Diurnal Intraocular Pressure and the Relationship With Swept-Source OCT–Derived Anterior Chamber Dimensions in Angle Closure: The IMPACT Study

Abstract

Purpose.: To evaluate diurnal intraocular pressure (DIOP) among individuals with primary angle closure (PAC) or primary angle-closure suspect (PACS). Additionally, the hypothesis that greater DIOP fluctuation is related to smaller angle parameters was investigated.

Methods.: Forty Caucasian newly referred untreated patients with bilateral PAC or PACS were recruited. Intraocular pressure (IOP) was measured hourly between 9 AM and 4 PM with Goldmann applanation tonometry. Diurnal IOP fluctuation was defined as difference between maximum and minimum IOP. Angle opening distance (AOD), trabecular–iris angle (TIA), angle recess area (ARA), and trabecular–iris space area (TISA) were measured with anterior segment optical coherence tomography (AS-OCT) in dark (0.3–0.5 lux) and light (170–200 lux) on the same day as DIOP measurements in eight angle sections.

Results.: Intraocular pressure declined as the day progressed (P < 0.001), unrelated to presence of peripheral anterior synechiae (PAS). At each time point, eyes with PAS (n = 31) had significantly higher IOPs than eyes without PAS (n = 49; P = 0.043). Diurnal IOP fluctuation varied from 1.50 to 14.50 mm Hg (mean 5.99 mm Hg, SD 2.70 mm Hg). Diurnal IOP fluctuation was unrelated to PAS. Multiple-predictor models investigating association of angle dimensions and greater DIOP fluctuation were statistically significant for AOD 750 (light), ARA 750 (light and dark), TISA 500 (light), TISA 750 (light), TIA 500 (light), and TIA 750 (light and dark).

Conclusions.: Diurnal IOP variation has clinical implications given that IOP level is used to distinguish between diagnostic categories of PACS and PAC. Optical coherence tomography angle parameter measurements may predict for magnitude of IOP diurnal fluctuations in at-risk patients, which may be clinically useful when a clinical intervention is being considered.

Raised IOP is an important risk factor for glaucoma, and it is the principal modifiable factor in the treatment of patients with and at risk of glaucoma. However, it is recognized that there is considerable variability of IOP during the day (diurnal fluctuation). Intraocular pressure and the presence or absence of peripheral anterior synechiae (PAS) are used by clinicians to categorize a patient into differing diagnostic categories that reflect a differing risk for glaucoma-categorized individuals as primary angle-closure suspects (PACS), where only an occludable angle is present, and primary angle closure (PAC), in which PAS and/or a raised IOP are additionally observed; this latter diagnosis is accepted as a more advanced preglaucomatous state.¹ 

Given the importance of the IOP level in this diagnostic classification, it is important to understand how representative a single IOP measurement taken in the seated position is of the seated IOP profile throughout the day. The majority of studies that have investigated such diurnal variation have been conducted in individuals with open anterior chamber angles.^2,3 Diurnal measurement of IOP, commonly termed phasing, is an important management tool in diagnosing or treating patients with diagnosed or suspected open-angle glaucoma. Peripheral anterior synechiae are areas of iridotrabecular contact. A histological study demonstrated that PAS are accompanied by adjacent damage to the trabecular meshwork.⁴ It is hypothesized that greater diurnal fluctuation would be observed in eyes with PAS than without. 

New advances in anterior segment optical coherence tomography (AS-OCT) technology have made three-dimensional (3D) swept-source OCT possible. This technology, based on the Fourier domain technique, gives the highest scanning resolution (11.6 μm axial) for the angle space currently described.⁵ This higher resolution gives a more precise identification of the position of the scleral spur, and high intraclass coefficients of repeatability and reproducibility have been reported for this device, marginally higher than that for two-dimensional AS-OCT.⁶ The substantial improvement in scan speed (30,000 A-scans per second) and the ability to image in 128 cross sections are additional advantages of the swept-source OCT, which have enabled more precise and extensive measurements of angle structure.^7,8 The relationship between the degree of narrowing of an anterior chamber angle and the fluctuation of diurnal IOP (during office hours) has received minimal scientific attention.⁹ One may hypothesize that eyes with narrower anterior chamber angles would exhibit a greater diurnal IOP variation. 

Methods

Forty Caucasian consecutive patients newly referred to a hospital glaucoma service with a gonioscopic diagnosis (less than 180° posterior pigmented trabecular meshwork visible on applanation gonioscopy) of bilateral PAC, PACS, or a combination of both conditions and no other ocular comorbidity were recruited for the Investigating Management of Angle Closure and Treatment (IMPACT) study. The initial clinical examination and gonioscopy were performed by a single consultant ophthalmic surgeon with a specialist interest in glaucoma, specifically angle-closure glaucoma (RRAB). 

Diurnal Intraocular Pressure Measurement

Following recruitment to the study, participants attended for IOP measurement every hour from 9 AM to 4 PM, a total of eight measurements (a time window of ±15 minutes around each clock hour was permitted). Measurements involved Goldmann tonometry (Goldman tonometer AT900; Haag-Streit International, Koeniz, Switzerland) using disposable prisms to reduce the risk of cross-contamination. The same tonometer was used for every IOP measurement for every participant and regular calibration checks were undertaken, with no calibration errors detected during the study. Two IOP measurements were taken per eye, with a maximum of 1 mm Hg difference permitted between these measurements. 

Image Acquisition

Three-dimensional AS-OCT (Casia device; Tomey, Nagoya, Japan) images were obtained on the same day as the IOP measurements. The scans were taken in darkness (between 0.3 and 0.5 lux) and in light conditions (between 170 and 199 lux), and the images taken were subsequently analyzed using the commercially available software with this instrument. Acquisition and analysis of images were undertaken by the same examiner (LS-P) throughout. 

Image Analysis

The analysis of AS-OCT images acquired in dark and light conditions involved calculation of the following parameters in each eye (Fig. 1): the angle opening distance (AOD), the trabecular–iris angle (TIA),¹⁰ the angle recess area (ARA),¹¹ and the trabecular–iris space area (TISA).¹² 

Figure 1

 

Iridotrabecular angle parameters as measured with the Casia AS-OCT analysis software. AOD (angle opening distance), ARA (angle recess area), TISA (trabecular–iris space area), and TIA (trabecular–iris angle) at 500 and 750 μm are highlighted in bright green.

These parameters were quantified in eight sections of the angle (superior, superior-nasal, nasal, inferior-nasal, inferior, inferior-temporal, temporal, and superior-temporal) and at 500 and 750 μm from the scleral spur (Fig. 2). 

Figure 2

 

Schematic explanation of the eight iridotrabecular angle sections under study (please note that these correspond to the right eye). The abbreviations are those corresponding to the sections and position-degree in the ocular circumference. S, superior (90°); S-N, superior-nasal (45°); N, nasal (0°); I-N, inferior-nasal (315°); I, inferior (270°); I-T, inferior-temporal (225°); T, temporal (180°); S-T, superior-temporal (135°).

Right and left eyes of 35 participants were included in the analysis. Five out of a total of 40 participants in the study were imaged with a different AS-OCT device at the beginning of the study; therefore their results were excluded for this analysis. 

Statistical Analysis

A participant's diurnal intraocular pressure (DIOP) peak was defined as the highest pressure in either eye during this time period. Using both single-predictor and multiple-predictor regression models, DIOP fluctuation was related to each angle section in both light and dark conditions. Single-predictor variables included sex, age, presence of PAS (any observable PAS as assessed with applanation gonioscopy), and extent of PAS (circumferential angle degrees over which PAS extend). 

Ethical approval by Cambridgeshire Research Ethics Committee (REC) for the IMPACT study was obtained on August 3, 2010 (REC Reference 10/H0301/14). The study was entered on the National Institute for Health Research Clinical Research Network (NIHR CRN) Portfolio on September 9, 2010 (NIHR CRN Study ID: 8955). The research adhered to the tenets of the Declaration of Helsinki. 

Results

Of the 40 participants recruited, 27 were female and 13 were male. The average age in the group was 59.6 years at the time of recruitment (range, 25–77 years). 

All were Caucasian. At the time of recruitment, 23 participants were diagnosed with bilateral PAC, 14 with bilateral PACS, and 3 with a combination of the two conditions. 

Diurnal Intraocular Pressure

The mean IOP at each time point for 80 eyes of the 40 participants is presented in Figure 3. The highest mean IOP was found to be at 9 AM (18.5 mm Hg; SD, 4.27 mm Hg; range, 12.0–30.5 mm Hg). 

Figure 3

 

Mean (and standard deviation) intraocular pressure at hourly time points (80 eyes of 40 participants).

The maximal DIOP was found to be at 9 AM for 28 participants, at 10 AM for 5 participants, at 11 AM for 4, at 1 PM for 1, at 2 PM for 3, and at 3 PM for 1 participant. 

Effect of the Presence of PAS on DIOP Measurements

A repeated-measures analysis of variance showed a statistically significant decline in IOP as the day progressed (P < 0.001), which was not related to whether or not PAS were present. There was no statistically significant interaction between presence or absence of PAS and time of measurement (P = 0.458). 

However, at each time point, eyes with PAS (n = 31) had statistically significantly higher IOPs than eyes without PAS (n = 49). An average of difference between means was found to be 1.5 mm Hg higher for those eyes with PAS (P = 0.043). This effect was not related to the time of measurement. 

Diurnal IOP and the circumference of PAS (measured in degrees) showed a statistically significant positive relationship (P < 0.05, calculated using single-predictor regression) at each time point. These models showed a similar relationship between the response variable (IOP at different times) and the predictor variable (degree of PAS), which were all statistically significant except for the measurement taken at 12 PM (P = 0.08). 

DIOP Fluctuation and the Presence of PAS

The average fluctuation in DIOP was defined as the difference between the average for the maximum value of IOP attained during the DIOP (mean maximal IOP, 20.03 mm Hg; SD 4.18) and the minimum for a given eye (mean minimal IOP, 14.04 mm Hg; SD 2.82). The mean fluctuation for this sample of eyes was found to be 5.99 mm Hg (SD 2.70), and diurnal fluctuation of IOP ranged from 1.50 to 14.50 mm Hg within the group. 

Regression models were fitted in order to investigate any relationships between the response variable DIOP fluctuation and the predictors age, sex, presence/absence of PAS, and circumferential degrees of PAS (Table 1). No relationships were found between range of fluctuation of DIOP and the single predictors age, sex, presence/absence of PAS, or circumferential degrees of PAS. This model was adjusted for sex and age to enable comparison with the results of Baskaran et al.⁹ 

Table 1

 

Single-Predictor and Multiple-Predictor Regression Models of DIOP Fluctuation With Age, Sex, Presence/Absence of PAS, and Degree of PAS Adjusted

 

Relationship Between DIOP Fluctuation and Anterior Chamber Dimensions

The higher contribution to the model was achieved by negative regression coefficients showing an inverse relationship between magnitude of IOP fluctuation and angle dimensions. In the case of the single-predictor models, almost all the coefficients were negative (97%; 124 of 128 single-predictor models; Fig. 4). The multiple-predictor models (Table 2) were statistically significant (P < 0.05) for AOD 750 (light), ARA 750 (light and dark), TISA 500 (light), TISA 750 (light), TIA 500 (light), and TIA 750 (light and dark). 

Figure 4

 

Histograms of standardized regression coefficients for 128 single-predictor regression models of DIOP fluctuation for light and dark conditions with angle parameters adjusted for the eight angle sections.

Table 2

 

Single-Predictor and Multiple-Predictor Regression Models of DIOP Fluctuation for Light and Dark Conditions With Angle Parameters Adjusted for the Eight Angle Sections

 

Discussion

The dynamic balance between aqueous production and outflow leads to IOP fluctuation in healthy and glaucomatous eyes. The pattern of IOP fluctuation can be highly variable and sensitive to the effects of body posture, hydration, and aging. Maximal IOP in this study was measured in the morning (9–11:30 AM) for the majority of participants. Wilensky² observed that 65% of normal subjects (defined as subjects with normal IOPs, normal visual acuity, healthy optic nerve heads, and no history of ocular disease) had DIOP peaks between 8 AM and 2 PM while 30% exhibited a peak IOP between 4 and 8 AM. Differing results were reported for those diagnosed as ocular hypertensive (IOP > 22 mm Hg and no signs of glaucoma), with 51% presenting their peaks between 4 and 8 AM and 42% between 8 AM and 2 PM. In the case of the present study, if an IOP-based criterion equivalent to that in the study by Wilensky² is used (22 mm Hg or less) and the presence of PAS is ignored, 28 of 40 participants (70%) had IOP ≤ 22 mm Hg in both eyes during the diurnal period. Of these 28 participants, 27 (96%) exhibited an IOP peak between 9 AM and 2 PM. Of the participants with IOP > 22 mm Hg in at least one eye (n = 12), all had a peak IOP that occurred between 9 and 11 AM. To summarize, in both this study and that of Wilensky,² diurnal peaks are more frequently found in the morning than in the late afternoon (after 2 PM), and this was unrelated to a particular IOP cutoff. 

The DIOP pattern found for this group of subjects is similar to that in a study of 21 healthy individuals in a similar age group and of mixed ethnicity (15 of 21 subjects were Caucasian) by Liu et al.³ In that study, Liu et al.³ reported a peak in the early morning of approximately 18 mm Hg and a decrease throughout the morning to levels of 17 mm Hg with a moderate increase in the middle of the day (12 PM) of approximately 0.5 mm Hg, decreasing further to levels of 17 mm Hg in the early evening (4 PM). It is therefore an interesting observation that, despite the fact that the participants in the present study had narrow angles and higher DIOP fluctuation, the DIOP behavior was similar to that reported for patients with open angles in other studies. 

Of 80 eyes of 40 patients examined at visit 1, 49 were diagnosed as PAC and 31 as PACS. From those eyes diagnosed as PAC, 17 were due to presence of PAS only; 18 were due to a raised IOP only (IOP higher than or equal to 21 mm Hg at any time between 9 AM and 4 PM); and 14 were due to a combination of PAS and IOP criteria. Of the 18 eyes diagnosed with PAC due to IOP levels only, 15 would have been diagnosed as PACS had the IOP measurements been taken in the afternoon (12:30–4 PM). This highlights the observation that the timing of a single IOP measurement by a clinician is of importance when considering which diagnosis to ascribe to a patient with angle closure. In this case, six participants might be ascribed the lower-risk PACS diagnosis had the single afternoon IOP measurement been the only measure used to reach a diagnosis. This may be of clinical importance given that the management and follow-up of patients diagnosed as PAC differ from those for individuals diagnosed as PACS. 

To date there are no published studies that report the relationship of DIOP with PAS. The present study found a statistically significant effect of the presence of PAS on DIOP. The IOP of an eye with PAS was on average 1.5 mm Hg higher than in an eye without PAS. Furthermore, the increase in IOP was found to be directly related to the degree of PAS present in an eye at the majority of the diurnal time points. 

Few studies have reported diurnal fluctuation of IOP for normal (nonglaucomatous) and glaucomatous eyes.^9,13,14 A literature search failed to identify studies investigating DIOP fluctuation among untreated individuals with angle closure in the absence of glaucoma. In a study of Chinese patients whose eyes had previously been treated with laser peripheral iridotomy with a diagnosis of PAC or primary angle closure glaucoma, Baskaran et al.⁹ reported higher levels of fluctuations in these patients (fluctuation defined as the difference between peaks and troughs of DIOP).⁹ In that study, PAC and PACG patients presented with greater diurnal fluctuation of 5.4 ± 2.4 and 4.5 ± 2.3 mm Hg, respectively (IOP measured every hour from 8:30 AM to 4:30 PM), compared to those with PACS and normal subjects with open angles, 3.7 ± 1.2 and 3.8 ± 1.1 mm Hg, respectively. The same study reported a relationship between the diurnal fluctuation of IOP in the same eye and the degree of PAS of these patients. These findings differ from those in our study, in which fluctuation of DIOP was not related to age, sex, or PAS. In the case of the present study, the lack of a relationship is not unexpected given that the DIOP patterns of those eyes with presence of PAS and those eyes without were very similar (Fig. 5). Although there may have been differences between the peaks and troughs between patterns, the fluctuation obtained would have been similar. In the study by Baskaran et al.,⁹ the data showed a high degree of variation and, although the relationship was reported as statistically significant (P = 0.013), the relationship was weak (R², 0.139). 

Figure 5

 

Mean (and standard deviation) intraocular pressure at hourly time points in eyes with PAS (n = 31) and without PAS (n = 49).

DIOP Fluctuation and Anterior Chamber Dimensions

The results for DIOP fluctuation suggested that an eye with smaller angle dimensions would exhibit a greater range of IOP (difference between peak and trough) during the day. Furthermore, the multiple-predictor statistical models were able to predict this fluctuation from OCT measurements of anterior chamber angle parameters. This is a novel finding. Were this to be confirmed with a larger sample size, it is possible that OCT angle parameter measurements could be used to predict IOP diurnal fluctuations in at-risk patients, allowing clinicians to selectively offer laser treatment to those in whom a higher DIOP range would be judged as high-risk. 

No allowance in our analysis was made for the correlations between eyes of the same individual, which is the case with many similar studies in this field; some may consider this a limitation of this study. 

The enhanced scan speed, clarity of visualization of the scleral spur, and ability to take measurements of more than 100 cross sections of the anterior chamber angle that are possible with swept-source OCT lend advantage to using this technology as compared to conventional AS-OCT. 

Conclusions

Clinicians should be aware of changes in IOP that occur throughout the day in patients with occludable anterior chamber angles and should be aware that higher IOP levels during the day are related to the circumferential extent of PAS compared to normals. In clinical centers where laser peripheral iridotomy is applied only to those individuals with a more advanced preglaucomatous stage (PAC), the present findings would support measuring IOP in the early morning to establish the maximal IOP. 

Acknowledgments

The authors thank the staff of the Department of Ophthalmology at Hinchingbrooke Hospital, Huntingdon, United Kingdom, who hosted the study, in particular Paula Turnbull, Heather Pearman, and Jane Kean, who provided administrative and clinical support for the study. Sancy Low is also thanked for her participation in discussions on anterior chamber angle image analysis. 

The corresponding author (RRAB) confirms that he had full access to all the data in the study and had final responsibility for the decision to submit for publication. 

Supported by an Anglia Ruskin University student grant and a research grant from Allergan Ltd. Tomey Corporation (Nagoya, Japan) lent the instrument for the purposes of the study. 

Disclosure: L. Sanchez-Parra, None; S. Pardhan, None; R.J. Buckley, None; M. Parker, None; R.R.A. Bourne, Allergan Ltd. (F), Tomey Corporation (F)