Keywords
post intensive care syndrome - OSA - floppy eyelid syndrome - FES - sleep - CPAP
Introduction
Obstructive sleep apnea syndrome (OSA) is a common sleep disorder characterized by
recurrent episodes of partial or complete upper airway obstruction during sleep. It
causes arterial oxygen desaturation, sleep fragmentation, and daytime sleepiness.[1] It has been hypothesized[2] that frequent arousals, deoxygenation, and reoxygenation result in the activation
of the sympathetic nervous system, causing oxidative stress, an acute increase in
blood pressure, and systemic inflammation.
Due to the systemic inflammation, OSA could cause changes in the microvasculature,[3] abnormal vascular reactivity in the cerebral circulation,[4]
[5] stroke,[6]
[7] cardiovascular events such as hypertension[8]
[9] and coronary artery disease,[10] and even death. Obstructive sleep apnea syndrome can have a similar effect on the
eyes; the ocular manifestations of OSA derive from its mechanical and vascular effects,
and they include central retinopathy, retinal vein occlusion, glaucoma, papilledema,
corneal abnormalities, nonarteritic anterior ischemic optic neuropathy (NAION),[11] and floppy eyelid syndrome (FES). Kadyan et al.[12] observed that eye rubbing, gritty sensation, mucoid discharge, and photophobia were
significantly frequent in patients with OSA; FES is known to be one of the more common
eye diseases associated with OSA.[13]
First described in 1981 in obese middle-aged men by two ophthalmologists, Culbertson
and Ostler,[14] FES is a condition in which the upper eyelids easily evert with upward traction[15] due to underlying tarsal plate laxity; it is associated with chronic reactive papillary
conjunctivitis, which causes the eye to be vulnerable to discomfort and visual symptoms.
The prevalence of FES in the adult population ranges from 3.8% to 15.8%, although
this is likely an underestimation.[16]
Studies[11]
[16]
[17] in the literature have found a statistically significant association between FES
and OSA. Several studies have reported[11]
[17]
[20] a nearly 100% prevalence of OSA among FES patients, while other authors[16] have presented more conservative estimates. Although the prevalence of OSA is high
among FES patients, some studies[11]
[17] suggest that only 2% to 5% of OSA patients present simultaneously with FES. Chambe
et al.,[13] in a prospective study with 127 patients, observed FES in 22.8% of their OSA population
and higher FES prevalence in severe OSA cases. Controversial findings are reported
about the relationship between FES and OSA; however, why patients with OSA are at
risk for FES is not known.[18] There is some histologic evidence that suggests mechanisms linking FES and OSA.
The pharyngeal collapse in OSA occurs due to connective tissue compromise against
increased neck thickness, and FES histology reveals decreased elastin content and
increased matrix metalloproteinase activity in the eyelid's connective tissue, which
presents similar weakness.[15]
The association between FES and OSA has both diagnostic and therapeutic implications.
The current case report shows how an appropriate OSA treatment with continuous positive
airway pressure (CPAP) results in the improvement of FES-related symptoms.
Case Report
A 49-year-old man with hypothyroidism, hyperlipidemia, gastroesophageal reflux disease
(GERD), and mild obesity (body mass index [BMI]: 34 Kg/m2), with an 8-year history of snoring, sleep fragmentation, and daytime sleepiness,
was admitted as an outpatient to our sleep clinic. He also complained of nocturnal
groaning (catathrenia), restless legs syndrome before sleep, sweating, and palpitation.
The diurnal symptoms were excessive daytime sleepiness, sleep attacks, a recent history
of aggression, depressed mood, and asthenia (which caused a decrease in performance
in his job as medical equipment salesman), and his score on the Epworth Sleepiness
Scale (ESS) was of 13/24. Despite his daytime sleepiness, narcolepsy was excluded
due to lack of sleep paralysis, hypnagogic hallucinations, and cataplexy. The medication
he was taking included pantoprazole, domperidone, atorvastatin, and levothyroxine.
History of family diseases included diabetes mellitus, hypertension, and hyperlipidemia
on the mother's side. His habitual history included heavy smoking and opioid abuse.
Furthermore, the patient had experienced ocular symptoms such as burning eyes, redness,
and irritation for 5 years, which were felt upon waking up. Xerophthalmia in the presence
of burning and pain, palpebral laxity, conjunctival hyperemia and irritation, puffy
eyes, poor vision, and strabismus were also present. The ocular symptoms started in
the right eye and then spread to the left (the symptoms in the right eye have been
more severe), and they did not improve with artificial tears or proper ointments.
On the upper airway examination, the patient's presented a Mallampati score of 4,
and the tonsil grade was 1. Venus blood gas analysis showed pH of 7.434, partial pressure
of oxygen (PaO2) of 45.4 mmHg, and partial pressure of carbon dioxide (PaCO2) of 39 mmHg. The patient underwent polysomnography, which showed severe OSA that
worsened in the supine position. The total sleep time measured was of 276 minutes.
The patient had 301 apneas and hypopneas (192 obstructive apneas [41.7%], 17 mixed
apneas [3.7%], 61 central apneas [13.3%], and 31 hypopneas [6.7%]), which resulted
in a total apnea/hypopnea index (AHI) of 65.4. The patient was referred for a cardiologic
consultation, and the pulmonary artery wedge pressure in the echocardiogram was of
35 mmHg.
A positive airway titration study was recommended. After an in-laboratory positive
airway pressure (PAP) titration study, CPAP of 12 cmH2O resolved the respiratory events and snoring. Accordingly, the patient started undergoing
CPAP with a pressure of 12 cmH2O. Escitalopram 10 mg was prescribed daily to control anxiety. Orofacial myofunctional
therapy and weight loss were also recommended, but the patient did not adhere to them.
At the follow-up visit, the rate of adherence of the patient to the CPAP therapy was
of 81%, and he reported improvement in eye symptoms, snoring, and anxiety, although
the burning in the eyes was still present occasionally. He felt uncomfortable with
the Amara mask, so we recommended the use of a full-face mask to cover his nose bridge.
The treatment efficacy was confirmed by a further respiratory assessment that showed
a significant reduction in the AHI to 0 events/hour (−100% compared to the versus
baseline index). The obstructive apnea index, central apnea index, obstructive hypopnea
index, and central hypopnea index were also of 0 events/hour. Nocturnal oximetry data
significantly improved: Sleep efficacy was improved (from 58.9% to 77.4%) in the PAP
titration study. Other OSA symptoms were significantly reduced.
Discussion
Floppy eyelid syndrome is a condition in which the eyelids easily evert with upward
traction,[15] causing the eye to be vulnerable to discomfort and visual symptoms. Several studies
have reported[11]
[16]
[17] a statistically significant association between FES and OSA: FES may be a presenting
symptom in patients with undiagnosed OSA; in addition, the treatment of obesity and
OSA may have a favorable effect on the course of FES. This association (with an odds
ratio of 12.5) persists even when controlled for obesity and other confounding factors.[19]
Muniesa et al.[20] tried to determine the correlation between OSA and FES bidirectionally. They studied
OSA patients – among whom they determined the prevalence of palpebral hyperlaxity
– and patients already diagnosed with FES – in whom they performed polysomnography
studies, and they found a considerably higher incidence of eyelid hyperlaxity in OSA
than in non-OSA patients (p = 0.004). A total of 38 of the 45 patients with FES were diagnosed with OSA (85%),
and 65% had severe OSA. They[20] concluded that OSA might be an independent risk factor for eyelid hyperlaxity, and
severe OSA is common in patients with FES.
Histologic evidence suggests mechanisms linking FES and OSA. Connective tissue compromise
against increased neck thickness is the cause of the pharyngeal collapse in OSA, and
FES histology shows reduced elastin content and increased matrix metalloproteinase
activity in the eyelid's connective tissue, which presents similar weakness.[15] Analogous to the increased neck thickness in OSA, FES patients display tissue redundancy
in the lateral canthal tendon.[15] Patients with FES often experience symptoms on the side on which they sleep, verifying
the theory of mechanical stress as the cause of the syndrome.
Eyelid histology in FES also shows chronic inflammation with no tissue atrophy,[15] which suggests a second sleep apnea theory for the development of FES: pressure
from sleeping on a particular side induces transient ischemia in eyelid tissue, which
is aggravated by hypoxia during apneic events. With the resumption of normal breathing,
reperfusion oxidation injury may cause continuous eyelid inflammation.[15] The FES observed in OSA patients is related to chronic inflammation and underlying
connective tissue weakness. Histopathology alterations and the relationship between
FES and OSA seem to support the hypothesis that both processes could be different
manifestations of the same condition.
The treatment for FES is ophthalmological, with frequent instillation of artificial
tears and ocular lubricants. To date, few studies[11]
[12]
[18]
[21] have reported effect of the CPAP treatment on reversing FES-related symptoms on
the eye and ocular surface. Furthermore, a limited number of sleep medicine and ophthalmology
healthcare professionals are aware of the association between these entities.
Vieira et al.[22] conducted a prospective study with 47 patients with newly-diagnosed OSA who underwent
objective diagnostic testing for FES to analyze the effect of CPAP on FES before and
after 6 months of the therapy. Patients with nonreversible FES presented more severe
OSA and worse airway access according to the Mallampati score. A higher AHI in the
supine position might predict FES. After CPAP therapy, FES is resolved in 53.8% of
the patients. They[22] concluded that CPAP therapy might reverse FES symptoms.
In the case herein reported, CPAP therapy significantly corrected apnea/hypopnea,
oxygen nocturnal desaturation, and improved the quality of the sleep pattern and daytime
symptoms. The present report highlights the considerable effect of CPAP treatment
on signs and symptoms of FES associated with OSA. This would help raise awareness
regarding the ocular findings in patients with OSA and contribute to the identification
of hidden sleeping diseases needing a more appropriate investigation and possible
treatment. Sleep medicine specialists and ophthalmologists should pay greater attention
to the ocular symptoms of the patients and consider a deeper collaboration.
