Clinical manifestations

Presentation and course

Snoring and excessive daytime sleepiness are the most common presenting symptoms of obstructive sleep apnea syndrome (06).

At disease onset, the patient and bed partner report heavy, habitual, and continuous snoring (preclinical stage), mainly in a supine position (132) . Some patients report that they cannot go on camping trips and must have separate hotel rooms on business trips because of the obnoxious quality of their snoring. Weight gain often influences the advancement to overt disease. Snoring becomes loud and intermittent, appearing in all positions. The bed partner reports that the patient’s breathing appears interrupted: the patient seems to stop breathing for a few seconds, and then takes four to eight noisy breaths followed by silence. Bed partners also describe snorts and gasping or choking sounds, restless sleep, and frequent position changes. Often patients describe only non-restorative sleep.

In mild cases, apneas appear in clusters, mainly during light NREM and REM sleep or in the supine position. In more severe cases, the apneas occur continuously throughout the night and in all body positions. In the severest cases, especially in patients with chronic pulmonary diseases, mild hypoventilation also persists during wakefulness (overlap syndrome).

Patients may complain of daytime somnolence at any stage of the disease, but as a rule the severity of somnolence parallels the severity of the breathing disorder.

Daytime sleepiness is initially manifest during boring sedentary situations in the afternoon or evening. Patients may describe difficulty remaining awake during meetings after lunch or while driving or reading. As sleepiness becomes more severe, patients may fall asleep during conversation, on the telephone, or during sexual intercourse. Some patients present because daytime sleepiness and falling asleep have led to accidents or near accidents at work or while driving.

On awakening, patients do not feel refreshed. It is often difficult for them to get out of bed, and they may describe themselves as “slow starters.” Some feel mentally dull, groggy, confused, or disoriented.

The patient or spouse may report episodes of "automatic behavior" with amnesia, during which the patient performs complex activities. Some patients report driving for miles with no recollection, writing illegibly, or performing nonsensical.

Impotence or reduced libido are sometimes reported by obstructive sleep apnea syndrome patients and a study showed that testosterone and sex hormone binding protein levels presented significant negative correlations with baseline obstructive sleep apnea syndrome severity (210). Active treatment of sleep-disordered breathing produced sex hormone binding protein elevation (133).

Irritability, depression, and morning headaches are other common clinical manifestations of obstructive sleep apnea. Some patients complain of the need for frequent nighttime urination or of nocturnal enuresis (196). Heartburn or other symptoms of gastroesophageal reflux may be present if the repeated episodes of negative intrathoracic pressure associated with apneas lead to passage of gastric contents through the lower esophageal sphincter. Heavy nighttime sweating is an occasional complaint.

Restless sleep is another characteristic feature of sleep apnea. The restlessness is caused by arousals, which may be accompanied by jerks, twitches, and flailing arm movements. Restlessness is usually the spouse's complaint, whereas the patient rarely has much recollection of the arousals.

Lastly, some patients are referred because of a suspicion that sleep apnea may be contributing to systemic hypertension, cardiac arrhythmias, attention problems, impotence, morning headache, or pulmonary hypertension.

In the great majority of cases, the progression of snoring into serious disease is seen only after the age of 40 years. Women present with obstructive sleep apnea syndrome particularly in the post-menopausal period independently of age, suggesting a possible role of progesterone in respiratory stimulation likely increasing the tone of the upper airways’ muscles.

Before menopause, sleep-disordered breathing is more prevalent in women with polycystic ovary syndrome. The strongest predictor of obstructive sleep apnea in these patients is insulin resistance. There is compelling evidence that sleep-disordered breathing in polycystic ovary syndrome is not mediated simply through body mass index (67; 173; 144).

Some differences have been found when comparing the symptomatology of obstructive sleep apnea in female and male subjects (166; 197; 59). Morning fatigue, morning headache, and difficulty initiating sleep were more commonly reported by women. Women compared with males often had proportionally lower apnea-hypopnea index (188). Women with obstructive sleep apnea syndrome were significantly older than men.

In children with enlarged tonsils, snoring and restless sleep are relatively common complaints. Daytime sleepiness is usually not pronounced unless apnea is severe. Poor attention, decreased performance in school, enuresis, and hyperactivity may be presenting complaints (05). Research findings suggest that identifiable behavioral and daytime cognitive sequelae of obstructive sleep apnea do exist in children (112; 187; 115).

A meta-analysis published in 2005 concluded that studies in pediatric obstructive sleep apnea are limited, but the effects of sleep-disordered breathing in children are likely to be qualitatively similar to those seen in adults, with blood pressure increasing with the severity of obstructive sleep apnea. But another meta-analysis concluded that evidence for a significant effect of pediatric sleep-disordered breathing on blood pressure is still lacking due to a large heterogeneity among studies (211).

A study showed moderate evidence regarding a possible association between obstructive sleep apnea and right heart alterations, but more studies are needed (09).

Gottlieb, in a cross-sectional population-based study of 205 5-year-old children, assessed the relationship between sleep-disordered breathing symptoms and neurocognitive functions, showing that sleep-disordered breathing is associated with poorer executive function and memory skills and lower general intelligence (69).

On physical examination, excessive weight, increased neck circumference, and high blood pressure are common findings. Examination of the head and neck may reveal mandibular hypoplasia, craniosynostosis, or retrognathia. Allergic rhinitis and associated mucosal edema may compromise nasal patency and contribute to nasal obstruction and chronic mouth breathing. Common oropharyngeal findings include an elongated soft palate and uvula; a high-arched palate; edema and erythema of the peritonsillar pillars; uvula, soft palate, or posterior oropharynx; redundant pharyngeal mucosa; enlarged tongue; and enlarged tonsils. An enlarged thyroid or prominent fatty infiltration of the neck suggest that excess retropharyngeal adipose tissue is contributing to upper airway obstruction during sleep.

Although snoring is the norm, some patients snore softly or not at all. Patients with neuromuscular disease affecting muscles of the upper airway, chest wall, or diaphragm may be unable to generate sufficient inspiratory force to cause vibration of soft oropharyngeal tissues. Rare disorders, such as Marfan syndrome, may be associated with craniofacial abnormalities and lax upper airway, with upper airway obstruction during sleep and cardiovascular complications (138). Other patients, such as those who have had uvulopalatopharyngoplasty, may not have sufficient floppy airway tissue to vibrate, despite airway narrowing.

Patients with complex sleep apnea at first appear to have obstructive sleep apnea, but unlike typical obstructive sleep apnea patients, their breathing problem is not completely alleviated by CPAP. Once CPAP is applied to complex sleep apnea patients, the obstruction seems to subside, but central sleep apneas may appear (106; 96).

Prognosis and complications

There is increasing evidence that untreated severe obstructive sleep apnea can lead to serious or fatal complications. Only limited data exist regarding the natural progression of this disorder in untreated individuals. A study concluded that the respiratory disturbance index score does not necessarily increase over time, but associated hypertension or ischemic heart disease often develops. In addition, the patients who developed cardiovascular disease had significantly higher respiratory disturbance index (RDI = # of apneas + # of hypopneas + # of respiratory effort related arousals) than patients who did not (53; 131; 111; 207).

In a prospective study, respiratory disturbance index score proved an independent predictor of cardiovascular mortality in coronary artery disease patients during a follow-up period of five years (151).

Compared to normal controls, patients with myocardial infarction or stroke have an increased incidence of obstructive sleep apnea. Intracranial pressure may rise as much as 50 mm Hg during obstructive apneas, with a resulting fall in cerebral perfusion pressure, and there may be marked changes in cerebral blood flow velocity (183). A higher percentage of silent ischemic brain lesions has been described in patients with moderate to severe obstructive sleep apnea (25.0%) compared to obese control subjects (6.7%) or patients with mild obstructive sleep apnea (7.7%) (136). Yaggi and colleagues conducted an observational cohort study of 1022 patients and showed that, after adjustment for other risk factors (age, sex, race, smoking status, alcohol-consumption status, body mass index, diabetes, hyperlipidemia, atrial fibrillation, and hypertension), obstructive sleep apnea syndrome is significantly correlated with stroke and death from any cause (204).

Cardiovascular disease is a common comorbidity or complication of sleep apnea (206). The risk for ischemic heart disease is almost twice as high for habitual snorers as it is for non-snorers and remains elevated after controlling for the effects of age, hypertension, smoking, obesity, and alcohol use (100). Interestingly, one study showed that people with nocturnal sudden death from cardiac causes had a significantly higher apnea-hypopnea index than those with cardiac sudden death during daytime (62).

Cardiac arrhythmias are serious complications of obstructive sleep apnea. A pattern of repeated cycles of bradycardia during the apnea and followed by tachycardia with arousal that terminates the apnea is the most common. Other arrhythmias include sinus arrest lasting up to 10 seconds, second- or third-degree heart block, premature ventricular contractions, and potentially lethal tachyarrhythmias. The mechanism for bradycardia appears to be a reflex increase in vagal tone caused by stimulation of carotid body receptors by hypoxemia. Hypoxemia that occurs in the absence of apnea induces an increase in respiration that causes lung distention. Lung distention inhibits vagal activity (the Hering-Breuer reflex) and permits cardiac acceleration to occur. During apnea the increased vagal tone induced by hypoxia and by mechanical effects of obstructive sleep apnea associated with intrathoracic pressure swings leads to bradycardia. Increased vagal tone also contributes to periods of asystole and arteriovenous block. The increased sympathetic tone that accompanies the arousals at the end of apneas appears to contribute to premature ventricular contractions, sinus tachycardia, and ventricular tachyarrhythmias. Hypoxemia also increases ventricular irritability. Arrhythmias are more common during REM sleep, probably because of more severe hypoxemia and because of autonomic discharge related to phasic events of REM sleep. It is also suggested that obstructive sleep apnea represents an important independent risk factor for the appearance of atrial fibrillation in patients with hypertrophic cardiomyopathy (150). There is a strong relationship between sleep apnea and atrial fibrillation (41) and sleep apnea is considered a risk factor for new-onset atrial fibrillation. In one study including 3542 patients without atrial fibrillation who were followed for an average of five years, nocturnal oxygen desaturation predicted new-onset atrial fibrillation in patients less than 65 years of age (61). Recovery after atrial fibrillation interventions may have a poorer prognosis in patients with sleep apnea (175). The strong association between age and sleep apnea drives the increased frequency of stroke related to atrial fibrillation (158). Successful treatment of sleep apnea may decrease recurrence of atrial fibrillation, as noted in a 1-year study of patients undergoing management of atrial fibrillation (90). In this study recurrence of atrial fibrillation was found in 82% of patients with untreated sleep apnea compared to 42% with treated sleep apnea.

Habitual snoring also appears to be an independent risk factor for the development of hypertension, and even low levels of sleep-disordered breathing appear to increase the risk for hypertension (209; 143). Drug-resistant hypertension should prompt the clinician to consider a diagnosis of obstructive sleep apnea (201; 126; 156).

A position paper was aimed at addressing epidemiologic, pathophysiologic, and diagnostic procedures and treatment options for the appropriate management of obstructive sleep apnea in hypertensive patients, as well as for the management of arterial hypertension in obstructive sleep apnea patients (148; 149). This document was the result of work done by a panel of experts from different European countries participating in the European Union COST (Cooperation in Scientific and Technological research) ACTION B26 on obstructive sleep apnea, with the endorsement of the European Respiratory Society (ERS) and the European Society of Hypertension (ESH).

Epidemiologic studies show that approximately 40% to 50% of congestive heart failure patients suffer from sleep-disordered breathing. Much attention has focused on the effects of sleep-disordered breathing (central and obstructive sleep apnea syndrome) in determining cardiac failure, and vice versa; the role of cardiac dysfunctions can also be used as a possible determinant of sleep-disordered breathing (29; 93).

An interesting point is also the observation that the predominant type of sleep apnea in patients with heart failure can change over time in association with alterations in circulation time. It is suggested that spontaneous conversion from predominantly central events to obstructive ones is associated with an improvement in left ventricular systolic function (171).

Left ventricular systolic and diastolic dysfunction observed in patients with obstructive sleep apnea syndrome improved with 6-month CPAP (03; 76).

Pulmonary artery pressure is increased during apneas, most likely due to pulmonary artery constriction induced by hypoxemia. The greatest increase occurs during REM sleep, when hypoxemia is usually greatest. Cardiac output may fall in some patients due to right-to-left shifts of the cardiac interventricular septum, caused by increased negative intrathoracic pressure associated with attempts to breathe against a closed airway. Systemic blood pressure increases during repetitive apneas, with a peak in blood pressure occurring with resumption of ventilation. In patients with moderate to severe obstructive sleep apnea, blood pressure may rise by 25%, and in severe cases, pressure may reach 200 mm Hg systolic and 120 mm Hg diastolic at the end of each apnea. There appear to be several causes of the increase in blood pressure. Arteriolar constriction may occur as a result of hypoxemia and acidosis, leading to an increase in systemic vascular resistance. Arousals that terminate apnea are associated with increased sympathetic tone that may contribute to elevated blood pressure. Obstructive sleep apnea is also associated with increased release of atrial natriuretic peptide during sleep, with increased urine output, increased urine sodium, and decreased renin activity (101; 16; 55). Patients with coronary artery disease may develop myocardial ischemia during apneas.

Observations have led to a hypothesis that obstructive sleep apnea may trigger an inflammatory metabolic syndrome. In fact, various endocrine and cytokine alterations are observed in sleep-disordered breathing patients, such as an increase in IL6, tumor necrosis factor, C-reactive protein, adhesion molecules, leptin, insulin, nuclear factor-kappaB, and nitrotyrosine independently of obesity or age (199; 77; 11; 84; 161; 124). These conditions are ameliorated by CPAP therapy (38; 99).

It is known that obstructive sleep apnea syndrome patients present a nocturnal increase in leptin level associated with sympathetic function increase; these findings, reversed after treatment with nasal CPAP, may have significant effects on cardiovascular mortality (182) and respiratory control (125). Another study demonstrated elevated homocysteine levels in obstructive sleep apnea syndrome patients with ischemic heart disease in comparison with normal control subjects and ischemic heart disease patients without obstructive sleep apnea syndrome (108). Lavie and coworkers demonstrated that CD8+ T-lymphocytes in obstructive sleep apnea patients undergo phenotypic and functional changes. T-lymphocytes are implicated in the development of atherosclerosis, so that these results are compatible with the atherogenic sequelae of obstructive sleep apnea (46).

The Swedish Obese Subjects study is a long-term (2-year follow-up), prospective investigation in obese patients of the effects of surgical weight loss. This study has demonstrated that symptoms of sleep apnea (collected by questionnaire) are improved following surgical weight loss in a dose-dependent fashion and are similar in both men and women. Moreover, obesity-related comorbidities (such as diabetes, hypertension, and hyperlipidemia) are dramatically reduced (70). However, there is evidence that obstructive sleep apnea is independently associated with alterations in glucose metabolism (147; 164). There is clinical research evidence indicating that obstructive sleep apnea, through the effects of intermittent hypoxemia and sleep fragmentation, could contribute independently to the development of insulin resistance, glucose intolerance, and type 2 diabetes. Early identification of obstructive sleep apnea in patients with metabolic dysfunction, including type 2 diabetes, could reduce cardiovascular disease risk and improve the quality of life of patients with these chronic diseases (14).

Automobile accidents due to sleepiness are an additional cause of morbidity and mortality in obstructive sleep apnea patients (192), and a meta-analysis showed a significant risk reduction following CPAP treatment (195). Excessive daytime sleepiness is a frequent complication of sleep apnea. The mechanisms determining excessive daytime sleepiness in sleep apnea patients are still not completely clarified. Studies demonstrate an association between impairment of wakefulness and long-term cardiovascular mortality in obstructive sleep apnea syndrome patients (142; 180; 92). These data are supported by a study in which the authors showed that excessive daytime sleepiness in obstructive sleep apnea patients is related to impairment of baroreflex sensitivity and of specific indexes of heart rate variability (116).

Cognitive deficit was observed in obstructive sleep apnea syndrome patients. One study showed that obstructive sleep apnea syndrome patients did not present a procedural skill learning deficit, but a subgroup showed deficits in initial skill adaptation and other neuropsychological difficulties mainly correlated with frontal dysfunction (170).

From case-control studies of cognitive performances in obstructive sleep apnea syndrome, it emerged that deficits worsen with disease severity; both apnea-hypopnea index and minimum oxygen saturation link increase disease severity with poorer performance. Sleepiness and hypoxemia constitute major determinants of diurnal cognitive impairments. An association between obstructive sleep apnea and attention deficit hyperactivity disorder in adulthood has been reported (141). The reversibility of cognitive function deficits after obstructive sleep apnea treatment has been investigated, but the data are still controversial (50; 08; 60).

Early studies showed gray matter deficits in many important brain regions (frontal region, insular gyrus, bilateral caudate nuclei, thalami, amygdalo-hippocampi, temporal region, and cerebellum) in patients with obstructive sleep apnea as compared with healthy volunteers (140; 86). Moreover, a magnetic resonance spectroscopy study showed changes in creatine levels in the hippocampal area in obstructive sleep apnea syndrome patients. These data may represent adjustments to brain bioenergetics, similar to those seen in ischemic preconditioning, and may reflect a different susceptibility of these tissues to hypoxic damage in sleep-disordered breathing (15). A study on nocturnal cerebral hemodynamics in patients with snoring or obstructive sleep apnea of variable severity using near-infrared spectroscopy suggested that a significant impairment of autoregulatory mechanisms related to hypoxia is observed only in the presence of frequent obstructive apneas (AHI > 30) (157).

Moderate to severe obstructive sleep apnea may be a risk factor for development of vascular cognitive impairment as a result of cerebral subcortical small vessel disease (168) expressed as leukoaraiosis and silent infarctions (42). Old women with obstructive sleep apnea greater than 15 AHI were more likely to develop cognitive impairment (203); a study supporting the small vessel disease pathogenesis has been observed in additional studies (98). Intermittent nocturnal hypoxia in patients with moderate to severe obstructive sleep apnea contributes to ischemic damage in the cerebral periventricular territory of long penetrating terminal arteries. Intermittent hypoxia adds ischemic burden to this vascular borderzone territory with blood flow that may be already defective as a result of diabetes with vascular autonomic dysregulation and poorly controlled hypertension. Ischemic damage to the cerebral periventricular white matter partially disconnects the frontal cortex from the thalamus, leading to a form of subcortical dementia characterized by apathy, decreased executive functions, poor memory, and in advanced cases, difficulty walking and urinary incontinence. Patients with moderate to severe obstructive sleep apnea are almost four times more likely to have subcortical damage of vascular origin than those with mild obstructive sleep apnea, independently of demographics and cardiovascular risk factors (43).

Sleep apnea as a vascular risk factor was further studied by Cananzi and colleagues in a laboratory experiment showing that mice subjected to severe obstructive sleep apnea, likely damaging the vascular bed, had significantly increased brain injury if ischemia was induced (26). However, Culebras added in an editorial that mild as opposed to severe obstructive sleep apnea prior to stroke might have protective effects through the phenomenon called ischemia preconditioning (39). This phenomenon induces ischemic tolerance by activating innate defense mechanisms and enhancing endogenous repair processes.

The notion of structural and functional brain damage in patients with obstructive sleep apnea was further advanced by Huang and associates (81). The authors searched the literature for data from original studies looking at reported volumetric brain abnormalities and recreating a map of the differences in brain regional sizes between patients with obstructive sleep apnea and controls. They used the anisotropic effect-size version of Signed Differential Mapping. The authors found changes in the orbital frontal cortex with decreased gray matter volume and functional decreased response in obstructive sleep apnea patients. Changes were also found in both anterior cingulate/paracingulate gyri and hippocampus/parahippocompalgyri. The dorsolateral prefrontal cortex exhibited hypoactivation relative to controls whereas the insula showed hyperactivation. They suggested that underlying neural alterations in obstructive sleep apnea patients might explain psychiatric disorders, memory deficits, cardiovascular abnormalities, and even endocrine metabolic alterations.

CPAP applications may delay onset of dementia (145). There is some evidence that successful CPAP applications will modify structural lesions of the brain, implying that early diagnosis and treatment of sleep apnea before structural brain damage ensues should be undertaken (127). In a retrospective analysis of cognitive data from 171 obstructive sleep apnea patients with coexisting cognitive impairment, MoCA scores 2 to 12 months after CPAP initiation were 2.3 points higher than they were prior to the start of CPAP (36). In another small single-center study of 40 participants with obstructive sleep apnea and one or two neurocognitive disorders, patients showed significant benefits on repeated cognitive measures if they had complied with good adherence to CPAP (104).

One study has found a positive association between age-related macular degeneration and sleep apnea (94).

A study of brain cortical thickness in 48 mild to severe obstructive sleep apnea patients that used high-resolution magnetic resonance imaging to identify obstructive sleep apnea-related cortical thinning showed multiple regions of reduced cortical thickness bilaterally in the superior frontal lobe in female obstructive sleep apnea patients (122). Significant thinning within the pre- and post-central gyri and the superior temporal gyrus, extending into the insula, appeared also in the general obstructive sleep apnea populations compared to control subjects. The authors concluded that reduced cortical thickness in obstructive sleep apnea likely represents long-term injury from repeated intermittent hypoxic exposure, although disease comorbidities may also contribute to thinning.

Sleep apnea is a risk factor for increased mortality in patients infected with COVID-19 (25). In a sample of 443 patients with positive COVID-19 RNA PCR diagnostic results and sleep apnea, there was increased all-cause mortality rate (11.7%) compared with sleep apnea controls (6.9%) (P < 0.001; odds ratio [OR], 1.79; 95% confidence interval [CI], 1.31-2.45). Sleep apnea increases risk for COVID-19 comorbidities and may contribute to poor outcomes by exacerbating endothelial dysfunction, inflammation, oxidative stress, microaspiration, and lung injury.

CPAP use in sleep may prevent aspiration by stopping snoring and apnea. Snoring and sleep apnea may be significant mechanisms increasing aspiration during sleep and exposing the lungs to high levels of viral inoculates. Early use of nasal CPAP in sleep might offer a safe method of helping to reduce the progression to potentially fatal COVID-19 pneumonia (189).

Clinical vignette

A 55-year-old man complained of excessive sleepiness particularly during motor vehicle driving, difficulty with attention, and a sense that sleep was not refreshing. A snorer since 20 years of age, he complained of apneas during sleep, also witnessed by his wife, for at least 20 years. Excessive daytime sleepiness had appeared in the last 10 years. Over the previous several years, he had gained about 20 Kg to weigh 105 Kg. His height was 171 cm and neck circumference 48 cm. His wife noted loud snoring and reported that he had episodes of gasping during sleep. Although he usually slept for more than nine hours each night lying in bed, he often attempted to sleep only sitting on a chair. Every day he would take a nap in the afternoon, but he did not feel rested. On examination, he was obese and had a long soft palate and uvula and peritonsillar pillar hypertrophy.

A polysomnogram revealed 59 obstructive hypopneas and apneas per hour of sleep. The minimum oxyhemoglobin saturation was of 51% during a 48-second apnea during REM sleep. With nasal CPAP at 11 centimeters of water pressure, he essentially had complete resolution of obstructive sleep apnea, and he began using CPAP at home. Six months later, he reported that he was using nasal CPAP nightly without difficulty and felt "great." His snoring and daytime drowsiness had resolved. He slept for eight hours each night and no longer took naps.

Biological basis

Etiology and pathogenesis

Narrowing or occlusion of the upper airway during sleep is the cause of obstructive sleep apnea. The site of airway occlusion varies: it may be at the level of the velopharynx, oropharynx (most common), hypopharynx, epiglottis, or larynx. In some patients, the occlusion may be at more than one level or at different sites during different stages of sleep, owing to differential activity of muscles involved in maintenance of airway patency.

Any disorder that produces or contributes to upper airway narrowing can cause obstructive sleep apnea syndrome (Table 1). Obesity is the most common associated condition, but many individuals do not have obstructive sleep apnea despite being overweight/obese (body mass index, BMI> 25 kg/m2) for reasons that are not fully elucidated. A work showed that highly-responsive upper-airway dilator muscles seem to be able to play a protective role avoiding obstructive sleep apnea (174).

Also, anatomical abnormalities of the craniofacial complex such as retro- and micrognathia are considered an important risk factor for sleep-disordered breathing. These anatomical changes, sometimes with a genetic base, are often seen early in life but do not attract attention before the occurrence of socially disturbing snoring, daytime tiredness, or disrupted nocturnal sleep (32). Other causes include enlarged tonsils; major congenital anatomical malformations of the jaw and pharynx, including Crouzon syndrome, Treacher-Collins syndrome, and Pierre Robin syndrome; disorders associated with an enlarged tongue, including obesity (97), Down syndrome, hypothyroidism, and acromegaly; mucopolysaccharidoses and other disorders associated with deposition of material in upper airway structures; and neoplasms of the upper airway.

Edema of the nose and pharynx caused by snoring, allergies, or upper respiratory infections may narrow the upper airway. Pharyngeal muscle weakness caused by myasthenia gravis or any of the muscular dystrophies may lead to functional narrowing of the upper airway with subsequent development of obstructive sleep apnea. Incoordination of respiratory muscles during inspiration caused by stroke, Parkinson disease, and extrinsic and intrinsic brainstem diseases can also produce obstructive sleep apnea syndrome.

Narrowing of the nasal passages with increased resistance to airflow may increase the amount of negative inspiratory pressure developed by the diaphragm and other inspiratory muscles, leading in turn to pharyngeal collapse. Some evidence shows that chronic nasal obstruction early in life, due to allergies or other factors, may contribute to the development of obstructive sleep apnea in later years. In children, enlarged adenoids and chronic allergic rhinitis are associated with decreased mandibular size and retrognathia.

The prevalence of obstructive sleep apnea increases with aging, but the underlying mechanisms remain unclear. Data in wakeful normal volunteers showed a decrease in the genioglossus negative pressure reflex and anatomical compromise with increasing age, particularly in men, suggesting an age-related and gender-related predisposition to pharyngeal collapse (47).

Moreover, complete tooth loss favors upper airway obstruction during sleep (49). This effect seems to be due to the decreases retropharyngeal space and is associated with increased oral and exhaled NO concentration (22).

Sleep-disordered breathing may occur in familial aggregates (72; 95). This suggests that some genetic factors are involved in the development of the primary type of the clinical syndrome. These genetic factors are considered to be more related to the development of the naso-facial complex than anything else, but no further knowledge exists to date (97). Ethnicity has an impact on the severity of the syndrome. African-Americans develop clinical signs and complications early in life, and Far-East Asians with similar body mass index have a more severe syndrome than Caucasians (114).

Table 1. Causes of Upper Airway Narrowing in Obstructive Sleep Apnea

Narrowing and closure of the upper airway, specifically the pharynx, during sleep is the basis of snoring and obstructive sleep apnea syndrome. Other portions of the upper airway are less compliant, whereas the pharynx is more collapsible because it has additional functions related to swallowing and phonation. Anatomic studies indicate that during wakefulness, persons with obstructive sleep apnea tend to have narrow upper airways, increased inspiratory resistance, and increased pharyngeal compliance compared to persons without apnea. Snoring is produced by vibration of the soft tissues of the upper airway. The intensity is determined by the amount of floppy tissue that can vibrate and the velocity of airflow, which is, in turn, a function of the negative intrathoracic pressure and the diameter of the airway.

High resistance to airflow is associated with compensatory increased respiratory effort that minimizes changes in ventilation and oxygenation but still leads to arousals and sleep fragmentation. This condition has been described as the upper airway resistance syndrome (73).

In physiological conditions, during wakefulness, the contraction of pharyngeal dilator muscles slightly precedes (50 to 100 msecs) that of the diaphragm thereby maintaining airway patency. In sleep there is instead a delayed or weak contraction of oropharyngeal muscles during inspiration, and these favor both stenosis (snoring) and occlusion (apneas) of the upper airway.

The airway opens only after an arousal, a brief awakening, or a change in the sleep stage that leads to increased activity of pharyngeal dilators. The patient then takes a few deep breaths and returns to sleep, wherein the cycle repeats itself (80; 146).

In some neurologic diseases, incoordination of respiratory muscles that affects the pre-inspiratory activation of upper airway dilators may also contribute to airway obstruction (45). Obstructive apneas occur in patients with syringobulbia, olivopontocerebellar degeneration, and multiple system atrophy presumably because central abnormalities produce uncoordinated movements of upper airway muscles. In acute stroke and poststroke, incoordination of oropharyngeal muscles, particularly if associated with dysphagia and dysphonia, increases considerably the prevalence of obstructive sleep apnea. Up to 75% of patients poststroke have clinically significant sleep apnea (83).

Excessive daytime sleepiness was hypothesized to result from either fragmentation of sleep or hypoxemia during sleep but several studies have failed to confirm these findings.

It is, thus, clear from many studies that simple apnea or hypopnea indices do not account for much of the variation in daytime sleepiness.

Some studies seem to demonstrate a relation between excessive daytime sleepiness and metabolic factors, in particular visceral obesity, insulin resistance, and hypercytokinemia (199).

Plasma orexin-A levels were higher in obstructive sleep apnea syndrome patients than control subjects, suggesting that the orexin system may be involved in the vigilance level in sleep-disordered breathing patients (82).

Epidemiology

Obstructive sleep apnea syndrome is common. It can occur at all ages, but the incidence is highest in the middle-aged. It is more common in men than in women by a ratio of 2:1 to 8:1. In a random sample of employed American men and women aged 30 to 60 years, 9% of women and 24% of men had five or more apneas plus hypopneas per hour of sleep. Two percent of women and 4% of men in the sample had five or more respiratory events per hour of sleep combined with a complaint of daytime sleepiness (208). The prevalence of obstructive sleep apnea has been estimated at 1% in Israeli industrial workers (109), 1.3% in Swedish men (66), and 2.7% in Italian men (33).

However, the incidence and prevalence depend on the criteria used to define the syndrome. On the basis of laboratory criteria alone, the apnea-hypopnea index (AHI) and minimum oxygen saturation reached are higher in elderly people than in the young. By contrast, the peak prevalence of AHI greater than 10 and excessive daytime sleepiness occur in the middle-aged group (45 to 64 years). Even though the number of apneas increases with age, the clinical significance of apnea seems to decrease (102). Sleep apnea syndrome of moderate to severe intensity affects 17% of 50- to 70-year-old men and 9% of 50- to 70-year-old women (153).

That obstructive sleep apnea is an independent risk factor for hypertension was confirmed by the follow up of the sleep-heart cohort (143; 108). In patients with hypertension, the incidence of obstructive sleep apnea is increased by more than 25% (89; 185).

There is evidence for an association of snoring and obstructive sleep apnea with myocardial infarction, stroke, and sudden death (121; 155). A large study showed that in a population of 10,701 adults referred for polysomnography, obstructive sleep apnea predicted incident sudden cardiac death, and the magnitude of risk was predicted by multiple parameters characterizing obstructive sleep apnea severity (63).

Studies in middle-aged men and women show that the risk of developing cardiovascular disease is increased in obstructive sleep apnea subjects and remains elevated after controlling for the effects of age, hypertension, smoking, obesity, and alcohol use (100; 152). Obesity and the magnitude of nocturnal oxygen desaturation are independent risk factors for atrial fibrillation in individuals less than 65 years of age. Obstructive sleep apnea is a univariate predictor of atrial fibrillation (hazard ratio 2.18, [95% CI, 1.34 to 3.54]) (61).

Obstructive sleep apnea syndrome is associated with left ventricular dysfunction and pulmonary hypertension (58). In addition, idiopathic pre-tibial edema is also associated with obstructive sleep apnea in patients with normal left ventricular function, particularly in women (19). These data are probably confirmed by the reduction in amount of edema following nasal CPAP treatment of sleep-disordered breathing (20).

In a systematic review of sleep apnea, at greater than or equal to 15 events/h AHI (moderate to severe), the prevalence in the general adult population ranged from 6% to 17%, being as high as 49% in advanced ages (179). As anticipated, obstructive sleep apnea prevalence was greater in obese individuals. Advancing age, male sex, and higher body-mass index increase obstructive sleep apnea prevalence.

Prevention

Obesity and male sex are the most important risk factors for the development of severe obstructive sleep apnea.

But too great an emphasis on obesity has neglected many normal-weight patients with sleep-disordered breathing. Local deposition of fat in the pharynx and in the submental region is important in determining increased upper airway resistance; in fact, even relatively non-obese patients with obstructive sleep apnea have excess neck fat deposition.

Hormonal disease favoring snoring and obstructive sleep apnea include hypothyroidism, which induces structural (myxedematous) changes and altered muscular contractility, and acromegaly associated with macroglossia, thickening of the pharyngeal mucosa, and facial cartilaginous or bone changes.

Other risk factors include the presence of a positive family history of sleep-disordered breathing, wherein diagnosis of the syndrome in parents should lead to investigation of the children. Considerable evidence indicates that there is a genetic contribution to the causes of obstructive sleep apnea syndrome (159). Also included are anatomic variations or abnormalities of the nasopharynx that produce narrowing of the upper airway, craniofacial dysmorphism with retrognathia or micrognathia, high and narrow hard palate, or an abnormal score at the index (105). Additional risk factors are neurologic disorders affecting upper motor neurons of bulbar musculature, neuromuscular disorders that affect the upper airway muscles or thoracic respiratory muscles, autonomic disorders, mucopolysaccharidoses that produce glycosaminoglycan accumulation in soft tissues of the upper airway, and an enlarged tongue from Down syndrome.

The reason for the more frequent occurrence of obstructive sleep apnea in men than in women is not well understood.

The airway may be more compliant in men and close at lower pressures for a given airway diameter. One study confirmed that men have a larger but more collapsible airway than women (139).

In addition, when mild craniofacial anomalies occur during the prepubescent years and are not recognized and go untreated, puberty, with its testosterone flow, will lead to development of a normal-size tongue in a small mouth, as 90% of the adult face is developed between 11 and 12 years of age.

Testosterone may lead to increased bulk of pharyngeal and parapharyngeal muscles, which may lead to a preferential deposition of fat in upper airway structures.

Obstructive sleep apnea may occur as a complication of pharyngeal flap surgery to correct cleft palate and other causes of velopharyngeal surgery. In a series of 40 patients who underwent flap surgery, 14 (35%) had central or obstructive apnea following surgery (184). In susceptible persons, obstructive sleep apnea may be precipitated or made worse by sleep deprivation, evening alcohol use, sedative medications, and upper respiratory infections. Enhanced upper airway muscle relaxation, blunted chemoreceptor response to blood gas changes, and an elevated arousal threshold contribute to the exacerbation of obstructive sleep apnea by alcohol. The sedating effects of alcohol are enhanced in persons who are already excessively sleepy from sleep apnea or other causes.

Differential diagnosis

In patients who complain of excessive daytime sleepiness, obstructive sleep apnea syndrome must be differentiated from such disorders as narcolepsy, idiopathic hypersomnia and atypical depression.

Snoring, witnessed apneas, hypertension, and a neck circumference greater than 16.5 inches (43 cm) are useful predictors of obstructive sleep apnea in patients presenting with sleep complaints, but definitive diagnosis usually requires polysomnographic monitoring.

In patients who complain of nocturnal choking, gasping, coughing, or shortness of breath, the differential diagnosis includes gastroesophageal reflux, nocturnal asthma, congestive heart failure, central sleep apnea, nocturnal panic attacks, and sleep-related laryngospasm.

Daytime fatigue may be the only complaint, and sleep-disordered breathing may masquerade as chronic fatigue syndrome when associated with more prominent complaints of nocturnal disrupted sleep.

Diagnostic workup

According to ICSD-2014 and ICSD-3-TR, 3-TR 2023), the diagnostic criteria for obstructive sleep apnea are as follows:

A nocturnal polysomnogram performed in a sleep laboratory is the procedure of choice for diagnosis of most patients with suspected obstructive sleep apnea (91). During the video polysomnographic recording, EEG, eye movements, submental muscle activity, ECG, snoring sound, respiratory effort, airflow, oxygen saturation, and leg movements are assessed with continuous recording throughout the night. Additional sensors are sometimes used to assess expired carbon dioxide concentration, esophageal pH, body position, snoring sound, and intrathoracic pressure.

The nocturnal polysomnogram in patients with obstructive sleep apnea is characterized by frequent respiratory events (typically lasting for 15 to 30 seconds although they may last up to 3 minutes) that are followed by transient arousals and, consequently, oxygen saturation reduction. Arterial oxyhemoglobin saturation often falls below 70% in patients with severe obstructive sleep apnea. The event may be an apnea with complete cessation of airflow or a hypopnea during which airflow is reduced but not completely absent. In some other patients, increased resistance to airflow is matched by increased respiratory effort, minimizing changes in ventilation and oxygenation (upper airway resistance syndrome) (73). The frequency of apneas and hypopneas is usually expressed as the apnea-hypopnea index: the number of apneas plus hypopneas per hour of sleep. Systemic and pulmonary arterial pressure may increase during and immediately after apneas. Cardiac arrhythmias are frequent: bradycardia with sinus pauses is the most common, but more serious arrhythmias may occur, including premature ventricular contractions, atrioventricular block, ventricular tachycardia, and asystolic periods lasting as long as 12 seconds. During REM sleep, apneas and hypopneas are usually longer, and hypoxemia and cardiac arrhythmias are more likely severe. There are usually increased amounts of stage 1 sleep and wakefulness with reduced amounts of stage 3 sleep and REM sleep.

Assessment of the severity of obstructive sleep apnea is based on the frequency and duration of respiratory events. These events must be 10 seconds or longer in duration and include apneas, mixed apneas, and hypopneas. The number of respiratory events per hour of sleep is expressed as the apnea-hypopnea index (AHI). The respiratory disturbance index (RDI) includes respiratory effort related arousals (RERAs). Body positions and stages of sleep during which respiratory events occur, the type and frequency of associated cardiac arrhythmias, the severity of associated hypoxemia, and the degree of sleep fragmentation are also taken into consideration. The oxygen desaturation index (ODI) may be a useful measure particularly in REM sleep (18). During REM sleep, there is decrease in oropharyngeal muscle tone leading to a greater tendency to develop obstructive events. Furthermore, the diaphragm is the only respiratory muscle in REM sleep, and interference or weakness of its action in conjunction with a relaxed oropharyngeal muscle tone may lead to a high oxygen desaturation index. Patients with high BMI and large abdomen interfering with diaphragmatic activity are at particular risk. Similarly, patients with muscular dystrophies or neurogenic disorders affecting the diaphragm may exhibit higher oxygen desaturation index in REM sleep.

A multiple sleep latency test (MSLT) carried out the day after polysomnogram helps to assess the presence and severity of excessive sleepiness and assists with differential diagnosis. The mean latency to sleep provides an objective indicator of the severity of daytime sleepiness; however, the MSLT is not necessary for the diagnosis of sleep apnea.

A second approach involves the use of ambulatory recorders (OCST=out of center sleep testing). These devices record various combinations of pulse oximetry, breathing effort, airflow, snoring, heart rate, occasionally EEG, or other measures. Ambulatory studies may be useful in follow-up or for diagnosis when the likelihood of severe obstructive sleep apnea is high or when patients cannot be studied in a sleep laboratory because facilities are not available or because of concurrent medical illness (48). The term respiratory event index (REI) denotes event frequency based on monitoring time rather than total sleep time in patients undergoing OCST. Peripheral arterial tone (PAT) can be utilized to detect obstructive sleep apnea using a wrist worn peripheral arterial tone signal device (WatchPAT™) (193). Respiratory indexes calculated using PAT-based portable devices positively correlate with those calculated from the scoring of polysomnography (205).

Additional studies may be indicated for some patients. Fiber-optic endoscopy of the upper airway and cephalometric radiographs can be used to assess airway anatomy. Acoustic pharyngometry, performed in various body positions (sitting, supine, right and left lateral), has been proposed as a noninvasive method that geometrically quantifies complex pharyngeal structures (87). Arterial blood gases and pulmonary function tests obtained during the waking state and endocrine studies (particularly screening for hypothyroidism and acromegaly) are important. For patients with clinical evidence of right or left heart failure, complete blood count, ECG, and chest radiograph are indicated. Esophageal pH monitoring is occasionally helpful, and a head or neck MRI or CT scan may be indicated, if craniofacial or brainstem malformations or airway neoplasms are contributing to obstructive sleep apnea.

Structured interview or specific questionnaires can be helpful in the routine assessment of the clinical features of obstructive sleep apnea in patients. However, it is a difficult task to assess obstructive sleep apnea by simple measures due to the fact that the symptoms may be masked by various coping behaviors or a personal perception of normal or abnormal conditions (01).

Management

Treatment often includes a recommendation to lose weight. Unfortunately, weight loss is often difficult to achieve, particularly in persons who are excessively sleepy, and its effectiveness varies. Most patients who lose weight have less severe apnea, but it is difficult to predict the amount of improvement associated with loss of a specified amount of weight. Some patients may be substantially better after loss of just 20 pounds, whereas others have minimal benefit from loss of 50 pounds or more. However, according to a meta-analysis, weight loss via intensive lifestyle interventions should be encouraged as a treatment for mild to moderate obstructive sleep apnea (137).

Avoidance of precipitating factors, such as alcohol and hypnotic drugs sometimes is helpful. For patients in whom sleep apnea occurs only when supine (positional obstructive sleep apnea), training to avoid this sleeping position is often beneficial (positional therapy).

CPAP is the treatment of choice in moderate to severe obstructive sleep apnea, particularly with excessive daytime sleepiness. A meta-analysis showed that CPAP is superior to positional therapy in reducing severity of sleep apnea also in patients with positional obstructive sleep apnea syndrome (74).

Nasal CPAP appears to function primarily as an air splint to maintain positive intraluminal pressure in the upper airway. The optimal CPAP level is best determined with a sleep study because the treatment may be ineffective if the level of positive pressure is too low and may induce arousals and central apneas if the pressure is too high. In addition, patients with cardiopulmonary disease may develop arrhythmias or hypoventilation if CPAP is not at the optimum level (85). Nasal bilevel positive airway pressure, also applied by mask, may be necessary in severe and with overlap syndrome patients, particularly in patients who have difficulty exhaling against a high expiratory pressure. Bilevel positive airway pressure devices provide different pressures during inspiration and expiration. They are more expensive than CPAP devices, but are sometimes better tolerated, particularly by patients who have a sensation of being unable to breathe with CPAP. They are also more useful in patients with hypoventilation accompanying apnea, as the reduced expiratory pressure lowers the work of breathing.

Devices that automatically adjust CPAP are an alternative to manual titration. The mean positive pressure for the night is usually less than with manual systems, but the improvement in obstructive sleep apnea appears to be comparable to manual CPAP titration in most cases (37; 194). The ability to match pressure requirements to changing needs and the potential to eliminate costly polysomnography are the major advantages claimed. Some patients find the frequent changes in pressure annoying and prefer the manual systems, whereas others prefer the lower mean pressure. As arrhythmias may develop with CPAP titration in patients with cardiopulmonary disease, such patients should not have unattended monitoring. The major drawback of auto-titrating devices is that a mouth or nasal leak of 12 l/m will render the device inaccurate. A controlled trial of fixed versus auto-CPAP showed no difference in patient preference and only a marginal benefit of variable over fixed-pressure CPAP in terms of subjective sleepiness and CPAP use (198). AutoPap should not be used in patients with a component of central sleep apnea.

Adaptive servo-ventilation (ASV) has been proposed as a treatment alternative in patients with complex sleep apnea or heart failure (76; 106). Increased risk of cardiac mortality has been noted in patients with left ventricular ejection fraction (LVEF) of less than or equal to 45% and moderate or severe complex sleep apnea predominant sleep-disordered breathing. Data support a standard level recommendation against the use of ASV to treat congestive heart failure-associated central sleep apnea syndrome (CSAS) in patients with an LVEF of less than or equal to 45% and moderate or severe central sleep apnea syndrome (12).

Nocturnal ventilatory therapy is effective and can be used successfully in infants and children as well as adults. Successful treatment, however, requires close coordination between families, pediatricians, and sleep specialists.

With regular CPAP use, patients report improved alertness, fewer traffic accidents and near-miss accidents, less time off work, and better work efficiency. Improved cognitive function and reductions in nocturnal cardiac arrhythmias, blood pressure, ischemic heart disease (78; 04; 75; 163; 148; 149; 30), depressive symptoms, and sexual dysfunction are additional benefits in some patients.

Some patients treated with CPAP find it easier to lose weight than they did before treatment, perhaps because the increased alertness leads to more activity during the day or because of a decreased desire to eat snacks to enhance alertness.

However, treatment requires nightly use of a mask over the nose; it is cumbersome, and minor unpleasant side effects can occur. Obviously, patients are much more likely to use CPAP regularly if their symptoms improve, and they tolerate discomfort if the benefits are evident. Noncompliance with CPAP occurs mainly because of such side effects as dry nose, nasal congestion, skin irritation, and eye irritation from air leaks around the mask. A chin strap to ensure mouth closure, a better fitting mask, or humidification is often helpful.

Decreased CPAP compliance remains a challenging issue (169). CPAP treatment failures occur in patients who cannot breathe through the nose, who cannot tolerate the apparatus because of discomfort or claustrophobia, or who cannot sleep with the mouth closed. Repeated sinus or other upper respiratory infections may prevent some patients from using the apparatus. Some patients who cannot use nasal CPAP due to nasal problems are able to use it successfully after septoplasty or other nasal surgery. Other problems associated with the use of nasal CPAP include sleep disruption due to noise from the machine, facial discomfort from the mask, and air swallowing. Occasionally, patients complain of discomfort from misdirection of airflow into the eyes. Barotrauma to the lungs, a theoretical possibility, appears to be extremely rare.

Surgical procedures designed to maintain nocturnal airway patency are additional options. Tracheostomy, effective in almost all cases, is used less frequently than in the past due to the availability of nasal CPAP and bilevel positive airway pressure. Particularly in children, but also in adults (191), tonsillectomy and adenoidectomy can produce a dramatic improvement. Uvulopalatopharyngoplasty with removal of the uvula, portions of the soft palate, and redundant pharyngeal tissue has been used to treat obstructive sleep apnea syndrome for more than 10 years and is probably the most commonly performed operation for obstructive sleep apnea. Uvulopalatopharyngoplasty is sometimes combined with geniotubercle advancement or hyoid myotomy or both. Unfortunately, uvulopalatopharyngoplasty is beneficial in only 40% to 60% of cases; the success rate appears to be higher in younger patients, in those who undergo concurrent tonsillectomy, and in those with obstruction limited to the retropalatal segment. However, some patients who have had uvulopalatopharyngoplasty still have collapse at the retropalatal level, indicating that failure of uvulopalatopharyngoplasty is not always due to airway collapse at more caudal levels (181). A further concern with uvulopalatopharyngoplasty is the potential for relapse. Larsson and colleagues found that of 50 consecutive patients undergoing uvulopalatopharyngoplasty for obstructive sleep apnea, nine who responded initially relapsed after two years (107).

However, the surgical procedures may ameliorate and optimize the CPAP pressure setting as well as compliance postoperatively (57).

Laser-assisted uvulopalatopharyngoplasty is a procedure that allows resection of the uvula to occur in stages during procedures performed on an outpatient basis. In patients who snore loudly, laser-assisted uvulopalatopharyngoplasty leads to partial or complete elimination of snoring in about 90%. To date, however, no evidence shows that laser-assisted uvulopalatopharyngoplasty is more effective than uvulopalatopharyngoplasty for the treatment of obstructive sleep apnea, and it may be less effective. Radiofrequency ablation of the portion of the palate or tongue base may be effective in some patients (52).

Genioglossus muscle advancement is another proposed surgical technique in selected patients with mild to moderate obstructive sleep apnea and obstruction at the hypopharyngeal level (64).

Fully implantable hypoglossal nerve stimulating systems inducing electrical stimulation of the genioglossus muscles have been approved for nerve stimulation and prevention of pharyngeal collapse without arousing patients from sleep (176; 176). The apnea-hypopnea index should be 20 to 100 per hour with at least 15 events per hour occurring in non-REM sleep. Failure or intolerance to other forms of PAP applications should be documented while the body mass index should be less than or equal to 37 kg/m2. The diagnostic workup includes drug induced sedation endoscopy to perform nasoendoscopy intended to evaluate airway collapse. A complete concentric collapse pattern rather than anteroposterior or laterolateral collapse excludes patients from the procedure.

Procedures to advance the hyoid bone are also utilized for selected patients, mainly in association with other surgical interventions on the upper airways. Maxillofacial surgery, with advancement of the mandible, the maxilla, or both, appears to be beneficial for selected patients (113; 123), although the surgery is more extensive than uvulopalatopharyngoplasty and has a longer postoperative recovery period, these surgical procedures appear to obtain a profound improvement in the obstructive sleep apnea severity (54).

A meta-analysis reported that maxillomandibular advancement is considered a safe and highly effective treatment for obstructive sleep apnea (79). Younger age, lower preoperative weight and AHI, and greater degree of maxillary advancement were predictive of increased surgical success.

The American Academy of Sleep Medicine has published practice parameters for surgical modification of the upper airway in adults with obstructive sleep apnea (13; 28).

Bariatric surgery is an increasingly common intervention in morbidly obese patients with obstructive sleep apnea, due to the poor results obtained with diet or pharmacologic treatments (23; 165).

A wide variety of orthodontic appliances that advance the tongue or mandible are available (186). The oral devices could be effective in snorers or patients with mild to moderate obstructive sleep apnea and are sometimes preferred to nasal CPAP by many individuals (68). However, side effects are common, especially in the initial phase of use and include temporo-mandibular joint discomfort, dental misalignment, increased salivation and gum irritation. Some factors associated with the efficacy of mandibular advancing devices are proposed (135).

A proposed noninvasive treatment of obstructive sleep apnea is the oral pressure therapy designed to reduce airway obstruction. The system is composed of a bedside console, a custom thermoformed polymer mouthpiece, and a flexible tube connecting the mouthpiece to the console. The console contains a pump that is intended to create a vacuum in the oral cavity to pull the soft palate anteriorly and stabilize the tongue to reduce obstruction during sleep. Some studies show interesting results, but a clinically significant improvement in breathing pattern during sleep needs to be confirmed (35).

The European Respiratory Society has published a guideline on non-CPAP therapies for obstructive sleep apnea (162).

Excessive daytime sleepiness in patients with obstructive sleep apnea that fails to respond to PAP applications may respond to the administration of solriamfetol (schedule IV controlled substance), a selective dopamine and norepinephrine reuptake inhibitor. Starting at an oral dose of 37.5 mg and increasing to 150 mg, clinical trials using Epworth Sleepiness Scores and Patient Global Impression scores as well as Maintenance of Wakefulness Tests have shown a favorable effect (178). Adverse reactions have included elevations of blood pressure and heart rate increases along with headache, anxiety, and insomnia in less than 3% of patients. Modafinil up to 400 mg per day is a popular wake-promoting agent for patients who continue to complain of excessive daytime sleepiness and fatigue despite good PAP compliance (author’s note).

Outcomes

The Swedish Obese Subjects study is a long-term (2-year follow-up), prospective investigation in obese patients of the effects of surgical weight loss. This study has demonstrated that symptoms of sleep apnea (collected by questionnaire) are improved following surgical weight loss in a dose-dependent fashion and are similar in both men and women. Moreover, obesity-related comorbidities (such as diabetes, hypertension, and hyperlipidemia) are dramatically reduced (70). However, there is evidence that obstructive sleep apnea is independently associated with alterations in glucose metabolism (147; 164). There is clinical research evidence indicating that obstructive sleep apnea, through the effects of intermittent hypoxemia and sleep fragmentation, could contribute independently to the development of insulin resistance, glucose intolerance, and type 2 diabetes. Early identification of obstructive sleep apnea in patients with metabolic dysfunction, including type 2 diabetes, could reduce cardiovascular disease risk and improve the quality of life of patients with these chronic diseases (14). In one study CPAP treatment significantly reduced systolic blood pressure by an average of 7.3 mmHg and normalized nocturnal pressure patterns in patients with refractory hypertension and sleep apnea (128). In another study by the same group of authors patients with moderate to severe sleep apnea and stroke who did not tolerate CPAP had increased adjusted mortality risk (HR = 1.58; 95% CI 1.01-2.49) compared to patients with moderate to severe sleep apnea who tolerated CPAP (129). Thus, long-term CPAP treatment in moderate to severe sleep apnea patients and stroke patients may reduce mortality risk. In a metaanalysis of 10 randomized controlled trials the effectiveness of CPAP in stroke patients with sleep apnea showed overall neurofunctional improvement with CPAP (SMD 0.5406; 95% CI 0.0263-1.0548) in a combined analysis of NIH Stroke and Canadian Neurological Scales (21). Long-term survival was improved in one study. The data indicated that CPAP might be beneficial for neurologic recovery.

A highly publicized and controversial study indicated that therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate to severe sleep apnea and established cardiovascular disease (130). Patients received on average 3.3 hours of CPAP applications per night, a well-established subtherapeutic duration of therapy thus rendering the study results clinically invalid.

CPAP adherence may increase in obstructive sleep apnea patients treated with non-benzodiazepine sedative hypnotics, especially eszopiclone (200). The effect of zolpidem and zaleplon on CPAP adherence has not been determined as yet.

Special considerations

Excessive daytime sleepiness and fatigue are pervasive symptoms in patients with moderate to severe sleep apnea. As many as 52% of patients continue to report excessive daytime sleepiness despite compliance with PAP applications (10). It has been suggested that periventricular white matter structural lesions in patients with moderate to severe sleep apnea can be a possible mechanism to explain why obstructive sleep apnea patients with high levels of PAP use can have differing responses to treatment (202). Compromised myelin sheath, indicated by increased radial diffusivity in MRIs using diffusion tensor imaging, can be involved in the underlying white matter changes.

Pregnancy

Nasal CPAP has been applied throughout pregnancy without any problem. There have been several observations and retrospective studies performed on pre-eclamptic women. It seems that heavy snoring at night may be an independent factor for poor infant outcome. Also, a study of normal pregnant women observed during pregnancy has shown that snoring may be present during pregnancy alone and, despite the fact that blood pressure may stay within normal range, systolic pressure may increase more in women who snore loudly than in those who do not (56; 172; 154).

The benefit of nasal CPAP administration in pregnant women recognized to have hypertension early in pregnancy is associated with better blood pressure control and improved pregnancy outcomes. Indeed, nasal CPAP has been proposed as therapy for pre-eclampsia (71; 160; 40).

Anesthesia

Patients with obstructive sleep apnea syndrome are at increased risk for anesthetic complications. Obesity and a narrow airway may make intubation more difficult. Sedative medications may cause prolonged apneas with severe hypoxemia. Respiratory arrest may occur during premedication for anesthesia, at the time of induction of anesthesia, or immediately after extubation. These patients may also be at increased risk for developing anesthesia-related cardiac arrhythmias. Although the features of pediatric obstructive sleep apnea syndrome differ from those of adults, anesthetic management calls for particular attention also in this population. Sedation must be performed with caution for hypoventilation and airway obstruction risk, and intubation is often difficult (17; 27; 134; 02; 07).