on glaucomatous optic disk changes, corresponding VF defects, and a normal open angle on gonioscopic examination. Glaucomatous VF changes were defined according to the Anderson–Patella criteria.29

The eligibility criteria were as follows: POAG without anti-glaucoma medication for at least 4 weeks and VF mean deviation (MD) of −20 dB or better on SAP. Patients with ocular pathologies other than glaucoma or a history of intraocular surgery were excluded. The control group included healthy individuals with a normal optic nerve head appearance, IOP <21 mm Hg, no VF defects, normal open angle on gonioscopic examination, and no ocular diseases.

CH and IOP Measurements

IOP and CH were measured every 3 hours from 9:00 to 24:00 (6 sessions in total). IOP was measured by GAT, and CH was measured using an ORA (Reichert Ophthalmic Instruments, Depew, NY) in the sitting position by an experienced physician. The mean value of 2 reliable CH measurements with a quality index value ≥ 7 was used for the analysis.30 The GAT IOP was measured within 10 minutes of CH measurements. Measurements of GAT IOP and CH were performed in both right and left eyes. If both eyes met the inclusion criteria, statistical analysis was conducted using data from both eyes. The amplitude of CH or GAT IOP was defined as differences between the maximum and minimum values among 6 sessions.

Statistical Analyses

For comparisons between the POAG and normal groups, mixed-effects linear regression or mixed-effects logistic regression was utilized for continuous variables or categorical variables, respectively, after accounting for the correlation between fellow eyes. Univariate and multivariate mixed-effects analyses accounting for repeated measurements in the same eye and the correlation between fellow eyes were performed in the POAG and normal groups to investigate the factors associated with CH values. The independent variables were measurement time, age, sex, refractive errors, corneal curvature, CCT, anterior chamber depth, anterior chamber volume, axial length, MD of VF, GAT IOP, medication washout, smoking status, and a history of diabetes and hypertension. Factors with P-values <0.2 were entered in the multivariate analysis, and the final model that contained only variables with P<0.05 was created by backward elimination. Similarly, univariate and multivariate mixed-effects analyses accounting for the correlation between fellow eyes were performed to investigate the factors associated with CH amplitude (maximum values–minimum values). IOP changes after medication washout were analyzed using the mixed-effects model.

Patterns of diurnal variation in GAT IOP and CH were analyzed using mixed-effects models in each group, after accounting for repeated measurements in the same eye and correlations between fellow eyes. Significant variations in GAT IOP or CH were defined by significant differences between measurement times. Bonferroni-corrected P-values were used for multiple pairwise comparisons. To account for the possible influence of factors associated with CH values on diurnal variation, the mixed-effects model for diurnal variation was adjusted by entering factors that were significant in the multivariate model for factors associated with CH values in each group as independent variables in the model. Statistical analysis was performed using SPSS software (IBM SPSS Statistics 20, IBM Corp., NY) and Stata software (version 13.1; StataCorp, TX), and a P-value of <0.05 was considered statistically significant.

RESULTS

Patient characteristics are shown in Table 1. A total of 72 eyes of 53 patients with POAG and 53 eyes of 47 normal individuals were enrolled in this study. Glaucoma medication was washed out in 41 eyes of 31 patients with POAG, which significantly increased GAT IOP from 13.8 ± 2.0 mm Hg to 14.6 ± 3.2 mm Hg (P=0.03). The other 31 eyes of 22 patients were medication-naive. The diurnal average and amplitude of IOP and CH values are shown in Table 2. The average GAT IOP in POAG patients was significantly higher than that in normal individuals (P=0.001). The mean CH in the POAG group was significantly lower than that in the normal group (P=0.002). The amplitudes of GAT IOP and CH were not significantly different between the 2 groups.

TABLE 1 - Characteristics of the Study Participants
Factors Glaucoma Normal Subjects P
Number of patients/eyes 53/72 47/53
Age (yrs), mean ± SD (range) 50.7±11.4 (28–69) 52.6±12.0 (23–72) 0.06
Gender (eyes: male/female) 26/46 33/20 0.038
Spherical equivalent (Diopter) −5.9±3.2 (−16.1 – 0.3) −2.7±2.4 (−7.9 – 1.9) <0.001
Corneal curvature (mm), mean ± SD (range) 7.75±0.26 (7.30–8.35) 7.74±0.26 (7.20–8.44) 0.89
Central corneal thickness (μm), mean±SD (range) 539.1±29.7 (466–606) 546.3±33.7 (445–623) 0.28
Anterior chamber depth (mm) 3.1±0.4 (2.2 – 4.0) 2.8±0.4 (2.0 – 3.6) 0.001
Anterior chamber volume (mm3) 181±40 (104 – 270) 153±35 (89 – 234) <0.001
Axial length (mm), mean±SD (range) 26.4±1.5 (22.6–29.4) 25.0±1.1 (23.1–27.7) <0.001
Mean deviation (dB), mean±SD (range) −5.2±4.4 (−18.8 – 1.62) −0.5±1.4 (−5.04 – 2.24) <0.001
Smoking (patients) 7 16 1.00
Diabetes (patients) 3 5 1.00
Hypertension (patients) 16 12 1.00
SD indicates standard deviation.

TABLE 2 - Diurnal Averages and Amplitudes of the IOP and CH Values
Factors Glaucoma Normal Subjects P
Average GAT IOP (mmHg), mean±SD (range) 13.8±2.5 (9.2–21.6) 12.1±2.1 (7.7–18.5) 0.001
Average CH (mmHg), mean±SD (range) 10.4±1.0 (8.4–12.8) 11.1±1.1 (8.5–13.9) 0.002
GAT IOP amplitude (mmHg), mean±SD (range) 3.6±1.5 (0–7) 2.9±1.5 (0–6) 0.066
CH amplitude (mmHg), mean±SD (range) 1.00±0.51 (0.11–2.42) 0.96±0.73 (0.06–3.59) 0.80
Amplitude was defined as the difference between the maximum and minimum values during the day.
CH indicates corneal hysteresis; GAT IOP, intraocular pressure measured by Goldmann applanation tonometry; IOP, intraocular pressure; SD, standard deviation.

The factors associated with CH values in univariate and multivariate analyses are shown in Tables 3 and 4, respectively. Multivariate mixed-effects models revealed that CH values in POAG eyes were significantly associated with measurement times, corneal curvature, CCT, and GAT IOP. A smaller corneal curvature, larger CCT, and lower GAT IOP were associated with larger CH values (coefficient ± standard errors, −1.20 ± 0.44, 0.017 ± 0.004, −0.09 ± 0.02; P=0.007, <0.001, and <0.001, respectively). In the multivariate mixed-effects models for normal eyes, CH values were significantly associated with measurement time, age, CCT, and diabetes. Younger age, larger CCT, and diabetes were associated with larger CH values (coefficient ± standard errors, −0.03 ± 0.01, 0.015 ± 0.003, 0.91 ± 0.41, respectively; P=0.003, <0.001, and 0.027, respectively).

TABLE 3 - Univariate and Multivariate Analysis of Factors Associated With CH Values in Glaucomatous Eyes
Univariate Multivariate
Factors Coefficient (SE) P Coefficient (SE) P
Time (ref. = 9:00) −0.20 (0.08, 12:00), 0.21 (0.08, 21:00) 0.016 (12:00), 0.012 (21:00) −0.17 (0.08, 12:00) 0.036 (12:00)
Age (yrs) 0.005 (0.012) 0.68
Sex (ref. = female) −0.60 (0.24) 0.014
Spherical equivalent (Diopter) 0.027 (0.034) 0.43
Corneal curvature (mm) −0.78 (0.52) 0.13 −1.20 (0.44) 0.007
Central corneal thickness (μm) 0.012 (0.004) 0.002 0.017 (0.004) <0.001
Anterior chamber depth (mm) −0.05 (0.36) 0.88
Anterior chamber volume (mm3) −0.004 (0.003) 0.18
Axial length (mm) −0.07 (0.09) 0.46
Mean deviation (dB) 0.009 (0.015) 0.53
GAT IOP (mmHg) −0.11 (0.02) <0.001 −0.09 (0.02) <0.001
Medication washout (ref. = no) −0.38 (0.24) 0.11
Smoking (ref. = no) 0.64 (0.72) 0.37
Diabetes (ref. = no) −0.44 (0.71) 0.54
Hypertension (ref. = no) −0.35 (0.34) 0.31
All eligible CH values were evaluated after accounting for repeated measurements in the same eye and the correlations between fellow eyes.
Factors with P-values <0.2 were entered in the multivariate analysis, and the final model with only variables with P<0.05 was created by backward elimination.
CH indicates corneal hysteresis; GAT IOP, intraocular pressure measured by Goldmann applanation tonometry; SE, standard error.

TABLE 4 - Univariate and Multivariate Analysis of Factors Associated with CH Values in Normal Eyes
Univariate Multivariate
Factors Coefficient (SE) P Coefficient (SE) P
Time (ref. =9:00) 0.36 (0.11, 21:00), 0.37 (0.11, 24:00) 0.001(21:00), 0.001 (24:00) 0.36 (0.11, 21:00), 0.37 (0.12, 24:00) 0.001(21:00), 0.001 (24:00)
Age (yrs) −0.02 (0.01) 0.07 −0.03 (0.01) 0.003
Sex (ref. = female) −0.42 (0.31) 0.17
Spherical equivalent (Diopter) −0.02 (0.06) 0.75
Corneal curvature (mm) 0.24 (0.59) 0.68
Central corneal thickness (μm) 0.016 (0.004) <0.001 0.015 (0.003) <0.001
Anterior chamber depth (mm) 0.31 (0.43) 0.47
Anterior chamber volume (mm3) 0.003 (0.005) 0.58
Axial length (mm) 0.11 (0.13) 0.42
Mean deviation (dB) 0.07 (0.10) 0.49
GAT IOP (mmHg) −0.04 (0.02) 0.08
Smoking (ref. = no) −0.04 (0.30) 0.90
Diabetes (ref. = no) 0.71 (0.49) 0.15 0.91 (0.41) 0.027
Hypertension (ref. = no) −0.05 (0.36) 0.89
All eligible CH values were evaluated after accounting for repeated measurements in the same eye and the correlations between fellow eyes.
Factors with P-values <0.2 were entered in the multivariate analysis, and the final model with only variables with P<0.05 was created by backward elimination.
CH indicates corneal hysteresis; GAT IOP, intraocular pressure measured by Goldmann applanation tonometry; SE, standard error.

The factors associated with CH amplitude in univariate and multivariate analyses are shown in Tables 5 and 6, respectively. The multivariate mixed-effects model analysis revealed that a higher amplitude of GAT IOP was significantly associated with a larger CH amplitude in eyes with POAG (coefficient ± standard error, 0.10 ± 0.04, P=0.010). In the multivariate mixed-effects model for normal eyes, higher average GAT IOP and larger amplitude of GAT IOP were significantly associated with CH amplitude (coefficient ± standard error, 0.12 ± 0.04, 0.16 ± 0.06; P=0.04, 0.013, respectively).

TABLE 5 - Univariate and Multivariate Analysis of Factors Associated With CH Amplitude in Glaucomatous Eyes
Univariate Multivariate
Factors Coefficient (SE) P Coefficient (SE) P
Age (yrs) 0.003 (0.006) 0.53
Sex (ref. = female) −0.01 (0.13) 0.94
Spherical equivalent (Diopter) 0.024 (0.019) 0.21
Corneal curvature (mm) 0.10 (0.24) 0.67
Central corneal thickness (μm) 0.0007 (0.002) 0.74
Anterior chamber depth (mm) 0.13 (0.17) 0.42
Anterior chamber volume (mm3) 0.0007 (0.002) 0.62
Axial length (mm) −0.015 (0.04) 0.72
Mean deviation (dB) −0.008 (0.013) 0.57
Diurnal average GAT IOP (mmHg) 0.05 (0.02) 0.028
Diurnal amplitude of GAT IOP (mmHg) 0.10 (0.04) 0.010 0.10 (0.04) 0.010
Medication washout (ref. = no) −0.08 (0.13) 0.50
Smoking (ref. = no) −0.02 (0.32) 0.96
Diabetes (ref. = no) −0.18 (0.28) 0.53
Hypertension (ref. = no) 0.06 (0.15) 0.70
Amplitude was defined as the difference between the maximum and minimum values during the day. Factors with P-values <0.2 were entered in the multivariate analysis, and the final model with only variables with P<0.05 was created by backward elimination.
CH indicates corneal hysteresis; GAT IOP, intraocular pressure measured by Goldmann applanation tonometry; SE, standard error.

TABLE 6 - Univariate and Multivariate Analysis of Factors Associated With Diurnal CH Amplitude in Normal Eyes
Univariate Multivariate
Factors Coefficient (SE) P Coefficient (SE) P
Age (yrs) 0.015 (0.009) 0.09
Sex (ref. = female) 0.16 (0.21) 0.46
Spherical equivalent (Diopter) −0.04 (0.04) 0.28
Corneal curvature (mm) 0.38 (0.40) 0.33
Central corneal thickness (μm) 0.002 (0.003) 0.45
Anterior chamber depth (mm) −0.60 (0.28) 0.029
Anterior chamber volume (mm3) −0.006 (0.003) 0.038
Axial length (mm) 0.05 (0.09) 0.58
Mean deviation (dB) −0.047 (0.070) 0.50
Diurnal average GAT IOP (mmHg) 0.11 (0.05) 0.020 0.12 (0.04) 0.04
Diurnal amplitude of GAT IOP (mmHg) 0.12 (0.07) 0.065 0.16 (0.06) 0.013
Smoking (ref. = no) 0.17 (0.29) 0.55
Diabetes (ref. = no) 0.40 (0.34) 0.24
Hypertension (ref. = no) −0.10 (0.24) 0.68
Amplitude was defined as the difference between the maximum and minimum values during the day. Factors with P-values <0.2 were entered in the multivariate analysis, and the final model with only variables with P<0.05 was created by backward elimination.
measured by Goldmann applanation tonometry.
CH indicates corneal hysteresis; GAT IOP, intraocular pressure; SE, standard error.

The patterns of diurnal variation in GAT IOP and CH in patients with POAG and normal individuals are shown in Fig. 1. The GAT IOP in both groups showed similar significant variations: it was lower at 21:00–24:00 than at 9:00–18:00. The CH in both groups showed similar significant variations: it was higher at 21:00–24:00 than at 9:00–18:00. Moreover, the variations in CH adjusted by factors significantly associated with CH values remained significant in both glaucoma and control groups, although the number of pairs of measurement points with significant differences decreased.

F1
FIGURE 1:
Diurnal variations in GAT IOP, CH, and CH adjusted by factors associated with CH values in patients with untreated POAG and normal individuals. Variations in GAT IOP (A), CH (B), and CH adjusted for factors associated with CH values (C). The estimated marginal mean from the mixed-effects model is plotted. Solid and dashed lines indicate the untreated POAG and normal groups, respectively. Symbols indicate significant differences in comparisons of the values obtained at 9:00*, 12:00, 15:00, or 18:00§ (P<0.05, after Bonferroni correction for multiple comparisons). CH curves were adjusted for corneal curvature, CCT, and GAT IOP in the POAG group, and for age, CCT, and diabetes in the normal group. CH indicate corneal hysteresis; GAT IOP, intraocular pressure measured by Goldmann applanation tonometry; POAG, primary open angle glaucoma. Error bars indicate 95% confidence intervals.

DISCUSSION

In the present study, CH in both POAG and normal eyes showed similar small but significant diurnal variations even after adjusting for confounding factors, and was higher in the nighttime than in the daytime. In contrast, GAT IOP showed an antiphase pattern and was lower in the nighttime than in the daytime. In multivariate analysis, a larger diurnal amplitude of GAT IOP was associated with a larger diurnal amplitude of CH in both groups.

Previous studies have shown no significant diurnal variation in CH in normal individuals,14,17–19,21,26 except in 1 report.27 In all previous studies, the magnitude of CH variation was <1.0 mm Hg, which was comparable to the 0.3–0.4 mm Hg differences between the peak and trough values in the diurnal pattern of CH variation in the present study (Fig. 1). However, even though the magnitude of variation was similar, the statistical significance of diurnal variations of CH may depend on the sample size and the number and distribution of measurement time points during a 24-hour period. Kida et al.17 explored CH every 2 hours for 24 hours in both eyes of 15 normal individuals. Shen et al.18 investigated CH 9 times from 7:00 to 22:00 in both eyes of 20 normal participants. Oncel et al.19 analyzed diurnal CH changes every 3 hours from 8:00 to 17:00 in 62 eyes of 62 normal participants. Laiquzzaman et al.21 measured CH every 3 hours from 8:00 to 17:00 in both eyes of 21 normal participants. Gonzalez-Meijome et al.26 investigated diurnal CH changes from 9:00 to 19:00 in 58 eyes of 58 normal participants. Lau et al.27 measured CH every 2 hours from 17:00 to 23:00 and, on the following day, every 20 minutes from 7:00 to 9:00 and every 2 hours from 9:00 to 17:00 in 25 eyes of 25 normal participants. In the only study on diurnal CH changes in patients with glaucoma, the authors examined CH every 2 hours from 9:00 to 17:00 in 36 eyes of 36 patients with glaucoma and 26 eyes of 26 normal participants.14 Among these studies, the study by Lau et al.27 was the only 1 showing significant CH changes, an overnight increase of 0.4 mm Hg from 23:00 to 7:00. In the current study, we measured CH every 3 hours from 9:00 to 24:00 in 72 eyes of 53 patients with untreated POAG and 53 eyes of 47 normal individuals and found a significant increase in CH at night in both groups. The small sample sizes and/or lack of CH measurements at night in the previous studies might have resulted in the inability to detect statistical significance in the small diurnal variations in CH.

In the present study, diurnal variation patterns and the amplitude of CH in patients with glaucoma were similar to those in normal individuals, although the diurnal average CH was significantly different between the 2 groups. Thus, diurnal CH variation in eyes with glaucoma appeared to be comparable to that in normal eyes, at least in untreated POAG patients, with a mean GAT IOP within the normal range. However, the factors associated with CH values were different between the 2 groups, except for CCT, which has been consistently reported to be associated with CH.4–6,10–12,15–19 GAT IOP was negatively associated with CH only in eyes with glaucoma. A study on chronic primary angle closure glaucoma found that CH was not correlated with IOP after IOP-lowering treatment (11.47 ± 4.71 mm Hg), although CH was negatively correlated with a baseline IOP of 31.55 ± 10.48 mm Hg.31 According to the definition of CH, high IOP helps the cornea regain its baseline position after rapid deformation by an air pulse, which contributes to the negative correlation between CH and IOP at high IOP levels. Given that the average diurnal IOP was significantly higher in glaucomatous eyes than in normal eyes, the association between GAT IOP and CH is more likely to be significant in eyes with glaucoma. Therefore, an increase in CH at night may merely reflect a decrease in IOP at night. However, when adjusted for confounding factors, including GAT IOP, the diurnal pattern of CH remained almost the same as that before adjustment (Fig. 1). Furthermore, diurnal variation in CH in normal eyes was unaffected by adjustment for confounding factors. The similar diurnal variations of CH in both groups indicate that viscoelastic properties of the cornea may fluctuate diurnally independent of IOP and the presence of glaucoma.

In our study, multivariate analysis showed that a larger diurnal amplitude of GAT IOP was significantly associated with a larger diurnal amplitude of CH in both groups. In several studies, the greater the diurnal variation in IOP, the faster the progression of glaucoma.32,33 In patients with low-teens normal tension glaucoma, a 1-mm Hg increase in diurnal fluctuation of IOP (maximum IOP – minimum IOP among six IOP measurements performed every 2 h from 8:00 to 18:00) was associated with a 60.9% greater chance of glaucoma progression.33 Therefore, diurnal CH variation and IOP fluctuations could influence the VF progression in glaucomatous eyes. Additional studies are needed to investigate whether diurnal CH variation is a predictor of glaucoma progression.

The present study had several limitations. The study participants were Japanese and had POAG with untreated IOP mostly within the normal range. Therefore, the results may not be applicable to patients of other races, those with other types of glaucoma, or eyes with a higher IOP or glaucoma treatment. The glaucoma group included more female participants, more myopic refractive errors, and longer axial lengths than the control group. Although these factors have been reported to be significantly associated with CH values, they did not affect the results of the diurnal pattern of CH variation and were not associated with the magnitude of CH variation. A ≥4-week medication washout was performed to eliminate the effect of IOP-lowering therapy according to the medication washout period in the Ocular Hypertension Treatment Study and a randomized study on minimally-invasive glaucoma surgery.34,35 However, ocular hypotensive drugs may affect CH, dependent or independent of IOP decrease. For instance, a 6-week interruption in long-term treatment with prostaglandin analogs increased CH and IOP. The treatment reinitiation reversed the increase in CH, indicating that these medications cause a reversible decrease in CH.36 In our study, the effects of medication on CH might have lasted longer than the 4-week washout period and affected the diurnal variation in CH. We also examined whether diurnal changes in CH were different between eyes with and without glaucoma medication at enrollment. Washout was not significantly associated with CH values or CH amplitude. Furthermore, regarding the classes of medications, 33 eyes of 25 patients were washed out of PG analogs. Among them, 11 eyes of 8 patients were on PG monotherapy. The other 8 eyes of 6 patients used medications except for PG analogs at enrollment. In terms of variables of GAT IOP and ORA parameters, including CH and corneal-compensated IOP, 33 eyes washed out of prostaglandin analogs were not significantly different from 8 eyes washed out of other medications (see Table, Supplemental Digital Content 1, https://links.lww.com/IJG/A659). These results indicate that diurnal variations in CH were not significantly different between eyes with and without medication at enrollment. Therefore, the ≥4-week washout period was appropriate to minimize the effects of glaucoma medication on diurnal changes in CH.

In conclusion, we found that CH showed similar small but significant diurnal variations in both patients with POAG and normal individuals even after adjusting for confounding factors; CH was higher in the nighttime than in the daytime. These findings suggest that viscoelastic properties of the cornea may fluctuate diurnally independent of IOP. Furthermore, a larger diurnal amplitude of GAT IOP was associated with a larger diurnal amplitude of CH in both groups. Given the significant relationship between diurnal fluctuations of GAT IOP and glaucoma progression, diurnal fluctuations of CH may contribute to glaucoma progression independently or in accordance with diurnal IOP changes. Further studies on diurnal variations in CH are needed to explore the underlying mechanisms and their significance in glaucoma progression.

ACKNOWLEDGMENTS

The authors thank Prof. Hiroyuki Nakamura, Department of Environmental and Preventive Medicine in Kanazawa University Graduate School of Medical Sciences, Japan, for his invaluable expertise and assistance concerning the statistical analysis.

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Keywords:

corneal hysteresis; intraocular pressure; diurnal variations; glaucoma

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