Chapter 6

Clinical presentations of OSA in adults

R. Tkacova and Z. Dorkova

Summary
Obstructive sleep apnoea (OSA) is a common disorder affecting 24% of the adult population. Cardiovascular, metabolic and neurocognitive consequences of OSA underline the need for early diagnosis and treatment of the disorder. The diagnosis of OSA is based upon the combined assessment of clinical features alongside the objective demonstration of sleep-disordered breathing, using an appropriate sleep study. The typical presentation of OSA is represented by an overweight male patient complaining of loud snoring, nocturnal choking, nocturia, excessive daytime sleepiness and mild cognitive impairment, with a history of witnessed apnoeas during sleep. The physical examination can suggest increased risk and should include the respiratory, cardiovascular and neurological systems. Particular attention should be given to the presence of obesity, signs of upper airway narrowing and arterial hypertension. Nevertheless, OSA is a heterogeneous disorder with a broad range of nocturnal and daytime symptoms that may not conform to the typical history and physical findings, particularly among females, the elderly, during pregnancy, or in the presence of other disorders that can contribute to the development of OSA or to the adverse consequences of OSA, such as congestive heart failure, end-stage renal disease, chronic obstructive pulmonary disease and certain endocrine disorders. Since OSA is associated with adverse cardiovascular outcomes, increased awareness of the atypical presentation of OSA in different patient populations is warranted. Keywords: Assessment, diagnosis, obstructive sleep apnoea, symptoms
Dept of Respiratory Medicine, Faculty of Medicine, P.J. Safarik University and L. Pasteur Teaching Hospital, Kosice, Slovakia. Correspondence: R. Tkacova, Dept of Respiratory Medicine, Faculty of Medicine, P.J. Safarik University and L. Pasteur Teaching Hospital, Rastislavova 43, Kosice, 041 90, Slovakia, Email ruzena.tkacova@upjs.sk

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Eur Respir Mon 2010. 50, 86103. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024209

bstructive sleep apnoea (OSA) is a highly prevalent disorder affecting 24% of the adult population [1, 2]. The signs, symptoms and consequences of OSA are a direct result of the derangements that occur due to repetitive collapse of the upper airway during sleep, leading to markedly reduced (hypopnoea) or absent (apnoea) airflow. Acutely, repetitive apnoeas and hypopnoeas are accompanied by arousals from sleep/sleep fragmentation, hypoxaemia and marked swings in intrathoracic pressure, and result in surges in sympathetic nervous system activity, blood pressure and heart rate [3]. Chronically, patients with OSA are at an increased risk

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for the development of arterial hypertension [4, 5], stroke [6] and myocardial ischaemia [7], and have increased cardiovascular morbidity and mortality [8]. OSA relates independently to insulin resistance, diabetes and the metabolic syndrome [9, 10], and untreated patients with OSA are at increased risk of car accidents [11, 12]. However, despite the serious medical consequences, impairment of quality of life [13] and significant medical costs associated with OSA [14], the condition often remains unrecognised and undiagnosed. Patients may frequently regard their symptoms as normal variants and/or manifestations from a poor lifestyle, and have no readily detectable respiratory abnormality during their awakened periods [15]. Nevertheless, the high medical and economic burden of OSA underlines the importance for maximising the recognition and diagnosis of this disorder [13, 15]. The diagnosis of OSA is based upon the combined assessment of clinical features together with the objective demonstration of sleep-disordered breathing using an appropriate sleep study [16]. Although the assessment of patient history together with a clinical investigation may identify the presence of OSA with appropriate sensitivity (.80%), the specificity is low (,50%). Therefore, a final diagnosis of OSA requires a positive finding of sleep apnoea using an appropriate diagnostic sleep test. This chapter discusses the symptoms, signs and findings suggestive of OSA in the general population, and in specific patient populations.

Clinical assessment
A detailed clinical assessment forms an integral part of the evaluation procedure for a patient suspected of having OSA. The typical presentation is that of an overweight male patient complaining of loud snoring, nocturnal choking, nocturia, excessive daytime sleepiness and mild cognitive impairment, with a history of witnessed apnoeas during sleep and possibly cardiovascular consequences of OSA. Nevertheless, OSA is a heterogeneous disorder, and a broad range of nocturnal and daytime symptoms can be reported (table 1). Generally, symptoms of OSA develop over years and progress in association with increases in weight, aging and transition to menopause. A detailed longitudinal sleep history and physical examination are essential in identifying at-risk individuals. Nevertheless, symptoms compatible with OSA, such as snoring and daytime sleepiness, may be caused by disorders other than OSA, such as poor lifestyle habits and/or medical disorders that can predispose a patient to sleep disturbance. In such instances clinical features alone have limited value in the prediction of OSA. Therefore, the diagnosis of OSA requires the combined assessment of clinical features together with an objective sleep study [15, 17]. The importance of proper clinical assessment is underlined by epidemiological studies that indicate a relatively high prevalence of sleep-disordered breathing in the community, which falls significantly when relevant clinical features are taken into consideration. In the Wisconsin Cohort Study, a prevalence of 24% was seen for an apnoea index Table 1. Symptoms and signs of obstructive sleep apnoea exceeding 5 events per Night-time symptom Daytime symptom hour, which fell to 4% for the same index comWitnessed apnoeas Excessive daytime sleepiness Snoring Fatigue bined with excessive dayNocturnal choking Morning dry mouth time sleepiness [18]. In Disturbed unrefreshing sleep Morning headache population screening studThirst during the night Difficulty concentrating ies, self-reported questionNocturnal diuresis, enuresis Irritability, mood changes naires are sometimes given Nocturnal sweating to patients in advance of Nasal congestion clinical evaluation to simExcessive salivation plify the clinical assessGastro-oesophageal reflux ment. Among these, the Impotence Berlin Questionnaire [19]

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and the Multivariable Apnoea Prediction Index [20] are most widely used. Nevertheless, although such questionnaires may be useful for population screening studies, their value is limited in the assessment of individual patients in a sleep clinic setting [21].

Nocturnal symptoms
Clinical symptoms suggestive of OSA include daytime and night-time symptoms (table 1). For the correct evaluation of patients with suspected OSA, it is advantageous to interview the bed partner, who can usually provide important additional information based on direct observation of the patient while asleep [22]. The partners input often includes the identification and description of snoring, the witness of apnoeas, and/or a different perspective concerning daytime symptoms, such as sleepiness and reductions in neurocognitive performance. The common experience indicates that the partner observes and reports a higher degree of functional impairment than the patient alone. The basis for this discrepancy is likely to be complex and reflects a number of factors, such as denial, neurocognitive impairment and/or habituation to the symptoms by the patient [15].

Snoring
Snoring is the most frequent symptom of OSA occuring in up-to 95% of patients. Snoring is caused by the narrowing of the upper airway, and reflects, therefore, the basic pathophysiology underlying the disorder. Nevertheless, snoring has poor predictive value owing to a high prevalence in the general population [23]. The elderly are predisposed to snoring and OSA as a result of: weight gain, side-effects of certain medications (e.g. sedatives, analgesics and muscle relaxants), loss of muscle tone, and/or the development of associated medical conditions that predispose to OSA (e.g. hypothyroidism). In population surveys, the prevalence of snoring increases progressively with age. In fact, .60% of males and .40% of females aged 4165 yrs habitually snore during the night [18]. Despite its poor predictive value, snoring is a hallmark of OSA, and in its absence the diagnosis of OSA is unlikely [24]. Most snorers are unaware that they might cause a problem to others or to themselves until they share a sleeping space with someone else [25]. The snoring sound may exceed 85 dB, which is comparable with the sound of a busy road, and may disturb people even one or two rooms away. Periods of silence interrupting loud snoring may reflect either the resumption of normal breathing or pathological apnoeas. Generally, snoring is the loudest when lying on the back, and becomes either reduced or even absent whilst lying on the side or in the prone position. From a practical point of view, snoring should be taken seriously if it occurs more frequently than 2 nights per week, is loud enough to be audible in other rooms, induces a bed partner to move to a separate room, occurs in lateral as well as supine positions, is associated with witnessed apnoeas, dyspnoea or choking [25], and/or is associated with other symptoms of OSA, such as excessive daytime sleepiness or neurocognitive impairment. Snoring in patients with underlying medical conditions that predisposes them to upper-airway collapse should also alert the physician to investigate the possibility of comorbid OSA.

OSA: CLINICAL PRESENTATION IN ADULTS

Witnessed apnoeas
Complaint by a bed partner, concerning witnessed breathing pauses, is a common reason for referral to a sleep clinic. Indeed, the bed partners often provide useful information regarding the characteristics and frequency of breath pauses during sleep. However, the accounts of witnessed apnoeas may not be accurate, as even a physicians diagnosis of OSA severity on the basis of bedside estimates of disordered breathing rates and the duration of episodes, may not correlate with objective measurements [26]. Although witnessed apnoeas are considered a good diagnostic predictor of OSA [18], they do not predict the severity of the disorder [17, 27]. Witnessed breathing pauses are less common among female patients with OSA [28]. Importantly, witnessed

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apnoeas should be distinguished from nocturnal shortness of breath caused by conditions such as congestive heart failure, bronchial asthma and laryngospasm.

Nocturnal choking or gasping

Many patients with OSA report waking up choking or feeling acutely panicked during the night. Similarly to apnoeas, differential diagnosis between choking episodes due to sleep-disordered breathing and other medical conditions is required. Paroxysmal nocturnal dyspnoea resulting from congestive heart failure may resemble some of the characteristics of apnoea, including a similar sensation of choking. Nevertheless, patients with heart failure typically report prolonged dyspnoea and orthopnoea in association with daytime symptoms, such as shortness of breath during exercise, which makes the distinction more obvious.

Insomnia
Most patients with OSA have little difficulty in initiating sleep, and the sleep latency objectively recorded during a polysomnographic examination is typically shorter than in patients free from sleep-disordered breathing. Nevertheless, some patients complain of insomnia, which is most likely to reflect their perception of recurrent arousals from sleep and its nonrestorative pattern.

Other nocturnal symptoms

Nocturia, enuresis, excessive salivation, gastro-oesophageal reflux, diaphoresis, and impotence are symptoms of OSA that are less frequently reported by patients or their bed partners. Effective therapy with continuous positive airway pressure (CPAP) reduces occurrence of these symptoms [29], thus suggesting a causal relationship between them and OSA [15].

Daytime symptoms Excessive daytime sleepiness

Sleepiness is a ubiquitous phenomenon, experienced as a symptom in a number of somatic, psychiatric and primary sleep disorders, but also as a normal physiological state. Sleepiness represents a basic physiological need comparable with hunger or thirst, which is satisfied by sleeping, eating or drinking, respectively, and thus serves survival of the organism. Physiological sleepiness (i.e. sleep pressure) increases while being awake and underlies its dependence on circadian rhythm [30]. Subjectively, the feeling of sleepiness is characterised by a poorly defined transit zone between full wakefulness and overt sleep that may include subjectively perceived impairment of concentration, wandering thoughts, blurred vision, heavy eyelids and the increased craving for sleep. All these subjective indicators of sleepiness can only be described by the individual and are not amenable to direct measurement. The behavioural indicators of sleepiness include yawning, reduced activity, ptosis, eye rubbing and the drooping of both the head and eyelids. The consequences include shortened sleep latency, attention deficits, slowed cognitive functions and reaction times with consecutively impaired performance, resulting in the increased risk of a work or motor vehicle related accident [11, 12]. The only physiological method of reducing sleepiness is to get restorative sleep. Pathological sleepiness is represented by its pervasive presence (in narcolepsy), in its absence (in insomnia) or in conditions associated with excessive daytime sleepiness (in sleep-disordered breathing, mostly OSA). In an attempt to re-establish airflow in the collapsed airway during an obstructive apnoea, the patient makes progressively larger respiratory efforts until there is arousal from sleep and resumption of breathing. Repetitive arousals from sleep result in sleep fragmentation and impairments in sleep architecture with a marked reduction in rapid eye

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movement and slow-wave sleep [31]. Consequently, sleep looses its restorative function, resulting in excessive daytime sleepiness in association with impaired vigilance. The symptoms progress gradually, and many patients are not fully aware of their problems until their daytime function and performance is severely affected. Therefore, it is not surprising that only one quarter of OSA patients report sleepiness to be a leading symptom, while ,50% report lack of energy, exhaustion or fatigue as their main symptom [32]. Patients frequently underestimate the severity of sleepiness [33], which may reflect a genuine underestimation and/or reluctance to admit the symptom for social or work-related reasons [15]. Given the two and a half to three-fold increase in risk of accidents by patients with OSA [34], objectifying sleepiness is of central importance for the diagnosis and evaluation of the severity of sleep-related respiratory disorder [35] (refer to the section in this chapter entitled Objectifying sleepiness).

Other daytime symptoms

Patients with OSA often report daytime symptoms such as fatigue, memory impairment, personality changes, morning nausea, morning headaches, automatic behaviour and depression [24, 29]. Although these symptoms are helpful in assessing the impact of OSA on a patients quality of life and the effectiveness of therapy, no systematic study has been undertaken to analyse whether these features have the potential to predict the presence or absence of OSA [15]. Therefore, the utility of these symptoms in the objective clinical assessment of patients with suspected OSA remains uncertain.

Physical findings
OSA: CLINICAL PRESENTATION IN ADULTS

Multiple imaging studies, which used computed tomography, magnetic resonance imaging, fluoroscopy and acoustic reflection, demonstrated that patients with OSA have a small pharyngeal airway with the smallest area occurring at the level of velopharynx [36]. Since humans do not have a rigid support body for the pharyngeal airway, the patency of the upper airway relies on muscle activation and soft tissue structures. During wakefulness, the smaller upper airway in patients with OSA causes a reflexive increase in muscle activity thereby maintaining its patency. These protective reflexes are diminished or even lost during sleep, thus increasing the propensity for the smaller upper airway to collapse. Obesity and craniofacial abnormalities represent the most common risk factors for the reduction in the calibre of the upper airways (table 2).

Obesity
Obesity is common in patients with OSA, in particular central obesity represents one of the strongest risk factors of the disease. The Wisconsin Sleep Cohort has shown that patients with mild OSA have a six-fold increase in risk for developing moderate or severe OSA if they gain only 10%
Table 2. Physical characteristics associated with an increased risk factor for obstructive sleep apnoea
in adults

Male Post-menopausal female Obesity, particularly central obesity Upper airway anatomical abnormalities: retrognathia, micrognathia, midface or mandibular hypoplasia, macroglossia, hypertrophied tonsils, inferior displacement of the hyoid, and increased uvula size Arterial hypertension: particularly drug-resistant hypertension and nocturnal nondipping on 24-h blood pressure measurement Cardiovascular diseases: ischaemic heart disease, stroke or heart failure Metabolic syndrome with or without type 2 diabetes

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of their body weight [37]. Some 70% of subjects with a body mass index (BMI) o40 kg?m-2 suffer from OSA. Neck circumference and BMI correlate best with the presence and severity of OSA [38]. Predictive value of other anthropomorphic variables related to body weight, such as waist circumference, waist-to-hip ratio and skin-fold thickness, is generally lower except in extreme cases. Neck circumference measurements taken at the level of the cricoid membrane were strongly related to the presence of OSA in studies undertaken on sleep apnoea patients in both sleep centres [39] and in primary care settings [40]. Patients with OSA also have a smaller internal diameter of the pharyngeal airway, especially the distal part, suggesting that these patients have thick necks caused in part by excess deposition of adipose tissue. Indeed, there is an increase in excess fat in the areas anterolateral to the upper airway in both obese and nonobese patients with OSA [38]. In general, patients with a small neck circumference (,37 cm) are at a lower risk of having OSA, whereas patients with quite a large neck circumference (.48 cm) are at a substantially higher risk [41]. Despite these data, physicians should be aware that OSA is also being increasingly recognised in individuals who are not grossly overweight and who have neck circumferences ,48 cm.

Craniofacial and neck anatomy

Conditions such as retrognathia, micrognathia, midface or mandibular hypoplasia, macroglossia, hypertrophied tonsils, inferior displacement of the hyoid and increased uvula size can all lead to smaller upper airways. In addition, increased nasal resistance due to nasal polyps, deviated septa and congestion can worsen OSA. In one study, patients with rhinitis and OSA had reductions in their apnoeahypopnoea index (AHI) when treated with an intranasal corticosteroid [42]. Several rare complex hereditary syndromes are related to an increased risk of OSA in children e.g. Pierre Robin, Treacher Collins, Alpert, Hurler, Hunters, Down and Prader-Willi syndrome. Taken together it is not only obese patients who suffer from OSA and anatomical factors that predispose a patient to OSA should be sought during the physical examination of a patient suspected of having sleep-disordered breathing. Nevertheless, the most common physical finding in patients with OSA is a nonspecific narrowing of the oropharyngeal airway, with or without an increase in soft tissue deposition.

Hypertension
A link between OSA and hypertension has been consistently demonstrated in several studies [4, 5, 43]. A history of hypertension is associated with increased probability of OSA, and the finding of hypertension in a patient with symptoms suggestive of sleep-disordered breathing increases the chance that OSA will be present. The likelihood of OSA appears to be particularly high among patients with drug-resistant hypertension [44]. In addition, the presence of cardiovascular disease i.e. ischaemic heart disease, stroke or heart failure, and/or the metabolic syndrome, may be an important clue to the presence of OSA [9, 10, 43].

Clinical prediction models

In general, clinical prediction models (or rules) are based on a combination of signs and symptoms for a given disorder, with the aim of predicting the likelihood of confirming the presence of the disorder, by using a standard laboratory test procedure. This concept implies that data from a patients history and their physical status might be used to predict polysomnographically verified OSA. To date, several sleep apnoea clinical prediction models have been developed. They usually include anthropomorphic variables in combination with some type of witnessed breathing abnormality during sleep, i.e. snoring, apnoeas, choking and/or gasping. Overall, it has been found that the clinical prediction models for OSA have reasonably high sensitivities (7696%), but relatively low specificities (1354%) [45]. Therefore, such prediction models alone do not raise the probability of OSA high enough to warrant initiating therapy.

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As such, a clinical assessment is insufficient to make the diagnosis of a clinically significant OSA without some type of objective sleep study to confirm the diagnosis and clinical prediction models have not yet gained widespread use within the clinical sleep practice [15].

Objectifying sleepiness
Assessment of sleepiness encompasses a number of tests: 1) subjective self-assessment using standardised questionnaires, e.g. Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS); 2) determination of reaction times or the time taken to solve standardised tasks, e.g. Trail Making Test, Mackworth Clock Test and Psychomotor Vigilance Test; and 3) electroencaphalogram (EEG)-based measurements of sleep latency and/or ability to remain awake under standard conditions, e.g. Multiple Sleep Latency Test (MSLT), Maintenance of Wakefulness Test (MWT).

Questionnaires Epworth Sleepiness Scale

One often used and validated tool for the systematic assessment of impaired daytime alertness is the ESS [46]. ESS is applied frequently because of its simplicity and practicability in routine practice, especially to describe sleepiness of patients with OSA. ESS was constructed to measure the patients ability to remain awake or the propensity to doze off in typical daily situations (table 3). This questionnaire, answered by the patients, contains eight questions regarding the occurrence of unintended sleep periods during certain monotonous situations in daily life. The advantage of ESS is in representing the average sleep propensity [4749], and the test is frequently used in clinical practice [50]. A sum score o10 out of 24 points may indicate a clinically relevant impaired daytime wakefulness, and typically requires additional investigation [51]. Importantly, a score ,10 points does not exclude a relevant impairment of vigilance.

OSA: CLINICAL PRESENTATION IN ADULTS

Stanford Sleepiness Scale

Stanford Sleepiness Scale (SSS) reflects the actual state of sleepiness at the time when the questionnaire is administrated. This questionnaire contains a seven-point scale with a verbal description of the different stages of sleepiness [52]. The SSS, which involves introspective judgement of ones own sleepiness, has been well validated in control subjects, but patients with chronic sleepiness may not accurately assess their own level of sleepiness. Therefore, the main
Table 3. The Epworth Sleepiness Scale How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Situation Sitting and reading Watching TV Sitting, inactive, in a public place As a passenger in a car for an hour Lying down in the afternoon Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in traffic
Use the following scale to choose the most appropriate number for each situation: 0: would never doze; 1: slight chance of dozing; 2: moderate chance of dozing; 3: high chance of dozing.

Chance of dozing

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utility of the SSS is in research applications, where it is used for point-in-time estimation of the level of daytime sleepiness [50]. In this respect, SSS was applied in clinical studies to assess the effects of therapy with CPAP on daytime sleepiness [52]. Nevertheless, its value in routine clinical practice has not been firmly established.

MSLT and MWT

Objective measures of excessive daytime sleepiness include pupillometry, performance-based tasks, and the MSLT. The MSLT technique is standardised and has been published by the American Association of Sleep Medicine (AASM) [16]. In its report, the AASM indicated that the MSLT is considered to be the standard for the objective measurement of sleepiness [53]. The method aims to detect pathologically short latencies for sleep onset as an objective measure of increased daytime sleepiness. A polysomnogram should be performed the night before the MSLT to assess night-time sleep quality and quantity. Untreated OSA or other causes of disrupted sleep should be ruled out or treated before proceeding with the MSLT. The MSLT consists of a series of five 20-min naps at 2-h intervals. Patients are asked to try to sleep in a dark room with a recorded montage similar to that used during polysomnography the preceding night. The mean of the individual latencies in achieving sleep during the naps is considered to represent the MSLT score. A mean sleep latency of ,5 min is considered to represent excessive daytime sleepiness; by contrast, healthy adult subjects have a mean sleep latency of 1020 min [54]. Sleep latencies of 510 min indicate moderate sleepiness with less well-defined pathology and consequences. The most recent international classification of sleep disorders has identified a mean sleep latency of ,8 min to define sleepiness for diagnostic purposes [55]. In contrast to the MSLT, which measures a subjects ability to fall asleep, the MWT measures a subjects ability to stay awake in a quiet, nonstimulating situation for a given period of time. The MWT may be used to evaluate the response to therapy in OSA patients treated with CPAP, and is also helpful for those persons who must demonstrate the ability to stay awake for safety and/or employment purposes. The recommended recording montage for MWT is the same as that used for the MSLT. In contrast to MSLT, the subject is usually sitting rather than lying in a bed and most importantly, is instructed to stay awake. A four-trial, 40-min protocol is recommended, with a 2-h period between each trial. Sleep onset occurs with the first epoch demonstrating at least 15 s of consecutive sleep. The trial ends after 40 min if no sleep occurs. Staying awake for all four trials of a 40-min MWT provides the strongest support of an individuals ability to stay awake, and the AASM has called this standard an appropriate expectation for individuals requiring the highest level of safety [53]. Using the same data, a mean sleep latency on the 40-min MWT of ,8.0 min has been considered abnormal and values of 840 min are of uncertain significance.

Clinical presentation of OSA in different populations

Differences in clinical presentation of OSA between males and females result in the underdiagnosis of OSA in females, and therefore require special attention. In addition, typical symptoms of OSA are less predictive with advanced age and in the presence of several comorbid conditions. Hence, the diagnosis may be missed in an atypical patient [56]. Since OSA is both common and can be treated successfully, screening questions concerning sleep-disordered breathing should be included as part of the physicians, and/or the respective specialists examination of high-risk females, the elderly, patients with congestive heart failure, kidney failure, certain endocrine disorders and chronic obstructive pulmonary disease (COPD).

Sex differences
OSA remains under-recognised in females, largely due to: the differences in symptom profiles, the differences in tolerance to symptoms, and a lower suspicion by physicians for OSA in female patients [28, 56, 57]. As a result, females are less likely to be referred for evaluation of OSA, and

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OSA remains an underdiagnosed condition in this population. Interestingly, two recent studies suggested that at the time of diagnosis females with OSA are significantly older than males [58, 59]. The relatively low referral of females for a sleep study may explain the large sex disparity in prevalence of the disease in females; this can be as much as 1:10 in clinic-based studies [57]. Nevertheless, if females are screened for OSA independently of symptoms, the prevalence of OSA is half of that seen in males (1:2), suggesting that differences in clinical presentation may partially explain the differences in disease prevalence seen between clinic- and population-based samples [60]. In addition, females are more reluctant than males to complain of snoring, a symptom some believe is masculine. The discrepancy in the prevalence of OSA between males and females disappears after menopause. The original data from the Wisconsin Sleep Cohort Study did not reveal significant differences in the symptom profile between males and females [28]. However, several recent investigations showed that females are less likely to report the classic symptoms of obstructed breathing and daytime hypersomnolence than males, but rather report other less typical symptoms [56, 6163]. Although excessive daytime sleepiness is a cardinal symptom of OSA, BALDWIN et al. [62] observed that females were less likely to have an ESS score of .10, suggesting that this questionnaire, often used to screen for OSA-related daytime sleepiness, may be more sensitive for males than for females. It is also possible that the threshold at which females feel sleepy, or complain about it, is different from that of males [63]. Indeed, YOUNG et al. [28] observed that 40% of females versus 20% of males with an AHI .15 did not report any of the classic OSA symptoms. One additional factor that may account for sex differences in clinical presentation of OSA is that although females may feel similar symptoms to males they often present with vague, nonspecific symptomatology [63]. In general, females report more sleep problems than males, such as inadequate sleep time, insomnia, difficulty initiating sleep, fatigue, morning headaches, depression with the use of sedatives [18, 64], and tend to have more generalised nonspecific daytime symptoms. The large scale of vague symptoms widens the differential diagnosis and can either delay the true diagnosis or lead to a misdiagnosis [63]. In a recent study in a tertiary referral centre, female patients with mild OSA reported fewer witnessed apnoeas and lower rates of worsening of snoring in the supine position, compared with males matched for the same severity of the disease [57]. Nevertheless, there were no sex differences in these two symptoms in patients with AHI .15 events?h-1. In addition, males scored significantly higher on items related to worsening of snoring/apnoeas such as alcohol and smoking history, when compared with females. In contrast, females complained significantly more often of insomnia, restless legs, depression, nightmares, palpitations at night and hallucinations than males did. It has been suggested that some of the functional somatic syndromes that are seen more commonly in females, such as: chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome and migraine headaches, may be associated with milder forms of OSA and upper- airway resistance syndrome [65]. In addition, females reported comorbidities, such as hypothyroidism, asthma/allergies and depression, more frequently than males. Therefore, symptoms of daytime sleepiness might often be attributed to these medical disorders and consideration for OSA may be missed, thereby leading to an increased use of health resources in females than in males. Consequently sex-related differences in the presenting symptoms of patients with OSA, should be taken into consideration in the clinical evaluation of females with suspected sleep-disordered breathing. Hence clinicians need to remember OSA in their differential diagnosis when evaluating female patients [63].

OSA: CLINICAL PRESENTATION IN ADULTS

Pregnancy
A recent study suggested that .10% of pregnant females might be at risk of developing OSA [66]. Previously, a higher risk of snoring, oxygen desaturation, and daytime sleepiness, were reported in obese pregnant females when compared with patients of normal weight, or in pre-eclamptic females compared with nonpregnant females [67]. Physiological changes related to pregnancy,

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such as progressive weight gain, upward displacement of the diaphragm and hormonal changes, put pregnant females at a higher risk for developing OSA. Oestrogen induced hyperaemia and nasopharyngeal mucosal oedema may contribute to the narrowing of the upper airways. Indeed, reduced upper airway dimensions have been demonstrated in the third trimester of pregnancy [68]. Since chronic nasal congestion at night and narrowing of the upper airways are both independent risk factors for sleep-disordered breathing in the general adult population, it is reasonable to assume that worsening of these mechanisms by increased oestrogen levels and/or hypervolaemia contribute to a higher risk of OSA during pregnancy. In addition, progesteroneinduced increased respiratory drive increases diaphragmatic effort leading to greater suction pressure at the level of upper airway, thus increasing the propensity of the upper airway to collapse [69]. Typical symptoms of OSA, such as nonrefreshing sleep, excessive daytime sleepiness, fatigue and impaired concentration, are less specific in pregnant females as they often experience high rates of disturbed sleep and diminished daytime functioning for reasons other than OSA. Although snoring is frequently reported by pregnant females, and its rates increase in the third trimester of pregnancy [67], snoring per se is less specific for OSA compared with other symptoms, such as witnessed apnoeas and choking sensations during sleep. Excessive daytime sleepiness is also highly prevalent in pregnant females and becomes increasingly more common as pregnancy progresses [66, 67]. Several case reports and small-scale studies suggest that OSA might be related to adverse pregnancy outcomes, namely fetal heart rate decelerations accompanying maternal desaturations, fetal growth retardation and lower birth weights, lower Apgar scores, a higher need for placement in a neonatal healthcare unit, and fetal death [7072]. Also, OSA has been attributed to adverse maternal outcomes such as pre-eclampsia, gestational diabetes mellitus, and pulmonary hypertension (73, 74). Nevertheless, there is a lack of large-scale well-designed systematic studies on clinical presentation and severity of OSA in pregnant females and on the outcomes of pregnancies in such patients. Preliminary data of the only large-scale study that analysed the 2003 Health Care Cost and Utilization Project nationwide inpatient data of all pregnant females in the USA (n53,979,840 deliveries) suggested that OSA is associated with twice the likelihood of having gestational diabetes and four times the likelihood of having pregnancy-induced hypertension, after controlling for race, sex, and obesity [75]. Although some studies suggest that early application of CPAP to pregnant females alleviates sleep-disordered breathing [76], large-scale well-controlled studies are needed to evaluate the impact of CPAP therapy for OSA in pregnant females on all the diverse pregnancy outcomes. There are no specific guidelines for screening pregnant females for OSA because the data are limited in this population. PIEN et al. [66] suggested that excessive daytime sleepiness in pregnant females should not be explained only by insufficient sleep caused by other stresses associated with pregnancy. They proposed that excessive daytime sleepiness in association with loud snoring and witnessed apnoeas should prompt physicians to refer such pregnant females for an overnight polysomnography examination.

The elderly
The prevalence of sleep-disordered breathing increases steadily with age. The Sleep Heart Health Study examined a large cohort of 6,400 patients with a mean age of 63.5 yrs, and reported on prevalence of sleep-disordered breathing by 10-yr age groups: for those aged 6069 yrs, 32% had an AHI of 514 and 19% had an AHI o15; for those aged 8089 yrs, 36% had an AHI 514 and 20% had an AHI o15 [76]. Several mechanisms have been proposed to account for the increasing prevalence of OSA with increasing age, such as changes in pharyngeal mechanics, reduced pharyngeal size, changes in upper airway muscle function and respiratory instability. Among postmenopausal females, the reductions in circulating levels of sex hormones and pharyngeal lengthening contribute to increased risk of OSA [77]. Consequently, the prevalence of OSA is comparable in elderly females and males [2].

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The elderly population is heterogeneous, ranging from healthy, active, community-dwelling seniors to institutionalised, demented elderly patients with multiple medical conditions. Consequently, the clinical presentation of OSA in older subjects is greatly influenced by their general health status and comorbidities, and while some elderly subjects present with the typical signs and symptoms of OSA [78], others may present with symptoms not usually attributed to OSA, and the correct diagnosis may be missed [79]. Importantly, epidemiological studies suggest that the prevalence of obesity is lower among the elderly with OSA compared with younger patients [76]. Symptoms that require special consideration in the clinical assessment of an elderly subject with suspected OSA include cognitive impairment, attention deficit, nocturia and ophthalmic conditions [79]. The negative effect of severe OSA on cognitive function is well established, with consistent reports of impairment on tasks requiring the need for attention, immediate and delayed recall of verbal and visual material, executive tasks, planning and sequential thinking, and manual dexterity [80]. In addition to the cognitive deficits that may result from OSA, there is evidence that many of the progressive dementias, including Alzheimers disease and Parkinsons disease, involve degeneration in areas of the brainstem that is responsible for regulating respiration. Such degeneration may place the patient at an increased risk of developing OSA. Indeed, dementia and OSA are both prevalent among the elderly and may coexist in some patients [78]. High prevalence rates of sleep-disordered breathing ranging from 33 to 70% were observed among elderly nursing home patients with dementia, while lower prevalence rates were found in those elderly patients who lived independently [81]. Several studies have also found that the severity of the dementia was positively correlated with the severity of OSA, and that the sleep fragmentation and nocturnal hypoxaemia resulting from apnoeic episodes could be partly responsible for disrupted sleep in patients with Alzheimers disease. Alternatively, case reports of severe OSA presenting as dementia suggest that cognitive impairment, secondary to OSA-induced sleep fragmentation and/or intermittent hypoxia, can be misinterpreted as signs of dementia. In elderly patients, differential diagnosis of excessive daytime sleepiness requires particular attention and other conditions, such as sleep deprivation, hypothyroidism, depression and the effects of sedating medications, have to be considered. Inquiring about alcohol use and obtaining a detailed list of all medications, particularly sedative-hypnotics and opiate analgesics, is important. Nocturia is a common symptom among the elderly, and is usually attributable to prostate hypertrophy in males and overactive bladder or urinary incontinence in females. Nevertheless, nocturia is also commonly observed in adult patients with OSA and no concurrent urological disorder [82], and several reports also demonstrated an association between OSA and nocturia in elderly patients [8385]. OSA-related nocturia is associated with reduced quality of life, whereas elimination of nocturnal respiratory events by effective therapy with nasal CPAP reduces nocturia and improves well-being among the elderly [83]. A strong association between OSA and glaucoma and nonarteritic anterior ischaemic optic neuropathy has been demonstrated [86]. Although it remains unknown whether the increased prevalence of these ophthalmic conditions in elderly is mediated through the coexisting OSA, older patients who are diagnosed with glaucoma or nonarteritic anterior ischaemic optic neuropathy should be evaluated for sleep-disordered breathing [79]. Taken together, the diagnosis of OSA should be systematically considered in elderly patients, including those with Alzheimers disease, particularly since these patients appear to tolerate therapy with nasal CPAP reasonably well [87].

OSA: CLINICAL PRESENTATION IN ADULTS

Congestive heart failure

Epidemiological studies unequivocally confirm high prevalence of sleep-disordered breathing in patients with congestive heart failure (CHF) [8890]. The presence of obstructive, as well as central, types of sleep apnoea are associated with increased morbidity and mortality in these patients [91], and AHI represents a strong prognostic marker of future cardiac events [92]. Importantly, treatment of coexisting OSA by CPAP reduces systolic blood pressure and improves

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left ventricular systolic function [93]. In patients with coexisting central sleep apnoea, CPAP might improve both left ventricular ejection fraction and heart transplant-free survival if it is suppressed soon after its initiation [94]. These data imply that strategies to recognise sleep disordered breathing are highly warranted in CHF patients. The clinical picture of patients with CHF and concomitant sleep-disordered breathing is less characteristic than that of patients with OSA alone. The history and physical examination are less likely to suggest the presence of OSA, since the rate of obesity is lower in CHF patients than among those with the common form of OSA [90, 95, 96]. Also, the majority of patients with CHF and coexistent OSA or central sleep apnoea do not complain of excessive daytime sleepiness [95], possibly owing to chronically elevated sympathetic activation [97]. Since, in patients with CHF, sleep-disordered breathing is associated with adverse outcomes, and reversal of OSA by effective therapy using CPAP improves several prognostic markers of CHF, a special chapter in this monograph is devoted to sleep apnoea in heart failure.

End-stage renal disease

Although sleep-disordered breathing is highly prevalent in patients with end-stage renal disease (ESRD) [98], renal providers are largely unaware of the presence and severity of OSA-related symptoms in patients who are on maintenance haemodialysis [99]. The pathogenesis of OSA in this population is mainly related to factors unique to ESRD, such as pharyngeal narrowing associated with fluid overload and uraemic milieu [100, 101]. Patients with ESRD do not often conform to the stereotypical presentation of the disease. In contrast to the general population of patients with OSA, those with comorbid ESRD are generally not obese and the association between BMI and severity of OSA is weak [100, 102]. Sleep efficiency is poor in patients with ESRD, partly due to high frequency of periodic leg movements resulting in increased arousal frequency, high prevalence of restless legs syndrome and primary insomnia [103]. Therefore, it is not surprising that daytime sleepiness in ESRD has multifactorial aetiology and is commonly reported by patients with ESRD [104]. Recently, BEECROFT et al. [100] systematically evaluated clinical characteristics of OSA in patients with ESRD and found that clinical features differ from those of general sleep apnoea population, in that patients with ESRD were less likely to report snoring, witnessed apnoeas during sleep, unrefreshing sleep and morning headaches. Importantly, snoring alone is an unreliable indicator of sleep-disordered breathing in ESRD patients [105], since an increased proportion of central apnoeic episodes in patients with predominant OSA may account for less snoring. Taken together, patients with ESRD often have multiple sleep disorders, which may complicate the interpretation of signs and symptoms of OSA and may result in underdiagnosis of sleepdisordered breathing in this population [100]. In addition, some symptoms of OSA, such as fatigue, depression and impaired cognitive and sexual function, may be mistakenly attributed to ESRD itself or to another comorbid condition, thus further lessening the probability of proper assessment for OSA [99]. Since OSA in ESRD is associated with adverse cardiovascular outcomes [106], increased awareness of the atypical presentation of OSA in ESRD patients is highly warranted.

Chronic obstructive pulmonary disease

Both COPD and OSA are common disorders. Early small-scale studies conducted in patients who had been referred to sleep laboratories, suggested that the prevalence of sleep-disordered breathing in patients with COPD and that of COPD in patients with OSA, was high [107, 108]. Nevertheless, more recent data from the Sleep Heart Health Study did not reveal differences in the prevalence of OSA between subjects with and those without obstructive airway disease, suggesting that the coexistence of COPD and OSA is due to chance, rather than through a pathophysiological linkage between the two conditions [109]. Nevertheless, if COPD is present in

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approximately 10% of the adult population 40 yrs of age or older, and if the prevalence of OSA in the same population is in the range of 510%, the coincidence of the two conditions (i.e. overlap syndrome) can be expected to be present in 0.51% of the population aged .40 yrs, which is far from being negligible [110]. Many patients with severe COPD complain of poor quality of sleep resulting from nocturnal cough, dyspnoea, use of drugs and the effects of ageing on sleep. Nevertheless, in patients with mild COPD without concomitant OSA, sleep is minimally perturbed. However, compared with patients who only have COPD, those suffering also from OSA had higher ESS scores, lower total sleep time, lower sleep efficiency and higher arousal index. Only small differences were observed between subjects with OSA alone and those with both disorders (i.e. subjects with overlap syndrome) suggesting that the quality of sleep in COPD is influenced by the presence of OSA but not by the severity of airway obstruction [109]. The coexistence of COPD and OSA favours the presence of daytime hypoxaemia, which is rarely observed in patients with OSA alone. The Sleep Heart Health Study demonstrated that the odds ratio for nocturnal oxyhaemoglobin saturation below 90% was 30-fold greater in participants with overlap syndrome, compared with those who had neither disorder [109]. Consequently, patients with overlap syndrome are at risk of developing pulmonary hypertension, even though their obstructive pulmonary impairment is not severe [110]. The clinical picture of patients with OSA and comorbid COPD and pulmonary hypertension is frequently governed by symptoms of right heart failure. In addition, patients with overlap syndrome are 2.5 times more likely to experience nocturnal tachyarrhythmias, and have higher nocturnal death rate than patients with OSA alone [111]. Recently, increased risk of death and hospitalisation due to COPD exacerbations was reported in patients with overlap syndrome and alleviation of OSA by CPAP improved survival and decreased hospitalisations in this group of patients [112].
OSA: CLINICAL PRESENTATION IN ADULTS

Endocrine disorders Acromegaly

The prevalence of OSA in acromegaly is thought to be roughly 60%, ranging 1993% [113]. In acromegaly, the inspiratory pharyngeal collapse during sleep results mostly from the hypertrophy of para- and retropharyngeal soft tissue and an enlarged tongue, rather than the deposition of fat around the upper airway [114]. In contrast to OSA patients with no comorbid endocrine disorder, in patients with OSA and acromegaly the BMI is not significantly increased [115]. Conversely, the circumference of the index finger, a measure of soft tissue hypertrophy, is closely correlated with the severity of OSA when it is .8.5 cm [116]. Visceromegaly, due to acromegaly, induces serious cardiovascular and respiratory complications, and the coexistence of OSAS increases the risk of cardiorespiratory mortality in such patients [117].

Hypothyroidism
The prevalence of hypothyroidism among subjects with OSA is low (13%) but OSA can occur in 50100% of subjects suffering from hypothyroidism, particularly in those with myxoedema [118]. Extravasation of albumin and mucopolysaccharides in the tissues of the upper airways, hypothyroid myopathy and decreased ventilatory drive, and a mass loading effect of an enlarged goiter on the upper airways have been proposed as possible mechanisms of OSA in hypothyroidism [118, 119]. Apnoea duration and haemoglobin oxygen desaturation are significantly correlated with thyroxin levels [120]. Although symptoms of OSA in patients with comorbid hypothyroidism do not substantially differ from those with normal thyroid function, tests of thyroid function should be considered in those individuals who fail to show OSA of sufficient severity to explain symptoms or who do not show satisfactory improvement after effective therapy of OSA [119].

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Cushings disease and syndrome

The prevalence of OSA among patients with Cushings disease and syndrome is 1832% [121]. Skeletal muscle weakness and decreased activity of the geniohyoid and genioglossus muscles, weight gain, and adipose tissue accumulation according to a centripetal pattern in the subcutaneous tissue of the neck, including parapharyngeal spaces, face, trunk and waist can lead to development of OSA in these subjects [122]. The recognised features of Cushings disease and syndrome, such as fatigue, insomnia and a multitude of psychiatric syndromes, including frank psychosis and major depression, may by aggravated by concomitant OSA [117].

Metabolic syndrome and diabetes mellitus

Several independent epidemiological studies reported the association between sleep-disordered breathing and insulin resistance, type 2 diabetes and the metabolic syndrome [9, 10]. In a recent study, the prevalence of metabolic syndrome among patients with newly diagnosed OSA varied from 40 to 60% between different European populations [123]. The relationship between OSA and metabolic disturbances is most likely bidirectional. On the one hand, obesity and fat accumulation in the neck area increase the propensity for the upper airway to collapse; on the other hand, OSA-related increases in sympathetic nervous system activity and the direct effects of hypoxaemia alter the effects of insulin and affect glucose metabolism [124]. Clinical presentation of OSA in patients with metabolic syndrome does not differ substantially from that of patients with no glucose metabolic abnormality. Nevertheless, given the high prevalence of OSA among patients with metabolic syndrome and type 2 diabetes, specialists treating metabolic disorders abnormalities should consider investigation for sleep-disordered breathing in their patients. Such need is highlighted by several studies demonstrating improvements in insulin sensitivity in patients with metabolic syndrome after successful treatment of comorbid OSA by noninvasive ventilation [125, 126].

Statement of Interest
None declared.

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