Snoring and Witnessed Apneas

OSA is clinically characterized by heavy snoring. Snoring may be defined as a vibratory, sonorous noise made during inspiration. ⁴⁹ It is associated with a vibration of the soft pharyngeal tissues producing a fluttering noise. Often, snoring is more cumbersome for the bed partner than for the patient and it mostly exists for a long time. Four or five loud snores, followed by a silence (apnea) and another series of loud snores is a highly suggestive description of a subject with OSA. Resumption of respiration can be associated with loud stridorous breathing (“gasping” or “snorting”). Typically, these symptoms are most prominent in the supine position or after alcohol intake. However, in rare conditions, snoring may not be so prominent, even in the presence of severe OSA. ⁵⁰ There is also convincing evidence that snoring might cause daytime sleepiness in the absence of OSA. ¹⁹ This might occur due to UARS or by upper airway inflammation due to snoring induced vibrations within the pharynx. ^{38 , 51} In the general population, 25% of men and 15% of women are habitual snorers (snore almost every night) but the prevalence of snoring increases progressively with age: 60% of men and 40% of women between the ages 41 and 65 years snore habitually. ⁵² The prevalence of heavy snoring in the general population ranges from 15 to 47% in men and from 6 to 33% in women. ^{53 , 54 , 55} Snoring can be quantified either by frequency (how many nights per week) or by intensity, or by directly asking the patient how often they snore loudly or about vibratory qualities; but this information is only modestly helpful for making a clinical decision. ⁵⁶ In a large PSG study in 1,040 patients referred with suspicion of OSA, socially disturbing snoring was associated with OSA (AHI ≥ 10) in 37% of the patients referred to exclude sleep apnea (▶Fig. 2.1). The combination of heavy snoring with excessive daytime sleepiness revealed OSA in 56% of the referred patients. ⁵⁷ In the absence of snoring, the diagnosis of OSA becomes less likely but cannot be excluded (e.g., in patients after uvulopalatopharyngoplasty [UPPP]). Often, snoring is underestimated or denied by the snorers themselves and is reported by their bed partners and environment. Of the patients who deny snoring, 75% are proven to be snorers when measured objectively. ⁵⁸ Usually, patients develop strategies to cope with heavy snoring. Nevertheless, snoring is a cause of poor sleep quality for the patient’s bed partner, affecting the partner’s quality of life. ⁵⁹ Often alcohol intake and sleep deprivation aggravate snoring and sleep apneas. Symptoms of dry mouth during sleep or in the morning together with a globus sensation in the pharynx may also be suspected for heavy snoring.

Witnessed apneas and choking at night are related to apneic events and are reported by bed partners or roommates. Inquiring about the frequency of apneas observed by the partner has about the same (low) diagnostic utility as asking about snoring frequency. Bed partners seldom give accurate information about frequency of repetitive hypopneas. It is more useful to ask patients whether the bed partner reports to them choking or gasping during the night than it is to simply ask the patients if they wake up experiencing these symptoms. Attacks of choking or dyspnea that wake them from sleep may result in referral for a sleep study. Patients usually report it as being wakened by snoring, and are able to register events only after the airway has opened and they are in the middle of the postapneic snore. In conjunction with an arousal, patients often feel a sensation of tachycardia. Episodes of choking have to be differentiated from sleep choking (typically at initiating sleep) and sleep-related laryngospasm (typically in the middle of the night). ⁶⁰ In such conditions, patients describe dramatic episodes where they wake up during the night gasping because of complete airway closure, despite violent efforts to reopen the airway. After some time the airway suddenly opens and patients feel fine. Patients are usually extremely frightened, often feel they are going to die, and are unable to breathe properly for much longer than patients with OSA (often several minutes versus a fraction of < 15–30 seconds).

Pathological Daytime Sleepiness

Pathological or excessive daytime sleepiness is the second key symptom in the diagnosis of sleep apnea. ^{47 , 61 , 62} According to the AASM, excessive daytime sleepiness can be defined as “sleepiness that occurs in a situation when an individual would usually be expected to be awake and alert.” ⁶³ It is caused by increased respiratory effort and hypoxemia, which finally results in the so-called “arousal,” with sleep fragmentation and loss of rapid eye movement (REM) sleep and slow-wave sleep as a consequence. Extreme daytime sleepiness is characterized by falling asleep during motor activity (talking, eating). Unequivocal sleepiness is characterized by falling asleep in quiet conditions (under boring situations or during periods of physical inactivity) or while driving. Extension of physiological diurnal sleepiness is considered mild sleepiness.

Sleepiness casued by inadequate sleep is very common in the general population; therefore it is hard to distinghuish from sleepiness due to an underlying sleep disorder or a medical disease.

In general, patient and environment will not give too much attention toward this symptom, as far as it does not lead to repetitive traffic accidents or occupational accidents. Tasks arising at regular intervals can be performed at decreased levels of vigilance, but this is not the case for unexpected tasks and (traffic) events. Therefore, up to 9% of all traffic accidents are attributed to sleepiness and falling asleep, 13% of the accidents with physical harm, and 17% of the accidents with fatality. ⁶⁴ In car accidents where sleepiness was the obvious cause, the rate of deaths was three times as high as in other accidents. According to a French study, falling asleep while driving seemed to be the cause of 3% of the accidents causing material damage, 20% of the accidents causing injuries, and 50% of the accidents causing death. ⁶⁵ As a consequence, a recent accident can give occasion to consult a physician. On the other hand, sleepiness is often underestimated or denied by patients with OSA, since they get adapted to this condition over time. ⁶⁶

Different rating scales have been developed to assess sleepiness, such as visual analogue scales, ⁶⁷ the Karolinska Sleepiness Scale, ⁶⁸ the Stanford Sleepiness Scale (SSS), ⁶⁹ and the Epworth Sleepiness Scale (ESS). ⁷⁰ These tools have different indications and are useful to assess patient’s perception of current sleepiness and the feelings and symptoms associated with drowsiness. ^{67 , 68 , 69} These tools are fast, simple, easy to understand, cheap to administer, and reflect the patient’s own opinion on the severity of his/her sleepiness. Usually, these scales are used to supplement the history and to follow the effects of treatment. The SSS was one of the first self-rating scales introduced in 1972 to quantify sleepiness. ⁶⁹ This scale asks subjects to rate their degree of sleepiness at a single moment of time from seven descriptions, ranging from “feeling active and vital; alert wide awake” to “almost in reverie; sleep onset soon; lost struggle to remain awake.” The SSS is fast and easy to administer. However, there are no reference values and it has not been validated with other physiologic measures. ³⁴ The ESS is a measure to assess the tendency to nod off ⁷⁰ and enables the quantification of excessive daytime sleepiness. The ESS was developed in 1991 as a trait to measure the tendency to fall asleep in several specific situations. It is a subjective tool to measure how sleepiness interferes with an individual’s daily activities in eight situations. Although very popular in daily clinical practice, the test is limited by the situations assessed that patients may actually experience rarely or never (e.g., driving). Many sleepy subjects may also score in the normal range, since they do not actually fall asleep, despite being drowsy, either because of lack of opportunity or because of effective compensatory measures. ³⁴ Its reliability and validity have also been questioned because of its weak or absent correlation with objective measures of sleep, but it is still the most widely used instrument. These scales can only be used well if subjects have insight into their symptoms and the capacity to dissociate sleepiness from other symptoms, such as fatigue.

Specific tests have been developed to measure sleepiness more objectively, ^{36 , 71} such as the multiple sleep latency test (MSLT), maintenance of wakefulness test (MWT), and vigilance tests such as Oxford Sleep Resistance Test (OSLER) test or Psychomotor Vigilance Task (PVT). ^{63 , 72 , 73} MSLT and MWT are considered the gold standard measures of objective sleepiness. The MSLT is an objective measure of the tendency to fall asleep under standardized conditions and in the absence of altertness stimulating factors. The MWT is an objective measure of the ability to stay awake for a defined period of time. ^{63 , 73}

According to the AASM, the MSLT is not routinely indicated in the initial evaluation and diagnosis of OSA or in the assessment of change following treatment; however, it is strictly indicated when a patient with OSA is suspected of having narcolepsy. Patients with OSA frequently underestimate the severity of sleepiness. Objectifying sleepiness may be important for the evaluation of OSA severity and its consequences on the individual level. ⁷⁴ In daily practice, MSLT, MWT, and vigilance testing are restricted to patients with persistent hypersomnolence despite adequate continuous positive airway pressure (CPAP) therapy or surgical or oral device therapy. On the other hand, routine use of these tests can be recommended for medicolegal reasons, but is not routinely feasible. ^{65 , 73} Unfortunately, in MWT, completely normal values do not necessarily ensure absolute safety. Therefore, clinical judgement should always prevail in a context of ability to drive.

As with ESS, the AHI also poorly correlates with quantified measures of sleepiness, which could indicate that some individuals cope better with sleep fragmentation than others, while brain susceptibility and subjective perception of the consequences of hypoxemia could also be involved. ⁷⁵ Using a cutoff value of 18 respiratory events per hour, a sensitivity of 71% and a specificity of 60% for identifying subjects with excessive daytime sleepiness was obtained. When subtle flow limitations are not taken into account, the sensitivity/specificity is even worse. ⁷⁶ Hence, for clinical purposes, it is obvious that the respiratory disturbance index is a more reliable parameter, but even then, its correlation with daytime symptoms remains suboptimal. In the Sleep Heart Health Study (SHHS) a poor correlation between the AHI and sleepiness was reported: the ESS only rose from 7.2 to 9.3 when the AHI changed from less than 5 to more than 30. ⁷⁷ However, in clinical decision making, it is important to identify patients in whom CPAP therapy should be instituted to treat daytime sleepiness.

In severe cases of OSA it is difficult to identify excessive daytime sleepiness resulting from other causes than sleep apnea. Depression, disturbed mood, diabetes mellitus, and cardiovascular diseases are among the most important confounding factors, ^{78 , 79 , 80} as well as sleep disorders other than OSA or side effects due to medical treatment. ^{81 , 82 , 83} In a large epidemiological study (n = 16,583 subjects), depression was the most significant risk factor for excessive daytime sleepiness, followed by age, BMI, sleep duration, diabetes mellitus, smoking, and finally sleep apnea. ⁸¹ Obesity alone may interfere through systemic inflammation (adipokines and chemokines) being activated even in the absence of OSA. In OSA, stress activation involving both the sympathetic system and the hypothalamic pituitary adrenal (HPA) axis may also be involved. Some patients have persistent symptoms while on adequate treatment. Whether residual sleepiness (ESS ≥11) is related to residual apneas is an unanswered question. Some extrapolations could be made. In a series of adequately treated OSA (baseline ESS >10, 6 months CPAP, compliance ≥4 h/d), ⁸⁴ Koutsourelakis et al found that 55% of their patients had an abnormal ESS score (>10) (16 ± 3) at follow-up, which was related to a history of depression, diabetes, heart disease, and a higher ESS score (16 ± 3 vs 14 ± 3) and lower AHI (44 ± 28 vs 59 ± 34) at baseline conditions. Unfortunately, their study group was blurred by patients with mild OSA (AHI > 5). Stradling et al studied 572 patients on CPAP and compared them with a control group of 525 individuals from a community survey. ⁸⁵ There was no difference in the percentage of patients with an ESS above 10 in the CPAP group compared with the controls (16 vs 14%). In the study of Pépin et al, 12% remained sleepy on CPAP, or 6% after exclusion of associated major depression, restless legs syndrome, and narcolepsy. ⁸⁶ This again emphasizes that mood disturbance is often involved in (residual) sleepiness. However, a link between residual sleepiness and residual apneas in selective patients is not ruled out. Maybe more insight will be obtained when pathophysiology of (obstructive) sleep apnea identified on CPAP or oral devices is disentangled. Verbruggen et al reported residual excessive sleepiness in 27 out of 84 patients (32%) on oral appliance therapy, despite normalization of AHI in patients with mild to moderately severe OSA. These patients had a significantly higher baseline ESS (15 ± 4 vs 9 ± 4; P < 0.001) and were younger (43 ± 9 vs 47 ± 9; P = 0.028) compared with patients without residual sleepiness. ⁸⁷

Fatigue

Fatigue can be defined as an overwhelming sense of tiredness, lack of energy, and a feeling of exhaustion, associated with impaired physical and/or cognitive functioning. ⁸⁸ Exhaustion could potentially reflect changes in mood, known to be common in chronic illness, but can also be the symptom of unknown or neglected OSA. ¹⁴ Fatigue is frequently reported as the main symptom in patients with OSA, in up to 50% of referred cases, and is more common and more distressing to OSA patients than excessive daytime sleepiness. ^{89 , 90} Increased fatigue has also been closely related to increased levels of depressive symptoms in OSA patients. ^{91 , 92} Fatigue is also a common and distressing complaint in the general population and a major problem in a wide range of diseases in internal and sleep medicine. Previous studies have demonstrated that self-reported sleep quality is independently associated with fatigue, even after taking into account demographic, comorbid conditions, OSA severity, sleepiness, and depressive symptoms. Hence, patients complaining about fatigue have a worst perception of sleep quality. ⁹³ It has important implications for clinical practice, where lack of energy, fatigue, and tiredness may lead to investigations, including sleep studies, and differential diagnosis that do not address the medical problem. The fatigue of the various disorders is not disease-specific, and is likely caused from interplay of physiological, psychological, and lifestyle-related factors. However, typical symptoms of OSA are less predictive in the presence of comorbid conditions, or might be attributed to these medical disorders, while consideration for OSA may be missed. Instruments to assess fatigue are the Fatigue Severity Scale, ⁹⁴ visual analogue scales, ⁹⁵ and specific questionnaires such as the fatigue-inertia subscale of the Profile of Mood States ⁹⁶ and the vitality subscale of the SF-36 quality-of-life questionnaire. ⁹⁷

Fatigue or Sleepiness?

Excessive daytime sleepiness is a cardinal feature of OSA, which is frequently used interchangeably with fatigue, likely because patients often complain of both types of symptoms. Daytime sleepiness, reflecting a physiological need for sleep, can be objectively quantified with tests, while fatigue is more elusive and relies almost exclusively on self-report. ⁹⁸ Nevertheless, symptoms compatible with OSA may be caused by OSA itself, or by comorbid medical disorders that can predispose a patient to sleep disturbance. Clinicians must be aware that absence of complaints of fatigue, tiredness, sleepiness, or lack of energy does not rule out the possibility of OSA. ¹⁵

Other Daytime Symptoms

Thorough anamnesis of patient and bed partner can make clear the association between the main symptoms and sleep apnea syndrome by bringing to light complaints related to poor sleep quality. These complaints include profuse body sweating, matinal headache (due to nocturnal carbon dioxide [CO₂] accumulation, usually dull and generalized), not feeling fresh in the morning, nasal obstruction, behavioral alterations, memory and concentration problems, decreased cognitive performance, depressed mood, anxiety, automatic behavior, social problems, marital problems, decreased libido, unexplained muscle pain, all resulting in a decreased quality of life. Also, symptoms of reflux have been more frequently reported; however, these symptoms improve with OSA treatment.

These symptoms can be explained by pronounced intrathoracic pressure changes induced by vigorous breathing attempts against an occluded airway along with regurgitation of gastric fluid.

There is also evidence of an association between erectile dysfunction and OSA, based on self-report and small case series, ⁹⁹ but underreporting can be estimated. CPAP therapy has shown to reverse this problem.

Disturbed Sleep, Insomnia, Nocturnal Sweating

Most patients with OSA have little difficulty initiating sleep and have short sleep latencies during sleep studies. ¹⁰⁰ On the other hand, problems of maintaining sleep, early morning awakenings, nightmares, abnormal motor activity, nocturnal dyspnea, nocturnal asphyxia, and nocturia are frequently reported. OSA patients also often have a restless sleep. Apneas can be associated with body movements or movements limited to mild limb movements. Occasionally, abrupt arm and limb movements with involuntary hitting of the bed partner occur. ¹⁰¹ Due to this increased motor activity at night, patients with OSA often suffer from nocturnal sweating. It is striking that, despite these typical symptoms, the interval between the first symptoms and the final diagnosis can often take some years. Nevertheless, OSA patients are usually convinced that they are sleeping well and are unaware of the breathing stops. Infrequently, patients may have insomnia as their major symptom. Moreover, a significant proportion of insomniacs have sleep apnea (25–50%), which is most likely to reflect recurrent sleep fragmentation and increased wakefulness during the night. This manifestation is described as occult sleep apnea, provoked by an increased number of arousals and sleep/wake transitions, which per se may induce unstable breathing. Women may report more insomnia and less witnessed apneas. Rarely, arousal triggered by obstructive events may induce nonrapid eye movement (NREM) parasomnias, such as nocturnal eating syndrome. In case of increased nocturnal sweating, a number of medical reasons have to be checked, such as infections, endocrinological alterations (hypoglycaemia, thyroid dysfunction), cardiovascular disorders with increased sympathetic activity, malignancy, chronic pain, stress disorders, and substance abuse or withdrawal (benzodiazepines, opioids, ethanol).

Nocturia

Nocturia can be defined as waking up more than once during the night to urinate (each void is preceded by and followed by sleep). ¹⁰² The prevalence of nocturia is high and increases suddenly with age. About 20% of elderly males and 25% of elderly women report regular nocturia (NYHANES III study). ¹⁰³ It has been reported to be up to 50% in patients with OSA, and the number of voids at nights seems to correlate with the severity of OSA. ^{104 , 105 , 106} Nocturia can be attributed to increased levels of atrial natriuretic peptide (ANP) levels, related to the generation of negative intrathoracic pressures in OSA. These pressure swings cause false signals of volume overload to the endocardium, with resulting increase in ANP secretion and increased urine production. Umlauf et al found increased nocturia and elevated urinary ANP only when the AHI was more than or equal to 15 per hour. ¹⁰⁶ Fitzgerald et al demonstrated that CPAP could decrease nocturia in OSA patients. ¹⁰⁷ Although less well supported, nocturia in OSA could also develop due to an increased awareness of bladder fullness secondary to arousal and/or transmission to the bladder of positive intra-abdominal pressure provoked by repetitive obstructive events. ^{108 , 109} Thorough medical history taking with respect to hypertrophic benign prostate, diabetes mellitus, chronic heart failure, renal disease, and use of diuretics is mandatory. Increased intake or late consumption of liquids is also one potential explanation to be excluded.

Cardiovascular Morbidities

OSA is increasingly recognized as an independent risk factor for systemic hypertension, stroke, cardiac arrhythmias, and coronary artery disease (CAD). ^{144 , 145 , 146}

Cardiovascular Mortality

Observational cohort studies indicate that untreated patients with OSA have an increased risk of nonfatal and fatal cardiovascular events, an increased risk of sudden cardiac death during the night, and a higher risk of stroke or death from any cause. ^{144 , 145} In an older study, the probability of cumulative 8-year survival was 0.96 for patients with an apnea index below 20 and 0.63 for those with an apnea index above 20. Difference in mortality related to apnea index was particularly accurate in patients younger than 50 years and in whom mortality from other causes is uncommon. ²⁰⁰ In the study of Marin et al, multivariate analysis, adjusted for potential confounders, showed that untreated severe OSA significantly increased the risk of fatal (OR 2.87 [95% CI 1.17–7.51]) cardiovascular events compared with healthy subjects. ²⁵ Treatment with CPAP attenuated this risk. ^{144 , 200}

Since the group that received CPAP got more intensive follow-up during the first year after diagnosis (two additional visits), outcome could be improved in this group independent of the CPAP treatment itself. Moreover, these results were only valid in men. The occurrence of OSA was a significant predictor of premature death in patients with CAD and who are at increased risk of stroke. ^{201 , 202} These studies have the intrinsic limitation of lacking a randomized controlled design, which clearly limits the evidence level. In one prospective study, it was found that the apnea index was a predictor of excess mortality in the fourth and fifth decade, but not in aged population. ²⁰³ In some population-based cohorts, a decrease in survival was reported with increasing OSA severity, with an OR of 3.0 (95% CI 1.4–6.3) (Wisconsin) and 1.46 (1.14–1.86) (SHHS) in subjects with severe OSA compared with those in the normal range. ^{204 , 205} However, after stratification by age and gender in the SHHS, the OR remained only significant in males aged less than 70 years. Lavie and Lavie proposed a survival advantage in moderate OSA, suggesting, as a potential mechanism, that chronic intermittent hypoxemia during sleep may activate adaptive pathways in the elderly. ²⁰⁶ For example, older people have a reduced acute cardiovascular response to arousal from sleep, compared with younger subjects. ²⁰⁷ Hence, the poorer cardiovascular reactivity of aged adults may, paradoxically, reduce the impact of arousals from sleep and protect against cardiovascular morbidities and mortality. However, it has to be reminded that the cardiovascular consequences of sleep apnea in the aged population may also be influenced by survival bias, as middle-aged, hypertensive OSA patients may not survive into old age. Discrepancies between studies could probably be explained by the heterogeneity of the patients included in the elderly populations.