Journal of Ocular Pharmacology and Therapeutics 2014.30:12-20. Downloaded from online.liebertpub.com by Ucsf Library University of California San Francisco on 12/25/14. For personal use only.
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 1, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2013.0121
Effects of Several Anti-Glaucoma Medications on the Circadian Intraocular Pressure Fluctuations in Patients with Primary Open-Angle Glaucoma Sachie Tanaka, Megumi Watanabe, Shu-ichiro Inatomi, Kazushi Umeda, Kaori Yoshida, Ikuyo Ohguro, and Hiroshi Ohguro
Abstract Purpose: The purpose of the present study was to elucidate the effects of several anti-glaucoma medications on the circadian intraocular pressure (IOP) fluctuations in patients with primary open-angle glaucoma (POAG). Patients and Methods: POAG patients (n = 61; 61 eyes) with or without glaucoma medications were included. IOP measurement at 14 time points (12, 15, 18, 21, 0, 6, 9, 12, 15, 18, 21, 0, 6, and 9 o’clock) was performed over a period of 48 h. IOP changes occurring in the first 24 h and the subsequent 24 h were evaluated by several therapeutic factors. Results: A nocturnal acrophase pattern was observed in all the eyes with POAG. The shape of the first 24 h IOP curve was similar to that of the following 24 h IOP curves. However, there were fewer overall IOP levels in the second 24 h time period. Circadian IOP fluctuation patterns exhibited in each eye on the 1st and 2nd days were single acrophase patterns: diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%) and nocturnal acrophase (1st day, 36.1%; 2nd day, 31.1%), and no single acrophase patterns: flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Among the different medication groups, a nocturnal acrophase circadian pattern was observed in the patient groups being treated by combinations of prostaglandin analog (PG) and b blocker or PG, b blocker and carbonic anhydrase inhibitor (CAI). However, this was not apparent in patient groups with or without single anti-glaucoma medications or a combination of PG and CAI. Conclusions: The present study of IOP monitoring patients with POAG over a period of 48 h indicated that their changes in circadian patterns of IOP were affected by types of anti-glaucoma medications.
that large circadian fluctuations of IOP may be a risk factor for progression of glaucoma.8–10 In terms of variations of IOP profiles, many studies have reported on the diurnal and/or nocturnal variability of IOP in healthy subjects as well as in patients with primary open-angle glaucoma (POAG).8–10 Several of these reports have indicated that diurnal IOP profile patterns were not repeatable from day to day in healthy individuals11 or POAG patients.12 In addition, even in all subjects, circadian IOP variation is known to be different between both eyes.13,14 As such, a single-day assessment of the IOP circadian profile may be insufficient in order to characterize the circadian IOP variations, and an evaluation of the circadian IOP change in 1 eye as a control for the other may also be unreliable.14 In addition, underlying factors that affect the circadian IOP profile, such as types of anti-glaucoma medication, remain ambiguous.
Introduction
G
laucomatous optic neuropathy (GON) is known worldwide to be a major factor leading to irreversible blindness.1 Regarding the treatment of GON, several randomized control trials2–4 have disclosed that intraocular pressure (IOP) at adequate low levels by medication or surgical intervention is effective. IOP is, therefore, the most critical risk factor for the development and progression of glaucoma. Several previous studies have revealed that IOP shows marked diurnal and nocturnal variability.5–7 This circadian variability in IOP may be important both clinically and pathologically. From a diagnostic point of view, a single IOP measurement may mislead the maximal IOP and, thus, cause mistaken assumptions regarding the suitable IOP control. From a pathological point of view, it is suggested
Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo, Japan.
12
48 H IOP CHANGES IN GLAUCOMA PATIENTS
13
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Therefore, in the present report, to elucidate circadian IOP patterns and their inter-day variations in patients with POAG, a 48 h IOP profile in eyes with POAG was evaluated and its relationship with the several glaucoma clinical factors noted earlier was studied.
Methods This study was a prospective analysis of the 48 h IOP profile in subjects with POAG. It was conducted at the Eye Clinic of Sapporo Medical University Hospital, Japan, after approval by the local ethics committee and according to the tenets of the Declaration of Helsinki and national laws for the protection of personal data. Informed consent was obtained from all participants in the study.
Subjects All subjects underwent a complete ophthalmological examination before inclusion, including medical history, best-corrected visual acuity, slit-lamp biomicroscopy, central corneal thickness (CCT) measurements, Goldmann applanation tonometry, gonioscopy, standard automated perimetry using the Humphrey Field Analyzer II and the SITA-standard 30-2 algorithm, and a dilated fundus examination. A clinical diagnosis of the patients with POAG was assessed based on the following diagnostic criteria: (1) a history of IOP more than 21 mmHg; (2) glaucomatous visual field defects corresponding with the glaucomatous optic disc changes; (3) gonioscopically normal open angles; (4) no history or findings of pseudo-exfoliation or secondary glaucoma; and (5) no other ocular, neurological, otolaryngological, or systemic diseases affecting optic disc damage. Subjects were enrolled between April 1, 2011 and March 31, 2013. Participants were aged 20 years or older. All subjects were free from corneal pathology that might limit the accuracy of tonometry readings. In the group of patients with medical treatments, subjects who were administered on stable regimen at least 6 months before the study were included, and the medication regimens were continued during the study.
48 h IOP evaluation A measurement of circadian IOP patterns was repeated for 2 days. To record circadian IOP patterns, patients were hospitalized in the morning (at *10 o’clock) and remained there for the next 48 h. The awake period lasted from *6 to 21 o’clock. IOP was measured at 14 time points: 12, 15, 18, 21, 0, 6, 9, 12, 15, 18, 21, 0, 6, and 9 o’clock. For the daytime measurements (6–21 o’clock), patients were asked to relax for *15 min while in a sitting position, after which sitting IOP was measured in both eyes. During the night, to prevent a sudden change in IOP, the patients were awakened *10 min in a sitting position before relaxation time in prior for sitting IOP measurement. The IOP measurements were made with a non-contact automated pneumotonometer (Topcon Corporation model CT80, Tokyo, Japan). All measurements were taken at each time point by well-trained ophthalmologists. The value was the mean results of 3 to 6 consecutive measurements until the inter-measurement variability was less than 5%. Data of right eyes were used for analysis of the present study.
FIG. 1. Representative intraocular pressure (IOP) circadian fluctuation patterns: single acrophase patterns (diurnal acrophase and nocturnal acrophase) and no single acrophase patterns (flat and double acrophase). IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of primary open-angle glaucoma (POAG) patients during 24 h were plotted. Dotted curves demonstrate a polynomial regression of the IOP data against time. Dotted straight lines indicate mesor. Based on the position of the single acrophase, diurnal acrophase (peak IOP between 6 and 21 o’clock) and nocturnal acrophase (peak IOP between 21 and 6 o’clock) patterns were determined. Other IOP fluctuation curves were categorized as no single acrophase patterns, subdivided into a flat pattern and double acrophase pattern as described in the ‘‘Methods’’ section. Positions of IOP peak and bottom are indicated byYand[, respectively.
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SACHIE ET AL.
Journal of Ocular Pharmacology and Therapeutics 2014.30:12-20. Downloaded from online.liebertpub.com by Ucsf Library University of California San Francisco on 12/25/14. For personal use only.
Statistical analysis and analysis of 24 h IOP fluctuation rhythms An evaluation of similarity between the first and second 24 h IOP fluctuation was assessed by using an interclass correlation coefficient (ICC) of each time point. An ICC > 0.90 indicated high similarity, 0.75–0.90 equated to good similarity, 0.50–0.75 displayed intermediate similarity, and < 0.50 suggested poor similarity. Two-way repeated measures analysis of variance (ANOVA) (first 24 h/second 24 h cycle · time) was used to assess differences in IOP between the first and second 24 h IOP measurements, and an intergroup comparison of IOP was performed by the Dunnett multiple-comparison test. Several data, including age, bestcorrected visual acuity, refractive errors, CCT, and IOP, were compared through unpaired t-test between the non-treated and medicated POAG groups. For analysis of 24 h IOP fluctuation rhythms, a polynomial regression of the IOP data against time was used to generate mathematical models representing the circadian IOP fluctuation patterns. Based on this analysis, the presence and timing of the IOP acrophase were determined, and IOP fluctuation patterns were categorized into (1) single acrophase patterns, which were subdivided into a diurnal acrophase pattern (peak between 6 and 21 o’clock) and a nocturnal acrophase pattern (peak from 21 to 6 o’clock), and (2) no single acrophase patterns, which were subdivided into a flat pattern (no significant acrophase with IOP fluctuation levels of less than 2 mmHg during 24 h) and a double IOP acrophase pattern. An acrophase was defined as a situation in which the IOP peak and bottom fluctuation levels differed by 2 mmHg or more (Fig. 1). All statistical analyses were calculated with commercial software (SPSS, ver. 15.0; SPSS, Inc., Chicago, IL).
Results In the present study, we conducted a prospective analysis of 48 h IOP profiles of 61 eyes of 61 POAG patients with or without glaucoma medications (Tables 1 and 2). To study the effects of glaucoma medications on circadian IOP fluctuation, we compared the 48 h IOP profiles of several treatment groups of POAG patients. As shown in Table 2 and Figure 2, ICC showed a quite similar circadian IOP fluctuation between the first and second 24 h, but IOP levels of all time points were overall less in the second 24 h than the first 24 h in the total population of POAG, non-treated POAG, and medically treated POAG patient groups (2-way repeatedmeasures ANOVA, P < 0.05). Regarding IOP fluctuation patterns, a polynomial regression analysis and the Dunnett multiple-comparison test showed a nocturnal acrophase pattern in the total and medicated patients’ groups, although the non-treated patients group did not show such an apparent IOP circadian pattern (Fig. 2). With regard to circadian IOP fluctuation patterns of each patient, IOP fluctuation patterns (Table 3) exhibited during the 1st and 2nd days were single acrophase patterns; diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%), nocturnal acrophase (1st day, 36.1%; 2nd day, 31.1%), and no single acrophase patterns; flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Between the 1st and 2nd day, 67.1% of the population showed the same IOP fluctuation patterns. Regarding the circadian IOP fluctuation profile in each patient, the number of patients with a nocturnal acrophase-shaped pattern increased in patient groups with medication as compared with the non-treated patient group (Tables 4 and 5). These observations indicated that glaucoma medications may possibly affect circadian IOP fluctuation patterns. To further study this possibility, we
Table 1. Characteristics of the Primary Open-Angle Glaucoma Patients’ Groups
Gender (male/female) Age (years) BCVA Refractive errors (D) CCT (mm) Mean deviation (dB) IOP (mmHg)d IOP (mmHg)e No. of glaucoma medications One anti-glaucoma drop PG Other Two anti-glaucoma drops PG + b PG + CAI Others Three anti-glaucoma drops PG + b + CAI Four anti-glaucoma drops a
No medications (n = 18)
Medications (n = 43)
7/11 66.7 – 12.5b (60.9 to 72.5c) 0.89 – 0.44 (0.69 to 1.09) - 2.58 – 3.63 ( - 4.25 to - 0.90) 570.9 – 30.0 (557.0 to 584.8) - 5.90 – 7.70 ( - 9.46 to - 2.35) 16.2 – 2.6 (15.0 to 17.4) 15.6 – 2.4 (14.5 to 16.7) 0
20/23 66.4 – 11.6 (62.9 to 69.8) 0.98 – 0.31 (0.88 to 1.07) - 3.16 – 3.15 ( - 4.10 to - 2.22) 537.7 – 45.9 (524.0 to 551.5) - 9.06 – 8.44 ( - 11.58 to - 6.54) 15.5 – 3.4 (14.5 to 16.5) 14.8 – 3.1 (13.9 to 15.7) 2.16 – 0.95 (1.88 to 2.45) Total 13 12 1 Total 11 7 3 1 Total 16 16 Total 3
P-valuea 0.92 0.45 0.13 0.023 0.18 0.027 0.039
P-values for difference between treatment groups of POAG were calculated by unpaired t-test. Mean – SD (all such values). c Ninety-five percent confidence interval in parentheses (all such values). d Initial 24 h. e Following 24 h. BCVA, best-corrected visual acuity; CCT, central cornea thickness; PG, prostaglandin analog; b, b blocker; CAI, carbonic anhydrase inhibitor; IOP, intraocular pressure; POAG, primary open-angle glaucoma. b
15
a
15
18
21
9 15.7 – 3.2 (15.0–16.4) 0.92 (0.87–0.95) 16.2 – 2.6 (15.0–17.4) 0.87 (0.70–0.95) 15.5 – 3.4 (14.5–16.5) 0.95 (0.88–0.96) 16.1 – 3.5 (14.2–18.0) 0.94 (0.81–0.98) 13.4 – 2.5 (11.9–14.8) 0.96 (0.86–0.99) 15.9 – 3.4 (14.2–17.6) 0.95 (0.81–0.97) 15.8 – 3.4 (13.9–17.7) 0.97 (0.90–0.99) 12.8 – 1.6 (11.6–14.0) 0.98 (0.87–0.99) 15.5 – 3.4 (11.9–19.4) 0.97 (0.21–0.99) 15.9 – 3.4 (14.2–17.6) 0.93 (0.81–0.97)
MESOR
15
18
21
0
6
9
MESOR
13.0 – 3.0 15.7 – 4.5 15.7 – 5.5 15.7 – 3.5 15.0 – 4.4 14.3 – 4.17 14.7 – 4.0 (9.6–16.4) (10.6–20.8) (9.4–21.9) (11.7–19.6) (10.1–19.9) (9.0–19.7) (10.2–19.2) 14.3 – 3.1 15.3 – 4.0 15.8 – 2.5 15.5 – 3.9 17.7 – 4.6 16.3 – 3.7 14.7 – 3.4 15.6 – 3.2 (12.7–15.8) (13.3–17.2) (14.6–17.1) (13.6–17.4) (15.4–20.0) (14.5–18.1) (13.0–16.4) (14.1–17.2)
13.7 – 4.0 (9.1–18.2)
12.7 – 1.3 12.6 – 1.8 12.9 – 1.6 11.9 – 1.7 13.0 – 3.4 11.7 – 2.8 11.4 – 1.63 12.3 – 1.6 (11.8–13.6) (11.2–13.9) (11.7–14.0) (10.6–13.1) (10.5–15.5) (9.6–13.8) (10.5–12.4) (11.1–13.5)
15.3 – 3.6 15.0 – 3.0 14.4 – 3.7 14.3 – 3.3 15.4 – 4.2 14.8 – 3.1 15.4 – 3.2 14.9 – 3.2 (13.2–17.3) (13.3–16.7) (12.3–16.5) (12.4–16.1) (13.0–17.8) (13.0–16.5) (13.6–17.2) (13.1–16.7)
14.3 – 3.1 15.3 – 4.0 15.8 – 2.5 15.5 – 3.9 17.7 – 4.6 16.3 – 3.7 14.7 – 3.4 15.6 – 3.2 (12.7–15.8) (13.3–17.2) (14.6–17.1) (13.6–17.4) (15.4–20.0) (14.5–18.1) (13.0–16.4) (14.1–17.2)
12.8 – 2.2 12.4 – 2.2 13.4 – 2.9 13.1 – 3.3 13.8 – 3.3 12.7 – 3.3 12.2 – 2.7 12.9 – 2.5 (11.5–14.1) (11.0–13.7) (11.6–15.1) (11.1–15.0) (11.9–15.8) (10.8–14.7) (10.6–13.8) (11.4–14.4)
15.1 – 3.5 15.2 – 2.9 14.6 – 3.6 14.4 – 3.2 15.4 – 4.1 14.8 – 3.0 15.6 – 3.1 15.0 – 3.1 (13.2–17.0) (13.6–16.8) (12.6–16.6) (12.6–16.1) (13.2–17.6) (13.2–16.4) (13.9–17.3) (13.3–16.7)
14.2 – 3.0 14.6 – 3.4 14.9 – 3.0 14.6 – 3.5 16.2 – 4.4 14.8 – 3.1 14.3 – 3.3 15.0 – 3.5 (13.3–15.1) (13.6–15.6) (14.0–15.8) (13.6–15.7) (14.9–17.5) (13.9–15.7) (13.3–15.3) (13.9–16.0)
15.6 – 2.8 15.6 – 3.2 16.4 – 1.8 14.8 – 2.8 15.2 – 3.4 15.9 – 3.2 15.8 – 3.4 15.6 – 2.4 (14.3–16.9) (14.1–17.0) (15.6–17.2) (13.5–16.1) (13.6–16.7) (14.5–17.4) (14.2–17.3) (14.5–16.7)
14.6 – 3.0 14.9 – 3.3 15.3 – 2.8 14.7 – 3.3 15.9 – 4.1 15.2 – 3.4 14.8 – 3.4 15.1 – 2.9 (14.0–15.3) (14.2–15.6) (14.7–15.9) (14.0–15.4) (15.0–16.8) (14.5–16.0) (14.0–15.5) (14.4–15.7)
12
Following 24 h (o’clock)
c
b
Mean – SD (all such values). Ninety-five percent confidence interval in parentheses (all such values). ICC of IOP at each time point between first and second 24 h (all such values). d Ninety-five percent confidence interval in parentheses (all such values). No med, no medications; med, glaucoma medication; one drop, one anti-glaucoma drop; two drops, two anti-glaucoma drops; three drops, three anti-glaucoma drops; ICC, interclass correlation coefficient; MESOR, midline estimating statistic of rhythm.
a
6
16.5 – 4.4 15.8 – 3.7 14.9 – 3.3 (15.6–17.5) (15.0–16.6) (14.2–15.7) 0.75 0.72 0.80 (0.62–0.84) (0.57–0.82) (0.69–0.88) 15.7 – 2.8 16.1 – 2.6 15.8 – 2.7 (14.4–17.0) (14.9–17.3) (14.5–17.0) 0.70 0.55 0.74 (0.35–0.87) (0.13–0.81) (0.43–0.89) 16.9 – 4.9 15.7 – 4.2 14.6 – 3.5 (15.4–18.3) (14.4–16.9) (13.5–15.6) 0.76 0.76 0.82 (0.60–0.86) (0.59–0.86) (0.68–0.90) 16.2 – 4.8 15.8 – 4.9 15.3 – 3.5 (13.6–18.7) (13.2–18.5) (13.4–17.2) 0.73 0.70 0.90 (0.33–0.91) (0.27–0.90) (0.70–0.97) 14.5 – 3.1 13.1 – 3.0 12.6 – 3.1 (12.7–16.4) (11.3–14.9) (10.8–14.5) 0.93 0.74 0.91 0 (0.76–0.98) (0.28–0.92) (0.72–0.98) 18.4 – 5.6 16.9 – 3.9 14.9 – 3.1 (15.6–21.1) (15.0–18.8) (13.4–16.4) 0.65 0.71 0.73 (0.25–0.86) (0.35–0.89) (0.38–0.90) 16.0 – 4.9 15.1 – 4.2 15.2 – 3.6 (13.2–18.8) (12.7–17.5) (13.1–17.2) 0.74 0.90 0.90 (0.33–0.92) (0.67–0.97) (0.68–0.97) 13.7 – 2.9 12.9 – 3.4 11.4 – 1.8 (11.5–15.9) (10.3–15.4) (10.1–12.8) 0.92 0.82 0.86 (0.61–0.99) (0.27–0.97) (0.40–0.98) 17.0 – 3.0 14.3 – 2.5 16.0 – 4.0 (13.6–20.4) (11.5–17.2) (11.5–20.5) 0.98 0.63 0.94 (0.53–0.99) ( - 0.80–0.99) ( - 0.10–0.99) 18.4 – 5.6 16.9 – 3.9 14.9 – 3.1 (15.6–21.1) (15.0–18.8) (13.4–16.4) 0.65 0.71 0.73 (0.25–0.86) (0.35–0.89) (0.38–0.90)
0
Initial 24 h (o’clock)
Intraocular Pressure Values During 48 h IOP Measurements of Open-Angle Glaucoma Patients
15.8 – 3.7 15.4 – 3.3 15.9 – 3.5 15.6 – 3.7 (15.1–16.7) (14.8–16.4) (15.0–16.7)b (14.7–16.1) c ICC 0.83 0.81 0.66 0.74 (0.49–0.78) (0.60–0.83) (0.74–0.90)d (0.71–0.88) No med 16.9 – 3.8 16.2 – 3.6 16.9 – 2.9 16.1 – 3.5 (n = 18) (15.2–18.7) (14.6–17.9) (15.6–18.2) (14.4–17.7) ICC 0.82 0.77 0.24 0.67 (0.59–0.93) (0.48–0.91) ( - 0.23–0.63) (0.31–0.86) Med 15.4 – 3.7 15.0 – 3.1 15.5 – 3.6 15.4 – 3.7 (n = 43) (14.3–16.5) (14.1–16.0) (14.4–16.6) (14.3–16.5) ICC 0.83 0.83 0.73 0.76 (0.71–0.90) (0.70–0.90) (0.55–0.84) (0.60–0.86) One drop 16.9 – 3.5 16.2 – 3.2 16.4 – 3.6 16.0 – 3.4 (n = 13) (15.0–18.8) (14.5–18.0) (14.4–18.4) (14.1–17.9) ICC 0.77 0.94 0.78 0.85 (0.41–0.779) (0.81–0.98) (0.43–0.93) (0.58–0.95) Two drops 13.4 – 3.0 13.0 – 2.3 13.5 – 2.6 13.4 – 2.5 (n = 11) (11.6–15.2) (11.6–14.4) (12.0–15.1) (11.9–14.8) ICC 0.87 0.73 0.88 0.56 (0.58–0.96) (0.26–0.92) (0.63–0.97) ( - 0.02–0.86) Three drops 14.9 – 3.5 14.9 – 3.0 15.4 – 3.9 15.8 – 4.2 (n = 16) (13.2–16.6) (13.5–16.4) (13.5–17.3) (13.7–17.8) ICC 0.95 0.76 0.64 0.79 (0.87–0.98) (0.45–0.91) (0.22–0.86) (0.49–0.92) PG 16.8 – 3.6 16.0 – 3.2 15.9 – 3.3 15.7 – 3.3 (n = 12) (14.8–18.9) (14.2–17.8) (14.0–17.8) (13.8–17.6) ICC 0.81 0.93 0.79 0.0.86 (0.45–0.94) (0.79–0.98) (0.43–0.94) (0.60–0.96) PG + b 13.0 – 1.4 12.9 – 1.8 13.0 – 0.6 12.9 – 1.9 (n = 7) (12.0–14.0) (11.5–14.2) (12.6–13.4) (11.5–14.2) ICC 0.84 0.39 0.36 00.73 (0.33–0.97) ( - 0.43–0.86) ( - 0.47–0.85) (0.59–0.95) PG + CAI 15.7 – 4.7 14.3 – 3.2 15.7 – 4.7 15.7 – 2.3 (n = 3) (10.3–21.0) (10.7–18.0) (10.3–21.0) (13.1–18.3) ICC 0.97 0.93 0.93 0.41 (0.32–0.99) ( - 0.13–0.99) ( - 0.17–0.99) ( - 0.88–0.98) PG + b + CAI 14.9 – 3.5 14.9 – 3.0 15.4 – 3.9 15.8 – 4.12 (n = 16) (13.2–16.6) (13.5–16.4) (13.5–17.3) (13.7–17.8) ICC 0.98 0.76 0.63 0.79 (0.87–0.98) (0.45–0.91) (0.22–0.86) (0.49–0.92)
All (n = 61)
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Table 2.
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16
SACHIE ET AL. ANOVA, P < 0.05); whereas in the other medication groups, these levels were similar on both days (2-way repeatedmeasures ANOVA, P > 0.05). Analysis of several combinations of the anti-glaucoma medications showed the nocturnal acrophase in a double medication of prostaglandin analog (PG) and b blocker and triple medication of PG, b blocker, and carbonic anhydrase inhibitor (CAI) (Dunnett multiplecomparison test, P < 0.05) (Fig. 4). In contrast, a single medication of PG or a double medication of PG and CAI did not show a specific acrophase or acrophase pattern (Fig. 4).
Discussion
FIG. 2. Average circadian IOP fluctuation of total POAG patients, non-treated POAG patients, and medicated treated POAG patients. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Numbers of patients and eyes were as follows: all POAG (61 patients, 61 eyes), non-treated POAG (18 patients, 18 eyes), and medicated POAG (43 patients, 43 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. * Indicates P < 0.05 (Dunnett multiple-comparison test).
compared the 48 h IOP fluctuation profiles among subdivided groups in POAG patient groups receiving antiglaucoma medication. As shown in Figure 3, no evident IOP acrophase was detected in the groups of patients receiving 1 anti-glaucoma medication, while nocturnal acrophase circadian patterns became evident in patient groups treated with 2 or 3 anti-glaucoma medications (Dunnett multiplecomparison test, P < 0.05). In the single medication group, general IOP levels on the 2nd day decreased in comparison with those seen on the 1st day (2-way repeated-measures
Romanet et al.10 have reported that during the circadian fluctuation, IOP levels are higher at night than during the day, with a nocturnal acrophase present in healthy subjects. In contrast, Wang et al. have reported that IOP values are higher during the day, with a diurnal acrophase, than during the night in most glaucoma patients.15 Magacho et al.16 have described how diurnal IOP fluctuations were closely similar when IOP was measured on different days, and that there was no difference in the diurnal IOP curve on different days. Accordingly, the difference between the time course of the circadian IOP curve of IOP is considered to play an important role in the prognosis of glaucoma. This information is pertinent in that it provides insights regarding manners of treatment for POAG patients. However, several other studies have demonstrated that the circadian IOP curve in patients with glaucoma is more complicated than this. Among these studies, Renard et al.9 reported on 2 major IOP fluctuation patterns in 22 NTG subjects: diurnal acrophase (54.5%) and nocturnal acrophase (36.4%). Similarly, in Mosaed et al.,17 there was a significantly greater number of eyes with diurnal acrophase (n = 12, 54.5%) than with nocturnal acrophase (n = 8, 36.4%). In contrast, Lee et al.8 described 3 major IOP fluctuation patterns among 177 patients with POAG: diurnal acrophase (15.8%), nocturnal acrophase (51.4%), and no acrophase (32.8%). Our present study, using 61 eyes of 61 patients with POAG, revealed that diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%) or nocturnal acrophase patterns (1st day, 36.1%; 2nd day, 31.14%) were much higher than the no single acrophase patterns; flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Inconsistencies in results between our study and others may be due to the differences in study populations, number of enrolled subjects, study designs including method for IOP measurements, subjects’ posture (sitting or supine), and clinical factors affecting IOP levels, such as glaucoma medications and general conditions. Our present study also revealed that only 67.1% of population showed the same IOP fluctuation patterns between the 1st and 2nd day. Such variability of the circadian IOP fluctuation may be due to the following considerations mentioned in other studies: (1) Diurnal IOP fluctuations are not repeatable in short periods in healthy subjects11 or in individuals with glaucoma12; (2) IOP in pre-medicated patients with glaucoma or ocular hypertension is significantly variable from day to day.18 With regard to study design of IOP measurement, several previous studies about IOP rhythm used a 1 or 2 h time lag. However, in contrast, we measured IOP every 3 h except at 3 o’clock during 24 h. In terms of effects of subjects’ posture (sitting or supine) on circadian IOP fluctuation, Mansouri et al. described that sitting and supine IOP fluctuation
48 H IOP CHANGES IN GLAUCOMA PATIENTS Table 3.
17
Comparison of Intraocular Pressure Fluctuation Patterns of Total Population of Primary Open-Angle Glaucoma Patients (n = 61, 61 Eyes) Between Initial 24 h and the Next 24 h Initial 24 h
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Single acrophase Following 24 h Single acrophase Diurnal acrophase 37 (60.7%)b Nocturnal acrophase 19 (31.1%)b No single acrophase Flat pattern 3 (4.9%)b Double acrophase 2 (3.3%)b
No single acrophase
Diurnal acrophase 33 (54.0%)a
Nocturnal acrophase 22 (36.1%)a
Flat pattern 4 (6.6%)a
Double acrophase 2 (3.3%)a
27 (44.2%)c 5 (8.2%)
6 (16.4%) 13 (21.3%)
3 (4.9%) 1 (1.6%)
1 (1.6%) 0 (0%)
1 (1.6%) 0 (0%)
2 (3.3%) 1 (1.6%)
0 (0%) 0 (0%)
0 (0%) 1 (1.6%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
Table 4.
Comparison of Intraocular Pressure Fluctuation Patterns of Non-treated Primary Open-Angle Glaucoma Patients (n = 18; 18 Eyes) Between Initial 24 h and the Next 24 h Initial 24 h Single acrophase
Following 24 h Single acrophase Diurnal acrophase 15 (83.3%)b Nocturnal acrophase 1 (5.5%)b No single acrophase Flat pattern 1 (5.5%)b Double acrophase 1 (5.5%)b
No single acrophase
Diurnal acrophase 11 (61.1%)a
Nocturnal acrophase 2 (11.1%)a
Flat pattern 3 (16.6%)a
Double acrophase 2 (11.1%)a
10 (55.5%)c 0 (0%)
1 (5.5%) 1 (5.5%)
3 (16.6%) 0 (0%)
1 (5.5%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 1 (5.5%)
1 (5.5%) 0 (0%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
Table 5. Comparison of Intraocular Pressure Fluctuation Patterns of Primary Open-Angle Glaucoma Patients Treated by Anti-glaucoma Medication (n = 43; 43 eyes) Between Initial 24 h and the Next 24 h Initial 24 h Single acrophase Following 24 h Single acrophase Diurnal acrophase 22 (51.5%)b Nocturnal acrophase 18 (41.9%)b No single acrophase Flat pattern 2 (4.7%)b Double acrophase 1 (2.3%)b
No single acrophase
Diurnal acrophase 22 (51.1%)a
Nocturnal acrophase 20 (46.5%)a
Flat pattern 1 (2.3%)a
Double acrophase 0 (0%)a
17 (39.5%)c 5 (11.6%)
5 (11.6%) 12 (27.9%)
0 (0%) 1 (2.3%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
2 (4.7%) 1 (2.3%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
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FIG. 3. Average circadian IOP fluctuation of several antiglaucoma medicated POAG patients. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Treatment for patients was as follows: single antiglaucoma drop (13 patients, 13 eyes), double anti-glaucoma drops (11 patients, 11 eyes), and triple anti-glaucoma drops (16 patients, 16 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. *Indicates P < 0.05 (Dunnett multiple-comparison test).
patterns of 24 h were similar and parallel, but these levels were quite different.19 In the present study, to exclude these effects, *15 or 25 min while in a sitting position during daytime or night were required before sitting IOP measurements as described in the ‘‘Methods’’ section. This preconditioning procedure between IOP measurements in every 1 or 2 h time lag may have affected the data. In addition, the local ethics committee at our University did not grant approval to measure IOP between 0 and 6 o’clock because of concerns that disturbance of the patients’ sleep could significantly affect the regular life style balance, including IOP fluctuation patterns, on the 2nd day. It was due to these
FIG. 4. Average circadian IOP fluctuation of POAG patients medically treated with several anti-glaucoma drops. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Treatment for patients was as follows: prostaglandin analog (PG) (12 patients, 12 eyes), PG + b blocker (7 patients, 7 eyes), and PG + carbonic anhydrase inhibitor (CAI) (3 patients, 3 eyes), or PG + b blocker + CAI (16 patients, 16 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. *Indicates P < 0.05 (Dunnett multiple-comparison test).
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48 H IOP CHANGES IN GLAUCOMA PATIENTS considerations that we decided to perform IOP measurements every 3 h except 0 through 6 o’clock. In the present study, we found that 24 h circadian IOP patterns may be affected by anti-glaucoma medications based on the following observations: (1) the nocturnal acrophase-like pattern during the 24 h IOP profile was recognized in total POAG patients; (2) the patients in the POAG group treated with anti-glaucoma medications showed the more apparent nocturnal acrophase pattern, while no significant acrophase was observed in the group of pre-medicated POAG patients; and (3) the nocturnal acrophase-like pattern became apparent in the combination of PG and b blocker, or PG, b blocker, and CAI, while it was not as significant in the groups of patients treated with single anti-glaucoma medications and the combination of PG and CAI. Therefore, we speculated that the combinations of PG and b blocker may facilitate the nocturnal acrophase during the 24 h circadian IOP fluctuation, and this effect may be further facilitated by continued additions of CAI. Timolol (TM), a major anti-glaucoma drop of b blocker, lowers the IOP by reducing the aqueous humor flow, but has no effect on outflow resistance or on episcleral venous pressure.20 Since the sympathetic nervous system is known to be activated during daytime, it follows that TM could mostly be effective toward daytime IOP reduction. In fact, several investigators have reported that TM induced a greater reduction in IOP during the day (8–20 o’clock) and a less, albeit still significant, reduction during the night.21,22 Consequently, to get the most effective IOP reduction from TM, it is recommended that its once-daily administration take place in the morning (Timoptic XE; Merck, West Point, PA).22 Similar to TM, CAIs such as dorzolamide or brinzolamide also inhibit aqueous humor formation with no effect on aqueous outflow during the diurnal period.23–25 With regard to PGs such as latanoprost, numerous studies have shown that they facilitate uveoscleral outflow by activating extracellular matrix degradation through metalloproteinase, inducing a great reduction of IOP.26 Latanoprost given once in the evening lowers the IOP throughout the 24 h day.26 Such IOP reduction is also obtained by other PGs such as travoprost, bimatoprost,27 and tafluprost.28 Therefore, as our standard anti-glaucoma medication, PG is used as a first choice, and then b blocker or CAI is added in case further IOP reduction is required.29 In cases of the combination of PG and then b blocker, it may be hypothesized that b blocker further reduces diurnal IOP levels in addition to reduced 24 h IOP levels by PG, while the additional activity of the b blocker during the night is due to the inability of b adrenergic antagonists to reduce nocturnal aqueous humor flow, resulting in a nocturnal IOP acrophase pattern. In contrast, such additional effects were not observed in the combination of PG and CAI, as CAI, such as dorzolamide, is known to induce a more pronounced reduction in IOP during the night (from 22 to 6 o’clock).30,31 In our present study, the nocturnal acrophase pattern was more significantly observed in the combination of PG, b blocker, and CAI. This phenomenon is not simply explained but can be speculated through the synergistic effects by b blocker and CAI. In fact, we have recently found that a statistically significant and transient decrease of heart rates due to 0.5% TM disappeared with the addition of 1% dorzolamide. Moreover, a potent increase in the effect on ocular blood flow by 1% dorzolamide was
19 evident through the addition of 0.5% TM in healthy subjects.32 These observations suggested that 0.5% TM and 1% dorzolamide may have synergistic effects on ocular and systemic conditions. Furthermore, Martı´nez and SanchezSalorio33 have recently reported that the addition of 2% dorzolamide to 0.5% TM in glaucoma patients caused a significant decrease in IOP and an improvement in retrobulbar hemodynamics, while the addition of 1% brinzolamide to 0.5% TM exhibited IOP reduction that was identical to cases involving the addition of 2% dorzolamide, but had no effects on the retrobulbar hemodynamics. Such differences between dorzolamide and brinzolamide may be ascribed to their different pharmacokinetics toward CA in the eye as well as the synergistic effect of their combinations. A limitation in the present study is its single-centered nature, which means there is a limited number of subjects. However, despite the relatively small number of subjects, a proper statistical analysis was used as much as possible. Another limitation is that due to the reasons described in the ‘‘Methods’’ section, when taking circadian measurements, we could not measure IOP at 3 o’clock, which prevented us from being able to use COSINOR or other similar analyses which are commonly utilized. Although these methods were not used, we could evaluate circadian IOP fluctuation patterns by using a polynomial regression analysis and Dunnett multiple-comparison test. Nevertheless, these limitations will need to be addressed as we embark on our next project. In conclusion, we found that circadian IOP fluctuations may be affected by their anti-glaucoma medications. An analysis of IOP patterns in individual patients indicated 3 distinct IOP patterns: diurnal acrophase, nocturnal acrophase, and no acrophase, among our POAG subjects. However, *67.1% of these patterns in individual patients varied in other different patterns. Thus, our study suggests that an analysis of more than 1 day of circadian IOP measurements may help in better estimating the circadian IOP fluctuation status of individual glaucoma patients.
Acknowledgments The authors especially thank Dr. Tomoko Sonoda, Department of Public Health, Sapporo Medical University School of Medicine, and Dr. Keisuke Kamihara, Department of Ophthalmology, Sapporo Medical University School of Medicine, for their excellent comments on the statistical analysis of the present data.
Author Disclosure Statement No competing financial interests exist.
References 1. Shields, M.B. An overview of glaucoma. In: Shields, M.B., ed. Textbook of Glaucoma. 4th ed. Baltimore, MD: Williams & Wilkins; 1998; p. 1–2. 2. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 126: 498–505, 1998. 3. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AIGIS):7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130:429–40, 2000.
Journal of Ocular Pharmacology and Therapeutics 2014.30:12-20. Downloaded from online.liebertpub.com by Ucsf Library University of California San Francisco on 12/25/14. For personal use only.
20 4. Kass, M.A., Heuer, D.K., Higginbotham, E.J., et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701–13, 2002. 5. Liu, J.H., Zhang, X., Kripke, D.F., and Weinreb, R.N. Twenty-four hour intraocular pressure pattern associated with early glaucomatous changes. Invest. Ophthalmol. Vis. Sci. 44:1586–1590, 2003. 6. Wilensky, J.T., Gieser, D.K., Dietsche, M.L., Mori, M.T., and Zimer, R. Individual variability in the diurnal intraocular pressure curve. Ophthalmology. 100: 940–949, 1993. 7. Ido, T., Tomita, G., and Kitazawa, Y. Diurnal variation of intraocular pressure of normal-tension glaucoma. Ophthalmology. 98:296–300, 1991. 8. Lee, Y.R., Kook, M.S., Joe, S.G., Na, J.H., Han, S., Kim, S., and Shin, C.J. Circadian (24-hour) pattern of intraocular pressure and visual field damage in eyes with normaltension glaucoma. Invest. Ophthalmol. Vis. Sci. 53:881–887, 2012. 9. Renard, E., Palomibi, 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. 51:882–889, 2010. 10. Romanet, J.P., Maurent-Palombi, K., Noe¨l, C., et al. Nyctohemeral variations in intraocular pressure. J. Fr. Ophtalmol. 27:2S19–2S26, 2004. 11. Realini, T., Weinreb, R.N., and Wisniewski, S. Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals. Ophthalmology. 117:1700–1704, 2010. 12. Realini, T., Weinreb, R.N., and Wisniewski, S. Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals. Ophthalmology. 118:47–51, 2011. 13. Dinn, R.B., Zimmerman, M.B., Doan, A.P. et al. Concordance of diurnal intraocular pressure between fellow eyes in primary open angle glaucoma. Ophthalmology. 114:915–920, 2007. 14. Liu, J.H., Realini, T., and Weinreb, R.N. Asymmetry of 24hour intraocular pressure reduction by topical ocular hypotensive medications in fellow eyes. Ophthalmology. 118: 1995–2000, 2011. 15. Wang, N.L., Friedman, D.S., Zhou, Q., et al. A populationbased assessment of 24-hour intraocular pressure among subjects with primary open-angle glaucoma: the handan eye study. Invest. Ophthalmol. Vis. Sci. 52:7817–7821, 2011. 16. Magacho, L., Toscano, D.A., Freire, G., Shetty, R.K., and Avila, M.P. Comparing the measurement of diurnal fluctuations in intraocular pressure in the same day versus over different days. Eur. J. Ophthalmol. 20:542–545, 2010. 17. Mosaed, S., Liu, J.H., and Weinreb, R.N. Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients. Am. J. Ophthalmol. 139:320–324, 2005. 18. Rotchford, A.P., Uppal, S., Lakshmanan, A., and King, A.J. Day-to-day variability in intraocular pressure in glaucoma and ocular hypertension. Br. J. Ophthalmol. 96:967–970, 2010. 19. Mansouri, K., Weinreb, R.N., and Liu, J.H.K. Effects of aging on 24-hour intraocular pressure measurements in sitting and supine body positions. Invest. Ophthalmol. Vis. Sci. 53:112– 116, 2012. 20. Coakes, R.L., and Brubaker, R.F. The mechanism of timolol in lowering intraocular pressure in the normal eye. Arch. Ophthalmol. 96:2045–2048, 1978. 21. Konstas, A.G., Maltezos, A.C., Gandi, S., Hudgins, A.C., and Stewart, W.C. Comparison of 24-hour intraocular pressure
SACHIE ET AL.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
reduction with dosing regimens of Latanoprost and timolol maleate in patients with primary open-angle glaucoma. Am. J. Ophthalmol. 128:15–20, 1999. Liu, J.H.K., Kripke, D.F., and Weinreb, R.N. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am. J. Ophthalmol. 138:389–395, 2004. Topper, J.E., and Brubaker, R.F. Effects of timolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest. Ophthalmol. Vis. Sci. 26:1315–1319, 1985. Fuchja¨ger-Mayrl, G., Georgopoulos, M., Hommer, A., et al. Effect of dorzolamide and timolol on ocular pressure: blood flow relationship in patients with primary open-angle glaucoma and ocular hypertension. Invest. Ophthalmol. Vis. Sci. 51:1289–1296, 2010. Konstas, A.G., Maltezos, A., Bufidis, T., Hudgins, A.G., and Stewart, W.C. Twenty-four hour control of intraocular pressure with dorzolamide and timolol maleate in exfoliation and primary open-angle glaucoma. Eye. 14:73–77, 2000. Larsson, L.I., Mishima, H.K., Takamatsu, M., Orzalesi, N., and Rossetti, L. The effect of latanoprost on circadian intraocular pressure. Surv. Ophthalmol. 47:S90–S96, 2002. Orzalesi, N., Rossetti, L., Bottoli, A., and Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology. 113: 239–246, 2006. Swymer, C., and Neville, M.W. Tafluprost: the first preservative-free prostaglandin to treat open-angle glaucoma and ocular hypertension. Ann. Pharmacother. 46:1506–10, 2012. Orzalesi, N., Rossetti, L., Invernizzi, T., Bottoli, A., and Autelitano, A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest. Ophthalmol. Vis. Sci. 41:2566–2573, 2000. Vanlandingham, B.D., Maus, T.L., and Brubaker, R.F. The effect of dorzolamide on aqueous humor dynamics in normal human subjects during sleep. Ophthalmology. 105:1537– 1540, 1998. Orzalesi, N., Rossetti, L., Invernizzi, T., Bottoli, A., and Autelitano, A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest. Ophthalmol. Vis. Sci. 41:2566–2573, 2000. Ohguro, I., and Ohguro, H. The effects of a fixed combination of 0.5% timolol and 1% dorzolamide on optic nerve head blood circulation. J. Ocul. Pharmacol. Ther. 28:392–396, 2012. Martı´nez, A., and Sa´nchez-Salorio, M. Effects of dorzolamide 2% added to timolol maleate 0.5% on intraocular pressure, retrobulbar blood flow, and the progression of visual field damage in patients with primary open-angle glaucoma: a single-center, 4-year, open-label study. Clin. Ther. 30:1120–1134, 2008.
Received: June 14, 2013 Accepted: October 21, 2013 Address correspondence to: Dr. Hiroshi Ohguro Department of Ophthalmology Sapporo Medical University School of Medicine Sapporo 060-8543 Japan E-mail: [email protected]
JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 30, Number 1, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2013.0121
Effects of Several Anti-Glaucoma Medications on the Circadian Intraocular Pressure Fluctuations in Patients with Primary Open-Angle Glaucoma Sachie Tanaka, Megumi Watanabe, Shu-ichiro Inatomi, Kazushi Umeda, Kaori Yoshida, Ikuyo Ohguro, and Hiroshi Ohguro
Abstract Purpose: The purpose of the present study was to elucidate the effects of several anti-glaucoma medications on the circadian intraocular pressure (IOP) fluctuations in patients with primary open-angle glaucoma (POAG). Patients and Methods: POAG patients (n = 61; 61 eyes) with or without glaucoma medications were included. IOP measurement at 14 time points (12, 15, 18, 21, 0, 6, 9, 12, 15, 18, 21, 0, 6, and 9 o’clock) was performed over a period of 48 h. IOP changes occurring in the first 24 h and the subsequent 24 h were evaluated by several therapeutic factors. Results: A nocturnal acrophase pattern was observed in all the eyes with POAG. The shape of the first 24 h IOP curve was similar to that of the following 24 h IOP curves. However, there were fewer overall IOP levels in the second 24 h time period. Circadian IOP fluctuation patterns exhibited in each eye on the 1st and 2nd days were single acrophase patterns: diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%) and nocturnal acrophase (1st day, 36.1%; 2nd day, 31.1%), and no single acrophase patterns: flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Among the different medication groups, a nocturnal acrophase circadian pattern was observed in the patient groups being treated by combinations of prostaglandin analog (PG) and b blocker or PG, b blocker and carbonic anhydrase inhibitor (CAI). However, this was not apparent in patient groups with or without single anti-glaucoma medications or a combination of PG and CAI. Conclusions: The present study of IOP monitoring patients with POAG over a period of 48 h indicated that their changes in circadian patterns of IOP were affected by types of anti-glaucoma medications.
that large circadian fluctuations of IOP may be a risk factor for progression of glaucoma.8–10 In terms of variations of IOP profiles, many studies have reported on the diurnal and/or nocturnal variability of IOP in healthy subjects as well as in patients with primary open-angle glaucoma (POAG).8–10 Several of these reports have indicated that diurnal IOP profile patterns were not repeatable from day to day in healthy individuals11 or POAG patients.12 In addition, even in all subjects, circadian IOP variation is known to be different between both eyes.13,14 As such, a single-day assessment of the IOP circadian profile may be insufficient in order to characterize the circadian IOP variations, and an evaluation of the circadian IOP change in 1 eye as a control for the other may also be unreliable.14 In addition, underlying factors that affect the circadian IOP profile, such as types of anti-glaucoma medication, remain ambiguous.
Introduction
G
laucomatous optic neuropathy (GON) is known worldwide to be a major factor leading to irreversible blindness.1 Regarding the treatment of GON, several randomized control trials2–4 have disclosed that intraocular pressure (IOP) at adequate low levels by medication or surgical intervention is effective. IOP is, therefore, the most critical risk factor for the development and progression of glaucoma. Several previous studies have revealed that IOP shows marked diurnal and nocturnal variability.5–7 This circadian variability in IOP may be important both clinically and pathologically. From a diagnostic point of view, a single IOP measurement may mislead the maximal IOP and, thus, cause mistaken assumptions regarding the suitable IOP control. From a pathological point of view, it is suggested
Department of Ophthalmology, Sapporo Medical University School of Medicine, Sapporo, Japan.
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Therefore, in the present report, to elucidate circadian IOP patterns and their inter-day variations in patients with POAG, a 48 h IOP profile in eyes with POAG was evaluated and its relationship with the several glaucoma clinical factors noted earlier was studied.
Methods This study was a prospective analysis of the 48 h IOP profile in subjects with POAG. It was conducted at the Eye Clinic of Sapporo Medical University Hospital, Japan, after approval by the local ethics committee and according to the tenets of the Declaration of Helsinki and national laws for the protection of personal data. Informed consent was obtained from all participants in the study.
Subjects All subjects underwent a complete ophthalmological examination before inclusion, including medical history, best-corrected visual acuity, slit-lamp biomicroscopy, central corneal thickness (CCT) measurements, Goldmann applanation tonometry, gonioscopy, standard automated perimetry using the Humphrey Field Analyzer II and the SITA-standard 30-2 algorithm, and a dilated fundus examination. A clinical diagnosis of the patients with POAG was assessed based on the following diagnostic criteria: (1) a history of IOP more than 21 mmHg; (2) glaucomatous visual field defects corresponding with the glaucomatous optic disc changes; (3) gonioscopically normal open angles; (4) no history or findings of pseudo-exfoliation or secondary glaucoma; and (5) no other ocular, neurological, otolaryngological, or systemic diseases affecting optic disc damage. Subjects were enrolled between April 1, 2011 and March 31, 2013. Participants were aged 20 years or older. All subjects were free from corneal pathology that might limit the accuracy of tonometry readings. In the group of patients with medical treatments, subjects who were administered on stable regimen at least 6 months before the study were included, and the medication regimens were continued during the study.
48 h IOP evaluation A measurement of circadian IOP patterns was repeated for 2 days. To record circadian IOP patterns, patients were hospitalized in the morning (at *10 o’clock) and remained there for the next 48 h. The awake period lasted from *6 to 21 o’clock. IOP was measured at 14 time points: 12, 15, 18, 21, 0, 6, 9, 12, 15, 18, 21, 0, 6, and 9 o’clock. For the daytime measurements (6–21 o’clock), patients were asked to relax for *15 min while in a sitting position, after which sitting IOP was measured in both eyes. During the night, to prevent a sudden change in IOP, the patients were awakened *10 min in a sitting position before relaxation time in prior for sitting IOP measurement. The IOP measurements were made with a non-contact automated pneumotonometer (Topcon Corporation model CT80, Tokyo, Japan). All measurements were taken at each time point by well-trained ophthalmologists. The value was the mean results of 3 to 6 consecutive measurements until the inter-measurement variability was less than 5%. Data of right eyes were used for analysis of the present study.
FIG. 1. Representative intraocular pressure (IOP) circadian fluctuation patterns: single acrophase patterns (diurnal acrophase and nocturnal acrophase) and no single acrophase patterns (flat and double acrophase). IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of primary open-angle glaucoma (POAG) patients during 24 h were plotted. Dotted curves demonstrate a polynomial regression of the IOP data against time. Dotted straight lines indicate mesor. Based on the position of the single acrophase, diurnal acrophase (peak IOP between 6 and 21 o’clock) and nocturnal acrophase (peak IOP between 21 and 6 o’clock) patterns were determined. Other IOP fluctuation curves were categorized as no single acrophase patterns, subdivided into a flat pattern and double acrophase pattern as described in the ‘‘Methods’’ section. Positions of IOP peak and bottom are indicated byYand[, respectively.
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SACHIE ET AL.
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Statistical analysis and analysis of 24 h IOP fluctuation rhythms An evaluation of similarity between the first and second 24 h IOP fluctuation was assessed by using an interclass correlation coefficient (ICC) of each time point. An ICC > 0.90 indicated high similarity, 0.75–0.90 equated to good similarity, 0.50–0.75 displayed intermediate similarity, and < 0.50 suggested poor similarity. Two-way repeated measures analysis of variance (ANOVA) (first 24 h/second 24 h cycle · time) was used to assess differences in IOP between the first and second 24 h IOP measurements, and an intergroup comparison of IOP was performed by the Dunnett multiple-comparison test. Several data, including age, bestcorrected visual acuity, refractive errors, CCT, and IOP, were compared through unpaired t-test between the non-treated and medicated POAG groups. For analysis of 24 h IOP fluctuation rhythms, a polynomial regression of the IOP data against time was used to generate mathematical models representing the circadian IOP fluctuation patterns. Based on this analysis, the presence and timing of the IOP acrophase were determined, and IOP fluctuation patterns were categorized into (1) single acrophase patterns, which were subdivided into a diurnal acrophase pattern (peak between 6 and 21 o’clock) and a nocturnal acrophase pattern (peak from 21 to 6 o’clock), and (2) no single acrophase patterns, which were subdivided into a flat pattern (no significant acrophase with IOP fluctuation levels of less than 2 mmHg during 24 h) and a double IOP acrophase pattern. An acrophase was defined as a situation in which the IOP peak and bottom fluctuation levels differed by 2 mmHg or more (Fig. 1). All statistical analyses were calculated with commercial software (SPSS, ver. 15.0; SPSS, Inc., Chicago, IL).
Results In the present study, we conducted a prospective analysis of 48 h IOP profiles of 61 eyes of 61 POAG patients with or without glaucoma medications (Tables 1 and 2). To study the effects of glaucoma medications on circadian IOP fluctuation, we compared the 48 h IOP profiles of several treatment groups of POAG patients. As shown in Table 2 and Figure 2, ICC showed a quite similar circadian IOP fluctuation between the first and second 24 h, but IOP levels of all time points were overall less in the second 24 h than the first 24 h in the total population of POAG, non-treated POAG, and medically treated POAG patient groups (2-way repeatedmeasures ANOVA, P < 0.05). Regarding IOP fluctuation patterns, a polynomial regression analysis and the Dunnett multiple-comparison test showed a nocturnal acrophase pattern in the total and medicated patients’ groups, although the non-treated patients group did not show such an apparent IOP circadian pattern (Fig. 2). With regard to circadian IOP fluctuation patterns of each patient, IOP fluctuation patterns (Table 3) exhibited during the 1st and 2nd days were single acrophase patterns; diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%), nocturnal acrophase (1st day, 36.1%; 2nd day, 31.1%), and no single acrophase patterns; flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Between the 1st and 2nd day, 67.1% of the population showed the same IOP fluctuation patterns. Regarding the circadian IOP fluctuation profile in each patient, the number of patients with a nocturnal acrophase-shaped pattern increased in patient groups with medication as compared with the non-treated patient group (Tables 4 and 5). These observations indicated that glaucoma medications may possibly affect circadian IOP fluctuation patterns. To further study this possibility, we
Table 1. Characteristics of the Primary Open-Angle Glaucoma Patients’ Groups
Gender (male/female) Age (years) BCVA Refractive errors (D) CCT (mm) Mean deviation (dB) IOP (mmHg)d IOP (mmHg)e No. of glaucoma medications One anti-glaucoma drop PG Other Two anti-glaucoma drops PG + b PG + CAI Others Three anti-glaucoma drops PG + b + CAI Four anti-glaucoma drops a
No medications (n = 18)
Medications (n = 43)
7/11 66.7 – 12.5b (60.9 to 72.5c) 0.89 – 0.44 (0.69 to 1.09) - 2.58 – 3.63 ( - 4.25 to - 0.90) 570.9 – 30.0 (557.0 to 584.8) - 5.90 – 7.70 ( - 9.46 to - 2.35) 16.2 – 2.6 (15.0 to 17.4) 15.6 – 2.4 (14.5 to 16.7) 0
20/23 66.4 – 11.6 (62.9 to 69.8) 0.98 – 0.31 (0.88 to 1.07) - 3.16 – 3.15 ( - 4.10 to - 2.22) 537.7 – 45.9 (524.0 to 551.5) - 9.06 – 8.44 ( - 11.58 to - 6.54) 15.5 – 3.4 (14.5 to 16.5) 14.8 – 3.1 (13.9 to 15.7) 2.16 – 0.95 (1.88 to 2.45) Total 13 12 1 Total 11 7 3 1 Total 16 16 Total 3
P-valuea 0.92 0.45 0.13 0.023 0.18 0.027 0.039
P-values for difference between treatment groups of POAG were calculated by unpaired t-test. Mean – SD (all such values). c Ninety-five percent confidence interval in parentheses (all such values). d Initial 24 h. e Following 24 h. BCVA, best-corrected visual acuity; CCT, central cornea thickness; PG, prostaglandin analog; b, b blocker; CAI, carbonic anhydrase inhibitor; IOP, intraocular pressure; POAG, primary open-angle glaucoma. b
15
a
15
18
21
9 15.7 – 3.2 (15.0–16.4) 0.92 (0.87–0.95) 16.2 – 2.6 (15.0–17.4) 0.87 (0.70–0.95) 15.5 – 3.4 (14.5–16.5) 0.95 (0.88–0.96) 16.1 – 3.5 (14.2–18.0) 0.94 (0.81–0.98) 13.4 – 2.5 (11.9–14.8) 0.96 (0.86–0.99) 15.9 – 3.4 (14.2–17.6) 0.95 (0.81–0.97) 15.8 – 3.4 (13.9–17.7) 0.97 (0.90–0.99) 12.8 – 1.6 (11.6–14.0) 0.98 (0.87–0.99) 15.5 – 3.4 (11.9–19.4) 0.97 (0.21–0.99) 15.9 – 3.4 (14.2–17.6) 0.93 (0.81–0.97)
MESOR
15
18
21
0
6
9
MESOR
13.0 – 3.0 15.7 – 4.5 15.7 – 5.5 15.7 – 3.5 15.0 – 4.4 14.3 – 4.17 14.7 – 4.0 (9.6–16.4) (10.6–20.8) (9.4–21.9) (11.7–19.6) (10.1–19.9) (9.0–19.7) (10.2–19.2) 14.3 – 3.1 15.3 – 4.0 15.8 – 2.5 15.5 – 3.9 17.7 – 4.6 16.3 – 3.7 14.7 – 3.4 15.6 – 3.2 (12.7–15.8) (13.3–17.2) (14.6–17.1) (13.6–17.4) (15.4–20.0) (14.5–18.1) (13.0–16.4) (14.1–17.2)
13.7 – 4.0 (9.1–18.2)
12.7 – 1.3 12.6 – 1.8 12.9 – 1.6 11.9 – 1.7 13.0 – 3.4 11.7 – 2.8 11.4 – 1.63 12.3 – 1.6 (11.8–13.6) (11.2–13.9) (11.7–14.0) (10.6–13.1) (10.5–15.5) (9.6–13.8) (10.5–12.4) (11.1–13.5)
15.3 – 3.6 15.0 – 3.0 14.4 – 3.7 14.3 – 3.3 15.4 – 4.2 14.8 – 3.1 15.4 – 3.2 14.9 – 3.2 (13.2–17.3) (13.3–16.7) (12.3–16.5) (12.4–16.1) (13.0–17.8) (13.0–16.5) (13.6–17.2) (13.1–16.7)
14.3 – 3.1 15.3 – 4.0 15.8 – 2.5 15.5 – 3.9 17.7 – 4.6 16.3 – 3.7 14.7 – 3.4 15.6 – 3.2 (12.7–15.8) (13.3–17.2) (14.6–17.1) (13.6–17.4) (15.4–20.0) (14.5–18.1) (13.0–16.4) (14.1–17.2)
12.8 – 2.2 12.4 – 2.2 13.4 – 2.9 13.1 – 3.3 13.8 – 3.3 12.7 – 3.3 12.2 – 2.7 12.9 – 2.5 (11.5–14.1) (11.0–13.7) (11.6–15.1) (11.1–15.0) (11.9–15.8) (10.8–14.7) (10.6–13.8) (11.4–14.4)
15.1 – 3.5 15.2 – 2.9 14.6 – 3.6 14.4 – 3.2 15.4 – 4.1 14.8 – 3.0 15.6 – 3.1 15.0 – 3.1 (13.2–17.0) (13.6–16.8) (12.6–16.6) (12.6–16.1) (13.2–17.6) (13.2–16.4) (13.9–17.3) (13.3–16.7)
14.2 – 3.0 14.6 – 3.4 14.9 – 3.0 14.6 – 3.5 16.2 – 4.4 14.8 – 3.1 14.3 – 3.3 15.0 – 3.5 (13.3–15.1) (13.6–15.6) (14.0–15.8) (13.6–15.7) (14.9–17.5) (13.9–15.7) (13.3–15.3) (13.9–16.0)
15.6 – 2.8 15.6 – 3.2 16.4 – 1.8 14.8 – 2.8 15.2 – 3.4 15.9 – 3.2 15.8 – 3.4 15.6 – 2.4 (14.3–16.9) (14.1–17.0) (15.6–17.2) (13.5–16.1) (13.6–16.7) (14.5–17.4) (14.2–17.3) (14.5–16.7)
14.6 – 3.0 14.9 – 3.3 15.3 – 2.8 14.7 – 3.3 15.9 – 4.1 15.2 – 3.4 14.8 – 3.4 15.1 – 2.9 (14.0–15.3) (14.2–15.6) (14.7–15.9) (14.0–15.4) (15.0–16.8) (14.5–16.0) (14.0–15.5) (14.4–15.7)
12
Following 24 h (o’clock)
c
b
Mean – SD (all such values). Ninety-five percent confidence interval in parentheses (all such values). ICC of IOP at each time point between first and second 24 h (all such values). d Ninety-five percent confidence interval in parentheses (all such values). No med, no medications; med, glaucoma medication; one drop, one anti-glaucoma drop; two drops, two anti-glaucoma drops; three drops, three anti-glaucoma drops; ICC, interclass correlation coefficient; MESOR, midline estimating statistic of rhythm.
a
6
16.5 – 4.4 15.8 – 3.7 14.9 – 3.3 (15.6–17.5) (15.0–16.6) (14.2–15.7) 0.75 0.72 0.80 (0.62–0.84) (0.57–0.82) (0.69–0.88) 15.7 – 2.8 16.1 – 2.6 15.8 – 2.7 (14.4–17.0) (14.9–17.3) (14.5–17.0) 0.70 0.55 0.74 (0.35–0.87) (0.13–0.81) (0.43–0.89) 16.9 – 4.9 15.7 – 4.2 14.6 – 3.5 (15.4–18.3) (14.4–16.9) (13.5–15.6) 0.76 0.76 0.82 (0.60–0.86) (0.59–0.86) (0.68–0.90) 16.2 – 4.8 15.8 – 4.9 15.3 – 3.5 (13.6–18.7) (13.2–18.5) (13.4–17.2) 0.73 0.70 0.90 (0.33–0.91) (0.27–0.90) (0.70–0.97) 14.5 – 3.1 13.1 – 3.0 12.6 – 3.1 (12.7–16.4) (11.3–14.9) (10.8–14.5) 0.93 0.74 0.91 0 (0.76–0.98) (0.28–0.92) (0.72–0.98) 18.4 – 5.6 16.9 – 3.9 14.9 – 3.1 (15.6–21.1) (15.0–18.8) (13.4–16.4) 0.65 0.71 0.73 (0.25–0.86) (0.35–0.89) (0.38–0.90) 16.0 – 4.9 15.1 – 4.2 15.2 – 3.6 (13.2–18.8) (12.7–17.5) (13.1–17.2) 0.74 0.90 0.90 (0.33–0.92) (0.67–0.97) (0.68–0.97) 13.7 – 2.9 12.9 – 3.4 11.4 – 1.8 (11.5–15.9) (10.3–15.4) (10.1–12.8) 0.92 0.82 0.86 (0.61–0.99) (0.27–0.97) (0.40–0.98) 17.0 – 3.0 14.3 – 2.5 16.0 – 4.0 (13.6–20.4) (11.5–17.2) (11.5–20.5) 0.98 0.63 0.94 (0.53–0.99) ( - 0.80–0.99) ( - 0.10–0.99) 18.4 – 5.6 16.9 – 3.9 14.9 – 3.1 (15.6–21.1) (15.0–18.8) (13.4–16.4) 0.65 0.71 0.73 (0.25–0.86) (0.35–0.89) (0.38–0.90)
0
Initial 24 h (o’clock)
Intraocular Pressure Values During 48 h IOP Measurements of Open-Angle Glaucoma Patients
15.8 – 3.7 15.4 – 3.3 15.9 – 3.5 15.6 – 3.7 (15.1–16.7) (14.8–16.4) (15.0–16.7)b (14.7–16.1) c ICC 0.83 0.81 0.66 0.74 (0.49–0.78) (0.60–0.83) (0.74–0.90)d (0.71–0.88) No med 16.9 – 3.8 16.2 – 3.6 16.9 – 2.9 16.1 – 3.5 (n = 18) (15.2–18.7) (14.6–17.9) (15.6–18.2) (14.4–17.7) ICC 0.82 0.77 0.24 0.67 (0.59–0.93) (0.48–0.91) ( - 0.23–0.63) (0.31–0.86) Med 15.4 – 3.7 15.0 – 3.1 15.5 – 3.6 15.4 – 3.7 (n = 43) (14.3–16.5) (14.1–16.0) (14.4–16.6) (14.3–16.5) ICC 0.83 0.83 0.73 0.76 (0.71–0.90) (0.70–0.90) (0.55–0.84) (0.60–0.86) One drop 16.9 – 3.5 16.2 – 3.2 16.4 – 3.6 16.0 – 3.4 (n = 13) (15.0–18.8) (14.5–18.0) (14.4–18.4) (14.1–17.9) ICC 0.77 0.94 0.78 0.85 (0.41–0.779) (0.81–0.98) (0.43–0.93) (0.58–0.95) Two drops 13.4 – 3.0 13.0 – 2.3 13.5 – 2.6 13.4 – 2.5 (n = 11) (11.6–15.2) (11.6–14.4) (12.0–15.1) (11.9–14.8) ICC 0.87 0.73 0.88 0.56 (0.58–0.96) (0.26–0.92) (0.63–0.97) ( - 0.02–0.86) Three drops 14.9 – 3.5 14.9 – 3.0 15.4 – 3.9 15.8 – 4.2 (n = 16) (13.2–16.6) (13.5–16.4) (13.5–17.3) (13.7–17.8) ICC 0.95 0.76 0.64 0.79 (0.87–0.98) (0.45–0.91) (0.22–0.86) (0.49–0.92) PG 16.8 – 3.6 16.0 – 3.2 15.9 – 3.3 15.7 – 3.3 (n = 12) (14.8–18.9) (14.2–17.8) (14.0–17.8) (13.8–17.6) ICC 0.81 0.93 0.79 0.0.86 (0.45–0.94) (0.79–0.98) (0.43–0.94) (0.60–0.96) PG + b 13.0 – 1.4 12.9 – 1.8 13.0 – 0.6 12.9 – 1.9 (n = 7) (12.0–14.0) (11.5–14.2) (12.6–13.4) (11.5–14.2) ICC 0.84 0.39 0.36 00.73 (0.33–0.97) ( - 0.43–0.86) ( - 0.47–0.85) (0.59–0.95) PG + CAI 15.7 – 4.7 14.3 – 3.2 15.7 – 4.7 15.7 – 2.3 (n = 3) (10.3–21.0) (10.7–18.0) (10.3–21.0) (13.1–18.3) ICC 0.97 0.93 0.93 0.41 (0.32–0.99) ( - 0.13–0.99) ( - 0.17–0.99) ( - 0.88–0.98) PG + b + CAI 14.9 – 3.5 14.9 – 3.0 15.4 – 3.9 15.8 – 4.12 (n = 16) (13.2–16.6) (13.5–16.4) (13.5–17.3) (13.7–17.8) ICC 0.98 0.76 0.63 0.79 (0.87–0.98) (0.45–0.91) (0.22–0.86) (0.49–0.92)
All (n = 61)
12
Table 2.
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16
SACHIE ET AL. ANOVA, P < 0.05); whereas in the other medication groups, these levels were similar on both days (2-way repeatedmeasures ANOVA, P > 0.05). Analysis of several combinations of the anti-glaucoma medications showed the nocturnal acrophase in a double medication of prostaglandin analog (PG) and b blocker and triple medication of PG, b blocker, and carbonic anhydrase inhibitor (CAI) (Dunnett multiplecomparison test, P < 0.05) (Fig. 4). In contrast, a single medication of PG or a double medication of PG and CAI did not show a specific acrophase or acrophase pattern (Fig. 4).
Discussion
FIG. 2. Average circadian IOP fluctuation of total POAG patients, non-treated POAG patients, and medicated treated POAG patients. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Numbers of patients and eyes were as follows: all POAG (61 patients, 61 eyes), non-treated POAG (18 patients, 18 eyes), and medicated POAG (43 patients, 43 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. * Indicates P < 0.05 (Dunnett multiple-comparison test).
compared the 48 h IOP fluctuation profiles among subdivided groups in POAG patient groups receiving antiglaucoma medication. As shown in Figure 3, no evident IOP acrophase was detected in the groups of patients receiving 1 anti-glaucoma medication, while nocturnal acrophase circadian patterns became evident in patient groups treated with 2 or 3 anti-glaucoma medications (Dunnett multiplecomparison test, P < 0.05). In the single medication group, general IOP levels on the 2nd day decreased in comparison with those seen on the 1st day (2-way repeated-measures
Romanet et al.10 have reported that during the circadian fluctuation, IOP levels are higher at night than during the day, with a nocturnal acrophase present in healthy subjects. In contrast, Wang et al. have reported that IOP values are higher during the day, with a diurnal acrophase, than during the night in most glaucoma patients.15 Magacho et al.16 have described how diurnal IOP fluctuations were closely similar when IOP was measured on different days, and that there was no difference in the diurnal IOP curve on different days. Accordingly, the difference between the time course of the circadian IOP curve of IOP is considered to play an important role in the prognosis of glaucoma. This information is pertinent in that it provides insights regarding manners of treatment for POAG patients. However, several other studies have demonstrated that the circadian IOP curve in patients with glaucoma is more complicated than this. Among these studies, Renard et al.9 reported on 2 major IOP fluctuation patterns in 22 NTG subjects: diurnal acrophase (54.5%) and nocturnal acrophase (36.4%). Similarly, in Mosaed et al.,17 there was a significantly greater number of eyes with diurnal acrophase (n = 12, 54.5%) than with nocturnal acrophase (n = 8, 36.4%). In contrast, Lee et al.8 described 3 major IOP fluctuation patterns among 177 patients with POAG: diurnal acrophase (15.8%), nocturnal acrophase (51.4%), and no acrophase (32.8%). Our present study, using 61 eyes of 61 patients with POAG, revealed that diurnal acrophase (1st day, 54.0%; 2nd day, 60.7%) or nocturnal acrophase patterns (1st day, 36.1%; 2nd day, 31.14%) were much higher than the no single acrophase patterns; flat (1st day, 6.6%; 2nd day, 4.9%) and double acrophase (1st day, 3.3%; 2nd day, 3.3%). Inconsistencies in results between our study and others may be due to the differences in study populations, number of enrolled subjects, study designs including method for IOP measurements, subjects’ posture (sitting or supine), and clinical factors affecting IOP levels, such as glaucoma medications and general conditions. Our present study also revealed that only 67.1% of population showed the same IOP fluctuation patterns between the 1st and 2nd day. Such variability of the circadian IOP fluctuation may be due to the following considerations mentioned in other studies: (1) Diurnal IOP fluctuations are not repeatable in short periods in healthy subjects11 or in individuals with glaucoma12; (2) IOP in pre-medicated patients with glaucoma or ocular hypertension is significantly variable from day to day.18 With regard to study design of IOP measurement, several previous studies about IOP rhythm used a 1 or 2 h time lag. However, in contrast, we measured IOP every 3 h except at 3 o’clock during 24 h. In terms of effects of subjects’ posture (sitting or supine) on circadian IOP fluctuation, Mansouri et al. described that sitting and supine IOP fluctuation
48 H IOP CHANGES IN GLAUCOMA PATIENTS Table 3.
17
Comparison of Intraocular Pressure Fluctuation Patterns of Total Population of Primary Open-Angle Glaucoma Patients (n = 61, 61 Eyes) Between Initial 24 h and the Next 24 h Initial 24 h
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Single acrophase Following 24 h Single acrophase Diurnal acrophase 37 (60.7%)b Nocturnal acrophase 19 (31.1%)b No single acrophase Flat pattern 3 (4.9%)b Double acrophase 2 (3.3%)b
No single acrophase
Diurnal acrophase 33 (54.0%)a
Nocturnal acrophase 22 (36.1%)a
Flat pattern 4 (6.6%)a
Double acrophase 2 (3.3%)a
27 (44.2%)c 5 (8.2%)
6 (16.4%) 13 (21.3%)
3 (4.9%) 1 (1.6%)
1 (1.6%) 0 (0%)
1 (1.6%) 0 (0%)
2 (3.3%) 1 (1.6%)
0 (0%) 0 (0%)
0 (0%) 1 (1.6%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
Table 4.
Comparison of Intraocular Pressure Fluctuation Patterns of Non-treated Primary Open-Angle Glaucoma Patients (n = 18; 18 Eyes) Between Initial 24 h and the Next 24 h Initial 24 h Single acrophase
Following 24 h Single acrophase Diurnal acrophase 15 (83.3%)b Nocturnal acrophase 1 (5.5%)b No single acrophase Flat pattern 1 (5.5%)b Double acrophase 1 (5.5%)b
No single acrophase
Diurnal acrophase 11 (61.1%)a
Nocturnal acrophase 2 (11.1%)a
Flat pattern 3 (16.6%)a
Double acrophase 2 (11.1%)a
10 (55.5%)c 0 (0%)
1 (5.5%) 1 (5.5%)
3 (16.6%) 0 (0%)
1 (5.5%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 1 (5.5%)
1 (5.5%) 0 (0%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
Table 5. Comparison of Intraocular Pressure Fluctuation Patterns of Primary Open-Angle Glaucoma Patients Treated by Anti-glaucoma Medication (n = 43; 43 eyes) Between Initial 24 h and the Next 24 h Initial 24 h Single acrophase Following 24 h Single acrophase Diurnal acrophase 22 (51.5%)b Nocturnal acrophase 18 (41.9%)b No single acrophase Flat pattern 2 (4.7%)b Double acrophase 1 (2.3%)b
No single acrophase
Diurnal acrophase 22 (51.1%)a
Nocturnal acrophase 20 (46.5%)a
Flat pattern 1 (2.3%)a
Double acrophase 0 (0%)a
17 (39.5%)c 5 (11.6%)
5 (11.6%) 12 (27.9%)
0 (0%) 1 (2.3%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
0 (0%) 0 (0%)
2 (4.7%) 1 (2.3%)
Single acrophase patterns: diurnal acrophase or nocturnal acrophase; and no single acrophase patterns: flat pattern or double acrophase is shown in Figure 1. a Numbers and percentage of eyes of each category of IOP fluctuation patterns during initial 24 h. b Numbers and percentage of eyes of each category of IOP fluctuation patterns during the next 24 h. c Numbers and percentage of eyes of each combination pattern during both 24 h periods (all such values).
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SACHIE ET AL.
FIG. 3. Average circadian IOP fluctuation of several antiglaucoma medicated POAG patients. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Treatment for patients was as follows: single antiglaucoma drop (13 patients, 13 eyes), double anti-glaucoma drops (11 patients, 11 eyes), and triple anti-glaucoma drops (16 patients, 16 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. *Indicates P < 0.05 (Dunnett multiple-comparison test).
patterns of 24 h were similar and parallel, but these levels were quite different.19 In the present study, to exclude these effects, *15 or 25 min while in a sitting position during daytime or night were required before sitting IOP measurements as described in the ‘‘Methods’’ section. This preconditioning procedure between IOP measurements in every 1 or 2 h time lag may have affected the data. In addition, the local ethics committee at our University did not grant approval to measure IOP between 0 and 6 o’clock because of concerns that disturbance of the patients’ sleep could significantly affect the regular life style balance, including IOP fluctuation patterns, on the 2nd day. It was due to these
FIG. 4. Average circadian IOP fluctuation of POAG patients medically treated with several anti-glaucoma drops. Average IOP at 12, 15, 18, 21, 0, 6, and 9 o’clock of POAG patients during 48 h was plotted. Treatment for patients was as follows: prostaglandin analog (PG) (12 patients, 12 eyes), PG + b blocker (7 patients, 7 eyes), and PG + carbonic anhydrase inhibitor (CAI) (3 patients, 3 eyes), or PG + b blocker + CAI (16 patients, 16 eyes). First and second 48 h IOP fluctuations were indicated by closed circles and closed triangles, respectively. Dotted curves represent polynomial regression. *Indicates P < 0.05 (Dunnett multiple-comparison test).
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48 H IOP CHANGES IN GLAUCOMA PATIENTS considerations that we decided to perform IOP measurements every 3 h except 0 through 6 o’clock. In the present study, we found that 24 h circadian IOP patterns may be affected by anti-glaucoma medications based on the following observations: (1) the nocturnal acrophase-like pattern during the 24 h IOP profile was recognized in total POAG patients; (2) the patients in the POAG group treated with anti-glaucoma medications showed the more apparent nocturnal acrophase pattern, while no significant acrophase was observed in the group of pre-medicated POAG patients; and (3) the nocturnal acrophase-like pattern became apparent in the combination of PG and b blocker, or PG, b blocker, and CAI, while it was not as significant in the groups of patients treated with single anti-glaucoma medications and the combination of PG and CAI. Therefore, we speculated that the combinations of PG and b blocker may facilitate the nocturnal acrophase during the 24 h circadian IOP fluctuation, and this effect may be further facilitated by continued additions of CAI. Timolol (TM), a major anti-glaucoma drop of b blocker, lowers the IOP by reducing the aqueous humor flow, but has no effect on outflow resistance or on episcleral venous pressure.20 Since the sympathetic nervous system is known to be activated during daytime, it follows that TM could mostly be effective toward daytime IOP reduction. In fact, several investigators have reported that TM induced a greater reduction in IOP during the day (8–20 o’clock) and a less, albeit still significant, reduction during the night.21,22 Consequently, to get the most effective IOP reduction from TM, it is recommended that its once-daily administration take place in the morning (Timoptic XE; Merck, West Point, PA).22 Similar to TM, CAIs such as dorzolamide or brinzolamide also inhibit aqueous humor formation with no effect on aqueous outflow during the diurnal period.23–25 With regard to PGs such as latanoprost, numerous studies have shown that they facilitate uveoscleral outflow by activating extracellular matrix degradation through metalloproteinase, inducing a great reduction of IOP.26 Latanoprost given once in the evening lowers the IOP throughout the 24 h day.26 Such IOP reduction is also obtained by other PGs such as travoprost, bimatoprost,27 and tafluprost.28 Therefore, as our standard anti-glaucoma medication, PG is used as a first choice, and then b blocker or CAI is added in case further IOP reduction is required.29 In cases of the combination of PG and then b blocker, it may be hypothesized that b blocker further reduces diurnal IOP levels in addition to reduced 24 h IOP levels by PG, while the additional activity of the b blocker during the night is due to the inability of b adrenergic antagonists to reduce nocturnal aqueous humor flow, resulting in a nocturnal IOP acrophase pattern. In contrast, such additional effects were not observed in the combination of PG and CAI, as CAI, such as dorzolamide, is known to induce a more pronounced reduction in IOP during the night (from 22 to 6 o’clock).30,31 In our present study, the nocturnal acrophase pattern was more significantly observed in the combination of PG, b blocker, and CAI. This phenomenon is not simply explained but can be speculated through the synergistic effects by b blocker and CAI. In fact, we have recently found that a statistically significant and transient decrease of heart rates due to 0.5% TM disappeared with the addition of 1% dorzolamide. Moreover, a potent increase in the effect on ocular blood flow by 1% dorzolamide was
19 evident through the addition of 0.5% TM in healthy subjects.32 These observations suggested that 0.5% TM and 1% dorzolamide may have synergistic effects on ocular and systemic conditions. Furthermore, Martı´nez and SanchezSalorio33 have recently reported that the addition of 2% dorzolamide to 0.5% TM in glaucoma patients caused a significant decrease in IOP and an improvement in retrobulbar hemodynamics, while the addition of 1% brinzolamide to 0.5% TM exhibited IOP reduction that was identical to cases involving the addition of 2% dorzolamide, but had no effects on the retrobulbar hemodynamics. Such differences between dorzolamide and brinzolamide may be ascribed to their different pharmacokinetics toward CA in the eye as well as the synergistic effect of their combinations. A limitation in the present study is its single-centered nature, which means there is a limited number of subjects. However, despite the relatively small number of subjects, a proper statistical analysis was used as much as possible. Another limitation is that due to the reasons described in the ‘‘Methods’’ section, when taking circadian measurements, we could not measure IOP at 3 o’clock, which prevented us from being able to use COSINOR or other similar analyses which are commonly utilized. Although these methods were not used, we could evaluate circadian IOP fluctuation patterns by using a polynomial regression analysis and Dunnett multiple-comparison test. Nevertheless, these limitations will need to be addressed as we embark on our next project. In conclusion, we found that circadian IOP fluctuations may be affected by their anti-glaucoma medications. An analysis of IOP patterns in individual patients indicated 3 distinct IOP patterns: diurnal acrophase, nocturnal acrophase, and no acrophase, among our POAG subjects. However, *67.1% of these patterns in individual patients varied in other different patterns. Thus, our study suggests that an analysis of more than 1 day of circadian IOP measurements may help in better estimating the circadian IOP fluctuation status of individual glaucoma patients.
Acknowledgments The authors especially thank Dr. Tomoko Sonoda, Department of Public Health, Sapporo Medical University School of Medicine, and Dr. Keisuke Kamihara, Department of Ophthalmology, Sapporo Medical University School of Medicine, for their excellent comments on the statistical analysis of the present data.
Author Disclosure Statement No competing financial interests exist.
References 1. Shields, M.B. An overview of glaucoma. In: Shields, M.B., ed. Textbook of Glaucoma. 4th ed. Baltimore, MD: Williams & Wilkins; 1998; p. 1–2. 2. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am. J. Ophthalmol. 126: 498–505, 1998. 3. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AIGIS):7. The relationship between control of intraocular pressure and visual field deterioration. Am. J. Ophthalmol. 130:429–40, 2000.
Journal of Ocular Pharmacology and Therapeutics 2014.30:12-20. Downloaded from online.liebertpub.com by Ucsf Library University of California San Francisco on 12/25/14. For personal use only.
20 4. Kass, M.A., Heuer, D.K., Higginbotham, E.J., et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch. Ophthalmol. 120:701–13, 2002. 5. Liu, J.H., Zhang, X., Kripke, D.F., and Weinreb, R.N. Twenty-four hour intraocular pressure pattern associated with early glaucomatous changes. Invest. Ophthalmol. Vis. Sci. 44:1586–1590, 2003. 6. Wilensky, J.T., Gieser, D.K., Dietsche, M.L., Mori, M.T., and Zimer, R. Individual variability in the diurnal intraocular pressure curve. Ophthalmology. 100: 940–949, 1993. 7. Ido, T., Tomita, G., and Kitazawa, Y. Diurnal variation of intraocular pressure of normal-tension glaucoma. Ophthalmology. 98:296–300, 1991. 8. Lee, Y.R., Kook, M.S., Joe, S.G., Na, J.H., Han, S., Kim, S., and Shin, C.J. Circadian (24-hour) pattern of intraocular pressure and visual field damage in eyes with normaltension glaucoma. Invest. Ophthalmol. Vis. Sci. 53:881–887, 2012. 9. Renard, E., Palomibi, 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. 51:882–889, 2010. 10. Romanet, J.P., Maurent-Palombi, K., Noe¨l, C., et al. Nyctohemeral variations in intraocular pressure. J. Fr. Ophtalmol. 27:2S19–2S26, 2004. 11. Realini, T., Weinreb, R.N., and Wisniewski, S. Diurnal intraocular pressure patterns are not repeatable in the short term in healthy individuals. Ophthalmology. 117:1700–1704, 2010. 12. Realini, T., Weinreb, R.N., and Wisniewski, S. Short-term repeatability of diurnal intraocular pressure patterns in glaucomatous individuals. Ophthalmology. 118:47–51, 2011. 13. Dinn, R.B., Zimmerman, M.B., Doan, A.P. et al. Concordance of diurnal intraocular pressure between fellow eyes in primary open angle glaucoma. Ophthalmology. 114:915–920, 2007. 14. Liu, J.H., Realini, T., and Weinreb, R.N. Asymmetry of 24hour intraocular pressure reduction by topical ocular hypotensive medications in fellow eyes. Ophthalmology. 118: 1995–2000, 2011. 15. Wang, N.L., Friedman, D.S., Zhou, Q., et al. A populationbased assessment of 24-hour intraocular pressure among subjects with primary open-angle glaucoma: the handan eye study. Invest. Ophthalmol. Vis. Sci. 52:7817–7821, 2011. 16. Magacho, L., Toscano, D.A., Freire, G., Shetty, R.K., and Avila, M.P. Comparing the measurement of diurnal fluctuations in intraocular pressure in the same day versus over different days. Eur. J. Ophthalmol. 20:542–545, 2010. 17. Mosaed, S., Liu, J.H., and Weinreb, R.N. Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients. Am. J. Ophthalmol. 139:320–324, 2005. 18. Rotchford, A.P., Uppal, S., Lakshmanan, A., and King, A.J. Day-to-day variability in intraocular pressure in glaucoma and ocular hypertension. Br. J. Ophthalmol. 96:967–970, 2010. 19. Mansouri, K., Weinreb, R.N., and Liu, J.H.K. Effects of aging on 24-hour intraocular pressure measurements in sitting and supine body positions. Invest. Ophthalmol. Vis. Sci. 53:112– 116, 2012. 20. Coakes, R.L., and Brubaker, R.F. The mechanism of timolol in lowering intraocular pressure in the normal eye. Arch. Ophthalmol. 96:2045–2048, 1978. 21. Konstas, A.G., Maltezos, A.C., Gandi, S., Hudgins, A.C., and Stewart, W.C. Comparison of 24-hour intraocular pressure
SACHIE ET AL.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
reduction with dosing regimens of Latanoprost and timolol maleate in patients with primary open-angle glaucoma. Am. J. Ophthalmol. 128:15–20, 1999. Liu, J.H.K., Kripke, D.F., and Weinreb, R.N. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am. J. Ophthalmol. 138:389–395, 2004. Topper, J.E., and Brubaker, R.F. Effects of timolol, epinephrine, and acetazolamide on aqueous flow during sleep. Invest. Ophthalmol. Vis. Sci. 26:1315–1319, 1985. Fuchja¨ger-Mayrl, G., Georgopoulos, M., Hommer, A., et al. Effect of dorzolamide and timolol on ocular pressure: blood flow relationship in patients with primary open-angle glaucoma and ocular hypertension. Invest. Ophthalmol. Vis. Sci. 51:1289–1296, 2010. Konstas, A.G., Maltezos, A., Bufidis, T., Hudgins, A.G., and Stewart, W.C. Twenty-four hour control of intraocular pressure with dorzolamide and timolol maleate in exfoliation and primary open-angle glaucoma. Eye. 14:73–77, 2000. Larsson, L.I., Mishima, H.K., Takamatsu, M., Orzalesi, N., and Rossetti, L. The effect of latanoprost on circadian intraocular pressure. Surv. Ophthalmol. 47:S90–S96, 2002. Orzalesi, N., Rossetti, L., Bottoli, A., and Fogagnolo, P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension. Ophthalmology. 113: 239–246, 2006. Swymer, C., and Neville, M.W. Tafluprost: the first preservative-free prostaglandin to treat open-angle glaucoma and ocular hypertension. Ann. Pharmacother. 46:1506–10, 2012. Orzalesi, N., Rossetti, L., Invernizzi, T., Bottoli, A., and Autelitano, A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest. Ophthalmol. Vis. Sci. 41:2566–2573, 2000. Vanlandingham, B.D., Maus, T.L., and Brubaker, R.F. The effect of dorzolamide on aqueous humor dynamics in normal human subjects during sleep. Ophthalmology. 105:1537– 1540, 1998. Orzalesi, N., Rossetti, L., Invernizzi, T., Bottoli, A., and Autelitano, A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest. Ophthalmol. Vis. Sci. 41:2566–2573, 2000. Ohguro, I., and Ohguro, H. The effects of a fixed combination of 0.5% timolol and 1% dorzolamide on optic nerve head blood circulation. J. Ocul. Pharmacol. Ther. 28:392–396, 2012. Martı´nez, A., and Sa´nchez-Salorio, M. Effects of dorzolamide 2% added to timolol maleate 0.5% on intraocular pressure, retrobulbar blood flow, and the progression of visual field damage in patients with primary open-angle glaucoma: a single-center, 4-year, open-label study. Clin. Ther. 30:1120–1134, 2008.
Received: June 14, 2013 Accepted: October 21, 2013 Address correspondence to: Dr. Hiroshi Ohguro Department of Ophthalmology Sapporo Medical University School of Medicine Sapporo 060-8543 Japan E-mail: [email protected]
