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TheRelationshipbetweenCPAPUsageandCornealThickness.PDF
The Relationship between CPAP Usage and Corneal Thickness Ethem Gelir1*, Murat Timur Budak1, Sadik Ardıc2
1 Physiology Department, Hacettepe University Medical School, Ankara, Turkey, 2 Sleep Laboratory, Pulmonary Medicine Department, SGK Ankara Education Hospital,
Ankara, Turkey
Abstract
The purpose of this study was to determine whether there is a correlation between CPAP usage and corneal thickness in patients with sleep disordered breathing. Full-night polysomnography (PSG) recordings were collected. Ten patients had undergone PSG recordings with continuous positive airway pressure (CPAP), and seven patients had undergone PSG recordings without CPAP. We measured corneal thickness by ultrasonic pachymeter before sleep and ten minutes after waking. We also measured visual acuity with a routine ophthalmologic eye chart before and after sleep. We asked patients to fill out a post-sleep questionnaire to get their subjective opinions. In the without-CPAP group, corneal thickness increased significantly during sleep in both eyes (left, p = 0.0025; right, p,0.0001). In the with-CPAP group, corneal thickness did not increase significantly (p.0.05 for both left and right cornea). There was no significant difference in visual acuity tests (p.0.05 for both left and right eye) between the two groups. According to our results, there is a significant increase in corneal thickness in the without-CPAP group. Our data show that a low percentage of Rapid Eye Movement (REM) sleep may cause an increase in corneal thickness, which can indicate poor corneal oxygenation. In fact, many sleep- disordered breathing (SDB) patients have low REM. Since a contact lens may cause low corneal oxygenation, SDB patients with contact lenses should be monitored carefully for their corneal thickness.
Citation: Gelir E, Budak MT, Ardıc S (2014) The Relationship between CPAP Usage and Corneal Thickness. PLoS ONE 9(1): e87274. doi:10.1371/ journal.pone.0087274
Editor: Karen L. Gamble, University of Alabama at Birmingham, United States of America
Received April 30, 2013; Accepted December 26, 2013; Published January 24, 2014
Copyright: � 2014 Gelir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: [email protected]
Introduction
SDB is the most common sleep disorder associated with
excessive sleepiness. SDB is characterized by episodes of sleep
apnea (cessation of breathing over 10 s or more) or hypopnea
(significant reduction of breathing), oxygen desaturations, and
frequent arousals [1]. The most common form of SDB is
obstructive sleep apnea (OSA) and is associated with airway
collapse as the cause of breathing cessation or reduction. The
standard, first-line treatment for OSA is continuous positive
airway pressure (CPAP) [2]. CPAP is fan-generated air pressure
delivered via a nasal mask and titrated to offset negative
intrathoracic pressures produced during inhalation. As such,
CPAP acts as a pneumatic splint to maintain airway patency. It
has been shown to be very effective in most patients leading to
improved daytime alertness, cognitive function, and quality of life
[3–5].
Since the discovery of rapid eye movement (REM) sleep in
1953, it has been established that REM sleep is homeostatically
regulated. Selective REM sleep deprivation produces compensa-
tory increases in REM on subsequent sleep opportunities [6]. This
phenomenon is commonly called ‘‘REM rebound’’. REM
rebound occurs regardless of whether the original REM suppres-
sion was instrumental [7] (i.e., waking subjects up when they
entered REM sleep), pharmacologic [8] (e.g., amitryptaline or
fluoxetine), or disease related [9] (e.g., sleep-related breathing
disorders). Subsequently, researchers have found that in adults,
REM occupies 20–25% of total sleep time and many physiologic
changes are associated with REM sleep, including atonia [10],
poikilothermia [11], nocturnal penile tumescence [12,13], middle
ear muscle activity [14], and increased cerebral blood flow [15].
Recently, corneal thickening was added to the list of physiologic
properties affected by REM sleep. The hypothesis was advanced
by Maurice (1998) who proposed that eye movements in REM
sleep help corneal oxygenation. According to Maurice, thermal
circulation of the aqueous humor is needed for adequate corneal
respiration. This circulation is suppressed when the lids are closed,
and REM is required to stir the anterior chamber and thus prevent
corneal anoxia during sleep [16].
Corneal thickness measurements give valuable information
about the physiological status of the cornea [17–19]. Healthy
human corneal thickness is around 500 microns [20]. However the
thickness can change under some circumstances, such as hypoxia
and hypercapnia. It has also been shown that corneal thickness
significantly affects intraocular pressure measurement, and may
itself be a risk factor for developing glaucoma [21,22]. Early
studies showed that the normal human cornea would swell by 7%
every hour in an oxygen-free environment [23]. Diurnal variation
of central corneal thickness (CCT) has also been described, with
swelling overnight; this swelling resolved by early afternoon,
suggesting it was caused by the lid closure creating hypoxia [24].
Corneal swelling caused by hypoxia is a well-known phenomenon,
especially in relation to contact lens wear [25]. Long-term use of
contact lenses was shown to alter the following conditions in the
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cornea: epithelial oxygen uptake, epithelial thickness, stromal
thickness, and corneal endothelial morphology [26,27].
OSA causes decreased REM sleep percentage and CPAP usage
can usually reverse this decrease. If Maurice’s hypothesis is right,
then decreased REM percentage should jeopardize corneal
oxygenation. So far, no study has elucidated the relationship
between the CPAP usage and the corneal thickness. Thus, the
purpose of this study was to determine whether a correlation exists
between CPAP use and corneal thickness in patients with OSA.
Materials and Methods
Ethics statement We obtained Institutional Review Board approval from Baylor
College of Medicine (Houston,TX) for the procedures of the study.
Our study has been carried out in accordance with The Code of
Ethics of the World Medical Association (Declaration of Helsinki)
for experiments involving humans.
Subjects In this study, patients underwent standardized sleep center
clinical procedures. Men and women, admitted to the Sleep
Laboratory at Baylor College of Medicine, Michael E. DeBakey
Veterans Affairs Medical Center, for overnight polysomnography,
were eligible for this study. Subjects who met the following
inclusion criteria were selected for this study: patients must be
diagnosed with OSA, be 21–65 years of age (inclusive), and
provide written informed consent. We excluded patients with eye
(e.g., glaucoma) or neurological (e.g., periodic leg movement)
diseases. Twenty patients participated in the study, subjects were
randomly assigned to one of two groups (10 subjects in each
group). Patients who had used CPAP were called the ‘‘with-
CPAP’’ group, and patients who had not used CPAP were called
the ‘‘without-CPAP’’ group. However three subjects in the ‘‘with-
CPAP’’ group were excluded because they did not tolerate the
CPAP treatment. All subjects (1 woman and 16 men) were CPAP
naı̈ve. The ‘‘with-CPAP’’ group subjects underwent full-night
manual CPAP titration. The mean age in the with-CPAP group
was 5763.5 years and in the without-CPAP group 5962.2 years
(mean 6 S.E.M.). These age distributions were normal, as
demonstrated by normograms. The only additional procedures
for this study were pre- and post-sleep ultrasonic corneal thickness
measurement and visual acuity testing.
Corneal thickness measurement A DGH500 Pachette ultrasonic pachymeter with a hand-held
transducer (DGH Technology, Inc. Exton,PA) was used to
measure corneal thickness. The ultrasonic pachymeter calculates
readings based on an ultrasonic velocity of 1640 m/s for normal
human corneal thickness. To locate the center of the cornea, each
subject was instructed to stare directly at an ophthalmic pen light
positioned at eye level, approximately 2 meters from the subject.
Although there are other methods to measure corneal thickness,
such as optic and electronic digital methods, the ultrasonic method
is the most preferred one, because it is accurate, easy to use, and
reliable [28,29]. Thickness measurement of each cornea was done
15 times for each measurement and the arithmetic mean of 15
measurements was used as a parameter of statistical analysis of
each eye.
Visual acuity testing This procedure involves a standard eye chart. A second chart
was used to prevent memorization of letters by the subject, as each
individual was exposed to the chart twice. Right and left eyes of
patients were examined separately to assess visual acuity. In this
method, normal vision was accepted as 20/20 (Snellen unit). We
transformed these values to their decimal equivalents as 20/20 =
1. Normal vision is represented by ‘‘1’’. So, an increase in this
numerical value should be considered as better vision and vice
versa. These decimal values were then converted into a logarithm
of the minimum angle of resolution (logMar) equivalents.
Standardized sleep center clinical procedure Analysis included overnight polysomnography for diagnosis
followed by a night of CPAP titration. These procedures were
performed as part of a routine clinical evaluation. Full-night PSGs
were recorded according to standard practice. We made sleep
recordings using Grass Heritage computerized polysomnographic
systems. Standard surface electrodes were used to record
electroencephalographic, electrooculographic, electromyographic
(submental and anterior tibialis), and electrocardiographic activ-
ities. Nasal oral thermocouples monitor airflow, while thoracic and
abdominal movements indicate respiratory effort. Respiratory
tracings were scored for the presence of apneas (a 10 second, or
longer, cessation in nasal-oral airflow) or hypopneas (a 10 second,
or longer, reduction of nasal-oral airflow of 50%, or more). Blood
oxygen saturation was monitored with pulse oximetry (with the
sensor placed on the earlobe). Sleep latency, sleep efficiency,
percentage of time in each sleep stage, and other polysomno-
graphic parameters were calculated. Recording and scoring
techniques followed currently published standards for human
subjects; this includes procedures for sleep stages [30], respiration
[31], and leg movement [32]. In the morning, monitoring devices
were removed and the subject completed a post-sleep question-
naire detailing subjective sleep quality and quantity. A registered
polysomnographic technologist analyzed the sleep record and
oximetry data. Then, a staff physician reviewed the records. In
addition to the mentioned measurements, we also elicited REM
density value, which measures the frequency of rapid eye
movements during REM sleep. The formula used to calculate
REM density is described elsewhere [33].
Table 1. Pre and post sleep comparison of left and right corneal thickness of each group.
Group n Pre-Sleep Left Cornea Post-Sleep Left Cornea Pre-Sleep Right Cornea Post-Sleep Right Cornea
Without-CPAP 10 537.5611.6 * 553.5613.2 538.0610.8 ** 559.0611.5
With-CPAP 7 544.869.5 545.2610.2 545.768.9 551.469.7
Values are given as microns for corneal thickness (means 6 S.E.M.). *p = 0.0025 very significant (t = 4.134 with 9 degrees of freedom). The comparison is between Pre-Sleep and Post-Sleep of left corneal thickness in without-CPAP group. **p, 0.0001 extremely significant (t = 9.257 with 9 degrees of freedom). The comparison is between Pre-Sleep and Post-Sleep of right corneal thickness in without-CPAP group. doi:10.1371/journal.pone.0087274.t001
CPAP and Corneal Thickness
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Sleep questionnaires As a part of routine sleep center clinical procedure, we
administered a post-sleep questionnaire to subjects. In this
questionnaire, among many others, there were four questions
regarding vision after sleep. These questions were about ‘‘Clearer
Vision’’, ‘‘Dimmer Vision’’, ‘‘Blurred Vision’’, and ‘‘Eye Discom-
fort’’. They were asked to check one of the three options, which
were ‘‘less’’, ‘‘same’’, and ‘‘more’’.
Results
Subjects There was no statistically significant difference in the age
distribution between the two groups (p = 0.35). Thus, the groups
were considered comparable. In this study, patients underwent
standardized sleep center clinical procedures.
Corneal thickness versus REM percentages and REM density
Statistical analysis for corneal thickness was performed by
Student’s t-test using GraphPad InStat 3.1 and Prism 5.03,
GraphPad Software, San Diego, CA, USA. In the without-CPAP
group, corneal thickness increased significantly after one night’s
sleep. The two-tailed p value was 0.0025 for left cornea, and p was
, 0.0001 for right cornea. In the with-CPAP group, corneal
thickness did not increase significantly after one night’s sleep, as
measured using a two-tailed t-test.
The average percentages of REM sleep were 13.062.1 and
15.9864.0 in without-CPAP and with-CPAP groups, respectively.
An Unpaired test was performed to compare REM sleep
percentages of both groups and no significant difference was
found. The Pearson correlation coefficient was calculated to test
the null hypothesis that there was no correlation between REM
sleep percentages and corneal thickness values. No significant
correlation was found (r 2
= 0.124 for right cornea, 0.187 for left
cornea in with-CPAP group and; 0.123 for right cornea, 0.275 for
left cornea in without-CPAP group). Corneal thickness values of
both groups are listed in Table 1, and associated REM sleep
percentages and REM density values are listed in Table 2. Values
are given as microns for corneal thickness, and as a percentage for
REM sleep (mean 6 S.E.M.).
The average REM density values were 9.160.6 and 11.560.7
in without-CPAP and with-CPAP groups, respectively. An
Unpaired test was performed to compare REM density values of
both groups and, we observed that the REM density value of the
with-CPAP group is noticeably higher than that of the without-
CPAP group (p, 0.05). The Pearson correlation coefficient was
calculated to test the null hypothesis that there was no correlation
between REM density and corneal thickness values. No significant
correlation was found (r 2
= 0.308 for right cornea, 0.458 for left
cornea in with-CPAP group and; 0.003 for right cornea, 0.015 for
left cornea in without-CPAP group).
Visual acuity Eye chart examination revealed vision improvement in 7 eyes
and deterioration in 3 eyes, while it revealed no change in 10 eyes
of the without-CPAP group (10 patients, 10 pairs of eyes). In the
with-CPAP group (7 patients, 7 pairs of eyes), vision improvement
was observed in only one eye, and deterioration was observed in 5
eyes, while no change was observed in 8 eyes. There was no
Table 2. Demographic and polysomnographic variables in all subjects.
Group n Age (years old) BMI (kg/m 2
) SpO2 (%) Pre-CPAP AHI AHI Baseline REM (%) REM (%) REM Density
Without-CPAP 10 5962.2 30.461.8 90.961.2 --- 24.063.2 --- 13,062,17 9.160.6
With-CPAP 7 5763.5 32.562.1 92.661.9 25.963.1 6.560.7 12,362,0 15,964,0 11.560.7
p value --- 0,6730 0.4883 0.4615 --- 0.0005 --- 0.4858 0.0354
All values are presented as means 6 S.E.M. doi:10.1371/journal.pone.0087274.t002
Table 3. Visual acuity values of each patient.
Without-CPAP Group With-CPAP Group
Right Eye Pre- sleep
Right Eye Post-sleep
Left Eye Pre-sleep
Left Eye Post-sleep
Right Eye Pre-sleep
Right Eye Post-sleep
Left Eye Pre-sleep Left Eye Post-sleep
20/16 20/16 20/16 20/16 20/16 20/16 20/16 20/16
20/20 20/20 20/16 20/16 20/25 20/20 20/25 20/25
20/60 20/40 20/20 30/20 20/25 20/25 20/30 20/40
20/20 20/16 20/20 20/16 20/20 20/25 20/20 20/25
20/16 20/20 20/16 20/20 20/25 20/25 20/25 20/25
20/20 20/20 20/25 20/25 20/25 20/25 20/25 20/25
20/20 20/20 20/20 20/20 20/16 20/20 20/16 20/20
20/25 20/20 20/20 20/16 --- --- --- ---
20/30 20/30 20/40 20/25 --- --- --- ---
20/50 20/50 20/25 20/30 --- --- --- ---
Values are given as Snellen units. doi:10.1371/journal.pone.0087274.t003
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statistically significant difference in visual acuity before and after
sleep (p.0.05) for both groups. Visual acuity values of each patient
before and after sleep are given as Snellen units in Table 3. Figure
1 shows eye chart visual acuity results as logMar equivalents.
Overnight polysomnography values Apnea-hypopnea index (AHI), blood oxygen saturation levels
(SpO2) and REM Density values of both groups are given in Table
2. Values are presented as mean 6 S.E.M. by using Student’s t
test.
Sleep questionnaires According to the sleep questionnaire results, all of the with-
CPAP group patients claimed that they had better vision after
sleep. Our results showed that there were statistically significant
changes in blurred vision and dimmer vision while there were no
significant changes in clear vision and eye discomfort between
groups. However, following Bonferroni adjustment for four
comparisons and the adoption of p = 0.0125 as the border level
of statistical significance, the indicated differences became
statistically insignificant. Figure 2 shows these post-sleep question-
naire results.
Discussion
In this study, we assessed the relationship between CPAP usage
and corneal thickness. According to our results, there is a
significant increase in corneal thickness in the without-CPAP
group. Our results show that REM density value for the with-
CPAP group was higher than that of the without-CPAP group (p,
0.05); however, the raw REM percentages of both groups were not
significantly different, and no significant correlation was found
between REM sleep percentages and corneal thickness values. The
reason for this inconsistency is that REM sleep percentages and
REM densities are different measurements, even though REM
density is a derivative of REM percentage. REM density is defined
as the percentage of time (in minutes) in which rapid eye
movements occurred during the respective period of REM sleep,
considering that amplitude of eye movements is higher than
25 mV [33]. Calculation of this index was made by the following
equation: total minutes of rapid eye movements/total minutes of
REM sleep x 100.
The tonic components of REM sleep (REM duration, the REM
percent of sleep period time) may be increased while the REM
density is significantly decreased due to prolongation of total REM
duration and a parallel reduction of the total number of eye
movements [34]. Several studies confirm the independence of
REM density from other REM sleep parameters observed after
selective paradoxical sleep deprivation and after the administra-
tion of cholinergic drugs [35]. Another reason for inconsistency
may be the small sample size of our study. Increasing the sample
size may cause a significant difference in the raw REM
percentages.
During night sleep, REM sleep has been proposed as a factor
aiding corneal oxygenation [16]. The literature shows that
extended usage of contact lenses diminishes corneal tissue
Figure 1. Results of eye chart visual acuity test for the without-CPAP group (A) and with-CPAP group (B) are presented in bar graph. There is no significant difference between groups. Error bars = S.E.M. doi:10.1371/journal.pone.0087274.g001
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oxygenation [26]. Our study demonstrated that REM density
decreased in OSA patients. However, there is no study to analyze
corneal oxygenation data for contact lens usage in OSA patients.
Based on this study and a literature review, we believe that OSA
patients who wear hard contact lenses might be at risk for corneal
thickening. However, this hypothesis requires further studies to be
confirmed. Finally, this study is also limited by the lack of a formal
control group of individuals who did not have OSA.
To our knowledge, this is the first study showing that OSA
patients experience corneal thickness increase during sleep.
Because our data are concerned with the acute effect of OSA on
the cornea, we only analyzed one night of pre and post sleep data.
Therefore, further studies of long term effects of OSA on corneal
thickness are required. Our study emphasizes the following points.
First, OSA patients who wear hard contact lenses should be
monitored carefully, because their corneal thickness can also be
affected by decreased REM percentages. Second, it may be
prudent for clinicians to consider the possibility of glaucoma in
OSA patients and vice versa. Glaucoma is one of the leading
causes of visual impairment and blindness [36]. OSA patients have
a higher prevalence of glaucoma and ocular hypertension [37], so
any patients with increased corneal thickness should be evaluated
carefully.
In summary, we do not claim that rapid eye movements are
indispensable for a healthy cornea or that the only function of
REM sleep is to provide oxygen to the cornea. But our data show
that corneal thickness increased in OSA patients, and this finding
must be kept in mind when evaluating these patients. Further
research would be useful with larger numbers of patients, and
longer follow-ups are required to confirm the effect of OSA on the
cornea.
Author Contributions
Conceived and designed the experiments: EG. Performed the experiments:
EG. Analyzed the data: EG MTB SA. Contributed reagents/materials/
analysis tools: EG MTB SA. Wrote the paper: EG MTB.
Figure 2. Results of post-sleep questionnaire of ‘‘with-CPAP’’ (CPAP) and ‘‘without-CPAP’’ (wo/CPAP) groups. The questionnaire is made-up of four categories, which are Blurred Vision (BV) – panel A, Dimmer Vision (DV) – panel B, Clear Vision (CV) – panel C and Eye Discomfort (ED) –panel D. Statistically significant (i.e., accepted as p,0.05) p values are shown in the figure. Non-significant p values are not shown. The possible three answers to each of the categories are summarized as ‘‘Less answer’’ = ‘‘Less’’, ‘‘Same answer’’ = ‘‘SameMore’’ and ‘‘More answer’’ = ‘‘SameMore’’ to make an easy interpretation of data. doi:10.1371/journal.pone.0087274.g002
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