Obstructive sleep apnea syndrome
Massimo R. Mannarino⁎, Francesco Di Filippo, Matteo Pirro
Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
a b s t r a c ta r t i c l ei n f o
Received 6 March 2012
Received in revised form 8 May 2012
Accepted 11 May 2012
Available online 24 June 2012
Obstructive sleep apnea
Continuous positive airway pressure
Obstructive sleep apnea (OSA) syndrome is a common but often unrecognized disorder caused by pharyngeal
collapse during sleep and characterized by frequent awakenings, disrupted sleep and consequent excessive
daytime sleepiness. With the increasing epidemic of obesity, the most important risk factor for OSA, preva-
lence of the disease will increase over the coming years thus representing an important public-health prob-
lem. In fact, it is now recognized that there is an association between OSA and hypertension, metabolic
syndrome, diabetes, heart failure, coronary artery disease, arrhythmias, stroke, pulmonary hypertension,
neurocognitive and mood disorders. Diagnosis is based on the combined evaluation of clinical manifestations
and objective sleep study findings. Cardinal symptoms include snoring, sleepiness and significant reports of
sleep apnea episodes. Polysomnography represents the gold standard to confirm the clinical suspicion of OSA
syndrome, to assess its severity and to guide therapeutic choices. Behavioral, medical and surgical options are
available for the treatment. Continuous positive airway pressure (CPAP) represents the treatment of choice in
most patients. CPAP has been demonstrated to be effective in reducing symptoms, cardiovascular morbidity
and mortality and neurocognitive sequelae, but it is often poorly tolerated. The results of clinical studies do
not support surgery and pharmacological therapy as first-line treatment, but these approaches might be use-
ful in selected patients. A better understanding of mechanisms underlying the disease could improve thera-
peutic strategies and reduce the social impact of OSA syndrome.
© 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Obstructive sleep apnea (OSA) syndrome is a common sleep disor-
der in which complete or partial airway obstruction, caused by pharyn-
geal collapse during sleep, causes loud snoring or choking, frequent
awakenings, disrupted sleep and excessive daytime sleepiness. When
obstruction of the airway occurs, the inspiratory airflow can be either
reduced (hypopnea) or completely absent (apnea). OSA syndrome is
defined as five or more episodes of apnoea or hypopnoea per hour of
sleep with associated symptoms (e.g., excessive daytime sleepiness,
fatigue, or impaired cognition) or 15 or more obstructive apnea-
hypopnea events per hour of sleep regardless of associated symptoms
[1,2]. Itisnow recognized that OSA is often associatedwithsevere com-
plications including major cardiovascular disorders, neurocognitive se-
quelaeand mood disorders. Indeed,there is a growingbody of evidence
that a strong correlation exists between the disease and hypertension,
impairment with changes in attention and concentration, executive
function and fine-motor coordination are common complaints of
patients with OSA. Finally, depression can represent a significant prob-
lem in the course of the disease.
With the increasing prevalence of obesity, the most important risk
factor in sleep breathing disorders, the number of patients diagnosed
as suffering from OSA has increased drastically in the last few years
 and it will increase over the coming years. Today, OSA syndrome
represents a major public health issue with potential societal conse-
quences and recognition of this syndrome is essential if a significant
burden of risk is to be prevented.
Population-based studies suggest that 4 percent of men and 2 per-
cent of women aged more than 50 years suffer from symptomatic
OSA . However, OSA is often asymptomatic and the prevalence of
patients with OSA, who do not present clinical syndrome, might be
as high as 20–30% in the middle-aged population .
Patients with OSA are more frequently male, obese and aged
65 years or more. Obesity is certainly the most important risk factor:
a 10% weight gain increases the risk of developing OSA by six-times
. The androgenic pattern of body fat distribution, in particular
deposition in the trunk, including the neck area, may predispose
men to OSA. Furthermore, sex hormones may affect neurologic
control of the upper airway dilating muscles and ventilation .
Postmenopausal women are at higher risk of developing OSA than
are their premenopausal counterparts , an effect that hormone
replacement therapy could prevent or ameliorate .
European Journal of Internal Medicine 23 (2012) 586–593
⁎ Corresponding author at: Unit of Internal Medicine, Angiology and Arteriosclerosis,
University of Perugia, Perugia, Italy, Hospital “Santa Maria della Misericordia”, Piazzale
Menghini, 1‐06129, Perugia, Italy. Tel.: +39 075 5783172; fax: +39 075 5784022.
E-mail address: firstname.lastname@example.org (M.R. Mannarino).
0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Contents lists available at SciVerse ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
The risk of OSA increases with increasing age. OSA prevalence in-
creases 2–3 times in older persons (>65 years) compared with indi-
viduals aged 30–64 years . Nevertheless, OSA is also described
in children with adenotonsillar hypertrophy . Finally the risk of
developing the disease appears to be related to race. African Ameri-
cans are more frequently affected and develop OSA at a younger age
than white people .
Both anatomic and neuromuscular factors are involved in the de-
velopment of obstruction of the upper airway in OSA. The human
pharynx can be considered as a collapsible tube that serves several
purposes including speech, swallowing and respiration; it is not pro-
vided with a rigid skeletal support and, during normal inhalation, it
undergoes numerous stresses promoting its collapse. Negative pres-
sure within the airway and the presence of soft tissues and bony
structures, which increase extraluminal tissue pressures, can predis-
pose the pharynx to collapse; on the other hand, the tonic and phasic
contractile activity of the dilator muscles of the pharynx contribute to
the maintenance of pharyngeal patency . An imbalance between
these opposite forces is responsible for the upper airway obstructions
that recur in patients with sleep-disordered breathing.
From an anatomic perspective, a narrow upper airway is generally
more prone to collapse than a larger one. Moreover, according to the
Venturi effect, while airflow velocity increases at the site of stricture
in the airway, pressure on the lateral wall of the pharynx decreases
and the likelihood of pharyngeal collapse increases significantly.
A number of imaging studies have demonstrated that during wake-
fulness the cross-sectional area of the upper airway in OSA patients is
reduced compared with control subjects [14,15]. Accordingly, OSA is
frequently associated with a number of alterations in upper airway
ticularly enlarged parapharyngeal fat pads, have been described in pa-
tients with OSA. Thickness of the lateral parapharyngeal muscular
walls also represents a relevant factor causing airway narrowing in ap-
neic subjects .
The disease has been associated with the presence of tonsillar and
tongue hypertrophy, retrognathia and inferior displacement of the
and accumulation of fat inperipharyngealtissues; moreoveritmay also
increase pharyngeal collapsibility through reduction in lung volumes.
Another anatomically based predisposing factor of pharyngeal collapse
in OSA may be the length of the pharynx . In fact, it has been ob-
with those without OSA .
It is relevant to point out that disordered breathing events occur
only during sleep, emphasising the importance of the sleep state in
the pathogenesis of this disorder; accordingly, in addition to the ana-
tomically imposed mechanical loads on upper airways, the impaired
activity of the pharyngeal dilator muscle during sleep plays a critical
role in determining airway collapse.
In healthy subjects, the phasic activity of some dilator muscles has
been found to decline during rapid eye movement sleep  and the
pharyngeal cross-sectional area has been found to be smaller during
sleep than during wakefulness . Indeed, reflex mechanisms from
both chemoreceptors and mechanoreceptors which control the activ-
ity of pharyngeal dilator muscles are reduced during sleep [23,24].
It has been observed that during wakefulness the activity of pha-
ryngeal dilator muscles in OSA patients is increased to overcome
compromised pharyngeal anatomy . This compensatory mecha-
nism is lost during sleep leading to pharyngeal collapse. Indeed it
has been observed that, in OSA patients, the onset of sleep is associat-
ed with significantly larger decrements in the activity of pharyngeal
dilator muscles' activity compared to controls .
Finally, ventilatory control instability has been proposed as a poten-
tial contributing factor for the development of obstructive events .
4. Clinical features
The typical clinical presentation for OSA includes signs of upper air-
way obstruction during sleep, insomnia and diurnal hypersomnolence.
Symptoms usually begin insidiously and are present for years before
the patient is referred for evaluation. Nocturnal obstructive breathing
symptoms include snoring, snorting, gasping and choking. Patients
may report intermittent awakenings and insomnia, with reduced total
sleep time, fragmented sleep or early morning awakenings .
Nocturia is also frequently reported , possibly due to an elevation
in plasma levels of atrial natriuretic peptide secondary to hypoxemia
and/or exaggerated intrathoracic pressure swings increasing urine out-
put. Nocturnal symptoms are often under-appreciated by the patient
leading to a delay in diagnosis until the appearance of more obvious
daytime symptoms. Chronic fatigue and daytime sleepiness, secondary
to sleep fragmentation, are the most significant diurnal complaints of
patients suffering from OSA. In the early stages of the disease, the pa-
tient can easily fall asleep during sedentary activities, such as watching
television; in these phases hypersomnolence, confused with tiredness,
fatigue or lethargy, is often undervalued. Severity of symptoms usually
progress over years and may increase with weight gain, aging or transi-
tion to menopause. As the disorder progresses, sleepiness encroaches
ingly, OSA represents a significant cause of motor vehicle crashes
resulting in a two-fold and up to seven-fold increased risk . Other
common daytime symptoms include morning headaches, dry mouth
and sorethroat at waking up time. In women, clinical presentation can
be rather different from that in men. Particularly, women are less likely
to report symptoms of obstructive breathing and daytime sleepiness
while reporting insomnia, palpitations and ankle edema . Chronic
fatigue syndrome, fibromyalgia, irritable bowel syndrome and migraine
headaches are seen more commonly in women and may be associated
withmilder forms ofOSA[32,33].Althoughallthesesymptoms are like-
ly to affect the quality of life, the clinical relevance of OSA is mainly due
to its strong association with hypertension, metabolic syndrome, diabe-
tes, heart failure, coronary artery disease, arrhythmias, stroke, pulmo-
nary hypertension, neurocognitive and mood disorders. Cardiovascular
and neurocognitive sequelae of OSA are summarized in Table 1.
5. Cardiovascular sequelae
A growing body of evidence links OSA to cardiovascular disorders
. Several risk factors for OSA such as obesity, age and male gender
are also known risk factors for cardiovascular disease. Moreover, OSA
is associated with additional cardiovascular risk factors, such as hyper-
tension and glucose intolerance. Nevertheless, part of the association
between OSA and cardiovascular diseases is independent of traditional
cardiovascular risk factors.
Cardiovascular and neurocognitive sequelae of OSA.
Cardiovascular sequelae Neurocognitive sequelae
Coronary heart disease
• Atrial fibrillation
• Supraventricular tachycardia
• Ventricular tachycardia/fibrillation
• Sinus bradycardia
• Heart block
Deficit in executive functioning
Impaired fine-motor coordination
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
Clinical and experimental evidences have shown the role of OSA in
atherosclerosis progression. In Apolipoprotein E-deficient (ApoE−/−)
plaque growth , and in humans a significant correlation between
OSA severity and carotid-artery intima-media thickness was found
. In addition to the development of chronic vascular damage it
should be noted that acute hypoxaemia during obstructive events can
activate pathophysiological responses that might also lead to acute noc-
turnal cardiac events [37,38]. The pathogenesis of cardiovascular com-
plications in OSA is not completely understood. Proposed mechanisms
include increased sympathetic activity, endothelial dysfunction, meta-
bolic dysregulation, oxidative stress and inflammation. OSA has also
been associated with increased platelet activation, increased fibrinogen
and other potential markers of thrombotic risk . Repetitive hypoxia
ic drive which persists even duringnormoxic daytimewakefulness .
posure to intermittent hypoxia, has been associated with increased
blood pressure levels . OSA is also associated with abnormal cardio-
vascular regulation during resting normoxic daytime wakefulness, with
a faster heart rate, higher blood pressure variability and lower RR vari-
ability . Recurrent hypoxemic stress might promote release of vaso-
constrictors such as endothelin . Repetitive cycles of hypoxia and
reoxygenation promote the production of reactive oxygen species and
increase oxidative stress .
OSA is known to be associated also with endothelial dysfunction
. An imbalance between endothelial injury and repair has been
proposed as a novel theory for atherosclerosis. In particular endothe-
lial fragmentation and increased endothelial microparticles on the
one hand, and impaired endothelium repair by endothelial progenitor
cells on the other, might promote atherosclerosis development .
In sixteen patients with OSA, Jelic and colleagues found an increased
number of endothelial microparticles and a reduced mobilization of
endothelial progenitor cells compared to healthy controls, suggesting
that the disease can cause an imbalance between endothelial injury
and repair .
Chronic inflammation is relevant in the pathogenesis of athero-
sclerosis ; elevated C-reactive protein (CRP) is associated with in-
creased cardiovascular risk . Chronic intermittent hypoxia can
activate the nuclear factor kappa-light-chain-enhancer of activated
B cells (NF-κB) pathway which, in turn, can stimulate the production
of proinflammatory mediators . Accordingly, OSA is associated
with elevated CRP levels which are correlated with disease severity
. Plasma levels of cytokines, adhesion molecules  and serum
amyloid-A have been found to be increased in OSA . Metabolic
dysregulation may also play a role in the pathogenesis of cardiovascu-
lar diseases in OSA. Metabolic syndrome is more common in patients
with OSA than in the general population  and patients with OSA
have a higher prevalence of insulin resistance and glucose intolerance
even after adjusting for body weight .
Finally, a role in the development of cardiovascular diseases in
OSA may be played by repetitive intrathoracic pressure changes. Dur-
ing forced inspiration against the obstructed upper airway, intratho-
racic pressure significantly decreases; these intrathoracic pressure
swings probably exert a deleterious effect on intrathoracic blood ves-
sels. OSA patients were found to have a greater thoracic aortic size
than healthy subjects  and a higher prevalence of severe OSA
was observed in patients with thoracic aorta dissection .
5.1. OSA and hypertension
About of patients with one half OSA are affected by hypertension
 and a linear relationship was identified between the severity of
sleep-disordered breathing and prevalence of hypertension . Del-
eterious effects of OSA on blood pressure appear to be more relevant
in middle-aged compared with older subjects and are predominantly
associated with increased systolic blood pressure . Moreover, OSA
is the most common condition associated with drug-resistant hyper-
tension with an estimated prevalence of 64% among subjects with re-
sistant hypertension . OSA and hypertension share several risk
factors such as age, male gender, obesity, alcohol intake and smoking
. The Wisconsin Sleep Cohort Study found that the adjusted odds
ratio for developing hypertension was 2.9 in the group of patients
with moderate to severe OSA compared to controls .
Not only systemic hypertension, but also high blood pressure in pul-
monary circulation may complicate the course of the disease. In the
most recent pulmonary hypertension guidelines, sleep-disordered
breathing is included among the causes of secondary pulmonary hyper-
tension . Percentages of prevalence of pulmonary hypertension in
patients suffering from OSA ranging from 17% to 42% [65–68] and im-
provement in pulmonary hemodynamics have been observed after
CPAP therapy .
5.2. OSA and heart failure
In the Sleep Heart Health Study, the presence of OSA was associat-
ed with a 2.38 increase in the likelihood of having heart failure, inde-
pendent of confounders . OSA might induce deterioration of left
ventricular function mostly by raising blood pressure levels. Accord-
ingly, hypertension represents a risk factor for cardiac hypertrophy
and failure . Particularly, it should be noted that left ventricular
hypertrophy is more closely linked to blood pressure levels during
sleep than during wakefulness . Patients with heart failure and
OSA were found to have a significantly greater mortality than patients
without OSA . Accordingly, OSA might promote the progression of
cardiac dysfunction through several mechanisms, including an in-
creased risk of ischemic heart disease. Several cross-sectional and
longitudinal studies have reported an association between OSA and
coronary heart disease [74–76,34]. However in a more recent pro-
spective analysis from the Sleep Heart Health Study, after adjustment
for confounding factors, OSA remains a significant predictor of coro-
nary events only in men younger than 70 years and not in older
men or in women .
5.3. OSA and arrhythmias
A wide spectrum of conduction disturbances have been described
in patients with OSA, ranging from premature ventricular contrac-
tions to life-threatening arrhythmias. The likelihood of atrial fibrilla-
tion is increased 4-fold in patients with sleep-disordered breathing
even after adjusting for confounding factors . Other clinically rel-
evant arrhythmias such as ventricular tachycardia or fibrillation, com-
plex ventricular ectopy and supraventricular tachycardia have been
described . The increase in vagal tone during apneic events
might represent the underlying mechanism in the development of
bradyarrhythmias . Bradycardia during sleep apnea is often pre-
sent in patients with OSA  and various degrees of heart block
have been observed in up to 10% of patients, particularly during
rapid eye movement sleep . Significant rhythm disturbances
often occur only during the nighttime and a positive correlation be-
tween OSA severity and the severity of rhythm disturbance has
been observed . Guilleminault and colleagues monitored 400 pa-
tients with OSA during a single night of sleep; in this time interval,
48% had cardiac arrhythmias including ventricular tachycardia, sinus
arrest and second-degree atrioventricular conduction block .
5.4. OSA and stroke
There is also evidence that links OSA to cerebrovascular diseases.
OSA seems to be a risk factor for stroke. Conversely it is also true
that stroke appears to be a risk factor in the development of sleep-
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
disordered breathing . The association between OSA and hyper-
tension, accelerated atherosclerosis and atrial fibrillation certainly
plays a role in the development of cerebrovascular diseases, but
other mechanisms may be implicated. In particular, some observa-
tions suggest that OSA may also acutely impair the cerebral blood
flow supply. An increase in intracranial pressure has been reported
during obstructive apneas  and a reduction of up to 20% in the
middle cerebral artery blood flow has been observed . Cross-
sectional data from the Sleep Heart Health Study showed a greater
odds ratio of prevalent stroke among subjects with OSA . More re-
cently, analysis of prospective data from the Sleep Heart Health Study
suggests that severe OSA is an independent risk factor for stroke only
in men .
6. Neurocognitive sequelae
OSA is associated with impaired neurocognitive function. All cog-
nitive domains are affected, including attention and concentration, vi-
suospatial and verbal memory, executive function, constructional
abilities and psychomotor functioning . Magnetic resonance im-
aging has revealed diminished grey matter correlated with OSA se-
verity . In a meta-analysis of 1092 patients with OSA, Beebe 
found that vigilance was markedly impaired; accordingly, patients
with OSA often have difficulty in concentrating and sustaining atten-
tion for extended periods. The disease also substantially impairs the
domain of executive functioning, the ability to develop and sustain
an organized approach to problem situations, and it is deleterious
for fine-motor coordination.
OSA can promote cognitive impairment mainly through intermit-
tent hypoxia. An animal model of chronic episodic hypoxia developed
neurodegenerative changes in the hippocampus and cortex with im-
paired performance during acquisition of a cognitive spatial task .
Some studies in humans reported a significant correlation between
hypoxemia severity and neuropsychological impairment [93–95].
Findley and colleagues  found that patients who have sleep apnea
with associated hypoxemia have more severe cognitive impairment
than those without hypoxemia. Hypersomnolence due to sleep frag-
mentation may also play a role in the development of neurocognitive
The relationship between OSA and depression is not completely
clear. In a prospective cohort study of 1408 patients Peppard 
creased risk of developing depression. Other reports did not find any
significant relationship between OSA and depression [100,101]. In a
systematic review of the literature McMahon and colleagues observed
that continuous positive airway pressure (CPAP) had a significant and
positive impact on depression .
Medical history and physical examination are the cornerstones of
clinical diagnosis (Table 2). Patients should be asked about both their
nocturnal and daytime symptoms and interviewing the bedpartner
can provide important information about the patient's sleep. Given
the close association between OSA and cardiovascular disease, OSA
should be suspected in those individuals who have systemic or pul-
monary hypertension, metabolic syndrome, heart failure or arrhyth-
mias. Physical examination includes evaluation for obesity, neck
circumference, retrognathia, micrognathia, macroglossia, and inferior
displacement of the hyoid bone. Hypothyroidism, acromegaly and
Marfan's syndrome should always be considered as possible underly-
ing causes for OSA and thyroid function tests are often indicated.
The severity of daytime hypersomnolence can be quantified using
questionnaires and objective tests. One of the most widely used tests
to screen for sleepiness is the Epworth Sleepiness Scale, a self-report
questionnaire which measures an individual's likelihood of falling
asleep in routine life situations .
The Multiple Sleep Latency Test and the Maintenance of Wakeful-
ness Test can be used for objectively measuring sleepiness and alert-
ness. The first measures the number of minutes it takes the patient to
fall asleep while lying down in a dark room . The second is used
to assess a patient's ability to maintain wakefulness during specific
conditions such as sitting in a dimly lit room .
Objective sleep studies are necessary to confirm the clinical suspi-
cion of OSA, to assess its severity and to guide therapeutic choices.
One method used to screen obstructive sleep apnea is the continuous
recording of oxygen saturation during sleep. This method is economic
and easily practicable; however, it is often not sufficiently sensible or
specific and its utility in clinical practice is poor .
Polysomnography remains the gold standard for the diagnosis.
During polysomnographic studies several physiological variables are
measured and recorded while the patient sleeps including pulse ox-
imetry, electroencephalogram, an electro-oculogram, nasal and oral
air flow measurements, chest wall movements, electromyogram and
electrocardiogram. An obstructive apnea is defined as a cessation of
airflow for at least 10 seconds despite ongoing inspiratory effort; an
hypopnea is defined by one of the following three features: more
than 50% airflow reduction, moderate airflow reduction (b50%) asso-
ciated with oxyhemoglobin desaturation and moderate airflow re-
duction with electroencephalographic evidence of awakening .
Diagnostic criteria of OSA syndrome are summarized in Table 3 [1,2].
The apnea-hypopnea index (AHI), calculated by dividing the num-
ber of events by the number of hours of sleep, is the most useful and
objective way of classifying the severity of the disease (Table 3).
Using the AHI, OSA can be classified as ‘mild’ (AHI 5–14), ‘moderate’
(AHI 15–29) or ‘severe’ (AHI≥30) .
History and physical examination findings that should raise suspicion for OSA
• Morning headaches
• Dry mouth, sorethroat on waking
• Moodiness, irritability
• Forgetfulness, difficult to concentrate
• Insomnia, fragmented sleep
• Large neck circumference
• Crowded airway appearance
Diagnostic criteria and classification of severity of OSA syndrome.
A Excessive daytime sleepiness that is not better explained by other factors
BTwo or more of the following that are not better explained by other factors:
• Choking or gasping during sleep
• Recurrent awakenings from sleep
• Unrefreshing sleep
• Daytime fatigue
• Impaired concentration
COvernight monitoring demonstrates ≥5 obstructed breathing events per hour
Diagnosis of OSA syndrome is confirmed by the presence of criterion A or B, plus
criterion C or by the presence of 15 or more obstructed breathing events per
hour of sleep regardless of symptoms.
Classification of severity of OSA on the basis of apnea-hypopnea index (AHI).
AHI 5–14AHI 15–29AHI≥30
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
8. Treatment options
Management of OSA requires a long-term multidisciplinary ap-
proach. Behavioral, medical and surgical options are available for
the treatment. An algorithm for the treatment of OSA is proposed in
Fig. 1. The most effective behavioral measure is weight loss. In a pro-
spective, randomized controlled study  a weight loss of 10.7 kg
was paralleled by 40% reduction in AHI in patients with mild disease.
Low energy diet was followed by significant clinical improvement
in obese men with moderate to severe sleep apnea; in this study a
67% reduction of the AHI was observed and patients with severe
OSA benefited most from the intervention . In sedentary over-
weight/obese adults, exercise may be beneficial for the treatment of
OSA beyond simply facilitating weight loss . A rise in respiratory
drive and stabilized muscle tone in the upper airway might explain
the beneficial influence of physical exercise on OSA severity .
CPAP is the treatment of choice in most patients with OSA because
of its remarkable effectiveness in reducing symptoms and the possi-
ble sequelae of the disease [112–114].
CPAP acts as a physical pressure splint to prevent partial or com-
plete collapse of the upper airway during sleep. Polysomnographic
studies have demonstrated that treatment with CPAP is able to re-
store patency of the airway throughout the respiratory cycle and to
reverse apneaand hypopnea
neurocognitive performance can be significantly improved by CPAP
In an observational study in men with OSA a reduced incidence of
fatal and non-fatal cardiovascular events was observed in patients
treated with nasal CPAP . In a recent placebo-controlled trial in
patients with metabolic syndrome, a three months CPAP treatment
improved blood pressure control and metabolic abnormalities .
Weight loss and reduction in intra-abdominal fat are observed after
CPAP therapy, probably as a consequence of decreased daytime hyp-
ersomnolence and of increased physical activity.
Patients' failure to adhere to the therapy represents a major limi-
tation of CPAP. Adverse effects of CPAP include irritation, pain, rash
and skin breakdown at mask contact points; dryness or irritation of
. Daytime sleepinessand
the nasal and pharyngeal membranes, nasal congestion and
rhinorrhea, and eye irritation from air leakage are also common.
Claustrophobia, gastric and bowel distension and ear and sinus infec-
tions are less common adverse effects . Provision of heated hu-
midification together with a systematic educational program is
suggested for improving patient adherence to CPAP .
Pharmacological treatments have been proposed in patients with
OSA with the aim of improving pharyngeal dilator muscle tone (tricy-
clic antidepressant, serotonergic agents), of increasing ventilatory
drive (methylxanthine derivatives, opioid antagonists), of reducing
airway resistance (oximethazoline or steroid nasal spray) and of im-
proving pharyngeal surface tension forces (soft tissue lubricants)
. In a systematic review of 26 studies of 21 drugs, the authors
concluded that there is still insufficient evidence to recommend any
systemic pharmacological treatment for OSA .
Although less effective than CPAP, oral devices designed for the
advancement of the mandible or tongue retainment have given posi-
tive results in the treatment of obstructive sleep apnea [121,122].
These devices have potential advantages over CPAP in that they are
unobtrusive, make no noise, do not need a power source and are, po-
tentially, less costly. When directly compared in randomized trials,
oral appliances are generally preferred by patients over CPAP
[123,124]. Thus, oral appliances should be considered for patients
who refuse CPAP treatment.
Surgery may represent an effective therapeutic alternative. Surgi-
cal modifications of the upper airway have been performed for de-
cades as a treatment for OSA. The use of such treatments, however,
remains controversial mainly because of the lack of controlled studies
and of standardized criteria to define the surgical efficacy. Appropri-
ate patient selection and surgeon experience are crucial for therapeu-
tic success. Surgical options include several procedures, with different
degrees of invasiveness, that aim to reduce anatomical airway ob-
struction. Maxillo-mandibular advancement osteotomy is designed
to enlarge the velo-orohypopharyngeal airway by advancing the an-
terior pharyngeal tissues (soft palate, tongue base, and suprahyoid
musculature) attached to the maxilla, mandible, and hyoid bone. Sub-
stantial and consistent reductions in the AHI were observed following
Fig. 1. Flow-chart for the treatment of OSA syndrome. Weight reduction by diet and increased physical activity should be recommended to all overweight patients. Patients should
be advised to avoid alcohol and sedatives before bedtime. CPAP is the treatment of choice in mild, moderate and severe OSA and should be offered to every patient. If CPAP is refused
or adherence is poor, alternative therapies including oral appliance, surgery and pharmacotherapy can be considered. When the results of treatment are satisfactory, the patient is
started on long‐term follow‐up.
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
this surgical procedure and adverse events were uncommon .
This type of intervention is particularly suitable in patients with skel-
etal hypoplasia and retrognathia . This procedure is technically
demanding and requires full anesthesia and inpatient treatment.
Less invasive palatal and pharyngeal surgery gave contrasting re-
sults. Uvulopalatopharyngoplasty that involves resection of the ton-
sils (if present), uvula, and posterior palate and reorientation of the
tonsillar pillars , has shown a significant reduction in AHI
. Laser Assisted Uvulopalatoplasty is an outpatient surgical tech-
nique that involves a series of laser incisions and vaporizations
designed to shorten the uvula and modify and tighten the soft palatal
tissue. In most studies such a procedure resulted in a modest reduc-
tion in AHI and little or no reduction in daytime symptoms .
Radiofrequency ablation aims to modify the anatomic site of the ob-
struction acting on nasal turbinates, tongue base and palate, with
minimal invasiveness and very few risks . These procedures
may be considered for patients whose main complaint is snoring,
with little or no apnea.
Innovative procedures are constantly being explored for OSA ther-
apy . Novel surgical techniques and evolving technology may
offer less invasive treatment modalities with broader patient accep-
tance and improvement in results. Further studies are needed to im-
prove the criteria for patient selection as well as processes for
matching appropriate surgery to individual patients with OSA taking
into account its efficacy and safety.
OSA syndrome is a common but often unrecognized condition
with potentially serious complications, mainly due to its important
cardiovascular and neurocognitive sequelae. As the obesity epidemic
is rising, the prevalence of this condition is likely to increase, thus
representing an important public-health problem. Adequate history
and proper use of diagnostic tests, such as polysomnography, enable
accurate identification of patients with OSA syndrome, definition of
the stage of the disease and tailoring of effective therapies. Weight re-
duction and lifestyle measures are effective as first line treatment in
mild to moderate OSA. On the basis of randomized trials, CPAP is con-
sidered the most effective treatment aimed at reducing symptoms
and cardiovascular and neurocognitive complications. However,
CPAP is often poorly tolerated by patients. Surgery is suitable for se-
lected patients, but its long-term benefits are still not supported by
a consistent body of evidence in large populations. A better under-
standing of the mechanisms that underlie obstructive sleep apnea
could lead to an improvement of therapeutic strategies and to a re-
duction of the social impact of this condition.
• Obstructive sleep apnea (OSA) syndrome is a common, but often
unrecognized, sleep disorder associated with serious cardiovascular
and neurocognitive consequences.
• OSA should always be suspected in obese patients referred with ex-
cessive daytime sleepiness particularly when associated with refrac-
tory hypertension, congestive heart failure, nocturnal arrhythmias,
glucose intolerance and pulmonary hypertension.
• Polysomnography is the gold standard for the diagnosis and the as-
sessment of OSA syndrome severity.
• Continuous positive airway pressure (CPAP) represents the treat-
ment of choice in mild, moderate and severe OSA, being effective
in reducing symptoms, cardiovascular morbidity and mortality
and neurocognitive sequelae.
Conflict of interest statement
None of the authors has any conflict of interest.
The authors thank Mrs. Shriyani Worsley and Mr. Peter Worsley for
their useful comments and suggestions in preparing the manuscript.
 The Report of an American Academy of Sleep Medicine Task Force. Sleep-related
breathing disorders in adults: recommendations for syndrome definition and
measurement techniques in clinical research. Sleep 1999;22:667–89.
 Park JG, Ramar K, Olson EJ. Updates on definition, consequences, and manage-
ment of obstructive sleep apnea. Mayo Clin Proc 2011;86:549–54.
 Leger D, Bayon V, Laaban JP, Philip P. Impact of sleep apnea on economics. Sleep
Med Rev 2012, doi:10.1016/j.smrv.2011.10.001 [Epub ahead of print].
 Strollo Jr PJ, Rogers RM. Obstructive sleep apnea. N Engl J Med 1996;334:99–104.
 Young T, Evans L, Finn L, Palta M. Estimation of the clinically diagnosed propor-
tion of sleep apnea syndrome in middle-aged men and women. Sleep 1997;20:
 Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of mod-
erate weight change and sleep-disordered breathing. JAMA 2000;284:3015–21.
 Redline S, Kump K, Tishler PV, Browner I, Ferrette V. Gender differences in sleep
disordered breathing in a community-based sample. Am J Respir Crit Care Med
 Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a
population health perspective. Am J Respir Crit Care Med 2002;165:1217–39.
 Shahar E, Redline S, Young T, Boland LL, Baldwin CM, Nieto FJ, et al. Hormone re-
placement therapy and sleep-disordered breathing. Am J Respir Crit Care Med
 Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep ap-
noea in men: prevalence and severity. Am J Respir Crit Care Med 1998;157:
 Gozal D. Sleep-disordered breathing and school performance in children. Pediat-
 Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial differences
in sleep-disordered breathing in African-Americans. Am J Respir Crit Care Med
 van Lunteren E, Strohl KP. The muscles of the upper airways. Clin Chest Med
 Schwab RJ, Gupta KB, Gefter WB, Metzger LJ, Hoffman EA, Pack AI. Upper airway
and soft tissue anatomy in normal subjects and patients with sleep-disordered
breathing: significance of the lateral pharyngeal walls. Am J Respir Crit Care
 Haponik EF, Smith PL, Bohlman ME, Allen RP, Goldman SM, Bleecker ER. Com-
puterized tomography in obstructive sleep apnea: correlation of airway size
with physiology during sleep and wakefulness. Am Rev Respir Dis 1983;127:
 Moser III RJ, Rajagopal KR. Obstructive sleep apnea in adults with tonsillar hy-
pertrophy. Arch Intern Med 1987;147:1265–7.
 Iida-Kondo C, Yoshino N, Kurabayashi T, Mataki S, Hasegawa M, Kurosaki N.
Comparison of tongue volume/oral cavity volume ratio between obstructive
sleep apnea syndrome patients and normal adults using magnetic resonance im-
aging. J Med Dent Sci 2006;53:119–26.
 Lyberg T, Krogstad O, Djupesland G. Cephalometric analysis in patients with ob-
structive sleep apnoea syndrome: I. Skeletal morphology. J Laryngol Otol
 Malhotra A, Huang Y, Fogel RB, Pillar G, Edwards JK, Kikinis R, et al. The male pre-
disposition to pharyngeal collapse: importance of airway length. Am J Respir Crit
Care Med 2002;166:1388–95.
 Pae EK, Lowe AA, Fleetham JA. A role of pharyngeal length in obstructive sleep
apnea patients. Am J Orthod Dentofacial Orthop 1997;111:12–7.
 Wiegand DA, Latz B, Zwillich CW, Wiegand L. Upper airway resistance and
geniohyoid muscle activity in normal men during wakefulness and sleep. J Appl
 Rowley JA, Zahn BR, Babcock MA, Badr MS. The effect of rapid eye movement
(REM) sleep on upper airway mechanics in normal human subjects. J Physiol
 Berthon-Jones M, Sullivan CE. Ventilation and arousal responses to hypercapnia
in normal sleeping humans. J Appl Physiol 1984;57:59–67.
 Shea SA, Edwards JK, White DP. Effect of wake-sleep transitions and rapid eye
movement sleep on pharyngeal muscle response to negative pressure in
humans. J Physiol 1999;520:897–908.
 Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal electromyogram in
sleep apnea patients versus normal controls (a neuromuscular compensatory
mechanism). J Clin Invest 1992;89:1571–9.
 Mezzanotte WS, Tangel DJ, White DP. Influence of sleep onset on upper-airway
muscle activity in apnea patients versus normal controls. Am J Respir Crit Care
 Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control
stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med
 Krakow B, Melendrez D, Ferreira E, Clark J, Warner TD, Sisley B, et al. Prevalence
of insomnia symptoms in patients with sleep disordered breathing. Chest
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
 Oztura I, Kaynak D, Kaynak HC. Nocturia in sleep-disordered breathing. Sleep
 Horstmann S, Hess CW, Bassetti C, Gugger M, Mathis J. Sleepiness-related acci-
dents in sleep apnea patients. Sleep 2000;23:383–9.
 Jordan A, McEvoy RD. Gender differences in sleep apnea: epidemiology, clinical
presentation and pathogenic mechanisms. Sleep Med Rev 2003;7:377–89.
 Gold AR, Dipalo F, Gold MS, O'Hearn D. The symptoms and signs of upper airway
resistance syndrome: a link to the functional somatic syndromes. Chest
 Gold AR, Dipalo F, Gold MS, Broderick J. Inspiratory airflow dynamics during
sleep in women with fibromyalgia. Sleep 2004;27:459–66.
 Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in
men with obstructive sleep apnoea–hypopnoea with or without treatment with
continuous positive airway pressure: an observational study. Lancet 2005;365:
 Jun J, Reinke C, Bedja D, Berkowitz D, Bevans-Fonti S, Li J, et al. Effect of intermit-
tent hypoxia on atherosclerosis in apolipoprotein E-deficient mice. Atheroscle-
 Suzuki T, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Yamauchi M, et al.
Obstructive sleep apnea and carotid-artery intima-media thickness. Sleep
 Gami AS, Howard DE, Olson EJ, Somers VK. Day–night pattern of sudden death in
obstructive sleep apnea. N Engl J Med 2005;352:1206–14.
 Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms
in obstructive sleep apnea. J Clin Invest 1995;96:1897–904.
 von Känel R, Loredo JS, Ancoli-Israel S, Mills PJ, Natarajan L, Dimsdale JE. Associ-
ation between polysomnographic measures of disrupted sleep and pro-
thrombotic factors. Chest 2007;131:733–9.
 Fletcher EC, Lesske J, Culman J, Miller CC, Unger T. Sympathetic denervation
blocks blood pressure elevation in episodic hypoxia. Hypertension 1992;20:
 Foster GE, Brugniaux JV, Pialoux V, Duggan CT, Hanly PJ, Ahmed SB, et al. Cardio-
vascular and cerebrovascular responses to acute hypoxia following exposure to
intermittent hypoxia in healthy humans. J Physiol 2009;587:5303–4.
 Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Al-
tered cardiovascular variability in obstructive sleep apnea. Circulation 1998;98:
 Gjørup PH, Sadauskiene L, Wessels J, Nyvad O, Strunge B, Pedersen EB. Abnor-
mally increased endothelin-1 in plasma during the night in obstructive sleep
apnea: relation to blood pressure and severity of disease. Am J Hypertens
 Lavie L, Lavie P. Molecular mechanisms of cardiovascular disease in OSAHS: the
oxidative stress link. Eur Respir J 2009;33:1467–84.
 Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive
sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:
 Mannarino E, Pirro M. Endothelial injury and repair: a novel theory for athero-
sclerosis. Angiology 2008;59:69S–72S.
 Jelic S, Lederer DJ, Adams T, Padeletti M, Colombo PC, Factor P, et al. Endothelial
repair capacity and apoptosis are inversely related in obstructive sleep apnea.
Vasc Health Risk Manag 2009;5:909–20.
 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:
 Pirro M, Bergeron J, Dagenais GR, Bernard PM, Cantin B, Després JP, et al. Age and
duration of follow-up as modulators of the risk for ischemic heart disease asso-
ciated with high plasma C-reactive protein levels in men. Arch Intern Med
 Greenberg H, Ye X, Wilson D, Htoo AK, Hendersen T, Liu SF. Chronic intermittent
hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem
Biophys Res Commun 2006;343:591–6.
 Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, et al. El-
evated C-reactive protein in patients with obstructive sleep apnea. Circulation
 Minoguchi K, Yokoe T, Tazaki T, Minoguchi H, Oda N, Tanaka A, et al. Silent brain
infarction and platelet activation in obstructive sleep apnea. Am J Respir Crit
Care Med 2007;175:612–7.
 Svatikova A, Wolk R, Shamsuzzaman AS, Kara T, Olson EJ, Somers VK. Serum am-
yloid A in obstructive sleep apnea. Circulation 2003;108:1451–4.
 Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive
sleep apnoea is independently associated with an increased prevalence of met-
abolic syndrome. Eur Heart J 2004;25:735–41.
 Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL.
Sleep-disordered breathing and insulin resistanceinmiddle-aged and overweight
men. Am J Respir Crit Care Med 2002;165:677–82.
 Serizawa N, Yumino D, Takagi A, Gomita K, Kajimoto K, Tsurumi Y, et al. Obstruc-
tive sleep apnea is associated with greater thoracic aortic size. J Am Coll Cardiol
 Sampol G, Romero O, Salas A, Tovar JL, Lloberes P, Sagalés T, et al. Obstructive
sleep apnea and thoracic aorta dissection. Am J Respir Crit Care Med 2003;168:
 Silverberg DS, Oksenberg A, Iaina A. Sleep-related breathing disorders as a major
cause of essential hypertension: fact or fiction? Curr Opin Nephrol Hypertens
 Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al. Association of
sleep-disordered breathing, sleep
community-based study: Sleep Heart Health Study. JAMA 2000;283:1829–36.
apnea,and hypertensionina large
 Haas DC, Foster GL, Nieto FJ, Redline S, Resnick HE, Robbins JA, et al.
Age-dependent associations between sleep disordered breathing and hyperten-
sion: importance of discriminating between systolic/diastolic hypertension and
isolated systolic hypertension in the Sleep Heart Health Study. Circulation
 Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Ob-
structive sleep apnea: the most common secondary cause of hypertension asso-
ciated with resistant hypertension. Hypertension 2011;58:811–7.
 Silverberg DS, Oksenberg A. Essential hypertension and abnormal upper airway
resistance during sleep. Sleep 1997;20:794–806.
 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association be-
tween sleep-disordered breathing and hypertension. N Engl J Med 2000;342:
 Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, et al.
Guidelines for the diagnosis and treatment of pulmonary hypertension: the
Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of
the European Society of Cardiology (ESC) and the European Respiratory Society
(ERS), endorsed by the International Society of Heart and Lung Transplantation
(ISHLT). ESC Committee for Practice Guidelines (CPG). Eur Heart J 2009;30:
 Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemody-
namics in the obstructive sleep apnea syndrome: results in 220 consecutive
patients. Chest 1996;109:380–6.
 Laks L, Lehrhaft B, Grunstein RR, Sullivan CE. Pulmonary hypertension in
obstructive sleep apnoea. Eur Respir J 1995;8:537–41.
 Sanner BM, Doberauer C, Konermann M, Sturm A, Zidek W. Pulmonary hyper-
tension in patients with obstructive sleep apnea syndrome. Arch Intern Med
 Yamakawa H, Shiomi T, Sasanabe R, Hasegawa R, Ootake K, Banno K, et al. Pul-
monary hypertension in patients with severe obstructive sleep apnea. Psychiatry
Clin Neurosci 2002;56:311–2.
 Sajkov D, Wang T, Saunders NA, Bune AJ, McEvoy RD. Continuous positive air-
way pressure treatment improves pulmonary hemodynamics in patients with
obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:152–8.
 Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Javier Nieto F, et al.
Sleep-disordered breathing and cardiovascular disease: cross-sectional results
of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25.
 Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hyper-
tension to congestive heart failure. JAMA 1996;275:1557–62.
 Verdecchia P, Schillaci G, Guerrieri M, Gatteschi C, Benemio G, Boldrini F, et al.
Circadian blood pressure changes and left ventricular hypertrophy in essential
hypertension. Circulation 1990;81:528–36.
 Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu KL, et al. Influence of
obstructive sleep apnea on mortality in patients with heart failure. J Am Coll
 Mooe T, Rabben T, Wiklund U, Franklin KA, Eriksson P. Sleep-disordered breath-
ing in men with coronary artery disease. Chest 1996;109:659–63.
 Schafer H, Koehler U, Ewig S, Hasper E, Tasci S, Luderitz B. Obstructive
sleep apnea as a risk marker in coronary artery disease. Cardiology 1999;92:
 Milleron O, Pilliere R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G, et al.
Benefits of obstructive sleep apnoea treatment in coronary artery disease: a
long-term follow-up study. Eur Heart J 2004;25:728–34.
 Gottlieb DJ, Yenokyan G, Newman AB, O'Connor GT, Punjabi NM, Quan SF, et al.
Prospective study of obstructive sleep apnea and incident coronary heart dis-
ease and heart failure: the sleep heart health study. Circulation 2010;122:
 Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, et al. Asso-
ciation of nocturnal arrhythmias with sleep-disordered breathing: the Sleep
Heart Health Study. Am J Respir Crit Care Med 2006;173:910–6.
 Harbison J, O'Reilly P, McNicholas WT. Cardiac rhythm disturbances in the ob-
structive sleep apnea syndrome: effects of nasal continuous positive airway
pressure therapy. Chest 2000;118:591–5.
 Somers VK, Dyken ME, Mark AL, Abboud FM. Parasympathetic hyper-
responsiveness and bradyarrhythmias during apnoea in hypertension. Clin
Auton Res 1992;2:171–6.
 Zwillich C, Devlin T, White D, Douglas N, Weil J, Martin R. Bradycardia during
sleep apnea: characteristics and mechanism. J Clin Invest 1982;69:1286–92.
 Becker HF, Koehler U, Stammnitz A, Peter JH. Heart block in patients with sleep
apnoea. Thorax 1998;53:S29–32.
 Olmetti F, La Rovere MT, Robbi E, Taurino AE, Fanfulla F. Nocturnal cardiac ar-
rhythmia in patients with obstructive sleep apnea. Sleep Med 2008;9:475–80.
 Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction dis-
turbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol
 Dyken ME, Im KB. Obstructive sleep apnea and stroke. Chest 2009;136:1668–77.
 Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest
 Loeppky JA, Voyles WF, Eldridge MW, Sikes CW. Sleep apnea and autonomic ce-
rebrovascular dysfunction. Sleep 1987;10:25–34.
 Redline S, Diener-West M, Geraghty E, Shahar E, O'Connor GT, Resnick HE, et al.
Obstructive sleep apnea hypopnea and incident stroke: the Sleep Heart Health
Study. Am J Respir Crit Care Med 2010;182:269–77.
 Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of ob-
structive sleep apnea–hypopnea syndrome: a critical review. J Int Neuropsychol
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593
 Macey PM, Henderson LA, Macey KE, Alger JR, Frysinger RC, Woo MA, et al. Brain
morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med
 Beebe DW, Groesz L, Wells C, Nichols A, McGee K. The neuropsychological effects
of obstructive sleep apnea: a meta-analysis of norm-referenced and case-
controlled data. Sleep 2003;26:298–307.
 Gozal D, Daniel JM, Dohanich GP. Behavioral and anatomical correlates of chron-
ic episodic hypoxia during sleep in the rat. J Neurosci 2001;21:2442–50.
 Bedard MA, Montplaisir J, Richer F, Rouleau I, Malo J. Obstructive sleep apnea
syndrome: pathogenesis of neuropsychological deficits. J Clin Exp Neuropsychol
 Greenberg GD, Watson RK, Deptula D. Neuropsychological dysfunction in sleep
apnea. Sleep 1987;10:254–62.
 Naegele B, Thouvard V, Pepin JL, Lévy P, Bonnet C, Perret JE, et al. Deficits of cog-
nitive executive functions in patients with sleep apnea syndrome. Sleep
 Findley LJ, Barth JT, Powers DC, Wilhoit SC, Boyd DG, Suratt PM. Cognitive im-
pairment in patients with obstructive sleep apnea and associated hypoxemia.
 Verstraeten E. Neurocognitive effects of obstructive sleep apnea syndrome. Curr
Neurol Neurosci Rep 2007;7:161–6.
 Verstraeten E, Cluydts R, Verbraecken J, De Roeck J. Neuropsychological func-
tioning and determinants of morning alertness in patients with obstructive
sleep apnea syndrome. J Int Neuropsychol Soc 1996;2:306–14.
 Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-
related breathing disorder and depression. Arch Intern Med 2006;166:1709–15.
 Pillar G, Lavie P. Psychiatric symptoms in sleep apnea syndrome: effects of gen-
der and respiratory disturbance index. Chest 1998;114:697–703.
 Kripke DF, Ancoli-Israel S, Klauber MR, Wingard DL, Mason WJ, Mullaney DJ,
et al. Prevalence of sleep-disordered breathing in ages 40–64 years: a population
based survey. Sleep 1997;20:65–76.
 McMahon JP, Foresman BH, Chisholm RC. The influence of CPAP on the neuro-
behavioral performance of patients with obstructive sleep apnea hypopnea
syndrome: a systematic review. WMJ 2003;102:36–43.
 Johns MW. A new method for measuring daytime sleepiness: the Epworth
Sleepiness Scale. Sleep 1991;14:540–5.
 Carskadon MA, Dement WC, Mitler MM, Roth T, Westbrook PR, Keenan S. Guide-
lines for the Multiple Sleep Latency Test (MSLT): a standard measure of sleepi-
ness. Sleep 1986;9:519–24.
 Sangal RB, Thomas L, Mitler MM. Maintenance of wakefulness test and multiple
sleep latency test. Measurement of different abilities in patients with sleep dis-
orders. Chest 1992;101:898–902.
 Netzer N, Eliasson AH, Netzer C, Kristo DA. Overnight pulse oximetry for
sleep-disordered breathing in adults: a review. Chest 2001;120:625–33.
 Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep apnea: implica-
tions for cardiac and vascular disease. JAMA 2003;290:1906–14.
 Tuomilehto HP, Seppa J, Partinen M, Peltonen M, Gylling H, Tuomilehto JO, et al.
Lifestyle intervention with weight reduction: first-line treatment in mild ob-
structive sleep apnoea. Am J Respir Crit Care Med 2009;179:320–7.
 Johansson K, Neovius M, Lagerros YT, Harlid R, Rössner S, Granath F, et al. Effect
of a very low energy diet on moderate and severe obstructive sleep apnoea in
obese men: a randomised controlled trial. BMJ 2009;339:b4609.
 Kline CE, Crowley EP, Ewing GB, Burch JB, Blair SN, Durstine JL, et al. The effect of
exercise training on obstructive sleep apnea and sleep quality: a randomized
controlled trial. Sleep 2011;34:1631–40.
 Netzer N, Lormes W, Giebelhaus V, Halle M, Keul J, Matthys H, et al. Physical
training of patients with sleep apnea. Pneumologie 1997;51:779–82.
 Pepperell J, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C,
Stradling JR, et al. Ambulatory blood pressure after therapeutic and sub-
therapeutic nasal continuous positive airway pressure for obstructive sleep
apnoea: a randomized parallel trial. Lancet 2002;359:204–10.
 Jenkinson C, Davies RJ, Mullins R, Stradling JR. Comparison of therapeutic and
subtherapeutic nasal continuous positive airway pressure for obstructive sleep
apnoea: a randomised prospective parallel trial. Lancet 1999;353:2100–5.
 Hack M, Davies RJ, Mullins R, Choi SJ, Ramdassingh-Dow S, Jenkinson C, et al.
Randomised prospective parallel trial of therapeutic versus subtherapeutic
nasal continuous positive airway pressure on simulated steering performance
in patients with obstructive sleep apnoea. Thorax 2000;55:224–31.
 Sullivan CE, Issa F, Berthon-Jones M, Eves L. Reversal of obstructive sleep apnoea
by continuous positive airway pressure applied through the nares. Lancet
 Sharma SK, Agrawal S, Damodaran D, Sreenivas V, Kadhiravan T, Lakshmy R,
et al. CPAP for the metabolic syndrome in patients with obstructive sleep
apnea. N Engl J Med 2011;365:2277–86.
 Basner RC. Continuous positive airway pressure for obstructive sleep apnea. N
Engl J Med 2007;356:1751–8.
 Kushida CA, Littner MR, Hirshkowitz M, Morgenthaler TI, Alessi CA, Bailey D,
et al. Practice parameters for the use of continuous and bilevel positive airway
pressure devices to treat adult patients with sleep-related breathing disorders.
 Hedner J, Grote L, Zou D. Pharmacological treatment of sleep apnea: current sit-
uation and future strategies. Sleep Med Rev 2008;12:33–47.
 Smith I, Lasserson TJ, Wright J. Drug therapy for obstructive sleep apnoea in
adults. Cochrane Database Syst Rev 2006:CD003002.
 Ferguson KA, Love LL, Ryan CF. Effect of mandibular and tongue protrusion on
upper airway size during wakefulness. Am J Respir Crit Care Med 1997;155:
 Redline S, Adams N, Strauss ME, Roebuck T, Winters M, Rosenberg C. Improve-
ment of mild sleep-disordered breathing with CPAP compared with conserva-
tive therapy. Am J Respir Crit Care Med 1998;157:858–65.
 Ferguson KA, Ono T, Lowe A, Keenan SP, Fleetham JA. A randomized crossover
trial of an oral appliance vs nasal continuous positive airway pressure in the
treatment of mild–moderate obstructive sleep apnea. Chest 1996;109:1269–75.
 Menn SJ, Loube DI, Morgan TD, Mitler MM, Berger JS, Erman MK. The mandibular
repositioning device: role in the treatment of obstructive sleep apnea. Sleep
 Bettega G, Pepin JL, Veale D, Deschaux C, Raphael B, Levy P. Obstructive sleep
apnea syndrome: fifty-one consecutive patients treated by maxillofacial surgery.
Am J Respir Crit Care Med 2000;162:641–9.
 Verse T, Hörmann K. The surgical treatment of sleep-related upper airway ob-
struction. Dtsch Arztebl Int 2011;108:216–21.
 Fujita S, Conway W, Zorick F. Surgical correction of anatomic abnormalities in
obstructive sleep apnea syndrome: uvulopalatopharyngoplasty. Otolaryngol
Head Neck Surg 1981;89:923–34.
 Caples SM, Rowley JA, Prinsell JR, Pallanch JF, Elamin MB, Katz SG, et al. Surgical
modifications of the upper airway for obstructive sleep apnea in adults: a sys-
tematic review and meta-analysis. Sleep 2010;33:1396–407.
 Kezirian EJ, Powell NB, Riley RW, Hester JE. Incidence of complications in radi-
ofrequency treatment of the upper airway. Laryngoscope 2005;115:1298–304.
 Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a re-
view of 306 consecutively treated surgical patients. Otolaryngol Head Neck
M.R. Mannarino et al. / European Journal of Internal Medicine 23 (2012) 586–593