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Nocturnal Elevation of Intraocular Pressure in
Young Adults
John H. K. Liu,1 Daniel F. Kripke,2 Rivak E. Hoffman,1 Michael D. Twa1
Richard T. Loving,2 Katharine M. Rex,2 Neeru Gupta,13 and Robert N. Weinreb1
distinguish 24-hour (circadian) and postural effects on intraocular pressure (IOP) in
healthy young adults.
PURPOSE. TO
METHODS. Thirty-three volunteers were housed in a sleep laboratory for 1 day under a strictly
controlled 16-hour light and 8-hour dark environment. Sleep was encouraged in the dark period.
Intraocular pressure was measured in each eye every 2 hours using a pneumatonometer. Researchers used night-vision goggles to perform IOP measurements in the dark, while the subject's light
exposure was minimized. In the first group of 12 subjects, measurements were taken with subjects
in the sitting position during the light-wake period and supine during the dark period. In the
second group of 21 subjects, all IOP measurements were taken with the subjects supine.
Average IOP was significantly higher in the dark period than in the light-wake period in
both groups. The lowest IOP occurred in the last light-wake measurement, and the peak IOP
occurred in the last dark measurement. The trough-peak difference in IOP was 8.2 ±1.4 mm Hg
(mean ± SEM) in the first group. Intraocular pressure changed sharply at the transitions between
light and dark. In the second group, the trough-peak IOP difference was 38 ± 0.9 mm Hg.
Intraocular pressure changed gradually throughout the 24-hour period. In comparison with the
sitting IOP in the first group, the supine IOP in the second group was significantly higher during
the light-wake period.
RESULTS.
Circadian rhythms of IOP were shown in young adults, with the peaks occurring in
the late dark period. A nocturnal IOP elevation can appear independent of body position change,
but change of posture from upright to recumbent may contribute to the relative nocturnal IOP
elevation. {Invest Ophthalmol Vis Set. 1998;39:2707-2712)
CONCLUSIONS.
I
ntraocular pressure (IOP) is essential to maintaining eye
structure and physiology. In various conditions, IOP may
change rapidly. Numerous studies in the past 30 years have
shown that human IOP is high in the morning and low in the
afternoon and evening.1 However, IOP has been monitored
beyond the light-wake period in only a handful of studies.2"14
Observations of nocturnal IOP have been inconsistent, and
almost opposite 24-hour (circadian) IOP patterns have been
described.
In some studies, IOP was lower in the dark-sleep period
than in the light-wake period. This observation was reported
in healthy subjects2'4 and in patients with glaucoma.3"611 In
some other studies, IOP was higher during the dark-sleep
period in young subjects and older subjects including those
with glaucoma.7"1012"14 Frequently, a sharp IOP elevation was
observed shortly after the change from the light-wake to the
dark-sleep period.7"914 The cause of the discrepancies in the
From the 'Departments of Ophthalmology and 2Psychiatry, University of California San Diego, La Jolla.
Present address: ^Department of Ophthalmology, University of
Toronto, Canada.
Supported in part by Grant EY07544 from the National Institutes
of Health, Bethesda, Maryland.
Submitted for publication February' 13, 1998; revised June 12,
1998; accepted July 31, 1998.
Proprietary interest category: N.
Reprint requests: John H. K. Liu, University of California, San
Diego, Department of Ophthalmology, La Jolla, CA 92093-0946.
nocturnal IOP pattern among these studies is unclear.'5 Nevertheless, a better understanding of die nocturnal variation of
IOP may allow better diagnosis and management of ocular
hypertension and glaucoma.16
Environmental light is the primary synchronizer of many
circadian rhythms.1718 In most previous studies of human
circadian IOP patterns, little attention was given to the environmental lighting conditions, particularly in the dark-sleep
period. One obvious reason is that the eyes were illuminated
during the measurement of IOP. In addition, subjects' body
positions varied when IOP measurements were taken. Postures
could be all upright,37"11 all supine, 2 ' 4 " 6 ' 1213 or upright during the day and supine at night.14 Altering body postures from
supine to sitting for IOP measurements in the dark-sleep period may cause excess arousal and affect the body's autonomic
and hormonal states. The influence on the natural IOP pattern
is unclear. In the present study, we collected 24-hour IOP data
from light-dark entrained, healthy young adults, while giving
particular attention to nocturnal light exposure and body posture. The IOP patterns observed may provide an indication of
what happens under normal living conditions.
METHODS
The study followed the tenets of the Declaration of Helsinki
and was approved by the institutional review board. Thirtythree paid volunteers were recruited, mainly from employees
Investigative Ophthalmology & Visual Science, December 1998, Vol. 39, No. 13
Copyright © Association for Research in Vision and Ophthalmology
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IOVS, December 1998, Vol. 39, No. 13
Liu et al.
and students of our university. Informed consent was obtained
from the volunteers after explanation of the nature and possible consequences of the study. Volunteers were nonsmoking,
healthy people aged 18 to 25 years (15 men and 18 women)
and racially diverse (23 white, 5 Hispanic, and 5 Asian). Each
volunteer underwent a complete ophthalmic examination to
ensure absences of eye disease and a narrow iridocorneal
angle. Individuals with myopia more than than 4 diopters were
excluded because of a possible link between myopia and high
IOP.19 Daytime sitting IOPs measured by the Goldmann tonometer were in the range of 11 mm Hg to 23 mm Hg (155 ± 0.2
mm Hg; mean ± SEM; N = 33).
Subjects were selected based on their having a regular
daily sleep cycle close to 11:00 PM to 7:00 AM (with a maximum deviation of 1 hour). To strengthen their circadian synchronization, subjects were asked to regularize their sleep
periods (lights-off) for 7 days before the laboratory study. This
assigned dark-sleep period of 8 hours matched the subject's
regular sleep cycle. Subjects wore a wrist device (Actillume;
Ambulatory Monitoring, Ardsley, NY) to monitor physical activity and light exposure. They also kept a daily sleep-wake
log. By these means, 7-day circadian entrainment was verified
before the recording session. Subjects were instructed to abstain from alcohol and caffeine for 3 days and to avoid use of
contact lenses for 24 hours before entering the laboratory.
The 24-hour IOP change was recorded in a laboratory
specifically designed for studying human circadian rhythms.
Subjects stayed in the laboratory for the entire recording session to avoid possible effects of bright sunlight on bodily
circadian rhythms.20 Light-dark conditions in the laboratory
were strictly controlled. Light intensity during the light-wake
period (from cool white fluorescent lights) was held constant
at 500 lux to 1000 lux at eye level when standing. During the
dark-sleep period, the room was absolutely dark. The onset of
darkness in each participant's sleep room was adjusted according to the accustomed dark-sleep period for that participant.
Measurements of IOP were also adjusted to each participant's
time in bed. Although bedtimes and IOP measurements were
thus individualized to each subject's accustomed pattern, the
data were transformed to present results as if each subject slept
from 11:00 PM to 7:00 AM.
Room activities were continuously videotaped using infrared recording systems. Intraocular pressure was measured every 2 hours in each eye (12 times in 24 hours) using a pneumatonometer (model 30 Classic; Mentor O&O, Norwell, MA).
One or two drops of 0.5% proparacaine was applied as local
anesthetic before tonometry. With subjects in a sitting position, the sensor probe of the pneumatonometer was applied
from above at 15° from the perpendicular to the corneal
surface. The probe was applied perpendicular to the corneal
surface when the subjects were supine. The difference in the
probe angles did not cause a difference in IOP of more than 0.5
mm Hg when calibrated against the manufacturer's verifier.
Measurements of IOP were assigned randomly to experienced
researchers working in 8-hour shifts to avoid fatigue. Before
the study, variations in IOP measurements by the various researchers were confirmed to be insignificant.
In the dark period, subjects were awakened, if necessary,
and IOP was measured in near-total darkness. Researchers
were equipped with infrared night-vision goggles (AN/PVS-7B
Dark Invader; Meyers, Redmond, WA) for these measurements.
If subjects were awakened, IOP measurement was taken
within 2 to 3 minutes. Subjects' light exposure during the
nocturnal IOP measurement was kept to a minimum. The only
light visible to subjects was a dim red light reflecting across the
ceiling (<1 lux). This light, originating from the pneumatonometer andfilteredthrough a 600-nm high-pass plastic filter
(Edmund Scientific, Barrington, NJ), was necessary for the
subjects to fixate during the IOP measurement. It was found in
pilot studies that some volunteer' eyes tended to track continuously in absolute darkness, which made IOP measurements
difficult. During IOP measurements in the dark period, the
researchers tried to disturb the subject as little as possible.
There were six men and six women in the first study
group. Recording sessions were conducted with as many as
three subjects in the laboratory at one time. Entry times into
the laboratory for individual subjects were balanced in 4-hour
intervals (at approximately 9:00 AM, 1:00 PM, 5:00 PM, and
9:00 PM; three subjects at each time point). This reduced the
confounding by circadian time of the order of measurement. In
the light-wake period, measurements of sitting IOP were taken
in subjects seated in the same location, 30 minutes after entering the laboratory and every 2 hours thereafter. Subjects were
encouraged to continue their normal activities (reading, exercising, watching TV, for example), but no naps were allowed.
Food and water were always available, and meal times were
not regulated. Visitors were permitted in the light-wake period. Subjects went to bed in individual sleep rooms just before
the room lights were turned off (e.g., at 11:00 PM). Sleep was
encouraged in the dark period. Measurements of IOP in the
dark period were taken with subjects supine, first at 30 minutes after lights out and then every 2 hours: 11:30 PM, 1:30 AM,
3:30 AM, and 5:30 AM, for example. Lights were turned on
after 8 hours (e.g., 7:00 AM) and subjects were awakened, if
necessary. Intraocular pressure was measured in sitting subjects 30 minutes later (e.g., 7:30 AM) and every 2 hours thereafter. After the 12th IOP measurement, a debriefing interview
was conducted in which the participants were asked how they
slept and whether there were difficulties and symptoms.
Recent studies have indicated that a difference in individual central corneal thickness may affect the accuracy of IOP
determined by the Goldmann tonometer.21 Although whether
a similar artifact is associated with the pneumatonometer is
uncertain, central corneal thickness was measured in six subjects by an ultrasonic pachymeter (Pachette 500, DGH Technology, Exton, PA) immediately after the IOP measurements at
two time points. One was at the last IOP measurement before
lights-off (e.g., 9:30 PM) and the other was at the first IOP
measurement after lights-on (e.g., 7:30 AM). Three consecutive
readings in individual eyes were averaged as the mean central
corneal thickness.
The second group included 9 men and 12 women. Entry
times to the laboratory were staggered; three subjects every 2
hours in the light-wake period (9 AM-9 PM). Procedures used
for IOP measurements were similar to those used in the first
group, except that all the IOP measurements were taken with
subjects supine. In the light-wake period, subjects were instructed to lie down in bed for 5 minutes before the IOP
measurement.
A hard-copy printout from the pneumatonometer was
collected for every IOP measurement. If the printout showed
an SD in IOP (calculated by the machine software) of more
than than 1 mm Hg, another IOP measurement was taken.
However, no more than three measurements were allowed.
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Nocturnal Elevation of Human Intraocular Pressure
IOVS, December 1998, Vol. 39, No. 13
•
LIGHT/WAKE
2709
^ • ^ S S ^ H LIGHT/WAKE
24 22 -
I
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supine
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sitting
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TIME of the 24 HOURS
FIGURE 1.
The 24-hour pattern of intraocular pressure (IOP) is contrasted in two groups of
entrained young adults, with and without the normal postural change from upright in the day
to recumbent at night. Intraocular pressure was measured by a pneumatonometer 30 minutes
after the odd hours. (•) Thefirstgroup of 12 subjects. Measurements of IOP were taken sitting
in the first light-wake period (before 11:00 PM), supine in the dark period (11:00 PM to 7:00
AM), and sitting in the second light-wake period (after 7:00 AM). (O) The second group of 21
subjects. All measurements of IOP were taken with subjects supine. Error bars, SEM.
Among the repeated measurements, the IOP value with the
least SD was selected. In most cases (>90%), one measurement
was sufficient at each time point.
Values of IOP from both eyes were averaged and used as
a single entry for data analyses. Statistical analyses were performed with P < 0.05 regarded as significant. To evaluate the
circadian rhythm of IOP for each subject, the best fitting
24-hour cosine was estimated for the 12 IOP averages of both
eyes. The circadian amplitude (height of the rhythm) and
acrophase (timing of the fitted peak) were estimated.1 To
compare the phase dispersion of each group of subjects, the
absolute deviation of each acrophase from the group median
acrophase was calculated.
RESULTS
All 33 subjects completed the laboratory measurements without adverse effects. Although sleep in the dark period was
interrupted for the IOP measurements, 25 (76%) of 33 subjects
in their debriefing interviews indicated that they had slept well
between the IOP measurements, because of the quiet and
darkness of the sleep rooms.
The mean 24-hour IOP was 17.1 mm Hg in subjects in the
first group and 20.4 mm Hg in subjects in the second group. In
the 12 subjects in the first group, the average of all IOP values
in the dark period (20.8 ± 1.1 mm Hg; mean ± SEM) was
significantly higher (P < 0.001; paired f-test) than the average
IOP in the light-wake period (15.2 ± 0.7 mm Hg). The latter
was close to the IOP value (16.0 ± 0.8 mm Hg) obtained with
the Goldmann tonometer during the prior eye examination.
The 24-hour pattern of the mean IOP in this group is presented
in Figure 1 (line with the solid circles). The lowest mean IOP
occurred at the last measurement in the light-wake period
(9:30 PM) and the highest IOP occurred at the last measurement in the dark period (5:30 AM). The difference in IOP
between these two time points (trough-peak) was 8.2 ±1.4
mm Hg (n = 12). Sharp elevations of IOP occurred between
9:30 PM and 11:30 PM and between 11:30 PM and 1:30 AM. A
sharp IOP reduction occurred between 5:30 AM and 7:30 AM.
Cosine fits of the individual IOP data showed the acrophases
between 2 AM and 5 AM in 11 of the 12 subjects (Fig. 2; solid
circles). One participant who had a nearly flat 24-hour IOP
pattern had the acrophase at approximately 12 noon. There
was no statistical difference (paired £-test) in the average central corneal thickness between 9:30 PM (553 ± 6 /mm; n = 12)
and 7:30 AM (558 ± 8 /mm) in the six subjects studied.
In the second group, the average IOP in die dark period
was 21.3 ± 0.7 mm Hg (n = 21), slightly higher (P < 0.05;
paired f-test) than the average IOP in the light-wake period,
20.0 ± 0.4 mm Hg. The average supine IOP in the light-wake
period in this group was significantly higher (P < 0.001,
Student's £-test) than the average sitting IOP observed in the
first group (152 ± 0.7 mm Hg). The 24-hour IOP pattern in the
second group showed gradual elevation and decrease throughout the 24 hours (Fig. 1; open circles). The trough and peak
IOPs occurred at 9:30 PM and 5:30 AM, the same times as those
in the first group. The trough-peak IOP difference was 3-8 ±
0.9 mm Hg. Cosine fits of IOP data from individual subjects
showed that all acrophases occurred between 2:30 AM and
3:00 PM (Fig. 2; open circles).
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Iiu et al.
IOVS, December 1998, Vol. 39, No. 13
10 PM
2 AM
• \
8 PM
4 AM
- 6 AM
6 PM -
8 AM
4 PM
10 AM
2 PM
NOON
2. Polar coordinates displaying the least-squares estimates of the 24-hour rhythms in intraocular pressure (IOP).
The position of the acrophase around the circle shows its
timing, and the radial distance from the center shows the
amplitude of the IOP rhythm. The circumference of the circle
represents an IOP amplitude of 8 mm Hg. (•) The first group
of 12 subjects whose IOP measurements were taken sitting in
the light-wake period (7:00 AM to 11:00 PM) and supine in the
dark period (11:00 PM to 7:00 AM). (O) The second group of
21 subjects whose IOP measurements were taken while supine
in both periods.
FIGURE
Inspection of Figure 2 showed that the acrophases in both
groups occurred in a nonrandom manner. The null hypothesis
of a random 360° distribution of phases was rejected with
Rayleigh's test in subjects in both groups (P < 0.001); therefore, significant 24-hour rhythms were detected. Although the
mean amplitude of the circadian rhythm in the first group
(33 — 0.5 mm Hg) was higher than the mean amplitude in the
second group (2.3 ± 0.2 mm Hg), the difference was not
significant (P > 0.05; two-tailed Mann-Whitney test). The
mean acrophase of subjects in the first group was at 4:22 AM,
whereas the mean in the second group was at 7:30 AM (P <
0.05; two-tailed Mann-Whitney test). The deviations of acrophases from the median were far greater in subjects in the
second group than in the first group (P < 0.01; two tailed
Mann-Whitney test).
DISCUSSION
It is unavoidable that study of human IOP during sleep is
confounded by awakening the subject. When the subject is
asleep, the eye positions itself under the upper lid (known as
the Bell's phenomenon). When it is time to measure the IOP,
the eye and eyelids must be repositioned, which may cause an
instant IOP change. Also, disturbing sleep in human subjects
may change the autonomic and hormonal parameters related
to IOP. Somewhat similar problems in rabbits (which, in general, sleep during the daytime) have been circumvented by
surgically implanting a pressure sensor in the eye and monitoring IOP through telemetry.22'23 Results of this telemetric
monitoring show a similar circadian IOP pattern to that demonstrated by the periodic IOP measurements using the pneumatonometer. However, as long as there is no technical advance to circumvent the problem with IOP measurement in
sleeping humans, whether the IOP determined after awakening the human subject reflects the real nocturnal steady state
IOP is uncertain. Therefore, interpretations of results in our
study and in many previous studies rest on the assumption that
artifacts associated with nocturnal IOP measurement are not
substantial, particularly when relating the result to the state of
sleep.
We observed consistent 24-hour IOP patterns in entrained
healthy young adults. In both groups, IOP peaked in the late
dark period, and the trough occurred in the late light-wake
period. The subjects in the first group had lower IOP when
awake (sitting) and approximately the same IOP in the dark
period as in the second group. Therefore, subjects measured
sitting in the day had a significantly lower 24-hour mean IOP
and somewhat larger amplitudes in their circadian rhythms.
Because of the masking effects of change of posture on the
24-hour IOP rhythms, the acrophases of subjects measured in
the first group were significantly earlier and less variable, but
even subjects in the second group GOP measurements were
performed in supine subjects throughout) had a nonrandom
distribution of acrophases, indicating a consistent circadian
rhythm.
The nocturnal IOP pattern in the present study is different
from many previous observations of nocturnal human IOP. Our
results did not show a nocturnal IOP reduction, as has been
described in some studies.2"611 The observation of a nocturnal
IOP elevation in the first group agrees in general with the
report in a previous study14 in which IOP was measured in
subjects while upright during the day and supine at night.
However, IOP in our study peaked in the late dark-sleep
period, not in the early dark-sleep period.14 Of interest, our
results in the second group are similar to the observations of
Duke-Elder 30 years ago.24
There are several possible explanations for the differences
among various studies. Enforcement of the subject's circadian
synchronization and strict control of the laboratory light- dark
conditions may contribute to the consistent 24-hour IOP patterns in the present study. Studies in rabbits have shown that
light exposure in the dark period suppresses nocturnal IOP
elevation.25 Although we suspect that uncontrolled light exposure in the dark period may have interfered with nocturnal IOP
elevation in some previous human studies, this issue of light
suppression needs further study. It should be noted that nocturnal exposure to strong light does not affect the circadian
rhythm of aqueous humor flow,26 which shows a nocturnal
reduction. Effects of light on other parameters of aqueous
humor dynamics, such as outflow resistance and episcleral
venous pressure, are unknown.
A comparison of results from our two groups indicates
that a significant portion of the nocturnal IOP elevation in the
first group was caused by the postural change from sitting to
supine in the dark period. This point of view is different from
that in the previous report14 in which similar positioning was
used for the IOP measurement as was vised in our first group.
An acute elevation of IOP because of postural change from
sitting to supine is well known.27 Such postural change causes
hydrostatic changes in the eye, particularly an elevation of
episcleral venous pressure.27 A nocturnal IOP elevation caused
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IOVS, December 1998, Vol. 39, No. 13
Nocturnal Elevation of Human Intraocular Pressure
by this postural change probably occurs in daily life, because
almost everybody sleeps in a near-recumbent position. This
kind of nocturnal IOP elevation, however, is not driven directly
by an endogenous circadian oscillator. Results from the second
group showed that the postural effect on IOP did not account
for all nocturnal IOP elevation. When all the IOP measurements were taken in supine subjects, a small nocturnal IOP
elevation still occurred. Similar to the subjects in whom IOP
measurements were taken sitting and supine, the mean IOP in
the subjects measured in the supine position throughout
reached the lowest value in the late light-wake period. The
highest IOP occurred similarly in the late- dark period, but the
magnitude of IOP elevation was smaller. What caused the
elevation of nocturnal IOP that was unrelated to posture is
unclear.28 Circadian effects on aqueous humor dynamics of
systemic hormones, local hormones, local neural activities, or
their combinations may all contribute to nocturnal IOP elevation. It is possible that some potential artifacts related to
awakening subjects, such as instant changes of eye position,
choroidal blood volume, or lid pressure, also contribute to this
IOP elevation. Nocturnal IOP elevation, however, is not caused
by an increase in the formation of aqueous humor. The rate of
aqueous humor flow during the dark-sleep period is apparently only approximately half of that during the early lightwake period in healthy adults.29"32 A similar nocturnal reduction in aqueous flow also occurs in patients with
glaucoma.3334 Our preliminary data indicate that nocturnal
IOP elevation is not an artifact caused by an increase in central
corneal thickness.
The physiological significance of nocturnal IOP elevation
is unknown in humans. Because the rate of nocturnal aqueous
humor flow is less than the flow rate in the light-wake period,
tissues in the anterior segment of the eye would not need a
faster turnover of aqueous humor in the dark-sleep period for
nutritional or metabolic purposes. No known function in the
posterior part of the eye requires elevated IOP in the darksleep period. It is possible that nocturnal IOP elevation is a
consequence of postural change plus physiological changes
unrelated to ocular functions. This physiological IOP elevation
in the dark-sleep period should cause no harm to a young
healthy eye. However, the effect on an aging or diseased eye is
uncertain. Usually measured in the light-wake period, high
IOP has been regarded as a major risk factor in the development of glaucoma. Because part of nocturnal IOP elevation is
caused by postural change, this posture-related nocturnal IOP
elevation at night in patients with glaucoma (compared with
their daytime values) is likely.35 Other factors involved in
nocturnal IOP elevation may behave differently in patients
with glaucoma.
The nocturnal elevation of human IOP coincides with the
time when systemic blood pressure, measured at the brachial
artery, is the lowest. Perfusion pressure to the optic nerve head
at night, however, may change in a different direction because
of the postural change from upright to supine. Further research
on nocturnal ocular perfusion in the supine position is warranted. Our data (Fig. 2) indicate a large variability in the
magnitude of nocturnal IOP elevation. It is unclear whether an
abnormally high IOP elevation in the dark period may further
interfere with ocular physiology in patients with glaucoma.
This may be an important consideration in patients with progressive glaucomatous optic neuropathy despite apparently
controlled daytime IOP. Studies of the 24-hour IOP patterns in
2711
patients with glaucoma and in healthy subjects of comparable
age are needed. Despite all the uncertainties raised, the present
results suggest that nocturnal elevation of human IOP (at least
the portion caused by the postural change) is a fundamental
physiological fact. We should not ignore its significance, because approximately one third of our life is spent in the
dark-sleep period.
The 24-hour IOP pattern has been extensively studied in
laboratory rabbits. The nocturnal elevation of human IOP observed in the present study is somewhat different from the
nocturnal IOP elevation seen in the laboratory rabbit.36 Under
normal living conditions, the sharp elevation of human IOP in
the early dark period is related to the postural change at
bedtime. There seems to be no postural change in rabbits
when awake and asleep, and generally, laboratory rabbits are
more active in the dark period. The sharp elevation of rabbits'
IOP at the onset of dark is mainly caused by the activation of
the ocular sympathetic nerves. In humans, there is no indication of a nocturnal increase in ocular sympathetic activity.37 As
in humans, the physiological significance of nocturnal IOP
elevation in rabbits is unclear.
Acknowledgments
The authors thank Richard F. Brubaker for his valuable advice and
comments.
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