**5. Symptoms**

Although OSAS and UARS share common symptoms, in most cases the clinical manifestations are different (Stoohs 2008). The most common symptoms of SAHS patients include chronic loud snoring, excessive daytime sleepiness, personality changes, depression and deterioration of quality of life (Pichel 2004). Hypersomnolence is the principal daytime manifestation of sleep disordered breathing. Excessive sleepiness resulting from increased breathing effort and sleep disruption is the guide symptom of UARS patients (Guilleminault 1993, 2001a). Drowsiness related to general exhaustion has a negative impact on quality of

disordered-breathing. Limited data is available on the prevalence of UARS in the general population in both children and adults. Some authors consider it an uncommon disease in clinical practice. In earlier descriptions, the estimated prevalence was 6% in men and 11% in women (Votteri 1994; Guilleminault 1995). Kristo found a prevalence of 8.4% in a one year polysomnography review (Kristo 2005). In an epidemiological study conducted in Brazil, the prevalence of UARS was 18.7%, being more common in women and young people (Tufik

The upper airway is a very complex structure. In SAHS patients, apneas during sleep are caused by upper airway obstruction, wich leads to progressive asphyxia and awakening. The inspiratory efforts to overcome occlusion lead to arousal, sleep fragmentation, and oxyhemoglobin desaturation. From a physiological standpoint, both UARS and OSAS present intermittent upper airway collapse. This increase in upper airway resistance occasionally accompanies airflow limitation and arousals, with little desaturation. Johnson, found that even minimal airflow limitation could produce arousals that occur before alterations in gas exchange (Johnson 2005). These episodes are of short duration, about four

Another interesting difference from OSAS is that UARS patients do not present neuropathological lesions in the upper airway (Friberg 1998; Guilleminault 2002a; Boyd 2004), which could explain why these patients tend to respond more rapidly to treatment and do not develop OSAS over the long-term. Early studies did not seem to reveal differences in sleep architecture between UARS and OSAS (Loube & Andrada 1999). However, today UARS patients are considered to have unstable sleep, characterized by a cyclic alternating pattern in nonREM sleep (Guilleminault 2005a), which predisposes to the occurrence of arousals. These findings correlate with symptoms such as tiredness and fatigue, for which these patients are often referred to sleep labs. The cyclic alternating pattern has been described in many other situations (Ferré 2006), such as fibromyalgia, chronic fatigue syndrome, and OSAS (Terzano 1996). Current research suggests that nearly 50% of fibromialgia syndrome patients experience intrusive alpha wave periods. Patients with UARS present an increase in the number of cyclic alternating patterns, with a decreased phase 1 and an increased phase A2 and A3 (Guilleminault 2005c) In recent years, polysomnography has revealed that UARS patients present nonREM-sleep instability. Alpha-delta sleep is characterized by an intrusion of alpha EEG waves into slow delta waves during deep sleep, which also occurs in insomnia

Although OSAS and UARS share common symptoms, in most cases the clinical manifestations are different (Stoohs 2008). The most common symptoms of SAHS patients include chronic loud snoring, excessive daytime sleepiness, personality changes, depression and deterioration of quality of life (Pichel 2004). Hypersomnolence is the principal daytime manifestation of sleep disordered breathing. Excessive sleepiness resulting from increased breathing effort and sleep disruption is the guide symptom of UARS patients (Guilleminault 1993, 2001a). Drowsiness related to general exhaustion has a negative impact on quality of

breaths, and present negative intrathoracic pressure increases.

and non-refreshing sleep (Guilleminault 2001a).

**5. Symptoms** 

2009).

**4. Pathophysiology** 

life. As in OSAS, snoring is a common symptom, predominantly in males, although the absence of snoring has also been described in this syndrome, the so-called silent UARS (Kristo 2005). In recent years, several studies have demonstrated strong associations between UARS and functional somatic syndromes, such as chronic fatigue syndrome, chronic insomnia, chronic pain, irritable bowel syndrome, fibromyalgia, depression, parasomnias and posttraumatic stress disorders (Gold 2003, 2011). Due to its association with chronic somatic diseases, UARS has been postulated to activate the hypothalamicpituitary-adrenal axis (HPA) (Gold 2010), although not all studies support the association of sleep disordered breathing with these somatic functional disorders. (Vgontzas & Fernandez-Mendoza 2011, Trakada 2007).

A number of studies compare the clinical characteristics of UARS patients to those of SAHS subjects. Patients with UARS are usually younger than those with SAHS and have a lower level of obesity. There is no major difference in terms of gender prevalence, although UARS appears to be more frequent in postmenopausal women. An overall ratio of prevalence for men to women of 3.3 has been reported in SAHS patients (Bixler 2001).

UARS patients report both onset and maintenance insomnia (Guilleminault 2002b). A state of physiologic hyperarousal in UARS patients with chronic insomnia is accepted (Gold 2008). Some authors have reported complex insomnia, which paradoxically involves nighttime insomnia and daytime sleepiness (Krakov 2001; Gold 2008). This type of insomnia has been associated with parasomnias (Guilleminault 2006a), which mainly occur in young patients together with sleepwalking and night terrors. Insomnia is more common in UARS than in OSAS.

Powers (Powers 2009) found a tendency to hypersomnia in UARS patients. These patients showed altered results on the maintenance of wakefulness test that were not correlated with the Epworth scale. This author considered non-obese premenopausal women, who often consult for chronic insomnia and parasomnias, to represent a specific attention group.

Approximately half of UARS patients present symptoms of increased vagal tone such as orthostatic hypotension and coldness of the extremities (Guilleminault 2001b). Disturbances in heart rate variability have also been reported along with a decrease in the HF component (associated with increased vagal tone). In contrast, OSAS patients have an increase in the LF/HF ratio, associated with increased activity sympathetic. (Guilleminault 2005).

SAHS is widely associated with cardiovascular risk. Long-term effects can lead to severe cardiovascular and cerebrovascular diseases. However, there is little data regarding the association of cardiovascular disease and UARS. Some studies have found an association between hypertension and UARS, with a good response to CPAP treatment (Guilleminault 1996), but this association has been put into question. Notably, this controversy sheds light on the importance of hypoxia and sympathetic activation (which are not present in UARS) in OSAS as intermediary mechanisms associated with cardiovascular events.

The diagnosis of UARS is often delayed becasue of the absence of respiratory events in polysomnography. Sometimes the symptoms of UARS have been confused with other medical conditions, such as asymptomatic habitual snoring, sleep deprivation, chronic fatigue syndrome, idiopathic hypersomnia, psychiatric disorders (Lewin & Pinto 2004) and asthma (Guerrero 2001).

Upper Airway Resistance Syndrome – A Twenty-Five Years Experience 79

Indeed, the presence of RERA in the absence of apneas and hypopneas is the key polysomnography finding for diagnosing UARS (Bonnet 2007). However, the difficulty of registering respiratory effort has prompted the search for other non-invasive methods that can provide similar information (Hosselet 1998; Loube 1999; Badia 2001; Mosler 2002; Kenach 2005; Popovic 2009)(Table 1). Most systems try to develop a reliable non-invasive tecnique for respiratory effort and upper airway resistance that could represent a noninvasive alternative to esophageal pressure measurement. Of these, the most widely used and accepted by the American Academy of Sleep Medicine are nasal pressure cannulas, inductance plethysmography or diaphragmatic/intercostal EMG. The nasal cannula is the tool of choice for monitoring respiratory airflow during sleep in both clinical and research sleep studies. Nasal cannula is more sensitive than thermistor for detecting RERA The use of new technologies such as pressure probes have made it possible to identify signs of UARS in

The diagnostic criteria for UARS have not been established. At present, the diagnostic polysomnography of UARS is based on careful analysis of the esophageal pressure reading and nasal cannula (Guilleminault 1995, 2001; Black 2000), together with an AHI under 5 and the presence of desaturation of no more than 92%. Visual identification of intermitent flow limitation is cumbersome, subjective and trought with variability and potential error. Some authors recommend determining the length of airflow limitation episodes as well as the total percentage of airflow limitation with respect to total sleep time. Termination of flow limitation was indicated either by respiratory events related to arousal or with essofageal pressure reversal (Guilleminault 1995; 2001) without alpha EEG arousal (Guilleminault 2005b). In UARS patients these episodes of airflow limitation that is not accompanied by desaturation, are of varying lengths, and are not always associated with an increase in esophageal pressure. The coincidence of EEG arousals and Pes events is well documented. A percentage of Pes events terminate without coincident EEG activity. However, Guilleminault describes that, in patients with UARS, apnoeas accompanied by arousals have a greater tachycardic effect, even if there is only a small reduction in blood oxygen saturation (Guilleminault 2005). The shape of the inspiratory flow contour has been proposed as a noninvasive predictor of increased upper airway obstruction, increasing the potential for erroneous classification of respiratorye events (Hosselet 1998; Rees 2000; Ayyapa & Rapoport 2003). Various definitions of airflow limitation exist (Norman 2007;

RERA is the most important event in UARS patients. In early studies, the definition of UARS included the presence of frequent arousals, indicating an RERA index >10/h as a diagnostic criteria. Owing to their relation, treating RERA tends to improve excessive daytime sleepiness. This index was established as a treatment criterion. UARS has not found its way into the International Classification of Sleep Disorders Diagnostic and Coding Manual, which is one of the main problems for the acceptance of UARS as a specific entity (AASM 1999; Iber 2007). RERA has been accepted by the American Academy of Sleep Medicine Task Force (AASM, 1999) but it has yet to be standardized. According to the AASM and a number of authors (Cracowski 2001), RERA episodes are rare and their encoding need not be mandatory. However, others consider it to be a key element, with an identifiable pathophysiology. RERAs have been incorporated into normal clinical practice, and the respiratory disturbance index used to quantify OSAS severity takes them into account

patients with high levels of arousal and airflow limitation (Krakow 2001).

Mansour 2004; Kaplan 2000;Aittokallio 2001)(Table 2).

together with apneas, and hypopneas.

Some authors report a greater likelihood of traffic accidents in UARS patients (Stoohs 1994). Among drowsy drivers, UARS is associated to a higher frequency of accidents. Thus, identification of this syndrome is of great practical importance.
