Obstructive sleep apnea and other sleep-related syndromes.

Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 18

Obstructive sleep apnea and other sleep-related syndromes 1 2

TERESA PAIVA1* AND HRAYR ATTARIAN2 Sleep Medicine Centre, Medical Faculty of Lisbon, Lisbon, Portugal

Circadian Rhythms and Sleep Research Laboratory, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

The International Classification of Sleep Disorders (ICSD2) (AASM, 2005a) divides the sleep-related breathing disorders into three groups: central apnea syndromes, obstructive syndromes, and hypoventilation syndromes. Due to their high prevalence and clinical repercussions, obstructive syndromes are presented here first.

OBSTRUCTIVE SLEEPAPNEA Definition Obstructive sleep apnea is a sleep-related breathing disorder associated with an obstruction in the upper airway that results in an increased breathing effort and inadequate ventilation. The clinical and neurophysiologic expression differs in adults and in children (ICSD2) (AASM, 2005a) and therefore they must be considered separately. Obstructive sleep apnea (OSA) in the adult is characterized by repeated episodes of cessation of breathing (apnea) or partial upper airway obstruction (hypopnea); each episode, whether apnea or hypopnea, should last at least 10 seconds. These events are often associated with reduced blood oxygen saturation. Snoring and sleep disruption are typical and common. Excessive daytime sleepiness or insomnia can result, with the first being more frequent in general and the second being more frequent in females. Five or more respiratory events (apneas, hypopneas, or respiratory effort-related arousals) per hour of sleep are required for diagnosis. Increased respiratory effort occurs during the respiratory event. Upper airway resistance syndrome has been recognized as a manifestation of obstructive sleep apnea syndrome.

Obstructive sleep apnea in children is characterized by features similar to those seen in the adult, but cortical arousals may occur, possibly because of a higher arousal threshold. At least one obstructive event, of at least two respiratory cycles duration, per hour of sleep is required for diagnosis. Hyperactivity or attention deficit manifestations are more common in children. These criteria are applied up to 18 years of age, although some authors consider that after 13 years the adult criteria can be applied; in fact, many neurophysiologic markers of maturation normalize by that age (Grigg-Damberger et al., 2007). The relation between sleep and obstructive sleep apnea syndrome (OSAS) is bidirectional. Sleep interferes with respiration and in susceptible individuals produces obstructive sleep apnea (OSA). Subsequently OSA causes organic diseases which themselves interfere with sleep. OSA interferes with sleep directly, inducing sleep fragmentation and reducing the core sleep stages (slow wave sleep and REM sleep). Indirect interference also occurs due to provocation of events that disturb sleep, such as nocturia, agitation, etc.

Control of breathing during sleep Breathing has a complex regulation, which is influenced by wakefulness and by sleep. It involves mainly the central and autonomic nervous systems, the respiratory muscles, the anatomy of the chest and the upper airways, hormones, and chemical mechanisms related to the blood gases. Respiration is generated in the caudal brainstem by various respiratory neural groups: the dorsal respiratory group, ventral respiratory group and B€otzinger Complex, ventral medullary surface and pontine respiratory group.

*Correspondenc to: Teresa Paiva, Associate Professor of Neurology, Medical Faculty of Lisbon, IMM, CENC – Sleep Medicine Centre, R. Conde Antas, 5, Lisbon, 1070-068, Portugal. Tel: þ351-96-801-1648, Fax: þ351-21-371-5459, E-mail: [email protected]

252 T. PAIVA AND H. ATTARIAN In sleep, two respiratory parameters, the respiratory In addition to the increased pharyngeal collapsibility, frequency and the ventilatory drive, change depending sleep interferes with respiration by reduction of the lung on the sleep stage. They are influenced by the central nervolume in lying positions, especially in obese people, vous system, the autonomic nervous system, hormonal reduced breathing response to CO2 during sleep, and respiratory variability depending on the sleep stage. regulation, and the peripheral structures involved in respiration. In general there is a decrease in the medullary activity in non-REM (NREM) sleep. In REM sleep Pathophysiology of obstructive apneas respiratory neural activity is very variable. There is good Whenever an obstructive sleep apnea occurs there are correspondence between the activity in ventral respiratory group neurons and irregular respiration during direct consequences both during the pharyngeal obstrucREM sleep. In addition to these neuronal changes, tion and at the end of the apnea event. Concomitant with the processing thresholds for afferent stimuli in the the apnea O2 desaturation can be observed, with possible respiratory centre typically change during sleep. hypoxemia and hypercapnia, intrathoracic pressure flucIn brief, during sleep there are marked changes in tuations, recorded by esophageal manometry, which lead breathing regulation due to the different controls in the to strong variations in the blood volume offered to the right and left heart, bradycardia, and persistence of several sleep stages, namely reduced ventilation, reduced respiratory effort. functional residual capacity (FRC), reduced activity in the intercostal muscles during REM sleep with a tendency to At the end of the apneic event changes in the blood paradoxical breathing and hypotonic airway tract muscles gases cause microarousals and/or sleep stage changes during REM. These changes have consequences with which stabilize the muscle tone in the upper airway by regards to blood gas concentrations, namely increased an activation chain aiming to stop the apnea; a gross PaCO2, reduced PaO2, and reduced SatO2. body movement is often present, together with a sympaDuring inspiration the upper airway is mechanically thetic activation, with tachycardia and transient blood relocated by a collapse of the pharyngeal muscles. pressure increase. With a loud snoring noise the airflow During sleep the upper airway resistance doubles with resumes and oxygen saturation returns to normal values. the onset of NREM sleep due to the phasic effect of The patient’s sleep structure pays a price for these reduced muscle tone, reduced tonic activity related to successive bouts of airflow arrest and restoration: sleep sleep onset, and reduction in the FRC. will be fragmented; the quantity of deep sleep and of The oropharynx is the collapsible part of the extraREM sleep will be reduced. Often, however, the affected thoracic respiratory airways. Its mandatory resistance individual does not perceive the transient arousals or against the negative pressure (pull) while breathing in, awakenings, being able to maintain sleep. inspiration, is based on the reinforcement of the pharynAirflow suspension occurs if the obstruction is geal muscles by increase of their muscle tone. The upper complete. This is called obstructive apnea. The obstrucairway patency is maintained if the transmural pressure tion can also be incomplete, known as hypopnea. is positive, that is, the endoluminal pressure exceeds the The breathing difficulty may not be accompanied by closing forces (mainly inspiratory subatmospheric obstructive apneas, but by snoring. This incomplete pressure and tissue pressure). obstruction can cause the same health risks as obstrucDuring sleep the regulation of the muscle tone changes. tive apneas. During inspiration, a dissociation of the muscle activity of If the snoring has no pathologic effects upon the the diaphragmatic respiration and pharyngeal musculablood gases, the sleep process or the cardiovascular ture may be produced. The activation of the pharyngeal system, it is called primary snoring. According to the muscles strongly decreases during sleep, increasing the ICSD definition it belongs to the group of normal varicollapsibility of the upper airways. The activation of the ants. However, histologic studies performed on segdiaphragm is, however, relatively unimpaired. ments have proved the existence of neurologic lesions The respiratory effort of the diaphragm (diaphragin patients with OSA. This is probably the reason for matic respiration) leads to a collapsing force on pharynthe abnormal sensory afferent input from the palatal geal structures during inspiration. The negative pressure mucosa during awake periods, which is independent of which then leads to the collapse is called the pharyngeal the sensory modality used for stimulation. critical pressure (Pcrit) due to its critical obstructive OSA patients have been proven to suffer a decreased pressure. The Pcrit is individually different, depending inspiratory occlusion response. It is now considered that on bodyweight and unfavorable anatomic conditions these neural-histologic alterations in combination with in the pharynx. The Pcrit can also vary intraindividually, the signs of inflammation of the upper airway tissue i.e., depending on body position, sleep stage, or conare due to polyneuropathy caused by the vibration of sumption of alcohol. chronic snoring.

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES

Prevalence The prevalence of the full picture of OSAS is 2–4% in males and 1–2% in females (Young et al., 2002; Al Lawati et al., 2009); these figures from population studies have been found in the USA (Young et al., 1993), Spain (Durań et al., 2001), Hong Kong (Ip et al., 2001), and Israel (Lavie, 1983). Some reports indicate a higher prevalence of snoring and sleep-disordered breathing in African Americans and Hispanics when compared to a Caucasian control group and matched for age and BMI (Ancoli-Israel et al., 1995; Redline et al., 1997). What appears more striking is the fact that China and India also report about a 4% prevalence of OSAS in males, although in these countries the average obesity-related factors (BMI, neck circumference, waist/hip ratio) are lower. This implies other causes, especially craniofacial particularities, as a possible reason for the high OSAS prevalence in Asia (Li et al., 1999; Lam et al., 2006). Recently, however, these figures have been challenged, with the finding of very high prevalence rates in the region of Sao Paulo, Brazil, when the community questionnaires were confirmed by laboratory polysomnography (PSG) (Tufik et al., 2010); the prevalence was 32.8%, with, as in other studies, an increased prevalence in males, obese subjects, in the elderly, and in low social class females. Furthermore the prevalence increases in certain populations. It is around 30% in hypertensive patients and it can reach 80% in drug-resistant hypertension (Logan et al., 2001).

Genetics The heritability of OSAS is around 30%. The Cleveland Family Study showed an increased risk of OSAS in first-degree relatives of patients and the susceptibility further increased with the number of affected family numbers (Redline et al., 1995). Obesity only explains 40% of the variability, and craniofacial morphology, together with soft tissue characteristics, has an important role in genetic transmission of OSAS (Schwab et al., 2006). Genetic studies elucidating the relevance of the genome and single nucleotide polymorphism (SNP) effects are just beginning. In Caucasians and African Americans a whole genome search showed a linkage of the apnea–hypopnea index (AHI) to chromosome 2p and 19p or 8q respectively, after adjustment for BMI (Palmer et al., 2004). However, obesity remains a major confounding factor and definitive conclusions are still to be established (Casale et al., 2009).

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Pathophysiology of the obstructive sleep apnea syndrome Besides association with hereditability and obesity, OSAS has been significantly linked to insulin resistance and some inflammatory markers. In a cohort of male patients, significant increases of insulin resistance, leptin levels, and C-reactive protein (CRP) were associated with OSAS severity; the waistto-hip ratio was the most significant determinant of insulin resistance; the percentage of total sleep time (TST) with hypoxemia was the best predictor of leptin levels (Kapsimalis et al., 2008). However, among the inflammatory markers usually considered in cardiovascular risk, tumor necrosis factor-a (TNFa), IL6, IL8, and CRP, only TNFa is significantly associated with OSAS, since the others give results which might be confounded by obesity (Ryan et al., 2009). Nitric oxide (NO) changes have also been evaluated as another putative indicator of upper airway inflammation; however, in a controlled study, no differences between OSAS and controls were found in the exhaled NO (Dias et al., 2008).

Clinical presentation Many patients have a longstanding history of snoring which has recently become worse and is, at the time of the medical consultation, associated with excessive daytime sleepiness. There is, in fact, a trend across the lifespan which starts with intermittent snoring; this becomes continuous and is often unbearable to the bed partner, and later is interrupted by silent pauses announcing respiratory arrests. Other patients consider themselves in perfect health, even enjoying their ability to fall asleep, and only attending the medical consultation because of complaints concerning snoring from the husband or wife. The main symptoms reported are loud and irregular snoring, hypersomnia manifested in an inability to tolerate anything monotonous and excessive daytime sleepiness, observed apneas during sleep, dry mouth upon awakening, nocturia, lack of concentration, reduced performance, risk of accidents, unexplained hypertension, and morning headaches. Other possible symptoms are disturbed sleep, unusual movement during sleep, insomnia, enuresis, excessive dreaming, difficulties in maintaining sleep, choking or suffocation, impotence (in 50% of affected men), depression, and nocturnal sweats. Snoring is the main reason for consultation, usually prompted by the bed partner. Patients might have two erroneous notions relative to snoring: that it indicates a “sound sleep,” or that it is so common, since

254 T. PAIVA AND H. ATTARIAN “everybody snores,” that it is of no importance. Snoring Morning headaches are not specific of OSAS (Paiva, is initially intermittent and affected by body position, 2011). The prevalence of chronic morning headaches ceasing whenever the bed partner, via a small kick or (CMH) is 7.6% as determined in a European study push, induces a change in body position. It increases (Ohayon, 2004); CMH are more common in females whenever there is a party or any unusual alcohol drinkand in subjects between 45 and 64 years of age. In heading. Later it will become persistent, independent of body ache clinics, 12–41.7% of patients with severe morning position, and unbearable, inducing separation of beds or and nocturnal headaches have sleep apnea (Neau et al., even the bedroom itself, and becoming a point of friction 2002) and 53% of them had headaches associated with between the couple. Snoring induces bed partner a sleep disorder (Paiva et al., 1997), mainly periodic leg insomnia. movements (PLM), restless legs syndrome (RLS), or Excessive daytime sleepiness is another frequent sleep deprivation (Paiva, 2011). According to the complaint. Patients in the initial stages cannot bear ICHD-II (Olesen, 2005), the headache in sleep apnea is monotony, falling asleep while viewing uninteresting a specific entity; it implies the existence of recurrent TV programs, for instance; however, progressively, headaches, present upon awakening, with confirmed sleepiness will become more severe, causing marked apnea in polysomnography and clinical improvement difficulties in daily life since it will interfere with work, with efficient apnea treatment; furthermore the frepleasure, and performance capacity, which ultimately quency should be higher than 15 days per month, it will have life risks for the subject and others. The should have a pressing quality, without nausea, without increased risk of traffic accidents is among them. photo- or phonophobia, and each headache should In children, excessive sleepiness is socially accepted, a resolve within 30 minutes. factor that might delay diagnosis; furthermore sleepHabitual snoring is more frequent in chronic daily deprived children may have hyperactive behaviors. headaches (24%) than in controls (14%) (Scher et al., 2003). Witnessed apneas are also a common complaint; this Complaints of insomnia, fatigue, and headaches are is, however, unspecific since, especially in mild cases, more frequent in females and they tend to underreport it may reflect excessive attention from the bed compansnoring. Insomnia might be a further difficulty in continion, and furthermore during apneas the respiratory uous positive airway pressure (CPAP) treatment effort persists. adaptation. A dry mouth upon awakening or dried saliva result Sleep may be disturbed and restless, with this nocturfrom mouth breathing during sleep. Mouth breathing nal agitation causing difficulties for the bed companduring daytime is common in children with OSAS. ion’s sleep. Usually agitation is due to the body Nocturia is common and is often confused with prosmovements associated with the termination of the apnea tatic dysfunction. It is a direct result of the increase in event; there may be erratic movements of the arms, thoracic negative pressure, which, extending to the kicks, a rising up of the upper body, or sudden body abdominal cavity, compresses the bladder. Severe cases turns. Differential diagnosis with other causes of nocturoften go to the toilet four or five times, or more, during nal agitation is required. the night. This has a negative impact upon sleep continuExcessive dreaming is usually attributed to sleep ity and might have implications for home accident risk in fragmentation and the consequent ability to remember elderly patients. dreams due to the successive awakenings. The dreams Lack of concentration and reduced performance are usually have no particular character, but sometimes they discussed within the framework of neurocognitive might include situations associated with drowning or deficits of OSAS. suffocation. The risk of accidents is high. In 2000 there were Choking and suffocation are associated with sudden 800 000 drivers suffering from OSAS involved in traffic awakenings, with the feeling of imminent death, tachyaccidents in the US. The corresponding costs were US cardia, and sweating. They are not specific of OSAS, $15.9 billion and 1400 lives. Adequate treatment of these since they can occur in panic attacks and laryngospam. subjects would have cost US$3.18 billion and saved 980 Impotence, poor sexual function, and reduced libido lives (Sassani et al., 2004). In Spain, an AHI score > 10/h are frequent in OSAS. predicts traffic accidents (Masa Jimenez et al., 2003). In Depression might be a confounding symptom, mainly Turkey, in a clinical population of 316 truck drivers, in females; this is further explained below, in the section 29.7% had traffic accidents and 29.8% of those accidents on the neuropsychiatric consequences of OSAS. caused loss of life. Snoring, increased neck circumferNocturnal sweats are usually associated with nocturence, and years of driving were significantly higher in nal agitation; they can occur in adults but they are drivers who had accidents (Fidan et al., 2007). particularly important in children.

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES Furthermore, patients are often obese or carrying excess weight. Whenever the BMI is normal craniofacial abnormalities are common. Hypertension is also common.

Neuropsychiatric symptoms Neurologists tend to forget the important impact of OSAS upon the central nervous system; in fact it is associated with both cognitive problems and with depression. Neurobehavioral and neurocognitive impairments are commonly encountered in both adults and children with untreated OSAS. Clinical trials have clearly demonstrated an increased prevalence of memory and concentration problems, mood disturbances, and fatigue in OSAS patients, and have shown a significant relationship between these deficits and OSAS. What remains unclear, however, is whether the OSAS is directly responsible for these complications. This is primarily because of the multiple comorbidities that OSAS patients themselves contribute to neurologic deficits. Significant improvement with CPAP treatment strongly supports the role of OSAS as a causative factor in these deficits. Full resolution of severe deficits, though, does not usually happen, raising the question whether OSAS can lead to irreversible neurologic damage (Dempsey et al., 2010).

COGNITIVE PROBLEMS The first observations of neurocognitive and neurobehavioral problems in OSAS date from the early 1990s. In 2003, Beebe et al. published a meta-analysis of all the papers that had appeared up to then discussing the neurobehavioral and cognitive effects of OSAS. For statistical analysis they used the random and mixed-effects method (0.2 is indicative of a small effect, 0.5 a medium and 0.8 a large effect size) (Engleman et al., 2000; Beebe et al., 2003). They found that general intelligence (IQ) and verbal ability are unaffected by OSAS but vigilance is markedly affected (effect size of 1.40) and executive functioning is also substantially affected (effect size of 0.53–0.73) (Beebe et al., 2003). Furthermore they found a high variability in OSAS’s impact on visual and motor skills, varying from an effect size of < 0.15 to 1.2; this was primarily test dependant. The effect on short-term memory was also found to be inconsistent (Beebe et al., 2003). Neuropsychological testing has revealed primarily frontal cortex dysfunction and cognitive impairment more similar to mild Alzheimer’s than any other type of dementia (Salorio et al., 2002). Both a higher cognitive reserve (Alchanatis et al., 2005) and a younger age (Alchanatis et al., 2008) are associated with fewer

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deficits and better response to treatment with positive airway pressure (PAP). Concerning treatment, not all studies have shown a total recovery of cognitive impairment with PAP. Performance on driving simulators improves greatly but it is not completely normal even after 12 months of compliant treatment (George et al., 1997). Verbal and visual learning seem to normalize (Feuerstein et al., 1997), but despite significant improvement in attention and executive function, which occurs after a few weeks of use (Ferini-Strambi et al., 2003), cognitive function remains impaired to some degree and no further improvement is demonstrated with longer treatment (Ferini-Strambi et al., 2003). Impact on short-term memory is inconsistent (Naegele et al., 1998). More rigorous placebo controlled testing, however, has not shown any significant improvements with PAP treatment in any of the following measures: speed of information processing, attention and working memory, executive functions, alertness and sustained attention, verbal memory, visuospatial memory, and psychomotor performance (Bardwell et al., 2001; Henke et al., 2001; Lim et al., 2007).

DEPRESSION AND OBSTRUCTIVE SLEEP APNEA SYNDROME

The prevalence of depression is high in patients with OSAS. In the community at large it is about 17% versus a prevalence of 4.3% in subjects without OSAS (Ohayon, 2003). In sleep clinic populations, 21–41% of patients with OSAS have depression versus 9% in nonapneics (Sharafkhaneh et al., 2005). OSAS is not only considered a risk factor for depression but depressed patients with sleep-related breathing disorders tend to report more sleepiness and fatigue (Kjelsberg et al., 2005; Bardwell et al., 2007a), and subsequently lower quality of life (Akashiba et al., 2002) and higher disability (Akashiba et al., 2002; Bardwell et al., 2007a; Sivertsen et al., 2008). Treating the OSAS sometimes, but not always, reverses depression, and treatment of depressive symptoms may increase compliance with PAP treatment (Kjelsberg et al., 2005; Santamaria et al., 2007). The burden of a chronic medical condition such as OSAS could clearly lead to depression (Harris et al., 2009) but its exact pathophysiology remains unclear. Both hypoxemia (Bardwell et al., 2007b) and sleep fragmentation (Yue et al., 2003) seem to play a role although there are contradictory studies which support the role of one while refuting that of the other (Yue et al., 2003; Bardwell et al., 2007b). Another theory involves proinflammatory cytokines such as cytokines IL6 and tumor necrosis factor that

256 T. PAIVA AND H. ATTARIAN have been shown to be elevated both in OSAS (Vgontzas between epidemiologic studies (male:female ratio is et al., 1997, 2000a, 2004) and in major depression (Irwin 2–3: 1) and clinical populations (the ratio is 5–8:1) and Miller, 2007). The studies, however, do not suggest (Guilleminault et al., 1988; Young, 1993; Redline causality nor take into account obesity, also associated et al., 1994; Bixler et al., 2001; Durań et al., 2001); in with elevated cytokines, as a confounding variable addition, in clinical populations, the male prevalence (Vgontzas et al., 2000a). becomes extremely high for the more severe cases. Abnormal serotonin transmission could also explain There are several possible explanations for OSAS genthe relationship between the two conditions, as der differences: decreased neurotransmission is associated with both 1. The epidemiologic and the clinical studies evaluate depressive symptoms (Jans et al., 2007) and decreased different disorders or different aspects of the activity of the upper airway dilator muscles (Fenik and disorder. Veasey, 2003). 2. Women, despite seeking medical advice more often, tend to underreport unpleasant symptoms. IMAGING AND NEUROLOGIC DAMAGE IN OBSTRUCTIVE 3. OSAS is underdiagnosed in women because their SLEEP APNEA SYNDROME chief complaints, insomnia, fatigue, depression, and Studies utilizing MRIs of the brain have produced morning headache, lead to other diagnoses. conflicting results. Macey and colleagues not only dem4. Excessive daytime sleepiness is predictive of sleep onstrated gray matter loss in the cingulate gyrus and the apnea in males but not in females (Young et al., hippocampus of subjects with OSAS (Macey et al., 1996). 2002), but the degree of reduction correlated to the 5. The bed partner role, with wives more attentive than severity of OSAS (Morrell et al., 2003). Morrel and husbands, could also play a part in the discrepancy coworkers corroborated these findings (Morrell et al., (Jordan and McEvoy, 2003). 2003) but in a younger cohort, O’Donoghue et al. found 6. Female hormones are protective against apnea, and no difference between patients with severe OSAS and this would explain the increased prevalence after age-, sex- and medical condition-matched healthy menopause (Ware et al., 2000; Hachul et al., controls (O’Donoghue et al., 2005). MRI spectroscopy 2010); however, it is well known that hormonal treathas also shown gliosis and neuronal loss correlating with ment does not improve OSAS. AHI in both adults (Kamba et al., 2001) and children 7. Women have an advantageous craniofacial anat(Halbower et al., 2006) with cognitive dysfunction and omy with larger airways, which would protect them OSAS. from apneas in NREM sleep, but, since they have Positron emission tomography (PET) scans of the stronger atonia and greater respiratory instability brain have shown decreased metabolism in the temporal in REM, they would have more REM-related and frontal cortices of the brain in subjects with OSAS apneas. which does not appear to reverse after CPAP treatment 8. Apneas and hypopneas are shorter in females and (Antczak et al., 2007). Similarly single photon emission therefore they have less desaturation (Ware et al., tomography (SPECT) has shown decreased blood flow 2000); this is so in spite of the fact the hypoxic venin the parahippocampal gyri of OSAS subjects (Joo tilatory response and the respiratory effort et al., 2007). responses to hypercapnia are similar in both genders Lastly, functional MRI studies have correlated (Sin et al., 2000). neurocognitive deficits in severe OSAS to decreased 9. Mortality is, however, higher in women for activation in both the prefrontal and the parietal cortices, equivalent levels of OSAS severity (Young and the latter being more affected in subjects with hypoxFinn, 1998). emia (Thomas et al., 2005). 10. Obesity and fat distribution also play a role: Could this mean permanent damage from OSAS that women with equivalent AHI have higher body is not reversible with PAP treatment (Dempsey et al., mass index then men (Quintana-Gallego et al., 2010)? This may make a case for early detection and diag2004); the fat distribution is different: males have nosis since the mean duration from onset of symptoms to more visceral fat deposition and a central obesity diagnosis is approximately 60–87.5 months (Rahaghi and type. Increased visceral fat correlates with Basner, 1999; Greenberg-Dotan et al., 2007). increased insulin resistance, increased cortisol levels, and abnormal sex hormones in both genders Gender differences (reduced testosterone in males, reduced progesterSymptoms of OSAS differ between the genders one and increased testosterone in females) (Jordan and McEvoy, 2003). The prevalence differs (Bj€orntorp, 1991).


Risks and predisposing factors for obstructive sleep apnea There are several factors which predispose to sleep apnea, namely male gender, ethnicity, increasing age, overweight, truncal obesity with increased abdominal fat, defined as a waist circumference 106 cm in men and 89 cm in women or a waist to hip ratio 1 in men and 0,85 in women, Pickwick morphotype, low soft palate (measured by the Mallampati scale), anatomic narrowing of the upper airway (e.g., short mandible with retrognathia, short cranial base, midface or mandible hypoplasia, macroglossia, hypertrophied tonsils, spacedemanding processes in the pharyngonasal cavity, lipopexia in the tongue base as well as in the cervical and pharyngeal muscles which is present in obesity), nasal obstruction, alcohol consumption, smoking, medication use, short sleep duration, and hereditary syndromes (Down, Pierre Robin, achondroplasia, Crouzon, Treacher Collins, Cornelia de Lange). As already discussed, OSAS prevalence increases with age; furthermore the AHI conventionally considered abnormal in elderly subjects should be higher than 15/h. Overweight and obesity are important contributors and risk factors. It has been shown that a 10% increase in bodyweight has a sixfold increase in apnea risk in the following 4 years, whereas a 10% decrease has 26% decrease in the AHI (Strobel and Rosen, 1996; Peppard et al., 2000). This has two important consequences: overweight and obesity are important risk factors and weight reduction is an important, but often not achieved, therapeutic objective. The Pickwickian morphotype can be associated with OSAS or with the hypoventilation obesity syndrome. The characteristics of the soft palate, namely the big dimensions of the uvula and tongue, the position of the pillars, the enlarged tonsils and adenoids, predispose to OSAS. Tonsil and adenoid enlargement are common in children. It must be noted that mouth-breathing children in fact have the same cephalometric characteristics as children with OSAS (Juliano et al., 2009), having therefore a higher risk of OSAS. The craniofacial anatomy is quite important in subjects with normal BMI; the so-called bird-like face, with retrognathia and a long nose with septal deviation, is very suggestive; however. many subjects have relatively normal facial characteristics with a long and oval face shape and slightly short mandible with backward chin placement; these subjects have a higher risk of upper airway resistance syndrome (Exar and Collop, 1999; Guilleminault and Los Reyes, 2011). Only 33% of the variance in the AHI is explained by cephalometric variables and BMI, since in the sleeping

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apneic patients the collapse of the pharynx commonly occurs at multiple sites (Zucconi et al., 1992; Morrison et al., 1993). Patients with any type of nasal obstruction and allergic seasonal rhinitis have a higher OSAS risk (Al Lawati et al., 2009). Congenital syndromes associated with maxillary hypoplasia and mandibular hypoplasia are significantly associated with OSAS; however, besides the abnormalities in the anatomic features and soft tissue enlargements, impaired neuromuscular control might be at stake (Lee-Chiong, 2008). Alcohol consumption, especially at dinner or during the evening, relaxes dilator muscles, increases upper airway resistance, and decreases respiratory reflexes, and so it increases snoring and sleep apnea duration in susceptible individuals. OSAS prevalence, however, is not increased in those who have been alcohol abusers (Al Lawati et al., 2009). Smoking increases OSAS risk, since current smokers have an odds ratio for OSAS of 4.44 when compared with those who have never smoked, with heavy smokers having the greatest risk (odds ratio of 6.47) (Wetter et al., 1994); current smokers are 2.5 times more likely to have OSAS than nonsmokers or those who have never smoked (Kashyap et al., 2001). Several medications provoke or aggravate OSAS; these include muscle relaxants, sedative hypnotics (benzodiazepines and barbiturates), narcotics, and opioid analgesics. Several mechanisms are in action here: the depression of the respiratory centers and reflexes decreases ventilator drive and increases apnea duration, while the associated respiratory muscle hypotonia tends to further intensify the problem (Lee-Chiong, 2008; Guilleminault et al., 2010). Short sleep duration has a metabolic and increased weight gain risk; therefore it is indirectly considered as a risk factor for OSAS (Al Lawati et al., 2009).

Diseases associated with obstructive sleep apnea syndrome, comorbidities Several sleep-related disorders are often associated with OSAS, such as periodic limb movement disorder (PLMD), restless legs syndrome (RLS), bruxism, and narcolepsy. The prevalence of PLMD in OSAS is around 14% (Iriarte et al., 2009; Monteiro et al., 2010). The association with narcolepsy is mainly due to the increased bodyweight currently observed in narcolepsy. The association with bruxism implies evaluation of the temporomandibular joint, the teeth and dental occlusion. Endocrine disorders. OSAS can appear symptomatically in acromegaly and hypothyroidism. Untreated hypothyroidism can precipitate or exacerbate OSAS;

258 T. PAIVA AND H. ATTARIAN several mechanisms might intervene: macroglossia, saturation seem to stimulate the inflammatory system myopathy, and impairment of ventilator control (Leeleading to endothelial alteration with an increased risk Chiong, 2008). OSAS prevalence in acromegaly is very for atherosclerosis. high, ranging from 75% to 93% of the cases (Grunstein The risk of sudden death due to cardiovascular events et al., 1991; Van Haute et al., 2008); several anatomic is clear in OSAS, death being significantly more frequent and neuroregulatory mechanisms are involved. in OSAS between midnight and 6 a.m. (Gami et al., 2005). Cardiovascular and pulmonary disorders. OSAS OSAS and stroke. The association between OSAS has also been found to be associated with arterial hyperand stroke has been well established. Throughout the tension, heart failure, pulmonary hypertension, cardiac past two decades there have been several case reports arrhythmias, and increased nocturnal death due to (Tikare et al., 1985), case series, and case control studies cardiovascular diseases. all demonstrating a higher prevalence (about 70%) and Arterial hypertension. The relation between arterial severity of OSAS (AHI of over 30/h) among stroke hypertension and OSAS is bidirectional: 40% of unpatients as compared to controls (Hudgel et al., 1993; treated OSAS patients have arterial hypertension and a Bassetti et al., 1996; Dyken et al., 1996). Symptoms of third of essential hypertensive patients (Silverberg and OSAS often precede the occurrence of stroke, suggestOksenberg, 2001) and 87% of refractory hypertension ing a causative relationship (Good et al., 1996). subjects have OSAS (Logan et al., 2001). These facts Large risk ratio studies have shown a strong association have led to specific guidelines in arterial hypertension between snoring and cerebral infarction with a risk ratio of evaluation: in hypertensive patients OSAS should be 10.3 (Partinen and Palomaki, 1985); whenever snoring is considered whenever it is drug-resistant or when there more frequent, the higher the risk of stroke. Snoring is also are witnessed apneas during sleep (Logan et al., 2001). an independent risk factor for cerebrovascular accidents Furthermore it is nowadays good clinical practice to mon(CVA) with a risk ratio of 3.16, especially in subjects having itor blood pressure over 24 hours in OSAS in order to their events during sleep or shortly after awakening evaluate arterial hypertension together with its circadian (Palomaki et al., 1989). This risk more than doubles if, in dipping pattern (Del Colle et al., 2005). In a number of addition to snoring, the subjects are obese and have daystudies therapy with positive pressure devices has been time sleepiness, and it becomes sevenfold higher if they found to reduce OSAS cardiovascular effects. also report witnessed apneas (Palomaki, 1991). Congestive heart failure (CHF). The prevalence of Even when subjects with mild OSA are included in the OSAS is increased in patients with moderate or severe analysis, the relative odds of prevalent stroke is 1.58 CHF. Furthermore CHF can be a result of OSAS: in fact, (Shahar et al., 2001) and the overall hazard ratio is one of the hallmarks of OSAS is the reduction (more 2.89 (Valham et al., 2008). When stratified for severity, negative) of intrathoracic pressure caused by the mild OSAS has 2.44 times the risk of stroke while modimpeded breathing during an OSA; this leads to acute erate or severe OSAS has 3.56 times the risk (Valham changes in pulmonary blood flow and pressure and et al., 2008). increased cardiac afterload. Sympathetic activation In 2005, Arzt and colleagues published one of the during OSAS is another putative mechanism. seminal papers on this topic. In a population of 1475 Pulmonary hypertension. Pulmonary hypertension subjects between 30 and 60 years of age, an AHI of and even cor pulmonale might be present. Two syn20 per hour or higher (determined by PSG) at baseline dromes often occur: the “overlap syndrome,” which was associated with a higher prevalence of stroke OR has both apnea and chronic obstructive pulmonary disof 3.83 after other confounding variables were conease, and the “obesity hypoventilation syndrome,” which trolled for. A subset of 1189 subjects was followed prointegrates OSAS and morbid obesity. spectively for 12 years and the presence of an AHI of 20 Cardiac arrhythmias. Sinus arrhythmia, bradycarper hour or more was associated with increased incidia, sinus pauses, premature ventricular contractions, dence of stroke in the subsequent 4, 8 ,and 12 years, with ventricular tachycardia, and atrioventricular block are an OR of 4.48. This was the first study to show two common. The mechanisms are due to the important important aspects: OSAS was prevalent among stroke impacts suffered by the heart at each obstructive apnea. patients and it also preceded stroke, and so, potentially, OSAS was found to increase morbidity and mortality. it was a risk factor (Arzt et al., 2005). In recent years several studies have investigated the augEven adjusting for age, sex, race, smoking, weight, mented risk of cardiovascular disease in these patients. hypertension, diabetes, atrial fibrillation, and hyperlipidThe sympathetic tone is elevated in OSAS patients due to emia, over a span of 6 years, OSAS is associated with the hypoxemia-induced chemoreflex response and the a significant risk of composite stroke, TIA, or death frequent arousals. Additionally, the dips in oxygen (hazard ratio (HR), 1.97; 95% CI, 1.12–3.48; p ¼ 0.01).

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES Furthermore, the more severe the OSAS, the higher is the risk for stroke, TIA, or death (Yaggi et al., 2005), with severe OSAS (AHI 30) having a HR of 2.52 (Munoz et al., 2006). Treatment does prevent cerebrovascular morbidity, the prevalence of stroke in untreated OSAS (on a weight loss regimen only) over 7 years being almost 4.5 (5.2%/ 1.2%) times that of treated patients (tracheostomized patients, since CPAP was not widely available at the time of these studies) (Partinen et al., 1988; Partinen and Guilleminault, 1990). Despite this robust data in favor of OSAS being a risk factor for stroke, the results are conflicting when one looks for OSAS as a specific risk factor for TIA. A small, 53 subject study showed a significantly higher risk for TIA in OSAS vs controls (Bassetti and Aldrich, 1999), but a similar but larger study with 86 subjects did not duplicate these results (McArdle et al., 2003). OSAS also worsens disability, morbidity, and mortality from stroke (Dyken and Im, 2009). In a number of small studies, hospital stay duration was longer and functional disability higher in the presence of OSAS (Kaneko et al., 2003) and so was mortality 5 and 10 years out (Hardie et al., 2005; Selic et al., 2005; Sahlin et al., 2008). Treatment with CPAP has been shown to reduce mortality (Hardie et al., 2005; Martinez-Garcia et al., 2009) but adherence to CPAP and compliance with it after stroke, although not impossible (Disler et al., 2002), has been fraught with problems (Strollo et al., 1998; Disler et al., 2002; Bassetti et al., 2006). There are no papers defining the exact pathophysiology of OSAS-induced stroke. The most likely reason is elevated sympathetic nerve activity (SNA) due to hypoxia, hypercarbia, and diminished activity of the thoracic stretch receptors (Somers et al., 1995; Dyken and Im, 2009). SNA can increase by up to 246% during a single 10 second apnea event. This also leads to persistent increase in mean blood pressure, especially in REM sleep where SNA is typically high and apneas worse (Somers et al., 1995). There is also a high prevalence of atrial fibrillation due to the same mechanism in OSAS (Gami et al., 2004). Atrial fibrillation in turn increases the risk of stroke (Lloyd-Jones et al., 2009). Worsening of OSAS in REM sleep and the related increased SNA, and increases in catecholamines (Fletcher et al., 1987), in addition to hemodynamic instability, potentiate the early morning hypercoagulable state (Geiser et al., 2002) (a state characterized by increased blood viscosity, low fibrinolytic activity, and high platelet aggregability) (Tofler et al., 1987). There is a link between elevated CD40 ligand and soluble P-selectin (two platelet activation proteins) and silent strokes as well as moderate to severe OSAS. Moreover the

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prevalence of silent strokes was 25% in moderate to severe OSAS subjects and only 6.7% in controls. CPAP therapy significantly reduces the levels of both CD40 ligand and soluble P-selectin (Minoguchi et al., 2007). Lastly, OSAS increases intracranial pressure and may reduce cerebral blood flow, hence further contributing to cerebral ischemia (Jennum and Borgesen, 1989; Klingelhofer et al., 1992). As well as the above, there are rare neurologic complications of OSAS, namely: Neuro-ophthalmologic problems. Nonarteritic optic neuropathy (NAON) has been reported in subjects with OSAS, and in fact the prevalence of OSAS in NAON is 71–89% (Mojon et al., 2002; Palombi et al., 2006) depending on the series. Recently a very small case series showed failure of improvement in NAON after successful OSAS treatment with CPAP (Behbehani et al., 2005). Another neuro-ophthalmologic problem is idiopathic intracranial hypertension (IIH) or pseudotumor cerebri (McNab, 2007). Several studies have shown the presence of papilledema and IIH in patients with OSAS, and CPAP treatment has been shown to reverse disc swelling (Lee et al., 2002). Peripheral neuropathy. Recurrent hypoxemia due to OSAS has been shown be associated with an axonal polyneuropathy (Mayer et al., 1999), with both ischemic and preischemic neuronal damage, and the severity of the former is associated with the severity of the latter (Ludemann et al., 2001). Treatment with CPAP partially reverses the neuropathic damage (Dziewas et al., 2007). Seizure disorder. Although there are no reports of OSAS causing seizures, it can exacerbate pre-existing epilepsy (Oliveira et al., 2000; Chihorek et al., 2007), and treatment with CPAP can improve seizure control (Malow et al., 2008). The association is particularly relevant in children with OSAS, in whom a prevalence of 16% of seizures/and or paroxysmal EEG activity has been described (Miano et al., 2010); this is higher than the prevalence observed in snoring children without OSAS (Miano et al., 2009). Cluster headache has a higher prevalence of sleep apnea (Kudrow et al., 1984; Chervin et al., 2000; Nath Zallek and Chervin, 2000; Paiva, 2011), which varies from 58.3% (Nobre et al., 2003) to 80.6% (GraffRadford and Newman, 2004); patients have 8.4 times more chance of sleep apnea than controls; the risk increases to 24.38 if the body mass index is higher than 25 kg/m2 and patients are male and older than their 40s (Nobre et al., 2003). CPAP treatment of sleep apnea in CH patients reduces CH severity (Nath Zallek and Chervin, 2000). Sleep-disordered breathing probably does not cause CH but may worsen CH attacks. Fibromyalgia may be associated with apnea (Sepici et al., 2007). The association is, however, complex since

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in females the chronic disordered breathing may lead to insomnia, fatigue, and pain, simulating the clinical presentation of fibromyalgia. Gastroesophageal reflux (GER) is also a cause and aggravating factor of OSAS, whereas OSAS due to the changes in abdominal/thoracic pressure increases reflux; but in spite of the relation recognized by some (Lee-Chiong, 2008), other authors deny this relationship (Kim et al., 2005). In fact the recumbent position aggravates both situations and it is common for OSAS patients to complain of heartburn sensations and a bitter taste in the mouth in the morning. GER is also important in children with OSAS, since in them it might contribute to increased psychological disturbance (Noronha et al., 2009). There are more respiratory arousals associated with GER events (Suzuki et al., 2010); furthermore the treatment of GER in mild to moderate OSAS improves the respiratory condition (Orr et al., 2009).

(respiratory effort), pulse oximetry, microphone, ECG, esophageal manometry (optional/standard), optional continuous blood pressure and optional end-tidal PCO2 or transcutaneous PCO2 measurement. Ambulatory recordings can be performed whenever they are requested by a physician expert in sleep medicine and the test is performed and evaluated by accredited specialists in sleep medicine (Collop et al., 2007); however, all patients with comorbidities should perform a standard in-laboratory PSG. In accordance to the findings in the patient’s history and the clinical examination, further investigation might include: evaluation of an anatomic upper airway alterations (cephalometry, CT scan), pulmonary disorders (body plethysmography, chest X-ray, blood gases, and pulmonary function), cardiac diseases (ECG, 24 hour ECG, echocardiography, cardiopulmonary function tests), specific hormonal disorders: hypothyroidism (TSH, FT3, FT4) and acromegaly (IGF1, glucose tolerance test).

Clinical observation

Estimating severity

From what has been said, several aspects are essential in the physical examination in OSAS:

The quantification of the obstructive sleep apnea results from the apnea/hypopnea index (AHI) and the respiratory disturbance index (RDI). Fewer than five apneas per hour of the total sleep time (IAH index < 5/h) is considered to be harmless. A third of all adults have an apnea index > 5/h. In most cases there is no need for treatment. According to the International Classification of Sleep Disorders (ICSD), an apnea index > 5/h with clinical daytime symptomatology constitutes an obstructive apnea syndrome. From 5 to 15 apneas/h the severity is considered mild; it is considered moderate when the AHI ranges from 15 to 30/h and severe in cases where the AHI is higher than 30/h.

1.

2.

3.

4. 5.

bodyweight: (i) measurement of BMI (kg/m2) (ii) waist: values above 102 cm for men and 88 cm for women increase cardiovascular risk, although the maximal values associated with no increased risk are 89 cm and 82 cm, respectively nose and nostrils: observation in order to look for asymmetries and bilateral nasal obstructions, septal deviation, nostril collapse during inspiration, all of them inducing increased nasal resistance upper airways: size and shape, looking for enlarged tonsils and/or adenoids, size of the uvula, tongue size, palate configuration evaluation of a low soft palate (Mallampati class III–IV) craniofacial and cephalometric characteristics, looking for the mandible, the teeth position (overbite, underbite, or superimposed teeth, etc.)

Based on a clear suspicion of sleep apnea, a diagnostic sleep study with polysomnography (PSG), according to standard recommendations should be carried out in the sleep laboratory (Collop et al., 2007). The polysomnographic parameters consist of EEG (at least three derivations), electro-oculogram (EOG), electromyogram (EMG) mentalis, EMG tibialis muscle, nasal and oral airflow (thermistor and nasal cannula for nasal flow and pressure), thoracic and abdominal respiratory signals measured by plethysmography

Assessment of sleepiness in obstructive sleep apnea syndrome Since sleepiness is very frequent, it should be evaluated in all suspected cases, in principle by questionnaires, and in specific cases by neurophysiologic tests. Available questionnaires are: 1. 2.

Stanford Sleepiness Scale (Hoddes et al., 1973): evaluates instantaneous sleepiness Epworth Sleepiness Scale (Johns, 1991): evaluates behavioral sleepiness and correlates with Multiple Sleep Latency Test (MSLT) and with OSAS severity. Scores up to 7 are considered normal; between 8 and 9 is borderline; between 10 and 12 the sleepiness is mild; between 13 and 16 the sleepiness is moderate; and scores higher than 17 indicate a severe degree of sleepiness

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES 3.

4.

Paediatric Sleepiness Scale: also evaluates behavioral situations and has been validated for sleep apnea in children (Drake et al., 2003; Perez-Chada et al., 2007) vigilance and performance tests include the Quatember and Maly Clocktest, driving simulators, and sustained attention tasks: evaluate vigilance and performance.

The neurophysiologic tests are used in specific situations: 1.

2.

Mulitple Sleep Latency Test (MSLT): evaluates the ability to fall asleep and is usually used whenever the suspicion of narcolepsy exists; it is not a routine test in OSAS (AASM, 2005a, b) Maintenance of Wakefulness Test (MWT): evaluates the ability to stay awake and is used whenever there is need to evaluate driving capacity (AASM, 2005a; Littner et al., 2005).

The MSLT is not routinely indicated in the initial evaluation and diagnosis of obstructive sleep apnea syndrome or in assessment of change following treatment with nasal CPAP. In two papers comparing subjects with obstructive sleep apnea with control subjects, there was significant overlap in mean sleep latency values on the MSLT. Nine studies showed statistically significant increases in mean sleep latency values following CPAP therapy (Littner et al., 2005). Pretreatment and post-treatment mean values were within one standard deviation of normal control means, indicating that mean sleep latency values are poor discriminators of response to treatment.

Diagnostic criteria The ICSD2 (AASM, 2005a) has established clear diagnostic criteria. For adults they are as follows: Diagnostic criteria: A, B and D or C and D satisfy the criteria: A. At least one of the following applies: I The patient complains of unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia. II The patient wakes with breath-holding, gasping, or choking. III The bed partner reports loud snoring, breathing interruptions, or both during sleep. B. Polysomnographic recording shows the following: I Five or more scored respiratory events (i. e., apneas, hypopneas, or RERAs/hour sleep. II Evidence of respiratory effort during all or a portion of each respiratory event.

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OR C. Polysomnographic recording shows the following: I Fifteen or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs/hour sleep. II Evidence of respiratory effort during all or a portion of each respiratory event. D. The disorder is not better explained by another current sleep disorder, medical or neurologic disorder, medication use or substance use disorder. The PSG diagnostic criteria for children are, as noted above, different: AHI higher than 1/h is considered abnormal; a set of rules both for recording and for scoring sleep apnea in children has been recently defined by the American Association of Sleep Medicine (AASM, 2007).

Treatment Before the 1980s, tracheotomy was considered to be the only reliable therapy for obstructive sleep apnea. Due to the surgical operation the airflow is able to bypass the pharyngeal obstruction. Medical treatment is nowadays a standard (Veasey et al., 2006).

POSITIVE AIRWAY PRESSURE THERAPY Application of noninvasive ventilation with positive airway pressure (PAP) is nowadays the gold standard for treatment. The rationale of PAP therapy is as follows: the positive airway pressure induces splinting the upper airways and prevents them from respiratory collapse and eliminates the apneas. The additional activation of stretch receptors possibly causes an increase of the pharyngeal muscle tone. It is undoubtedly proven by methods of evidencebased medicine that PAP treatment eliminates obstructive apneas, normalizes the sleep profile, and treats hypersomnia appropriately. In addition, PAP increases the pharyngeal volume and reduces the upper airway resistance. Particularly in obese men it causes an enlargement of the residual lung capacity (RC) which is accompanied by an increase in the tidal volume. Associated cardiovascular diseases such as hypertension, arrhythmia, or heart failure are improved by the treatment of obstructive sleep apnea. The indications for PAP therapy are (Gay et al., 2006): 1. 2. 3. 4.

moderate to severe OSAS (AHI 15/h) (standard) mild OSAS (AHI 5 to 14 events/h) (optional) OSAS patients with daytime excessive sleepiness (standard) improvement of quality of life of OSAS patients (optional)

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T. PAIVA AND H. ATTARIAN as an additional therapy in hypertensive OSAS patients and in patients with systemic hypertension (optional).

There are several types of equipment for PAP therapy in OSAS: CPAP – provides a continuous positive airway pressure APAP – the continuous positive airway pressure is provided automatically on demand BPAP – the expiratory and inspiratory pressures are set CFlex – the expiratory and inspiratory pressures change in each respiratory cycle in order to increase patient comfort. Compliance is the most important factor in PAP treatment. Frequent and disagreeable side-effects of the treatment lead to a decreasing compliance. Nevertheless, these can be improved to a great extent with adequate aftercare. Thus dry nasal mucous membranes can be avoided by the application of an additional humidifier. The careful choice of a mask is recommend: some fit the nose (nasal mask), others fit the nose and the mouth (facial mask), while others fit only the nostrils. In less than 10% the nCPAP therapy is not sufficient, and other forms of nasal ventilation must be applied such as bilevel positive airway pressure (n-biPAP). Recently, the American Academy of Sleep Medicine published guidelines concerning the manual titration of positive airway pressure in OSAS patients of all ages (Kushida et al., 2008). The widespread practice of unattended positive pressure titration with automatic positive pressure devices is not generally recommended by this society and should only be performed in patients with moderate to severe OSAS without any comorbidity. Guidelines for titration of APAP devices were also published (Morgenthaler et al., 2008).

SURGICAL PROCEDURES If CPAP therapy is not accepted by the patient despite being adjusted carefully, other less successful options may be considered. A recent meta-analysis provides relevant information in this issue (Caples et al., 2010). In the case of dysmorphia of the jaws, maxillomandibular osteotomy, or maxillomandibular advancement (MMA) may be an option after careful differential diagnosis. MMA has proven to be efficient with long-term benefits and few side-effects. Other surgical options, such as uvulopalatopharyngoplasty (UPPP), have been evaluated in controlled studies and these have been reviewed by the Cochrane

Collaboration for evidence-based medicine (Li, 2005; Elshaug et al., 2007; Elshaug et al., 2008). According to these reviews, this treatment achieves a reduction of only 50% in the apnea–hypopnea index (AHI). In addition, it is only in 50% of patients that a reduction of apneas and hypopneas is achieved at all. Thus this option cannot be considered as a recommended therapy. UPPP is associated with more adverse events (Caples et al., 2010). For Laser assisted uvulopalatoplasty (LAUP) and radiofrequency ablation (RFA) there are not consistent controlled studies evaluating the effect in AHI and adverse events (Caples et al., 2010). Surgical correction of the nasal cavities can be very useful also to improve efficacy of nasal CPAP ventilation therapy.

ORAL APPLIANCES (LOWER JAW PROTRUSION

PROSTHESES)

Oral appliances have recently been studied as a therapy option in the obstructive sleep apnea syndrome. The principle of all dental devices is based on a lower and upper jaw prosthesis, which creates forces on the lower jaw in order to advance it as well as the tongue. These prostheses are individually adapted by dental laboratories. The devices are used to mechanically enlarge the pharyngeal cross-sectional area and thus avoid upper airway obstruction during sleep. Efficacy of this method differs widely from person to person. In general, oral appliances are not as effective as positive pressure devices in the treatment of obstructive sleep apneas. However, the actual guideline of the American Academy of Sleep Medicine recommends oral appliances in (Kushida et al., 2006) primary snoring, in patients with mild to moderate OSAS who prefer oral appliances, in patients who do not respond to CPAP, and in patients who fail treatment attempts with CPAP.

PHARMACOLOGIC TREATMENT Subsequent and concomitant diseases must be treated. There have been successive attempts to implement pharmacologic treatments of OSAS (Veasey et al., 2006); nevertheless, there are as yet no studies fulfilling the requirements of evidence-based medicine regarding the results. A few examples are given: theophylline led to a significant decrease of apneas in some isolated cases; mirtazapine was initially found to reduce the AHI, but two recent studies could not reproduce this effect; furthermore, its frequent adverse effect of increasing weight precludes its use in OSAS.


BEHAVIOR MANAGEMENT The purpose of behavior management is the prevention of apneas as well as therapeutic support in mild cases or as an adjuvant treatment procedure in general reduction of weight, sleep hygiene, physical exercise, avoiding substances affecting vigilance and sleep (such as alcohol, smoking, hypnotics, sedative substances), and as support to CPAP adaptation.

CENTRAL SLEEPAPNEA AND HYPOVENTILATION SYNDROMES Central sleep apnea (CSA) syndromes can be divided in two groups according to the levels of CO2 and the characteristics of CO2 response; namely: Group I – CO2 in sleep decreases and/or CO2 response increased: 1. 2. 3. 4.

primary central sleep apnea Cheyne–Stokes breathing pattern high-altitude periodic breathing primary sleep apnea of infancy.

Group II – CO2 in sleep is increased and/or CO2 response is reduced: 1. 2. 3. 4. 5. 6.

sleep-related nonobstructive alveolar hypoventilation, idiopathic congenital central alveolar hypoventilation syndromes sleep-related hypoventilation/hypoxemia due to pulmonary parenchyma or vascular pathology sleep-related hypoventilation/hypoxemia due to neuromuscular and chest wall disorders sleep-related hypoventilation/hypoxemia due to lower airway obstruction central sleep apnea due to a medical condition not Cheyne–Stokes.

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decreased and close to the apnea threshold and tends to decrease further after a small increase in ventilation. Polysomnographic and other objective findings: as with OA, the duration is at least 10 seconds and an index higher than 5/h is required. Events are less frequent in stable NREM than in REM sleep; desaturations are commonly less severe than in OSAS since the chemoreflex is not blunted. PaCO2 is less than 40 mmHg (AASM, 2005a).

Cheyne–Stokes respiration pattern The Cheyne–Stokes respiration pattern (CSRP) includes both periodic breathing and Cheyne–Stokes respiration (AASM, 2005a). The CSRP is characterized by apneas, hypopneas, or both; these events alternate with prolonged hyperpneas during which the tidal volume gradually waxes and wanes in crescendo/decrescendo style (Fig. 18.2). The hypopneas and apneas are associated with reduced respiratory effort and respiratory drive. This recurrent cessation of breathing leads to repetitive hypoxic dips, to sleep fragmentation, and to frequent sleep stage changes. Pathophysiology: CSRP occurs at the transition of wake to sleep in chronic hyperventilating persons. The hyperventilation is caused by stimulation of pulmonary vagal irritant receptors (pulmonary congestion) and /or increased responsiveness of the peripheral and central chemoreceptors. The crescendo/decrescendo pattern is caused by the blood circulation time. The main clinical associations are congestive heart failure and less often, stroke and renal failure.

Primary central sleep apnea CSA is defined by recurrent cessation of respiration during sleep not associated with ventilatory effort (Fig. 18.1). Therefore there is sleep fragmentation due to respiratory events and associated arousals, but during wakefulness PaCO2 is normal or low, around 40 mmHg. As in OSAS there is a male predominance and daytime sleepiness-related frequent nocturnal awakenings. Insomnia is likely to increase occurrence of CSA. Pathophysiology: CSA is caused by the instability of the respiratory control system at the transition from wakefulness to sleep in individuals with an increased ventilatory responsiveness to CO2; in fact PaCO2 is

Fig. 18.1. Central apnea - There is a cessation of both nasal flow and respiratory effort for at least 10 seconds.

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Fig. 18.2. Cheyne Stokes breathing - There is a wax and waning periodic pattern, in which periods of hyperventilation alternate with respiratory pauses.

The polysomnographic and other objective findings are as follows: 1. 2. 3. 4. 5. 6.

recurrent central apneas/hypopneas alternating with ventilatory crescendo/decrescendo pattern occurrence decreases from WAKE to NREM 1–2 to slow wave sleep and to REM arousals are frequent but not mandatory; they usually follow the initial breaths desaturations are usually modest ( 80%) reduced amount of slow wave sleep PaCO2 is less than 45 mmHg.

At 5000 m periodic breathing might resolve over time, but at 7600 m it persists indefinitely. Again there is a male preponderance due to increased chemoresponsiveness in men (AASM, 2005a).

Central sleep apnea due to medical condition not Cheyne–Stokes This may be caused by neurologic and medical disorders, such as brainstem lesions, cardiac, or renal disorders (AASM, 2005a).

Central sleep apnea due to drug or substance Complex sleep apnea syndrome The complex sleep apnea syndrome (CompSAS) has only been recently defined and it is not included in the definitions of the ICSD2. It corresponds to central sleep apneas that occur following the treatment of obstructive sleep apneas with a positive pressure device (CPAP, BiLevel), usually whenever the pressure is too high. CompSAS may play an important role in the healthcare of sleep disordered breathing since it was observed in about 15% of the patients following CPAP treatment. The recommended treatment includes the more expensive adaptive servoventilation devices.

High-altitude periodic breathing High-altitude periodic breathing is a normal adaptation to altitude and there are no specific criteria regarding the frequency of central apneas that should be considered normal or abnormal. Occurrence depends on rapidity of the ascent, the altitude and individual preposition.

This may occur in patients taking a long-acting opioid regularly for at least 2 weeks. Opioid-induced ventilation disorders may also include Biot breathing and obstructive apneas/hypopneas (AASM, 2005a).

Primary sleep apnea of infancy Infants, especially small, preterm infants, have prolonged central, mixed, or obstructive apneas or hypopneas associated with hypoxemia, bradycardia, and need for intervention (ventilation). This disorder represents a deficit in respiratory control via direct depression of the respiratory center, disturbance of oxygen delivery, or ventilation defects; it may be due to brainstem immaturity or medical conditions. It does not include sudden infant death syndrome (SIDS). There are predisposing factors, namely: low birthweight (25% of infants below 2500 g and 84% of infants below 1000 g develop the disorder) and developmental

OBSTRUCTIVE SLEEP APNEA AND OTHER SLEEP-RELATED SYNDROMES alterations in the respiratory drive due to chemo- or mechanoreceptor responses and to upper airway reflexes. There are precipitating factors: thermal instability, gastroesophageal reflux, intracranial pathology, drugs, anesthesia, impaired oxygenation. and infection. The condition usually starts on the 2nd to 7th days after birth and at 37 weeks postconception 92% of the babies have no further symptoms (AASM, 2005a). The respiratory events increase during active sleep (REM).

Sleep-related nonobstructive idiopathic alveolar hypoventilation This idiopathic hypoventilation is also called central or primary and is associated with increased CO2. There is a blunted chemoresponsiveness without detectable abnormalities (pulmonary, endocrine, neurologic, ventilatory muscle, cardiac); its is eventually due to subtle medullar abnormalities. The ventilatory output during sleep is reduced, and therefore an initial nocturnal hypoventilation will become both diurnal and nocturnal. The PSG shows hypoventilation, which is increased in REM sleep with severe hypoxemia and hypercapnia and also sleep fragmentation. The main symptoms are: morning headaches, cor pulmonale, peripheral oedema, polycythemia, and sometimes daytime sleepiness (AASM, 2005a).

Congenital central alveolar hypoventilation syndrome Congenital central alveolar hypoventilation syndrome (CCAHS) is a central or primary alveolar hypoventilation syndrome; it was formerly also known as Ondine’s curse, but this term should no longer be used. The condition is due to failure of automatic central control of breathing and the onset of alveolar hypoventilation occurs usually in childhood; the child is otherwise relatively normal, but does not breathe spontaneously. Some patients hypoventilate only when asleep, others also during wakefulness. There are associated disorders: Hirschsprung disease occurs in 16% of the cases and there is an association with neural tumors. There is a familial pattern with an association with siblings and twins and the majority of the cases are PHOX2B gene-positive. There are other mild clinical symptoms, namely swallowing dysfunction, ocular abnormalities, and cognitive dysfunction due to hypoxemic events. Pulmonary function tests show hypoxemia and hypocapnia. Polysomnography shows a diminished arousal response which progresses in the course of sleep; the abnormalities are often more severe in SWS than in REM

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sleep; Cheyne–Stokes respiration may occur (AASM, 2005a).

Sleep-related hypoventilation due to neuromuscular and chest wall disorders This category includes: alveolar hypoventilation, secondary alveolar hypoventilation, and obesity hypoventilation syndrome. These syndromes are due to impairment of the chest wall musculature (AASM, 2005a). The essential features are: 1.

2. 3.

an abnormal ventilatory pump (VP) due to reduced respiratory muscle contractibility (neuromuscular) and/or distortion of chest wall structures (reduced muscular efficiency) the VP is unable to keep PaCO2 at values equal to or below 45 mmHg other factors may coexist, namely OSA, reduced central neural chemoresponsiveness.

Patients complain of daytime sleepiness. Prolonged alveolar hypoventilation may cause increased pulmonary hypertension and/or increased mortality. The predisposing factors are morbid obesity and neuromuscular disorders. The precipitating factors include excessive obesity, REM sleep (due to the respiratory burden on the diaphragm), hypoxemia and hypercapnia during wakefulness; bulbar dysfunction with abnormal swallowing increases the risk of sleep-related hypoventilation and hypoxemia, as in amyotrophic lateral sclerosis, and in myotonic dystrophy and other situations associated with reduced chemosensitivity. The polysomnographic findings are: 1. 2. 3. 4. 5.

frequent arousals (due to the respiratory effort) increased wakefulness hypoventilation with increased desaturations in REM sleep REM sleep reduction OSA and central apneas (not mandatory).

An example of hypoventilation is shown in Figure 18.3.

Sleep-related hypoventilation/hypoxemia due to lower airway obstruction This item includes: nocturnal oxygen desaturation; low oxygen saturation; nocturnal hypoxemia; sleep-related oxygen desaturation; sleep-related hypoxemia; secondary alveolar hypoventilation (AASM, 2005a). The main features are: 1. 2.

obstruction or increased resistance below laryngeal area heterogeneous ventilation

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Fig. 18.3. Hypoventilation – Notice the decreased amplitude of ventilation, the low values of O2 saturation, and the frequent arousals in the EEG and EMG channels.

3. 4.

absolute or relative increase in PaCO2 (>45 mmHg) during sleep prolonged sustained desaturation and hypoventilation without apneas, hypopneas, or airflow limitation.

The associated diseases are: COPD (emphysema, chronic bronchiolitis), asthma, bronchiectasis, cystic fibrosis, and disorders of the immune system.

Sleep-related hypoventilation due to pulmonary parenchymal or vascular pathology This includes: nocturnal oxygen desaturation; low oxygen saturation; nocturnal hypoxemia; sleep-related oxygen desaturation; sleep-related hypoxemia; secondary alveolar hypoventilation; excessive nocturnal hypoxemia. The essential features are: 1.

2. 3.

4.

significant sleep-related hypoxemia associated with lung parenchyma disease; pulmonary vascular pathology; hemoglobinopathies observed hypoxemia is not a function of other sleep disorders gold standard is the identification of sustained desaturation without apneas (central, mixed obstructive), inspiratory flow limitation and snoring PaCO2 does not necessarily reflect absolute alveolar hypoventilation (PaCO2 > 45 mmHg) but, in sleep, it is abnormally increased compared to wakefulness.

The pathophysiology implies reduced lung volume; decreased oxygen reserve; desaturation enhanced;

abnormal ventilation/perfusion; chemosensitivity compensation and increased elastic load; augmented activation of the ventilatory muscles; relative and absolute hypercapnia and low hemoglobin saturation at wakefulness ¼ close to the steep portion of the desaturation curve. The polysomnographic findings are: sustained oxygen desaturation; discrete or absent respiratory events; intermittent arousal associated with hypoxemia (AASM, 2005a).

ACKNOWLEDGEMENTS We would like to thank Dr. Richard Staats for his support and for collaboration in certain aspects of this chapter.

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The sleep apnea syndromes.

Obstructive sleep apnea.

Familial obstructive sleep apnea.

Asthma and Obstructive Sleep Apnea.

High risk for obstructive sleep apnea and other sleep disorders among overweight and obese pregnant women.

Diagnosis and treatment for obstructive sleep apnea: Fundamental and clinical knowledge in obstructive sleep apnea.

Obstructive sleep apnea and acute coronary syndromes: etiology, risk, and management.

Obstructive Sleep Apnea: Women's Perspective.

[Obstructive sleep apnea in women].

Obstructive sleep apnea in adults.

Treatments for Obstructive Sleep Apnea.

Obstructive sleep apnea: therapeutic alternatives.

Obstructive sleep apnea in Apert's and Pfeiffer's syndromes: more than a craniofacial abnormality.

Secondary hypertension: obstructive sleep apnea.

Mechanisms of obstructive sleep apnea.

Obstructive Sleep Apnea and Osteoporosis Risk.

Obstructive sleep apnea and central serous chorioretinopathy.

Laryngeal obstruction and obstructive sleep apnea syndrome.

22q11.2 Deletion syndrome and obstructive sleep apnea.

Endocan, Obstructive Sleep Apnea, and Vascular Risk.

White coat hypertension and obstructive sleep apnea.

Obstructive sleep apnea and endothelial progenitor cells.

Cardiovascular morbidity and obstructive sleep apnea.

Obstructive sleep apnea and hypertension: an update.