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Original Investigation | Clinical Sciences

24-Hour Intraocular Pressure Rhythm in Young Healthy Subjects Evaluated With Continuous Monitoring Using a Contact Lens Sensor FREE

Benjamin Mottet, MSc1,2,3; Florent Aptel, MD, PhD1,2,3; Jean-Paul Romanet, MD1,2; Ralitsa Hubanova, MD, MSc1,2; Jean-Louis Pépin, MD, PhD3; Christophe Chiquet, MD, PhD1,2,3
[+] Author Affiliations
1Joseph Fourier University–Grenoble 1, Grenoble, France
2Department of Ophthalmology, University Hospital, CHU Grenoble, Grenoble, France
3INSERM U1042, Lab Hypoxia and Physiopathology, Joseph Fourier University, Grenoble, France
JAMA Ophthalmol. 2013;131(12):1507-1516. doi:10.1001/jamaophthalmol.2013.5297.
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Published online

Importance  This study evaluates a new device that has been proposed to continuously monitor intraocular pressure (IOP) over 24 hours.

Objective  To evaluate 24-hour IOP rhythm reproducibility during repeated continuous 24-hour IOP monitoring with noncontact tonometry (NCT) and a contact lens sensor (CLS) in healthy participants.

Design, Setting, and Participants  Cross-sectional study of 12 young healthy volunteers at a referral center of chronobiology.

Interventions  Participants were housed in a sleep laboratory and underwent four 24-hour sessions of IOP measurements over a 6-month period. After initial randomized attribution, the IOP of the first eye was continuously monitored using a CLS and the IOP of the fellow eye was measured hourly using NCT. Two sessions with NCT measurements in 1 eye and CLS measurements in the fellow eye, 1 session with CLS measurements in only 1 eye, and 1 session with NCT measurements in both eyes were performed.

Main Outcomes and Measures  A nonlinear least squares, dual-harmonic regression analysis was used to model the 24-hour IOP rhythm. Comparison of acrophase, bathyphase, amplitude, midline estimating statistic of rhythm, IOP values, IOP changes, and agreement were evaluated in the 3 tonometry methods.

Results  A significant nyctohemeral IOP rhythm was found in 31 of 36 sessions (86%) using NCT and in all sessions (100%) using CLS. Hourly awakening during NCT IOP measurements did not significantly change the mean phases of the 24-hour IOP pattern evaluated using CLS in the contralateral eye. Throughout the sessions, intraclass correlation coefficients of the CLS acrophase (0.6 [95% CI, 0.0 to 0.9]; P = .03), CLS bathyphase (0.7 [95% CI, 0.1 to 0.9]; P = .01), NCT amplitude (0.7 [95% CI, 0.1 to 0.9]; P = .01), and NCT midline estimating statistic of rhythm (0.9 [95% CI, 0.9 to 1.0]; P < .01) were significant. When performing NCT measurements in 1 eye and CLS measurements in the contralateral eye, the IOP change at each point normalized from the first measurement (9 am) was not symmetric individually or within the population.

Conclusions and Relevance  The CLS is an accurate and reproducible method to characterize the nyctohemeral IOP rhythm in healthy participants but does not allow for estimating the IOP value in millimeters of mercury corresponding to the relative variation of the electrical signal measured.

Figures in this Article

Intraocular pressure (IOP) is known to vary throughout the 24-hour period of a day, defined as a nyctohemeral rhythm in healthy humans and patients with glaucoma.14 Currently, the only way used to study 24-hour IOP rhythm is to perform repeated IOP measurements with portable tonometers. They only allow episodic and noncontinuous IOP measurements, up to 1 measurement per hour in the best cases. They are far from physiologic conditions, as they require awakening patients during the nocturnal/sleep period, potentially introducing stress-related artifacts and disturbing sleep organization. They are performed in a fixed position, thus ignoring dynamic changes related to daily-life physical activities. A contact lens sensor (CLS) (SENSIMED Triggerfish; SENSIMED AG) was recently developed to continuously monitor IOP over 24 hours in an ambulatory setting. This novel method is based on the assumption that a correlation exists between IOP and corneal curvature.5 Studies have shown that an IOP variation of 1 mm Hg produces a change of central corneal curvature radius of approximately 3 μm.6,7 This new approach was validated in vitro on cannulated enucleated eyes.6 In a small number of studies,811 this new device was used in humans with glaucoma.

In healthy humans, this new device has not yet been validated and not yet been used to characterize the 24-hour IOP rhythm during repeated continuous 24-hour IOP monitoring sessions. We conducted a prospective study to evaluate the 24-hour IOP rhythm reproducibility during repeated continuous 24-hour IOP monitoring with noncontact tonometry (NCT) and the Triggerfish CLS in healthy participants. The study was designed to evaluate rhythm reproducibility in a given eye over several sessions and the rhythm symmetry between 2 eyes in a given session and compare the 2 tonometry methods’ variations in measurements.

This prospective investigation was conducted in a university-affiliated sleep laboratory following the tenets of the Declaration of Helsinki and was approved by the local institutional review board (8881, 2010-39). All participants provided both verbal and written informed consent.

Study Population

The eyes of healthy participants were studied in four 24-hour study sessions over a 6-month period. Inclusion criteria were participants free of sleep disturbance, endocrine illness, or ocular disease (spherical equivalent between −1 and +1 diopter), with regular lifestyle habits and a habitual total sleep time of approximately 8 hours. Exclusion criteria were shift workers, having taken a transmeridian flight less than 2 months before the beginning of the study, any medical treatment, and tobacco smokers. At the inclusion visit, all study participants underwent a complete ophthalmic examination (including refraction, biomicroscopy, Goldmann applanation tonometry [GAT], gonioscopy, fundus examination, and ultrasound pachymetry [Pocket II pachymeter; Quantel Medical]). All participants also filled out a general health questionnaire and underwent a complete physical examination. For each participant, 1 eye was randomized to the eyes 1 group and the fellow eye was automatically included in the eyes 2 group.

Instruments

The SENSIMED Triggerfish consists of a highly oxygen-permeable soft CLS, whose key elements are 2 sensing-resistive strain gauges that are capable of recording circumferential changes in the area of the corneoscleral junction. The contact lens (diameter, 14.1 mm; thickness, 585 µm at the center and 260 µm at the border) exists in 3 different base curves: steep, medium, and flat, with, respectively, an 8.4-, 8.7-, and 9-mm curvature radius. Ten data points/s are acquired during a 30-second measurement period, repeated every 5 minutes. The output of the sensor is expressed in electric arbitrary units (eqVm).

Pulsair intelliPuff (Keeler) is an NCT that measures IOP in patients in the sitting or supine position. An average of 3 readings were recorded hourly over the 24-hour session.12 Goldmann applanation tonometry was performed according to standard protocol, using a slitlamp (BQ900; Haag-Streit).

Experimental Sessions

The protocol, summarized in Table 1, was designed to compare the 2 tonometry methods, evaluate intersession reproducibility using each method, and assess the symmetry of IOP pattern in both eyes. The participants maintained a self-selected constant sleep-wake schedule (onset between 10 pm and 12 am and wake up between 7 am and 8 am) 2 weeks before and during the study, checked by sleep-wake diaries and ambulatory actigraphy monitoring using a wrist accelerometer (Actiwatch; CamNtech). During the experimental sessions, they were requested not to drink alcohol and caffeine-containing beverages.

Table Graphic Jump LocationTable 1.  Organization of the Four 24-Hour Sessions for Each Individual (9 am to 9 am)a

For each visit, immediately before inserting and removing the CLS, eyes in groups eyes 1 and eyes 2 were measured using NCT and GAT. Although the patients were housed in the hospital, they were allowed to have free activities between the NCT hourly IOP measurements at the first visit (M0), third visit (4-month) (M4), and fourth visit (6-month) (M6) and every time at the second visit (2-month) (M2) because there were no NCT hourly IOP measurements. At each visit, participants were asked to go to bed after the IOP measurement at 10 pm and were asked to get up after the IOP measurement at 8 am.

Statistical Analysis
IOP Rhythm Over a 24-Hour Session

From raw IOP data over 24 hours (Figure 1), a nonlinear least squares, dual-harmonic regression analysis13,14 was used to model the 24-hour IOP rhythms as: Graphic Jump LocationImage not available.

where A1 is the amplitude of the fundamental cosine fit, A2 is the amplitude of the first harmonic cosine fit, Φ1 is the acrophase of the fundamental cosine fit, Φ2 is the acrophase of the first harmonic cosine fit, τ is the endogenous circadian period (set at 24 hours because of entrained conditions), M is the midline estimating statistic of rhythm (MESOR), and t is time. Unbiased estimates and confidence limits of amplitude (half the difference between the highest and lowest IOP values in a 24-hour cycle), MESOR (average IOP values in a 24-hour cycle), acrophase (time of the highest IOP value in a 24-hour cycle), and bathyphase (time of the lowest IOP value in a 24-hour cycle) were obtained from modeling each IOP curve. The distribution of the acrophase and bathyphase over time was analyzed using the Rayleigh test of uniformity and Watson-Williams test for homogeneity of means.15 The averaged acrophase and bathyphase for visits M0 and M4 (awakening sessions) were calculated for each participant and compared with night sleep session acrophase and bathyphase (visit M2).

Place holder to copy figure label and caption
Figure 1.
Examples of 24-Hour Raw and Modeled Individual Intraocular Pressure (IOP) Curves of 1 Participant

CLS indicates contact lens sensor; eqVm, electric arbitrary unit; M0, first visit; M4, third visit (4-month); and NCT, noncontact tonometry.

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IOP Reproducibility Over 24-Hour Sessions Using the Same Tonometry Method

The 2-way random average agreement intraclass correlation coefficient (ICC) from Shrout and Fleiss16 was used to assess the agreement of IOP at the 3 visits; the analyses included (1) assessment of the IOP value at each point of the 24-hour IOP curve (eg, IOP at 10 am compared for 3 visits), (2) assessment of IOP changes at each point of the 24-hour IOP curve (IOP values were normalized according to the first IOP value at 9 am), and (3) assessment of calculated amplitude, acrophase, bathyphase, and MESOR of the rhythm modeled. The following interpretation scheme for ICC has been described17: less than 0.4 represents poor agreement beyond chance; 0.4 to 0.75 represents fair to good agreement beyond chance; and more than 0.75 represents excellent agreement beyond chance.

IOP Symmetry Within the Same 24-Hour Session

The coefficient of determination (R2) in linear regression was used to assess the correlation of the simultaneous IOP changes in the eyes 1 group and IOP changes in the eyes 2 group at the same visit. R2 represents the proportion of response explained by the model (ie, R2 = 1 indicates that all variability was explained by linear regression).

IOP Agreement Across Methods in the Same Eye

Bland-Altman graphs were used to plot general agreement of the same IOP changes in the eyes 1 group measured with the different tonometry methods. The better of either linear regression or polynomial (order 2) regression was used to model each agreement in the different tonometry methods.

Data analyses were performed using SPSS (version 17.0; SPSS Inc) and R software.18 Statistical significance was set at P < .05.

Population

Twelve healthy white participants (24 eyes) were included (8 female and 4 male; mean [SD] age, 22.3 [2.3] years; mean [SD] body mass index [calculated as weight in kilograms divided by height in meters squared], 20.8 [2.0]). Ten of 12 individuals (83%) received a medium CLS and the others received a steep CLS. At inclusion, mean (SD) IOP values using GAT were 13.8 (2.1) mm Hg in the right eye and 13.7 (1.9) mm Hg in the left eye (P = .90). Mean (SD) central corneal thickness was 550 (18) µm in the right eye and 554 (20) µm in the left eye (P = .61). The mean (SD) corneal power was 43.6 (1.1) diopters in both eyes.

Characterization of IOP Rhythm

A significant nyctohemeral IOP rhythm was found in 31 of thirty-six 24-hour sessions (86%) using NCT and in all 24-hour sessions (100%) using CLS. In all participants and throughout the sessions, mean (SD) nocturnal IOP was significantly higher than diurnal IOP using NCT in the eyes 2 group (15.6 [0.5] mm Hg vs 13.9 [0.5] mm Hg; P < .01) or CLS in the eyes 1 group (14.0 [4.2] eqVm vs −0.2 [4.8] eqVm; P < .01). Minimum, maximum, and mean IOP values and amplitude, acrophase, and bathyphase characteristics of the population are summarized in Table 2.

Table Graphic Jump LocationTable 2.  Characteristics of 24-Hour IOP Rhythms Calculated Using NCT and CLSa

In all visits in which CLS and NCT were simultaneously used, mean (SD) acrophases (3:05 am [37 minutes] vs 5:28 am [41 minutes]; P < .01) and bathyphases (3:14 pm [55 minutes] vs 7:32 pm [57 minutes]; P < .01) were significantly earlier in the eyes 1 group measured with CLS than in the eyes 2 group measured with NCT (Table 2). Using the same tonometry method (NCT), mean (SD) acrophases (5:21 am [51 minutes] vs 5:49 am [44 minutes]; P = .73) and bathyphases (6:16 pm [65 minutes] vs 7:49 pm [52 minutes]; P = .36) were not significantly different.

Hourly awakening during NCT IOP measurements did not significantly change the mean phases of the 24-hour IOP pattern evaluated using CLS. The mean (SD) value of the acrophases of visits M0 and M4 (with awakening) did not differ significantly from the acrophase of visit M2 (without awakening): 3:05 am (37 minutes) vs 3:51 am (43 minutes); P = .40. The mean (SD) value of the bathyphases of visits M0 and M4 (with awakening) did not differ significantly from the bathyphase of visit M2 (without awakening): 3:14 pm (55 minutes) vs 2:30 pm (34 minutes); P = .53.

Analyzing the rhythm parameters for visits M0, M4, and M6, the ICC of the NCT MESOR was significant (0.9 [95% CI, 0.9 to 1.0]; P < .01), with excellent agreement, and there was a trend for the significance of ICC of the CLS MESOR (0.5 [95% CI, −0.1 to 0.9]; P = .05). The ICC of the NCT amplitude was significant (0.7 [95% CI, 0.1 to 0.9]; P = .01), with fair to good agreement, and there was a trend for the significance of ICC of the CLS amplitude (0.5 [95% CI, −0.3 to 0.8]; P = .08). The ICC of the NCT acrophase (0.1 [95% CI, −1.6 to 0.9]; P = .38) was not significant, whereas the ICC of the CLS acrophase was significant (0.6 [95% CI, 0.0 to 0.9]; P = .03), with fair to good agreement. The ICC of the NCT bathyphase (0.3 [95% CI, −1 to 0.8]; P = .25) was not significant, and the ICC of the CLS bathyphase was significant (0.7 [95% CI, 0.1 to 0.9]; P = .01), with fair to good agreement.

Reproducibility of IOP Measurements Over 24-Hour Sessions
Reproducibility of CLS IOP Measurements

Nine hourly IOP values of 25 (Table 3) and 9 points of 24 for IOP changes (Table 4) presented significant ICCs, indicating generally fair to good agreement (ie, 95% CI) (Figure 2A and B).

Table Graphic Jump LocationTable 3.  Reproducibility of 24-Hour IOP Absolute Valuesa
Table Graphic Jump LocationTable 4.  Reproducibility of 24-Hour IOP Relative Changesa
Place holder to copy figure label and caption
Figure 2.
Reproducibility and Symmetry of 24-Hour Average Change in Intraocular Pressure (∆IOP) of All Individuals

A-D, Reproducibility of 24-hour ∆IOP. E-G, Symmetry of 24-hour ∆IOP. For each individual, 1 randomly chosen eye was randomized to the eyes 1 group and the fellow eye was included in the eyes 2 group. CLS indicates contact lens sensor; M0, first visit; M2, second visit (2-month); M4, third visit (4-month); M6, fourth visit (6-month); NCT, noncontact tonometry; and SD, standard deviation.

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Reproducibility of NCT IOP Measurements

Eighteen points of 25 presented significant ICCs, indicating generally fair to good agreement (ie, 95% CI) (Table 3). For IOP changes, 1 point of 24 presented a significant ICC (Table 4) (Figure 2C and D).

Symmetry of IOP Measurements Within a 24-Hour Session

Symmetry of simultaneous mean 24-hour IOP patterns in fellow eyes in all patients is summarized in Figure 2E-G and Figure 3.

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Figure 3.
Linear Regression of Simultaneous Hourly Mean Intraocular Pressure Values Between the Eyes 1 and Eyes 2 Groups

A, At the fourth visit (6-month) (M6) using noncontact tonometry (NCT). B and C, At the first visit (M0) and third visit (4-month) (M4) using a contact lens sensor (CLS) in the eyes 1 group and NCT in the eyes 2 group in all participants. For each individual, 1 eye was randomized to the eyes 1 group and the fellow eye was included in the eyes 2 group. eqVm indicates electric arbitrary unit.

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NCT in the Eyes 1 Group vs the Eyes 2 Group at Visit M6

Six of 12 participants (50%) exhibited a significant correlation of simultaneous hourly IOP values measured using NCT in fellow eyes (R2 ranged from 0.15 to 0.48; P < .05). Considering all participants, mean IOP values in fellow eyes measured using NCT in all patients exhibited a fairly significant correlation (R2 = 0.62; P < .01) (Figure 3A).

CLS in the Eyes 1 Group vs the Eyes 2 Group at Visits M0 and M4

At visit M0 and visit M4, 4 (33%) and 6 (50%) of 12 participants exhibited a significant correlation of hourly IOP values simultaneously measured using NCT in the eyes 2 group and CLS in the eyes 1 group (R2 ranged from 0.17 to 0.33; P < .05 and 0.14 to 0.56; P < .05, respectively). Considering all participants, mean IOP values in fellow eyes, measured using NCT in the eyes 2 group and CLS in the eyes 1 group, in all patients exhibited a poorly significant correlation at visit M0 (R2 = 0.32; P < .01) (Figure 3B) and a fair correlation at visit M4 (R2 = 0.62; P < .01) (Figure 3C).

Agreement of IOP Measurements Across CLS, NCT, and GAT

Comparison of mean IOP values (the first and the last of a 24-hour session) and mean IOP changes (between the first IOP value and the last IOP value of a 24-hour session) for GAT, NCT, and CLS IOP measurements in all patients are summarized in Table 5. The graphs in Figure 4 show the differences of IOP changes between pairs of tonometers and the means of IOP changes. The lower and upper bounds of the 95% CI of IOP change agreement were between CLS and NCT, −38.09 to 42.5 (Figure 4A); between CLS and GAT, −45.45 to 57.21 (Figure 4B), and between NCT and GAT, −25.75 to 32.58 (Figure 4C). The coefficient of determination of the differences between NCT and CLS IOP changes and the mean IOP changes was poor but significant (R2 = 0.17; P = .02) and modeling showed that CLS tended to overestimate the high IOP changes in comparison with NCT.

Table Graphic Jump LocationTable 5.  Mean IOP Values Before and After 24-Hour CLS Wear and Mean 24-Hour IOP Changes in the Eyes 1 Groupa
Place holder to copy figure label and caption
Figure 4.
Bland-Altman Graphs of Intraocular Pressure Changes Agreement in the Eyes 1 Group

Changes were calculated between day 0 at 9 am and day 1 at 9 am. A, Agreement between the contact lens sensor (CLS) and noncontact tonometry (NCT). B, Agreement between CLS and Goldmann applanation tonometry (GAT). C, Agreement between NCT and GAT. For each individual, 1 eye was randomized to the eyes 1 group. 95% CI, 95% modeling confidence interval; LCB, global lower 95% confidence bound; M0, first visit; M2, second visit (2-month); M4, third visit (4-month); UCB, global upper 95% confidence bound; and Δ, change in.

Graphic Jump Location

In the present study, we evaluated the 24-hour IOP rhythm reproducibility in healthy participants during repeated sessions, both with NCT and a new CLS. We combined sessions with NCT measurements in 1 eye and CLS measurements in the fellow eye, a session with CLS measurements alone (1 eye), and a session with NCT measurements in both eyes to evaluate the rhythm reproducibility in a given eye over sessions, the rhythm symmetry between 2 eyes in a given session, and 2 tonometry methods’ variations in measurements.

With the 2 tonometry methods, we found that all healthy participants exhibited a nyctohemeral IOP rhythm. As previously described1,2,19 with the currently available tonometry methods, the IOP nyctohemeral rhythm was characterized by an acrophase in the late night/early morning period. Interestingly, sessions performed with CLS measurements alone confirmed these previous results, thus demonstrating that the IOP rhythm previously described in healthy participants with the available tonometry methods is not an artifact due to awakening and related sleep disorganization. In a given session, the acrophases and bathyphases of 1 eye evaluated with 1 tonometry technique and of the fellow eye evaluated with the other technique were usually significantly different. In a given session, the acrophases and bathyphases of the 2 eyes evaluated with the same tonometry technique (NCT) were usually comparable. This cannot be evaluated with the CLS because simultaneous measurements are not possible for technical reasons. These latter results suggest that the differences obtained between 2 different techniques are related to technical methods (number of IOP measurements) and not biological variability.

Among the sessions, the 24-hour rhythm parameters found with the same tonometry technique (NCT or CLS) in a given participant and in a given eye were usually comparable. The most robust parameters among sessions were the MESOR and amplitude for NCT and the acrophase and bathyphase for CLS. The most reproducible IOP values were taken during the day (8 am to 10 pm) with NCT; the most reproducible IOP changes were taken between 11 am and 1 pm and between 6 pm and 8 pm with CLS. The discrepancy between agreement of absolute IOP and agreement of IOP change is consistent with the findings of Realini and al17,20 using GAT: agreement of diurnal IOP values was fair to good and agreement of diurnal IOP changes was poor. Interestingly, we found higher agreement of relative IOP changes among sessions during the first diurnal 12 hours using CLS measurements than using NCT measurements.

A few studies have been conducted in humans with this new CLS and focused on patients with glaucoma. These studies evaluated the 24-hour hypotensive drug activity in patients with normotensive glaucoma,11 corneal thickness after overnight wear in patients with ocular hypertension or established glaucoma,21 or the reproducibility of the 24-hour IOP pattern in patients with suspected and confirmed glaucoma.10

To our knowledge, the present study is the first to assess the reproducibility over several months of 24-hour IOP patterns in healthy participants both with the CLS and NCT. We found that the CLS is a more sensitive method than the NCT in detecting and characterizing the 24-hour IOP rhythm. The CLS allowed better nonlinear dual-harmonic modeling of the 24-hour IOP rhythm. Thus, the CLS usually detects acrophases and bathyphases significantly earlier (about 2 hours) than NCT. The NCT acrophases were similar to those found by Mansouri and al22 in the sitting or supine position in young participants. One reason explaining the greater ability of the CLS to detect and characterize the 24-hour IOP rhythm is likely the higher frequency of data acquisition, strongly reducing the potential influence of outliers.

Noncontact tonometry and CLS are different and complementary for the study of the 24-hour IOP rhythm. Regarding the reproducibility of the 24-hour IOP rhythms assessed with NCT among visits, amplitude showed significant fair to good agreement and MESOR showed excellent agreement. In contrast, reproducibility of NCT acrophases and bathyphases was limited and not significant. In contrast, CLS can define temporal phases that contribute to nyctohemeral rhythm (acrophases and bathyphases) with greater confidence than NCT.

The new CLS measures an electrical signal expressed in millivolts. Measurements are normalized to the first measurement of the session (in electric arbitrary units). The first measure of the recording session, just after activating the device, is therefore arbitrarily set at 0 eqVm. The subsequent measurements are the relative signal change. The unresolved question about this new device is whether these signal variations can be used to estimate the variations in IOP expressed in millimeters of mercury reached at each point using the IOP measured just before contact lens equipment with NCT or GAT. Our results, summarized in Figure 2 and Table 4, clearly show that the CLS cannot estimate the absolute value of IOP in millimeters of mercury when using the pre- and post-CLS GAT measurements or pre- and post-CLS NCT measurements. When performing NCT measurements in both eyes (visit M6), IOP changes at each point compared with the first measurement (9 am) are usually symmetric in a given participant or in the population. When performing NCT measurements in 1 eye and CLS measurements in the fellow eye (visits M0 and M4), IOP changes at each point compared with the first measurement (9 am) are not symmetric in a given participant or in the population. It is therefore not possible to use the relative change in CLS signal multiplied by the IOP measured before CLS equipment to estimate the absolute IOP at each point of the 24-hour session. Regarding the presession and postsession measurements with GAT and NCT, the agreement on the change in IOP in the CLS and NCT or GAT was also poor. Bland-Altman analyses suggest that CLS overestimates the large IOP changes in comparison of NCT.

This study could have some limitations. Other factors related to sleep such as the impact of the eyelid during the sleep phase could have influenced the CLS measurements and thus the difference between the tonometry methods. We are currently conducting complimentary studies in our laboratory using overnight polysomnography measurements. Regarding intereye symmetry, an earlier study found asymmetric spontaneous IOP changes in fellow eyes regardless of the tonometry method used. Realini et al23 showed that asymmetric spontaneous IOP changes commonly occur between fellow eyes in normal participants: 50% exhibited an asymmetric IOP change between 2 consecutive visits and overall asymmetric IOP changes were observed in 13.7% of follow-up visits. In the present study, the NCT-CLS comparisons were based on the finding that the 24-hour IOP value changes of the 2 fellow eyes are symmetric with the same tonometry method but cannot be checked directly in humans because the contact lens completely covered the cornea. Because of technical limitations, it is currently not possible to use the CLS simultaneously in both eyes. Finally, the artifacts of electrical signal measurement of the CLS method could have an impact regarding the results.

In conclusion, the CLS is an accurate and reproducible method to model IOP rhythm and characterize acrophases and bathyphases in healthy participants but does not estimate the absolute value and IOP changes in millimeters of mercury corresponding to the relative variation of the electrical signal measured.

Corresponding Author: Florent Aptel, MD, PhD, Department of Ophthalmology, University Hospital of Grenoble, 38043 Grenoble CEDEX 09, France (faptel@chu-grenoble.fr).

Published Online: October 24, 2013. doi:10.1001/jamaophthalmol.2013.5297.

Author Contributions: Drs Aptel and Mottet had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mottet, Aptel, Romanet, Pépin, Chiquet.

Acquisition of data: Mottet, Aptel, Hubanova, Chiquet.

Analysis and interpretation of data: Mottet, Aptel, Pépin, Chiquet.

Drafting of the manuscript: Mottet, Aptel, Pépin, Chiquet.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Mottet, Aptel, Pépin.

Obtained funding: Aptel, Romanet, Chiquet.

Administrative, technical, or material support: Mottet, Aptel, Romanet, Pépin, Chiquet.

Study supervision: Mottet, Aptel, Romanet, Pépin, Chiquet.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by Association de Recherche et de Formation en Ophtalmologie (ARFO) (Grenoble).

Role of the Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Claude Gronfier, PhD, for methodological advice using the nonlinear least squares, dual-harmonic regression analysis and Nathalie Arnol, MSc, for statistical advice.

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Pajic  B, Pajic-Eggspuchler  B, Haefliger  I.  Continuous IOP fluctuation recording in normal tension glaucoma patients. Curr Eye Res. 2011;36(12):1129-1138.
PubMed   |  Link to Article
Hubanova R, Aptel F, Zhou T, et al. Comparison of intraocular pressure measurements with the Reichert PT100, the Keeler Pulsair intelliPuff portable non-contact tonometers and Goldmann applanation tonometry. In: ARVO 2012 Annual Meeting Abstracts. Rockville, MD: Association for Research in Vision and Ophthalmology; 2012. Abstract 5063.
Brown  EN, Czeisler  CA.  The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data. J Biol Rhythms. 1992;7(3):177-202.
PubMed   |  Link to Article
Gronfier  C, Wright  KP  Jr, Kronauer  RE, Czeisler  CA.  Entrainment of the human circadian pacemaker to longer-than-24-h days. Proc Natl Acad Sci U S A. 2007;104(21):9081-9086.
PubMed   |  Link to Article
Zar JH. Biostatistical Analysis. Upper Saddle River, NJ: Prentice Hall; 1999:616-627.
Shrout  PE, Fleiss  JL.  Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86(2):420-428.
PubMed   |  Link to Article
Realini  T, Weinreb  RN, Wisniewski  S.  Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals [published correction appears in Ophthalmology. 2011;118(3):434]. Ophthalmology. 2011;118(1):47-51.
PubMed   |  Link to Article
R Development Core Team: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing [computer program]. Version 2.14. Vienna, Austria: R Development Core Team; 2012. http://www.r-project.org/.
Mottet  B, Chiquet  C, Aptel  F,  et al.  24-Hour intraocular pressure of young healthy humans in supine position: rhythm and reproducibility. Invest Ophthalmol Vis Sci. 2012;53(13):8186-8191.
PubMed   |  Link to Article
Realini  T, Weinreb  RN, Wisniewski  SR.  Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals. Ophthalmology. 2010;117(9):1700-1704.
PubMed   |  Link to Article
Freiberg  FJ, Lindell  J, Thederan  LA, Leippi  S, Shen  Y, Klink  T.  Corneal thickness after overnight wear of an intraocular pressure fluctuation contact lens sensor. Acta Ophthalmol. 2012;90(7):e534-e539.
PubMed   |  Link to Article
Mansouri  K, Weinreb  RN, Liu  JH.  Effects of aging on 24-hour intraocular pressure measurements in sitting and supine body positions. Invest Ophthalmol Vis Sci. 2012;53(1):112-116.
PubMed   |  Link to Article
Realini  T, Barber  L, Burton  D.  Frequency of asymmetric intraocular pressure fluctuations among patients with and without glaucoma. Ophthalmology. 2002;109(7):1367-1371.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
Examples of 24-Hour Raw and Modeled Individual Intraocular Pressure (IOP) Curves of 1 Participant

CLS indicates contact lens sensor; eqVm, electric arbitrary unit; M0, first visit; M4, third visit (4-month); and NCT, noncontact tonometry.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Reproducibility and Symmetry of 24-Hour Average Change in Intraocular Pressure (∆IOP) of All Individuals

A-D, Reproducibility of 24-hour ∆IOP. E-G, Symmetry of 24-hour ∆IOP. For each individual, 1 randomly chosen eye was randomized to the eyes 1 group and the fellow eye was included in the eyes 2 group. CLS indicates contact lens sensor; M0, first visit; M2, second visit (2-month); M4, third visit (4-month); M6, fourth visit (6-month); NCT, noncontact tonometry; and SD, standard deviation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Linear Regression of Simultaneous Hourly Mean Intraocular Pressure Values Between the Eyes 1 and Eyes 2 Groups

A, At the fourth visit (6-month) (M6) using noncontact tonometry (NCT). B and C, At the first visit (M0) and third visit (4-month) (M4) using a contact lens sensor (CLS) in the eyes 1 group and NCT in the eyes 2 group in all participants. For each individual, 1 eye was randomized to the eyes 1 group and the fellow eye was included in the eyes 2 group. eqVm indicates electric arbitrary unit.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.
Bland-Altman Graphs of Intraocular Pressure Changes Agreement in the Eyes 1 Group

Changes were calculated between day 0 at 9 am and day 1 at 9 am. A, Agreement between the contact lens sensor (CLS) and noncontact tonometry (NCT). B, Agreement between CLS and Goldmann applanation tonometry (GAT). C, Agreement between NCT and GAT. For each individual, 1 eye was randomized to the eyes 1 group. 95% CI, 95% modeling confidence interval; LCB, global lower 95% confidence bound; M0, first visit; M2, second visit (2-month); M4, third visit (4-month); UCB, global upper 95% confidence bound; and Δ, change in.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Organization of the Four 24-Hour Sessions for Each Individual (9 am to 9 am)a
Table Graphic Jump LocationTable 2.  Characteristics of 24-Hour IOP Rhythms Calculated Using NCT and CLSa
Table Graphic Jump LocationTable 3.  Reproducibility of 24-Hour IOP Absolute Valuesa
Table Graphic Jump LocationTable 4.  Reproducibility of 24-Hour IOP Relative Changesa
Table Graphic Jump LocationTable 5.  Mean IOP Values Before and After 24-Hour CLS Wear and Mean 24-Hour IOP Changes in the Eyes 1 Groupa

References

Buguet  A, Py  P, Romanet  JP.  24-Hour (nyctohemeral) and sleep-related variations of intraocular pressure in healthy white individuals. Am J Ophthalmol. 1994;117(3):342-347.
PubMed
Liu  JH, Kripke  DF, Hoffman  RE,  et al.  Nocturnal elevation of intraocular pressure in young adults. Invest Ophthalmol Vis Sci. 1998;39(13):2707-2712.
PubMed
Liu  JH, Zhang  X, Kripke  DF, Weinreb  RN.  Twenty-four-hour intraocular pressure pattern associated with early glaucomatous changes. Invest Ophthalmol Vis Sci. 2003;44(4):1586-1590.
PubMed   |  Link to Article
Renard  E, Palombi  K, Gronfier  C,  et al.  Twenty-four hour (nyctohemeral) rhythm of intraocular pressure and ocular perfusion pressure in normal-tension glaucoma. Invest Ophthalmol Vis Sci. 2010;51(2):882-889.
PubMed   |  Link to Article
Leonardi  M, Leuenberger  P, Bertrand  D, Bertsch  A, Renaud  P.  First steps toward noninvasive intraocular pressure monitoring with a sensing contact lens. Invest Ophthalmol Vis Sci. 2004;45(9):3113-3117.
PubMed   |  Link to Article
Leonardi  M, Pitchon  EM, Bertsch  A, Renaud  P, Mermoud  A.  Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes. Acta Ophthalmol. 2009;87(4):433-437.
PubMed   |  Link to Article
Hjortdal  JO, Jensen  PK.  In vitro measurement of corneal strain, thickness, and curvature using digital image processing. Acta Ophthalmol Scand. 1995;73(1):5-11.
PubMed   |  Link to Article
Mansouri  K, Shaarawy  T.  Continuous intraocular pressure monitoring with a wireless ocular telemetry sensor: initial clinical experience in patients with open angle glaucoma. Br J Ophthalmol. 2011;95(5):627-629.
PubMed   |  Link to Article
Mansouri  K, Liu  JH, Weinreb  RN, Tafreshi  A, Medeiros  FA.  Analysis of continuous 24-hour intraocular pressure patterns in glaucoma. Invest Ophthalmol Vis Sci. 2012;53(13):8050-8056.
PubMed   |  Link to Article
Mansouri  K, Medeiros  FA, Tafreshi  A, Weinreb  RN.  Continuous 24-hour monitoring of intraocular pressure patterns with a contact lens sensor: safety, tolerability, and reproducibility in patients with glaucoma. Arch Ophthalmol. 2012;130(12):1534-1539.
PubMed   |  Link to Article
Pajic  B, Pajic-Eggspuchler  B, Haefliger  I.  Continuous IOP fluctuation recording in normal tension glaucoma patients. Curr Eye Res. 2011;36(12):1129-1138.
PubMed   |  Link to Article
Hubanova R, Aptel F, Zhou T, et al. Comparison of intraocular pressure measurements with the Reichert PT100, the Keeler Pulsair intelliPuff portable non-contact tonometers and Goldmann applanation tonometry. In: ARVO 2012 Annual Meeting Abstracts. Rockville, MD: Association for Research in Vision and Ophthalmology; 2012. Abstract 5063.
Brown  EN, Czeisler  CA.  The statistical analysis of circadian phase and amplitude in constant-routine core-temperature data. J Biol Rhythms. 1992;7(3):177-202.
PubMed   |  Link to Article
Gronfier  C, Wright  KP  Jr, Kronauer  RE, Czeisler  CA.  Entrainment of the human circadian pacemaker to longer-than-24-h days. Proc Natl Acad Sci U S A. 2007;104(21):9081-9086.
PubMed   |  Link to Article
Zar JH. Biostatistical Analysis. Upper Saddle River, NJ: Prentice Hall; 1999:616-627.
Shrout  PE, Fleiss  JL.  Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86(2):420-428.
PubMed   |  Link to Article
Realini  T, Weinreb  RN, Wisniewski  S.  Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals [published correction appears in Ophthalmology. 2011;118(3):434]. Ophthalmology. 2011;118(1):47-51.
PubMed   |  Link to Article
R Development Core Team: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing [computer program]. Version 2.14. Vienna, Austria: R Development Core Team; 2012. http://www.r-project.org/.
Mottet  B, Chiquet  C, Aptel  F,  et al.  24-Hour intraocular pressure of young healthy humans in supine position: rhythm and reproducibility. Invest Ophthalmol Vis Sci. 2012;53(13):8186-8191.
PubMed   |  Link to Article
Realini  T, Weinreb  RN, Wisniewski  SR.  Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals. Ophthalmology. 2010;117(9):1700-1704.
PubMed   |  Link to Article
Freiberg  FJ, Lindell  J, Thederan  LA, Leippi  S, Shen  Y, Klink  T.  Corneal thickness after overnight wear of an intraocular pressure fluctuation contact lens sensor. Acta Ophthalmol. 2012;90(7):e534-e539.
PubMed   |  Link to Article
Mansouri  K, Weinreb  RN, Liu  JH.  Effects of aging on 24-hour intraocular pressure measurements in sitting and supine body positions. Invest Ophthalmol Vis Sci. 2012;53(1):112-116.
PubMed   |  Link to Article
Realini  T, Barber  L, Burton  D.  Frequency of asymmetric intraocular pressure fluctuations among patients with and without glaucoma. Ophthalmology. 2002;109(7):1367-1371.
PubMed   |  Link to Article

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