The sleep apnoea/hypopnoea syndrome

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1 European Journal of CIinical Investigation (1 995) 25, REVIEW The sleep apnoea/hypopnoea syndrome N. J. DOUGLAS Scottish National Sleep Laboratory, University of Edinburgh, Department of Medicine, Royal Infirmary, Edinburgh, UK Received 19 December 1994; accepted 27 January 1995 Introduction The sleep apnoea/hypopnoea syndrome is probably the commonest illness to be discovered in the second half of the 20th century. It affects 2-4% of middle-aged men and 1-2% of middle-aged women [ 1,2] causing daytime sleepiness, road traffic accidents [3] and impaired cognitive performance and predisposing to ischaemic heart disease and cerebrovascular accidents [4]. The combination of high prevalence with a wide range of sequelae has led to the conclusion that sleep apnoea may be as big a public health hazard as smoking [5]. Mechanisms of apnoea The vast majority of apnoeas are caused by pharyngeal collapse. The patency of the pharynx is dependent on a balance between intraluminal pressure and upper airway muscle activity. During inspiration, the negative intraluminal pressure tends to narrow the upper airway and this is opposed by the action of upper airway dilating muscles. These muscles tense with each inspiration, thus resisting collapse of the upper airway. The principal muscles involved are genioglossus which tenses the tongue, and palatoglossus which holds the soft palate in a downwards and forwards position resisting collapse of the nasopharynx, but others may also be involved. Muscle tone is generally decreased during sleep, and the relaxation of the upper airway dilating muscles results in relative narrowing of the pharynx. This narrowing results in increased airflow resistance in normal subjects [6] but is of no major significance. However, in about 50% of men and 30% of women by the age of 40, this upper airway narrowing is sufficient to cause turbulent flow and the vibration of snoring. In some, this tendency may progress to produce clinically significant upper airway narrowing or occlusion. Correspondence: N. J. Douglas MD FRCPE, Reader in Medicine and Director, Scottish National Sleep Laboratory, University of Edinburgh, Department of Medicine, the Royal Infirmary, Edinburgh EH3 9YW, UK. The upper airway in patients with the sleep apnoea/hypopnoea syndrome (SAHS) Patients with SAHS have narrower upper airways when awake than either normal subjects or simple snorers [7-91. The decrease in upper airway calibre on lying supine is smaller in patients with SAHS than in normal subjects [9], which probably reflects greater activity of the upper airway dilating muscles in awake patients with SAHS in comparison to normal subjects [lo] resulting in greater defence of the upper airway in SAHS patients. These data suggest that the upper airway narrowing in awake SAHS patients is due to anatomical factors rather than to abnormality of upper airway muscle function, and that the increased muscle activity results from the need to maintain patency in an anatomically narrowed airway. The two main factors likely to be contributing to upper airway narrowing in awake SAHS patients are deposition of adipose tissue within the neck and facial bony structure. Around 50% of SAHS patients have body mass indices of > 30kg m-*. In such obese patients, CT scanning and magnetic resonance imaging (MRI) show increased fat deposition around, and particularly lateral to, the upper airway [8,11,12] in comparison to normal subjects (Fig. 1). This results in narrowing of the upper airway in awake SAHS patients. SAHS patients also have enlargement of their soft palates due to increased fat deposition and muscle bulk [ 131 and also to increased oedema due to the trauma produced by recurrent upper airway occlusion. Patients with SAHS may also have abnormalities of facial structure with posterior displacement of the maxilla and/or mandible, both of which will predispose to narrowing of the upper airway [14]. These bony structural changes may be particularly important in relatively thin patients with SAHS with the location of fat deposits being more important in obese patients, although this supposition has still to be tested. Sleep causes narrowing of the upper airway in SAHS patients, as in normal subjects, but in SAHS 285

2 286 N. J. DOUGLAS Figure 1. Magnetic resonance imaging scans of a normal subject (left) and a patient of similar age and weight with the sleep apnoea/hypopnoea syndrome (right). The black area in the centre of the images is the upper airway which is smaller in the sleep apnoea patient than the normal subject, even during these awake scans. The white area lateral to the upper airway in the sleep apnoea patient represents adipose tissue. patients the upper airway narrowing is sufficient to cause occlusion or near occlusion of the airway. As in normal subjects, the area of maximal narrowing of the upper airway is at palatal level in half and retroglossal in the other half of the patients [15]. It is unclear whether anatomical or physiological factors are the main determinants of the primary site of occlusion during sleep. It seems, however, that anatomical rather that physiological factors determine whether the upper airway occludes during sleep (Fig. 2). SAHS patients have increased upper airway dilating muscle activity during sleep in comparison to normal subjects [16], and although one cannot directly equate EMG activity with muscle function, these data make it unlikely that there is greater inhibition of upper airway muscle function by sleep in SAHS patients compared to normal subjects. The upper airways of SAHS patients are not only narrower but also more compliant than normal both during wakefulness [ 171 and sleep [ 181. The reason for this increased compliance is unclear and differences in muscle tone or upper airway calibre do not provide ready explanations. Increased upper airway dilating muscle tone in SAHS patients when awake [ 101 would be expected to decrease deflationary compliance of the airways, whereas deflationary compliance is in fact increased [ 191. Alternatively, narrowing of the upper airway by fat deposition or retroposition of the jaw would be expected to decrease expiratory compliance in SAHS patients, whereas expiratory compliance is increased [ 171. SAHS are men. There have been several studies investigating whether upper airway calibre differs between men and women, some finding narrower upper airways in men [20] while others finding narrower upper airways in women [21,22]. The physical properties of the upper airway seem to be different between the sexes, with men showing bigger changes in airway dimension with changes in lung volume [21] or posture [22]. It is not known whether these differences result from anatomical factors or from differences in upper airway dilating muscle function. A recent preliminary report suggests that women have greater upper airway dilating muscle activity than men, at least when awake [23]. Androgens seem to be important in the pathogenesis of SAHS, the administration of androgens to either hypogonadal A 1 Retrognathla obeslty Yyxoadema Acromegaly sleep ngmuscles Alcohol Sedatives Predispositions to SAHS Any explanation of the aetiology of SAHS has to encompass the main predisposing factors-the male sex, middle age, obesity and a familial tendency. It is not clear why 85% of patients presenting with Figure 2. Schematic diagram of factors affecting upper airway calibre.

3 SLEEP APNOEA/HYPOPNOEA SYNDROME 287 Relatives Controls Figure 3. Numbers of apnoeas + hypopnoeas in 5 I first-degree relatives of patients with the sleep apnoea/hypopnoea syndrome and 51 age-, sex-, height- and weight-matched controls. The data show a significant increase in apnoeas + hypopnoeas in the relatives of SAHS patients. Data from [33]. P < , median. males [24] or women [25] precipitating SAHS in subjects who previously had normal breathing during sleep. However, anti-androgen drugs given for 1 week do not significantly affect SAHS severity [26]. It is possible, however, that androgens might have longer term effects on fat deposition in the neck or on upper airway muscle function that were missed in this study. Men have thicker necks than women even when matched for body mass index [27]. This would cause increased mass loading on the upper airway in men when they lie down, predisposing to Figure 4. Schematic cephalogram (lateral head X-ray) showing the anatomical landmarks which differ between sleep apnoea in relatives and controls. Sleep apnoea patients have decreased SNA and SNB angles compared to controls [33] indicating retroposition of the maxilla and mandible. Retroposition of these bones results in narrowed anteroposterior diameters of the upper airway. S, sella; N, nasian; PNS, posterior nasal spine; ANS, anterior nasal spine; A, point A; B, point B; Go, Goriari; Gn, Gnathion. upper airway narrowing during sleep. Recent evidence suggests testosterone may affect upper airway muscle function [28]. Another unresolved sex-related issue is that although 85% of SAHS patients are male, epidemiological studies have consistently found that men are only twice as likely as women to have abnormal breathing during sleep [2,29]. Clarification is needed as to whether this disparity results from referral bias or from genuine differences between the sexes in the severity of symptoms resulting from a given degree of breathing abnormality during sleep. SAHS occurs in all age groups, but is commonest in middle age, although the explanation for this is not clear. Upper airway resistance has been reported to increase with age in men [20], but a recent study indicated that upper airway calibre increased with increasing age [21]. This latter study also showed that the electromyographic response of the tongue to negative upper airway pressure was greater in subjects aged years than in either or year olds [21]. Thus, there is no convincing evidence of either anatomical narrowing or functional impairment of upper airway dilating muscles in middle age. It is easier to explain the association of SAHS with obesity. Indirect evidence of increased fat deposition in the neck comes from the observation that patients with SAHS tend to have larger neck circumferences [27]. MRI studies have shown that patients with SAHS have increased fat deposition adjacent to the pharyngeal airway [8,11,12] and both MRI [ll] and pathological [ 131 studies have also shown fat deposition within the soft palates and uvulae of SAHS patients. Such deposits will narrow the naso-pharyngeal airway, thus predisposing to critical airway narrowing during sleep. Therefore, fat deposition is greater in SAHS patients than in awake matched controls but the factors controlling fat deposition around the upper airway are unknown. It has recently become evident that SAHS is strongly familial. A few early case reports and more recent studies have indicated that there was a higher frequency of SAHS-related symptoms in the family members of SAHS patients than in control families [30]. However, the results of these studies could have been explained by the familial nature of obesity [31] and by reporting bias in SAHS families. Studies in families of non-obese patients with SAHS have shown clear evidence of familial clustering of SAHS [32]. A recent study has shown that family members of SAHS patients have more apnoeas and hypopnoeas during sleep (Fig. 3) and also abnormal facial bony structure with posterior displacement of the maxilla and mandible in comparison to normal subjects (Fig. 4) [33]. These bony changes probably account for the narrowing of the upper airways in SAHS family members in comparison to age-, weight-, height- and sex-matched controls. It remains to be seen whether these structural abnormalities are the primary inherited defect in the families of non-obese SAHS patients or whether,

4 288 N. J. DOUGLAS in some way, they are consequent upon some other factor. Whatever the mechanism, it is clear that sleep apnoea is strongly familial. The relationship between SAHS and Sudden Infant Death Syndrome (SIDS) has been an area for debate. Recent data suggest that SIDS is more common in the families of SAHS patients and that SIDS families have retroposed maxillae and mandibles, predisposing to upper airway narrowing [34]. The hypothesis that SIDS is due to upper airway occlusion in predisposed families would explain why SIDS is familial [35], the importance of posture in the aetiology of SIDS [36], and why SIDS is related to upper respiratory tract infections which would increase upper airways resistance and thus require the generation of a more negative airway pressure on inspiration, predisposing to upper airway collapse. Consequences of upper airway narrowing When the sleep apnoea syndrome was initially described, it was believed that only events associated with total occlusion of the airway and cessation of airflow produced clinical sequelae. However, subsequent studies have indicated that similar effects may result from hypopnoeas-episodes of continued but reduced ventilation [37]. More recently, it has been suggested that episodes of airway narrowing which result in marked increases in ventilatory effort but without diminution of ventilation may also produce arousals [38,39]. Such arousals restore upper airway dilating muscle activity, the patient gasps, takes a few deep breaths and falls back to sleep when the upper airway dilating muscle tone relaxes again and the cycle is initiated once more. These episodes of upper airway narrowing, terminated by arousal, may recur many hundred times per night and it is the recurrent arousals which cause the major clinical features of the condition. The frequency of brief arousals from sleep correlates significantly with the impairment in daytime performance found in SAHS patients. Specifically, arousal frequency is significantly correlated with reaction time and with the decrease in IQ found [40]. Further evidence that it is the sleep disruption which causes these symptoms comes from modelling experiments in which normal subjects have been woken very briefly every 2 min throughout the night without there being an overall decrease in nocturnal sleep duration. In such studies, recurrent arousals produce objective sleepiness and impaired daytime cognitive performance of the type found in SAHS [ In association with the sleepiness and impaired concentration, patients with SAHS have an increased frequency of road traffic accidents [3] with an approximated fourfold increase in total road accidents and a ninefold increase in single vehicle accidents-the form of accident most commonly associated with the driver falling asleep. There is evidence that accidents in which drivers have fallen asleep are associated with a higher mortality and morbidity than average road accidents [44] and thus the occurrence of SAHS in 4% of road users poses a very significant threat to the welfare of others. Untreated SAHS patients are at increased risk of cardiovascular and cerebrovascular accidents [4]. It is not clear whether SAHS patients have higher daytime blood pressures than normal subjects matched for age, sex, weight and alcohol consumption [45,46]. However, each apnoea or hypopnoea is associated with a transient rise ill systemic blood pressure which occurs synchronous with arousal [47]. This rise in blood pressure may occur even when there are no EEG manifestations of arousal. The excess of cardiovascular and cerebrovascular disease amongst SAHS patients probably results from hundreds of these blood pressure rises occurring every night for years or even decades. Apart from its effects on the systemic circulation, SAHS also results in raised pulmonary arterial pressure in about 25% of patients [48] and this may predispose to cor pulmonale, especially in patients with co-existing lung disease. Diagnosing SAHS It was originally believed that SAHS could only be diagnosed by the complex and expensive investigation of polysomnography. Polysomnography usually consists of recording electroencephalogram, electromyogram and electro-oculogram to allow staging of sleep, thoracic and abdominal movement along with respiratory airflow to detect breathing pattern and oxygen saturation by oximetry. While this remains the most foolproof system available it is expensive, and such facilities are limited in their availability and could not be used to diagnose a large percentage of patients given that 4% of the middle-aged population have this condition. In addition, it is unclear whether standard polysomnography can detect all patients who have a clinical disorder related to breathing during sleep as the upper airways resistance syndrome may be missed by standard polysomnography which neither records upper airways resistance nor detects all clinically significant arousals [49]. Considerable attention, therefore, has been focused on which components of polysomnography are diagnostically helpful. Such studies have shown that oximetry alone may detect around two-thirds of patients with sleep apnoea [49] but will miss one-third. These studies showed that the addition of thoracoabdominal movement and leg movement to oximetry very significantly improves the diagnostic rate [49]. A second generation of limited sleep study equipment is now becoming available. In the main, these are based on the ability to detect arousal by recording changes in autonomic function which occurs at arousal, either by examining changes in cardiovascular or respiratory pattern, for example by looking at changes in pulse rate, blood pressure, pulse transit time [50] or cardiac output. These arousal detectors, in conjunction with

5 SLEEP APNOEA/HYPOPNOEA SYNDROME 289 measurements of respiratory pattern, are likely to prove useful and cheap methods of diagnosing sleep apnoea in larger numbers of patients, but validation studies are awaited. Treatment of SAHS The conventional treatment is to encourage weight loss and alcohol avoidance but these rarely suffice on their own. Continuous positive airway pressure (CPAP) therapy [51] on a nightly basis is the main stay of treatment. CPAP has recently been shown to significantly improve symptoms, quality of life, cognitive performance, performance IQ and mood in SAHS patients [52]. Preliminary data indicates that similar improvements may also occur following CPAPinpatients withmore thanfiveapnoeas + hypopnoeas h-' of sleep [53]. However, CPAP therapy as currently used is obtrusive and compliance averages only around 4 h per night. Considerable efforts are being made to improve CPAP therapy with better masks and head gear and with the development of intelligent CPAP machines [54]. These machines will vary the CPAP pressure applied in response to changes in airway calibre. Thus, the average CPAP pressure used throughout the night is lower than would occur if a fixed CPAP pressure sufficient to abolish all apnoeas and hypopnoeas was applied. It is hoped that this reduction in pressure will improve patient comfort and thus patient use of CPAP. Considerable attention is also being paid to alternative modalities of therapy. The two with the greatest research credibility at present are mandibulomaxillary advancement and upper airway dilating muscle pacing. Mandibular/maxillary advancement has been carried out in Stanford for many years [55] but has recently been taken up in other centres. There is no doubt that this therapy can be effective in appropriately selected patients, but the availability of skilled surgeons and operating time limits the number of patients who are likely to benefit from this. There remains considerable debate whether upper airway opening muscle pacing by under chin surface electrodes diminishes apnoeas by selectively increasing tone in these muscles or by directly awakening the subjects [56]. Various centres are now investigating the possibility of intramuscular pacing of upper airway opening muscles in the hope that this will allow increased activity of the muscles during sleep without awakening the patient. Conclusion The past two decades have seen considerable strides taken in the recognition, understanding, diagnosis and treatment of the sleep apnoea/hypopnoea syndrome. 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