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Association Between Sleep Apnea Syndrome and Nonarteritic Anterior Ischemic Optic Neuropathy
Daniel S. Mojon, MD;
Thomas R. Hedges III, MD;
Bruce Ehrenberg, MD;
Emely Z. Karam, MD;
David Goldblum, MD;
Alex Abou-Chebl, MD;
Matthias Gugger, MD;
Johannes Mathis, MD
Arch Ophthalmol. 2002;120:601-605.
ABSTRACT
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Objective To determine if patients with nonarteritic ischemic optic neuropathy
(NAION) have sleep apnea syndrome (SAS), an entity characterized by repetitive
upper airway obstructions during sleep, inducing hypoxia and sleep disruption.
Methods We recruited 17 patients with NAION and 17 age- and sex-matched controls
from patients referred for treatment because of suspected restless legs syndrome.
We performed overnight polysomnography and determined the respiratory disturbance
index during night sleep, a value used to diagnose and grade SAS. We compared
the proportions of patients with SAS among patients with NAION and matched
controls using the  2 test. Additionally, we compared the proportions
of patients with SAS among patients with NAION and a large SAS prevalence
study using the binomial test.
Results Twelve (71%) of 17 patients with NAION had SAS. According to the respiratory
disturbance index, 4 patients (24%) had mild, 4 patients (24%) had moderate,
and 4 patients (24%) had severe SAS. Only 3 (18%) of 17 controls had SAS (P = .005). In the 45- to 64-year age group, 4 (50%) of
8 patients with NAION had SAS; 51 (11.9%) of 430 of the random sample in the
prevalence study had SAS (P = .005). In the group
older than 64 years, 8 (89%) of 9 patients with NAION had SAS; 18 (24%) of
75 of the random sample in the prevalence study had SAS (P<.001).
Conclusions We found a high prevalence of SAS in patients with NAION, which supports
previous case reports suggesting that such an association exists. This association
may explain why approximately 75% of all patients with NAION discover visual
loss on first awakening or when they first use vision critically after sleeping.
Our findings indicate that SAS may play an important role in the pathogenesis
of NAION.
INTRODUCTION
NONARTERITIC anterior ischemic optic neuropathy (NAION) is a disease
characterized by sudden, painless, mostly irreversible, and generally nonprogressive
visual loss accompanied by nerve fiber bundle field defects, a relative afferent
pupillary defect, and optic disc edema. The pathophysiologic characteristics
of NAION remains unclear. Although several risk factors have been associated
with this relatively common condition, the exact mechanism(s) that lead to
optic nerve infarction remain unknown. Risk factors include aging, a small
optic nerve head, and microvascular changes associated with diabetes and systemic
hypertension.1 No treatment is available since
neither steroids nor surgical optic nerve sheath fenestration has proved to
be effective. Prevention with aspirin has not been demonstrated to be effective,
although it is recommended.2
Many patients with NAION notice their symptoms in the morning.3 This has prompted investigations into changes in the
systemic blood pressure at night in patients with NAION3-4
and raises the question of whether other nocturnal events may predispose patients
to NAION. In a 1986 case report, optic disc edema was associated with sleep
apnea syndrome (SAS).5 Recently, reports by
Hayreh1 and Mojon et al6
suggest an association between NAION and SAS. Other ophthalmologic findings
in patients with SAS include floppy eyelid syndrome, keratoconus, reduced
tear film break-up time, endothelial dystrophy,7
and glaucoma.8
Sleep apnea syndrome is a disease characterized by recurrent complete
or partial upper airway obstructions during sleep.9-10
These obstructive respiratory disturbances may last from 10 seconds to 2 minutes,
leading to severe hypoxia and hypercapnia. Obstructions are terminated only
after arousal from sleep, when upper airway muscle tone increases. Several
hundreds of respiratory disturbances may occur during one night and cause
severe sleep disruption with consequential daytime sleepiness. Typically,
middle-aged and older, obese men with a long-lasting history of loud snoring
are affected.11 The repetitive sympathetic
activation during arousal from sleep may cause serious cardiac arrhythmias
and systemic hypertension. Such patients often show pulmonary-arterial hypertension,
cor pulmonale, and, in severe forms, polycythemia. Sleep apnea syndrome is
now recognized as an important risk factor for cardiovascular and neurovascular
diseases.10
Sleep apnea syndrome is usually diagnosed by overnight polysomnography,
including simultaneous electroencephalography, electromyography, electro-oculography,
electrocardiography, oxymetry, plethysmography, and air flowmetry through
the mouth and nose. From the polysomnographic data, the respiratory disturbance
index (RDI), a value used to diagnose and grade SAS, is calculated. The treatment
of first choice to prevent upper airway obstructions is the application of
nasal continuous positive airway pressure with a mask during sleep.10 In this study, we prospectively determined the prevalence
of SAS in patients with NAION.
PATIENTS AND METHODS
PATIENTS
We included all patients with NAION seen consecutively for 9 months
at the Department of Ophthalmology, University of Bern, Bern, Switzerland
(11 patients) and for 6 months at the New England Eye Center, Boston, Mass
(12 patients). Eight (73%) of 11 patients in Bern and 9 (75%) of 12 patients
in Boston agreed to undergo overnight polysomnography. The Epworth Sleepiness
Scale scores were not significantly different between the group of patients
not undergoing and the group undergoing polysomnography. The protocol was
approved by the ethics committees of the University of Bern and New England
Eye Center. All patients had partial loss of visual field, a relative afferent
pupillary defect, loss of color vision, and swelling of the optic nerve head.
All had crowded optic nerves with a cup-to-disc ratio of less than 0.1. None
of them had symptoms, signs, or laboratory evidence of giant cell arteritis.
In all patients with progressive visual loss, visual loss reached its maximum
before the 10th day after onset.
POLYSOMNOGRAPHY
Overnight polysomnography was recorded during at least 6 hours in quiet,
custom-built sleep laboratories. Recordings included electroencephalography,
electro-oculography, electromyography, and nasal and oral airflow by thermistors.
Simultaneously, inductive plethysmography (chest, abdomen, and sum) was performed
and oxygen saturation was measured with a pulse oximeter.
POLYSOMNOGRAPHIC DATA ANALYSIS
The raw data were stored on a personal computer and analyzed off-line
with sleep analysis software. Analysis was performed automatically by the
software. Sleep apnea syndrome was diagnosed and graded according to the RDI
(normal RDI, <10): mild SAS, RDI of 10 or more but less than 20; moderate
SAS, RDI of 20 or more but less than 40; severe SAS, RDI of 40 or more.10
CONTROLS FOR POLYSOMNOGRAPHY
Seventeen patients referred for polysomnography because of suspected
restless legs syndrome were used as controls. The controls were matched in
a masked fashion for age (15 within 5 years of age, 2 within 10 years of age),
sex, and participating Department of Ophthalmology (Bern or Boston). Additionally,
the prevalences of SAS that we found in patients with NAION were compared
with a 2-stage general random sample of men (aged 20 to 100 years) examined
and previously described by Bixler et al.12
This study represents the largest prevalence study available today. Their
telephone survey included 4364 subjects; a subsample of 741 had a sleep laboratory
evaluation. The subsample was grouped according to the RDI and age. Details
about systemic diseases other than SAS were not provided.
STATISTICAL ANALYSIS
Prevalences of SAS in patients with NAION were compared with the matched
controls and with the controls of the prevalence study using the 2 test or Fisher exact test and with the controls from the prevalence
study using the binomial test. Comparison of the clinical and polysomnographic
characteristics of the patients with NAION and matched controls was performed
using the unpaired t test or Fisher exact test.13
RESULTS
The clinical and polysomnographic data of all patients with NAION are
summarized in Table 1. The age
of the 17 patients (15 men and 2 women) ranged from 48 to 83 years.
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Table 1. Clinical and Polysomnographic Data of All Patients With Nonarteritic
Anterior Ischemic Optic Neuropathy*
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Table 2 gives the summarized
clinical and polysomnographic findings of the patients with NAION and matched
controls. Except for the RDI, no statistically significant difference was
found between the 2 groups. Six (75%) of 8 patients with NAION seen at the
University Eye Institute of Bern had SAS (RDI  10). Six (67%) of 9 patients
with NAION seen at the New England Eye Center had SAS. Twelve (71%) of all
17 patients with NAION seen at either center had SAS. All patients with SAS
were men. According to the RDI, 4 patients (24%) had mild, 4 patients (24%)
had moderate, and 4 patients (24%) had severe SAS. Table 2 gives the prevalences of SAS in patients with NAION (71%)
and the matched controls (18%). The difference is statistically significant
(P = .005). Also, the average RDI differed significantly
between these 2 groups (P = .04).
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Table 2. Summarized Clinical and Polysomnographic Findings of Patients
With Nonarteritic Anterior Ischemic Optic Neuropathy (NAION) and Controls
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The prevalences of SAS were also compared with data from a large prevalence
study.12 In the 45- to 64-year age group, 4
(50%) of 8 patients with NAION had SAS, whereas only 41 (10%) of 430 in the
prevalence study had SAS. The SAS prevalence in patients with NAION was significantly
higher than in the controls (P = .005). In the group
of patients older than 64 years, 8 (89%) of 9 patients with NAION had SAS,
whereas only 18 (24%) of 75 in the prevalence study had SAS. In this age group,
the difference in prevalence was also significantly higher (P<.001).
COMMENT
We found an increased prevalence of SAS in patients with NAION. Sleep
apnea syndrome is a frequent breathing disorder caused by intermittent upper
airway obstruction during sleep with concurrent hypoxia, negative intrathoracic
pressure, and sympathetic activation. Since airway obstructions are terminated
by repetitive arousal reactions, normal sleep is disrupted. Long-term cardiovascular
sequelae and complications include pulmonary and systemic arterial hypertension,
cardiac arrhythmias, myocardial infarction, and stroke.9, 14-15
Sometimes only episodic nocturnal systemic arterial hypertension or hypotension
occurs.16
Recently, Hayreh1 mentioned that he had
anecdotal evidence of SAS in several patients with NAION. Also, Mojon and
colleagues6 found that visual fields of patients
with SAS revealed defects consistent with an optic neuropathy. More recently,
SAS was found to be associated with optic disc swelling and visual field loss
apparently due to intermittent increased intracranial pressure.17
In this cross-sectional study, we further investigated if an association
between SAS and NAION exists. We found that approximately 70% of patients
with NAION had SAS. The prevalences we found in patients with NAION were significantly
higher than in age- and sex-matched controls. Regarding general characteristics
and cardiovascular risk factors, the NAION group did not differ significantly
from the matched controls. Also, when compared with the prevalences found
by Bixler et al12 in a large telephone random
sample of men, the prevalences were significantly higher. Grouping by age
is important because prevalence of SAS increases with increasing age.12 Other studies18-21
have shown prevalences similar to those of the study by Bixler and coauthors.
Because the prevalence of SAS for all ages is lower in women compared with
men,22 the differences between our subjects,
who were mostly men, and those in the prevalence study by Bixler and colleagues
might even be greater.
Our own control group consisted of age- and sex-matched subjects with
restless legs syndrome and were not age- and sex-matched healthy subjects.
These patients were referred from the outpatient sections of the departments
of neurology because of the clinical suspicion of restless legs syndrome and
were not recruited from the sleep clinics. This group of patients had a prevalence
of SAS similar to the general population, and this is consistent with other
studies23-24 of restless legs
syndrome and SAS.
Our sample size is relatively small and was obtained in 2 centers. However,
all patients were prospectively recruited, and the results from the 2 testing
centers were similar. There were more men than women, but when we calculated
if no sex predilection existed, each 10th sample of 17 patients with NAION
would be composed of 15 men just by chance. Since the restless legs control
group was age and sex matched and the control group of Bixler et al12 consisted of only men, no bias has been introduced
by our high percentage of men. Since we performed a double comparison of our
SAS prevalences among patients with NAION with our own and a historic control
group, and since we found similar prevalences in 2 independent centers, we
believe that our high SAS prevalence is real and clinically significant.
Our observational data do not allow any conclusions about a direct causal
relationship between SAS and NAION. However, if we hypothesize that SAS causes
NAION in some cases, the damage may result from impaired optic nerve head
blood flow autoregulation,25 secondary to repetitive
prolonged apneas. Alternatively, optic nerve vascular dysregulation might
be secondary to SAS-induced arterial blood pressure variations (episodic nocturnal
hypertension or hypotension) and arteriosclerosis1
or the imbalance between nitric oxide (a vasodilator) and endothelin (a vasoconstrictor).26 Repetitive prolonged hypoxia also might damage the
optic nerve directly. Because of the large stores of carbon dioxide and excellent
buffering capacity of the body, changes in PaCO2 and pH during
apneas remain modest in contrast to changes in PaO2, and, therefore,
PaCO2 variations do not seem to be harmful.27
Episodic increased intracranial pressure during apnea spells17
may also have adverse effects on the optic nerve head, either directly or
by compromising optic nerve circulation.
Approximately 75% of all patients with NAION discover visual loss on
first awakening or at the first opportunity to use vision critically after
sleeping.3 This might indicate that not only
nocturnal arterial hypotension but also SAS could play an important role in
the pathogenesis of NAION. Since there is no proven treatment of NAION, further
studies are needed to clarify whether repetitive nocturnal upper airway obstructions
might directly damage the optic nerve, whether continuous positive airway
pressure treatment might help affected patients recover from NAION, and whether
long-term treatment might help prevent involvement of the second eye. The
recognition of SAS in any patient also may reduce the risk of cardiovascular
or cerebrovascular disease.
AUTHOR INFORMATION
Submitted for publication January 9, 2001; final revision received December
21, 2001; accepted January 10, 2002.
This study was presented in part at the American Academy of Ophthalmology
Annual Meeting, New Orleans, La, November 8-11, 1998, and at the International
Neuro-Ophthalmology Society Meeting, Dublin, Ireland, July 19-23, 1998.
We thank Pietro Ballinari, PhD (Institute of Psychology, University
of Bern, Bern, Switzerland) for statistical advice, and Cathrin Morger, PSGT,
Heidi Mani, PSGT, and Kate E. Corbett, REEGT, PSGT, for performing the sleep
studies.
Corresponding author and reprints: Thomas R. Hedges III, MD, New
England Eye Center, 750 Washington St, Box 381, Boston, MA 02111.
From the Departments of Ophthalmology (Drs Mojon and Goldblum), Pneumology
(Dr Gugger), and Neurology (Dr Mathis), University of Bern, Bern, Switzerland;
Department of Strabismus and Neuro-ophthalmology, Kantonsspital, St. Gallen,
Switzerland (Dr Mojon); and Departments of Ophthalmology (Drs Hedges and Karam)
and Neurology (Drs Hedges, Ehrenberg, and Abou-Chebl), New England Medical
Center, Boston, Mass.
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